THE LIBRARY OF THE UNIVERSITY OF CALIFORNIA PRESENTED BY PROF. CHARLES A. KOFOID AND MRS. PRUDENCE W. KOFOID Digitized by the Internet Archive in 2007 with funding from IVIicrosoft Corporation http://www.archive.org/details/centuryofunitedsOOdumerich BULLETIN OF THE UNIVERSITY OF WISCONSIN Serial No. 980. Geaeral Seriet No. 764 A CENTURY OF THE UNITED STATES "^ PHARMACOPOEIA, 1820-1920 I— THE GALENICAL OLEORESINS BY ANDREW G. DUMEZ THESIS SUBMITTED FOR THE DEGREE OF DOCTOR OF< PHILOSOPHY UNIVERSITY OF WISCONSIN 1917 Repriated from vol. xix o( th« Transaction* of the Witconiin Academy of Scieneei, Am and Letters. PHARMACEUTICAL PUBLICATIONS OF THE UNIVERSITY OF WISCONSIN Monographs Price Nellie Wakeman, Plant pigments 0.35 A. G. Du Mez, The galenical oleoresins 0. 50 H. A. Langenhan, The arsenical liquors (In preparation) BULLETIXS A. F. Sievers, On the addition of organic acids to unsaturated hy- drocarbons 0.20 Nellie Wakeman, The Monardas, a phytochemical study 0.20 E. Kremers, The classification of carbon compounds . 40 H. A. Langenhan, The alkaloldal content of stramonium leaves. . 0.25 E. R. Miller, A chemical study of the oils of several species of Eupatorium; and A study of the chemical and physical prop- erties of Wisconsin wormwood oil 0.2.") E. R. Miller, The chemistry of the oil of Achillea millefolium, a study in economic drug culture 0.25 Grri)i:s E. V. Ljmn, Laboratory guide to pharmaceutical technique 0.25 Nellie Wakeman, Guide to chemistry 40. Plant chemistry for pharmacy students 0.20 E. Kremers, A bibliographic guide for students of the history of pharmacy 0.25 Station Reports Report of the Director of the Pharmaceutical Experiment Station for the fiscal year July 1, 1913, to June 30, 1914. Report of the Director of the Pharmaceutical Experiment Station for the fiscal years July 1, 1914, to June 30, 1916. Report of the Pharmaceutical Experiment Station for the fiscal vears, July 1, 1916, to June .30, 1918. Stattox CTi'cn.M's 1.) General announcement. 2.) The volatile oil of Pi/, nantri^ m nhi hnncoUthnn l^ursli, hv E. R. Miller. :•-.) Medicinal plants and designs, by Bernice Oehler. 4. ) The volatile oil of Monarda fistiilosa L., by E. R. Miller. 5.) N. F. petroxolins and parallel preparations, bv H. A. Langenhan and G. J. Noel. 6.) Preliminary report of the Conference on the Help Situation in Wisconsin, by its chairman. 7.) Water-soluble volatile products from peppermint, by E. R. Miller. S.) The application of the principles of breeding to drug planls, i)nr- ticnlarly DaUira, by C. M. Woodworth. (In press.) BULLETIN OF THE UNIVERSITY OF WISCONSIN SERIAL NO. 980. GENERAL SERIES NO. 764 C^ei^ A CENTURY OF THE UNITED STATES PHARMACOPOEIA, 1820-1920 I_THE GALENICAL OLEORESINS BY ANDREW G. DU MEZ THESIS SUBMITTED FOR THE DEGREE OF DOCTOR OF PHILOSOPHY UNIVERSITY OF WISCONSIN 1917 Reprinted from vol. xii of the Transactions of the Wisconsin Academy of Sciences, Arti and Letters. Ri<^0 CONTENTS CONTENTS PART I— GENERAL Page Historical Introduction 7 Definition l"? Drugs used 14 Solvents used 15 Methods of preparation 20 Apparatus employed 27 Yield 46 Chemistry 46 Physical and chemical proper- ties 47 Physical properties 47 Color 47 Odor 48 Taste 48 Page Consistence 48 Solubility 4» Specific gravity ■• . . 49 Refractive index 50 Chemical properties 51 Loss in weight on heating. . 51 Ash content 53 Acid number 54 Saponification vailue 54 Iodine value (....... 55 Special tests 55 Qualitative tests 56 Quantitative tests 5ft Adulterations 5S PART II — INDIVIDUAL OLEORESINS Page Oleoresin of aspidium 59 Synonyms 59 History 61 Drugs used, its collection, pres- ervation, etc 62 IT. S. P. text and comments thereon 67 Yield ./ 74 Chemistry of the oleoresin and of the drug from which prepared 79 Constituents of therapeutic importance 86 Physical properties 86 Color 86 Odor 87 Taste . . . .1 87 Consistence 87 Solubility 87 Specific gravity i 88 Refractive index 90 Chemical properties 92 Loss in weight on heating . . 9S Ash content 93 Acid number 94 Saponification value 95 Iodine vailue 97 Other properties 98 Page Special qualitative tests 9* Tests for filicin 99 Austrian Pharmacopoeia. . 99 Netherlands Pharmacopoeia 99' Hungarian Pharmacopoeia 99^ Tests for starch 100 German Pharmacopoeia. . . 100' Test for oleoresin of Dryop- teris spinulosa 101 Hausmann's method 101 Test for castor oil 101 Test for copper 101 Special quantitative tests .... 101 Methods for the determina- tion of filix acid 102^ Method of Kremel 102 Method of Bocchi 10^ Method of Kraft 102 Method of Fromme (orig- inal) 103 Method of Fromme (im- proved) . .1 103 Method of Stoeder '. 103 Comparison of above methods 104 Methods for the determin- ation of crude filicin . . . 104 Method of Rulle 105 CONTENTS Page Method of Daccomo and Scoccianti 105 Method of Schmidt 105 Method of Fromme 105 Influence of different alka- llies on yield of crude filicin 106 Crude filicin content of laboratory properations. 107 Crude filicin content of commercial samples . . . 108 Physiological tests 109 Method of Yagi 109 Adulterations . . . 110 Oleoresin of capsicum Ill Synonyms Ill History , 111 Drugs used, its collection, preservation, etc . Ill U. S. P. text and comments thereon 112 Yield . ., 117 Chemistry of the oleoresin and of the drug from which prepared 121 Constituents of therapeutic importance 124 Physical properties 124 CoHor , 124 Odor 124 Taste > 124 Consistence 124 Solubility 125 Specific gravity 125 Refractive index . 126 Chemical properties 127 Loss in weight on heating 127 Ash content 127 Acid number i 128 Saponification value 129 Iodine value 130 Special quantitative tests. . . 131 Physiological test 131 Adulterations ,. . . 132 Oleoresin of cubeb 132 Synonyms 132 History 132 Drug used, its collection, preservation, etc 134 U. S. P. text and comments thereon 134 Yield 139 Chemistry of the oleoresin • and of the drug from which prepared 143 Constituents of therapeutic k importance 147 Page Physical properties 147 Coilor 147 Odor 147 Taste 148 Consistence 148 Solubility 148 Specific gravity 148 Refractive ihdex 149 Chemical properties 150 Loss in weight on heating 150 Ash content 151 Acid number 151 Saponification value 152 Iodine value 153 Other properties 154 Special qualitative tests .... 154 Method of Dietrich 155 Method of Gluecksmann. . 156 Austrian Pharmacopoeia. . 156 French Pharmacopoeia ... 156 Swiss Pharmacopoeia .... 156 Hungarian Pharmacopoeia 156 German Pharmacopoeia . . 157 Special quantitative tests ... 157 Kremel's method for the determination of cube- bic acid 157 Adulterations 157 Oleoresin of ginger 158 Synonyms 158 History 158 Drug used, its collection, preservation, etc 158 U. S. P. text and comments thereon 160 Yield 163 Chemistry of the oileoresin and of the drug from which prepared 167 Constituents of therapeutic importance 170 Physical properties 171 Color 171 Odor 171 Taste 171 Consistence I7i Solubility 171 Specific gravity 172 Refractive index 172 Chemical properties 173 Loss in weight on heating 173 Ash content 174 Acid number 175 Saponification value 175 Iodine value 176 Special qualitative tests .... 177 Tests for oleoresin of cap- sicum , 177 CONTENTS Page Method of Garnet and Grier 178 Method of La Wall 178 Method of Nelson . . 178 Special quantitative tests . . 179 Methods for the estimation of the g-ing-erol content 179 Method of Garnet and Grier 179 Physioilogical tests 180 Adulterations 181 Oleoresin of lupulin 181 Synonyms 181 History 181 Drug used, its collection preservation, etc. 182 U. S. P. text and comments thereon 183 Yield 186 Chemistry of the oleoresin and of the drug from which prepared ....... 187 Constituents of therapeutic importance 190 Physical properties 191 Color 191 Odor 191 Taste 191 Consistence 191 Solubility 191 Specific gravity 192 Refractive index 192 Chemical properties 193 Loss in vsreight on heating 193 Ash content 194 Acid number 195 Saponification value 195 Iodine value 196 Adulterations 197 Oleoresin of parsley fruit . . . . 197 Synonyms 197 History 198 Drug used, its coQlection, preservation, etc. 198 U. S. P. text and comments thereon 199 Yield 201 Chemistry of the oleoresin and of the drug from which prepared . 202 Constituents of therapeutic importance 204 Page Physical properties "SOS Color 205 Odor 205 Taste 205 Consistence 205 Solubility 205 Specific gravity 205 Refractive index 206 Chemical properties 207 Loss in weight on heating 207 Ash content 207 Acid number 208 Saponification value 208 Iodine value 209 Adulterations 210 Oleoresin of pepper !210 Synonyms 210 History 210 Drug used, its collection, preservation, etc 211 U. S. P. text and comments thereon 212 Yield 216 Chemistry of the oleoresin and of the drug from which prepared 218 Constituents of therapeutic importance 222 PhysicaJl properties 222 Color 2122 Odor 222 Taste 222 Consistence 222 Solubility 222 Specific gravity 2122 Refractive index 223 Chemical properties 224 Loss in weight on heating 224 Ash content 225 Acid number 226 Saponification value 226 Iodine value 227 Special quanitative tests ... 228 Method for the estimation of the piperine content 228 Advilterations 229 I BIBLIOGRAPHY 29 INDEX TO BIBLIOGRAPHY 284 Abbreviations Used for the Titles of PHARMACOPOEiAe and Treatises on Pharmacy. AUg. P. — Strump, Allgemeine PJiarmakopoe. Argent. P. — Argentine Pharmacopoeia — Farmacopcea Na- cianal Argentina. Aust. P. — Austrian Pharmacopceia — PJiarmacopoea Austriaca. Bad. P. — Baden Pharmacopoeia — Pharmacopoea Badensis. Belg. P. — Belgian Pharmacopoeia — Pliarmacopcea Belgica. Bern. P. — Bernese Pharmacopoeia — Pharmacopoea Bernensis. B. P. — BritisJi Phdrmacoposa. B. P. C. — BritisJi Pharmaceutical Codex. Comp. to the U. S. P. — Companion to the United States Phar- macopoeia. Dan. P. — Danish Pharmacopoeia — Pharmacopoea Danica. Dan. Mil. P. — Danish Military Pharmacopoeia. Diet, of Pharm. Sc. — Schweringer, Dictionary of Pharmaceu- tical Science. Fin. P. — Finnish Pharmacopoeia — Pharmacopoea Fennica. Fr. P. — French Pharmacopoeia — Pharmacopoee Francaise. G. P. — German Pharmacopoeia — Pharmacopoea Germanica. Geiger's P. — Geiger's Pharmacopoe. Han. P. — Hannoverian Pharmacopoeia — Pharmahopbe fiir das Koenigreich Hannover. Hess. P. — Hessian Pharmacopoeia — Pharmakopde fiir das Kurfuerstenthum Hessen. Hung. P. — Hungarian Pharmacopoeia — Pharmacopoea Hun- garica. Xtal. P. — Italian Pharmacopoeia — Farmacopoea TJfficiale del Regno d' It alia. Jap. P. — Japanese Pharmacouoeia — The Pharmacopoeia of Japan. King's Am. Disp. — King's American Dispensatory, Mex. P. — Mexican Pharmacopoeia — Pharmacopoea Mexicana. Nat. Stand. Disp. — National Standard Dispensatory. Neth. P. — Netherlands Pharmacopoeia — Pharmacopoea Neder- landica — Nederlandische Apotheek. Nor. P. — Norwegian Pharmacopoeia — Pharmacopoea Nor- vegica. 6 ABBREVIATIONS Port. P. — Portuguese Pharmacopoeia — Pharmacopcra Portu- gueza. Pruss. P. — Prussian Pharmacopoeia — PJiarmacopoea Bonis- sica. Roum, P. — Roumanian Pharmacopoeia — PJiarmacopoea Ro- mana. Russ. P. — Russian Pharmacopoeia — PJiarmacopoea Russica. Schlesw. Holt. P. — Schleswig-Holstein Pharmacopoeia — PJiar- maJcopoe fur ScJileswig und Holstein, Sp. P. — Spanish Pharmacopoeia — Farmacopoea Oficial Es- panola. Swed. P. — Swedish Pharmacopoeia — PJiarmacopoea Suecica. Swiss P. — Swiss Pharmacopoeia — PJiarmacopoea Helvetica. U. S. Disp. — United States Dispensatory, U. S. P. — United States PJmrmacopceia. Univ. P. — Hirsch, Universal-PJiarmacopoe. Ver. P. der Lond., Edinb. und Dub . Med. Coll. — Yereinigte PJiarmacopceen der Londoner, EdinhurgJier, und Duhliner Medicines Collegien. PART I — GENERAL Historical Introduction The type of galenical preparation now known as an oleoresin has been official in the United States Pharmacopoeia since 1850, the oleoresins of cubeb and pepper being the first members of this class of preparations to receive recognition, however, under the title of fluid extract. The suggestion for the name oleoresin appears to have come from Buchner though first applied as the name of a galenical by Peschier. The latter, in 1825, had prepared an ethereal extract of male fern which he designated Huile de Fougere Male. To this name, Buchner objected, suggesting the title Extractum resinosum. In reporting Peschier 's work, however, Buchner •speaks of the constituents of the ethereal extract as the oelharzige BestandtJieile of male fern, and later in his account, he refers to the finished preparation as the oelJiarziges Extract, i, e. an oleoresinous extract. It would appear, therefore, that when Peschier, in his second account (1828), speaks of an oleoresine, our English oleoresin, he evidently took his suggestion from Buchner 's use of the German attribute, oelJiarzig. The suggestion of Buchner, that the above mentioned pre- paration of male fern be called an extract, appears to have met with general favor throughout Europe as is indicated by its title in the various European pharmacopoeias, past and present. Likewise, such other members of this class of preparations as have received recognition in the European countries are to be found in the respective pharmacopoeias of these countries under the heading, extracta. In the United States, a latinized form of Peschier 's title, oleoresine, has been adopted and these pre- parations are officially known as oleorsinae. The following table of titles will give a fair idea of the early development of the synonymy of these preparations : DU MEZ— THE GALENICAL OLEORESINS. Table I. Early titles of oleoresins 1825. Huile de Fougere Male — PescMer. 1826. Extractum Filicis maris resinosum — Buchner. 1827. Extractum oleo-resinosum Filicis — Brandes. Oleum Filicis Maris — Van Dyk. Oleo-Besina Filicis, PescMer — Ver. P. d. Lond., Edinb. and Dub. Med. Coll. 1828. Oleoresine de Fougere Male — Peschier. Extrait oleoresineux de Cuhehe — Dublanc. 1829. Extractum Filicis aethereum — App. to Pruss. P. Aetherisches FamJcrautextract — App. to Pruss. P. 1832. Extractum Filicis oleo-resinosum — Jourdan, Univ. P. 1834. Fiperoide du Gingemhre — Beral. 1841. Extractum Eadicis Filicis Maris aethereum — Bad. P. Aetherisches FarrnTcrautwurzel Extract — Bad. P. Extractum Cuheharum aethereum — Bad. P. Aetherisches Cuhehen Extract — Bad. P. 1845. Extractum Filicis Maris aethereum — Geiger's P. Farrnwurzelextract — Geiger 's P. Extrait eth^re de Cutehe — Geiger 's P. Oleoresinous Extract of Cuhehs — Bell Ethereal Extract of Cuheis — Procter. 1849. Oleoresinous Ethereal Extracts — Procter. 1852. Extractum Filicis Maris aethereum — Swiss P. Extrait oleo-r^sineux de Fougere — Swiss P. Huile de Fougere de Peschier — Swiss P. 1854. Extractum Stipitum Aspidii — Nor. P. 1857. Oleo-Besineux de Cultehe — Garot and Schaeuffele. 1859. Oleoresina (ae) — Procter. 1863. Oleoresina Capsici — U. S. P. Oleoresina Cuhehae — U. S. P. Oleoresina Lupulinae — U. S. P. Oleoresina Piperis — U. S. P. Oleoresina Zingiberis — U. S. P. As becomes apparent from the preceding table, oleoresins be- came a recognized class of galenical preparations with their in- troduction into the United States PJiarmacopma of 1860. The name, as applied to a class of galenicals, appears to have been sug- gested by Procter in 1846. Although this term thereby ac- quired a dual meaning,^) it was not only shorter, but in other respects more convenient than extracta aetherea, previously in use in some of the European pharmacopoeias. The disadvan-. ^As a class of natural plant products and as a class of galenicals. HISTORICAL. INTRODUCTION. Q tage accruing from the substitution of oleoresina for extracta uetherea lay in the fact that as a sub-class they were removed from the other sub-classes of extracts : e. g., the extracta (solida)^ extracta fluida, etc. With the substitution of acetone for ether as an extracting medium, in the eighth revision of the United States Pharmacopoeia, it is possibly fortunate that the designa- tion extracta aetherea never gained a footing in this country. The preparation of this particular class of galenicals was de- pendent upon the use of ether. Although, a number of chem- ists before the eighteenth century had obtained some ether as an ingredient of a mixture resulting from the action of sulphuric acid upon alcohol, it appears that the first commercial ether was prepared in 1730 by Frobenius,^) who, however, kept his process a secret. The use of the distillation residues for the preparation of more ether, known to Frobenius, was emphasized by several German chemists, and caused a considerable reduc- tion in the price of this article. Thus Cadet, in 1774, pointed out that he could sell an ounce of ether at 40 sous,^) whereas Baume had sold it at 12 livres. But even with this reduction in price, ether does not appear to have been a common phar- maceutical commodity at that time. Thus, e. g., Hermbstaedt^) in 1792, mentions ether and enumerates its properties evidently for the reason that it is of pharmaceutical interest primarily be- cause it is an ingredient of Liquor anodynus mineralis Hoff- manni. However, it should be remarked that Baume mentioned it in 1762 as a solvent in the preparation of resin of Jalap,*) and in 1790,^) he described its use in the preparation of ethereal, tinctures. The first positive reference concerning the use of ether as a solvent in the preparation of a galenical of the type of our pres- ent oleoresins, that appears in the literature, is to be found in Peschier's report (in 1825) on the preparation of the Huile de Fougere Male, the present oleoresin of aspidium. As a result of the almost immediate popularity of this preparation, other pharmacists were induced to experiment with ether in attempting duplicate or modify Peschier's process. However, none of the ^Kopp. Geschicht. d. Chem,, vol. 4, p. 302. 2 Ibid. 3 Grundriss d. exp. Pharm., part 2, p. 161. ♦Elements de Pharm. (1872), p. 284. •Ibid. (1790), p. 262. IQ DU MEZ— THE GALENICAL. OLEORESINS early workers attempted to employ it in the extraction of other plant drugs, and it was not until 1834, when Beral again called attention to the use of ether as a solvent in his preparation of Piperoide du Gingemhre, our present oleoresin of ginger, that its value in the extraction of oleoresinous drugs appears to have been recognized. From then on, however, its use seems to have widened rapidly as the French Pharmacopoeia of 1839 contained no less than nineteen ethereal tinctures. The increase in the number of oleoresins was not as rapid as might be expected in view of the statement concerning the ethereal tinctures. Only two other members of this class of preparations made their ap- appearance before 1850, namely, the Extractum Cxihehariim aethereum and the Extractum Seminis Cinae aefhereum. Some idea of the rate at which the Extracta aetJierae, our pres- ent oleoresins, came into existence and were given official recog- nition will become evident from the following : In the Prussian Pharmacopoeia of 1829, but one such prepara> tion was official, namely, Extractum Filicis aethereum. The Baden Pharmacopoeia of 1841 contained three prepara- tions of this class, viz: 1.) Extractum Badicis Filicis Maris aethereum. 2.) Extractum Cuheharum aethereum. 3.) Extractum Seminis Cinae aethereum. The Danish Pharmacopoeia of 1850 contained two prepara- tions of this class, viz: 1.) Extractum Cuheharum aethereum. 2.) Extractum Filicis Maris aethereum. The third edition of the United States Pharmacopoeia, which appeared in 1851, included two fluid extracts prepared with ether as a menstrum, viz: 1.) Extractum Culehae fluidum. 2.) Extractum Piper is fluidum. HISTORICAL INTRODUCTION. 11 The Belgian Pharmacopoeia of 1854 recognized no less than seven ethereal extracts, viz: 1) Extrait etJiere de Fougere 2) Extrait 4there de Cantharides 3) Extrait ^there de Croton 4) Extrait ^there de Culjehe 5) Extrait 4therS de d'Aunee 6) Extrait etMre de Bois garu 7) Extrait etMre de Semen-contra It will be seen from the above array of ethereal extracts of- ficial in European pharmacopoeias that the introduction of oleoresins into the fifth edition of the United States Pharmaco- poeia, which appeared in 1863, was well prepared. Procter is commonly given credit for having introduced oleore- sins into American materia medica. That he was instrumental in bringing them to the attention of the representatives of the regular medical school, and that he obtained a place for them in the United States PJiarmacopoeia, possibly no one has reason to doubt. A review of the early American literature on this subject not only reveals this fact, but it also brings out the fact that Procter appears to have been ignorant in large part of the use of this class of preparations in Europe,^) for nowhere does he mention it. It is note-worthy that it was a medical prac- titioner (Goddard) who first drew Procter's attention (1846), not to a typical representative of this class, but to the prepara- tion of Dublanc which was a representative of the extracta oleo- resina made by a very cumbersome process, now long discarded as being as unscientific as it is impractical. In the same year, the English pharmacist, Bell, had his attention drawn to this same preparation by Vore, thus showing that valuable prepara- tions not advertised were ignored, while a quasi scientific pre- paration heralded about apparently attracted general attention. To what extent the Eclectic school of medical practioners contributed to the popularization of this class of galenicals be- fore 1860 cannot be definitely stated from the scanty informa- 1 That Proctor did know of Mohr's work on this class of preparations becomes apparent when the fact is recalled that he adapted Redwood's translation of Mohr's Pharmaceutische Technik to American pharmacy under the title of Mohr, Redwood & Procter's Pharmacy in 1849, and that he bad previously reviewed Redwood's translation in the Am. Jour, of Pharm. 22 DU MBZ— THE GALENICAL. OLEORESINS. tion at hand. However, it is interesting to note that the American Dispensatory of 1854, gives the formula of Robinson for preparing the ethereal oil of xanthoxylum, the present Eclectic oleoresin of xanthoxylum. The same is directed to be prepared by extracting the bark with ether and subsequently removing the ether by evaporation — a process similar to the one now employed in preparing the official oleoresins. Of but slightly lesser interest is the advertisement of Wm. S. Merrel which appeared in the Eclectic Medical JournM in 1855. Under the heading, Class II. — Soft resinoids and oleo-resins, etc., the following preparations were listed: Apocynin (from Dogsbane). Ascelepedin (from Pleurisy Boot), Aletrin (from Star Koot). ; ^upurpurin (from Queen of the Meadow). I Iridin^ (from Blue Flag). Ptelein, or Oil of Ptelea (from Water Ash). Oil of Lohelia (from Lobelia Seed). Oil of Xanthoxylum (from Prickley Ash). Oil of Capsicum (from African Cayenne). i Oil of Stillingia .^p^ Oil of Male Fern In view of the fact that these preparations were already being manufactured and advertised commercially in 1855, there can be but little doubt that the Pharmacopoeial Revision Committee of 1860 must have been aware of their existence and have been in- fluenced to some extent thereby. Definition Oleoresins, as a class of galencials, are extracts prepared, as a rule, with the aid of a highly selective solvent. Ether is the solvent usually employed for this purpose at the present time, whereas, acetone was directed to be used in the eighth revised edition of the United States PJiarmacopma. Other solvents of this nature, namely: petroleum ether, benzene, chloroform, car- bon tetrachloride, et cetera, have been used, but have not been ofQcially recognized. The oleoresin of cubeb is an exception - Prof. John King is said to have prepared and used Irisin ( identical with Iridin) in 1844. Letter from J. U. Lloyd to Edward Kremers (1906). DEFINITION 13 to the rule as alcohol is the menstruum directed to be used in its preparation. These preparations derive their name from the fact that the drugs from which they were originally prepared con- tained appreciable amounts of fatty or volatile oil and resin, substances, for which ether and acetone were recognized to be good solvents. They do not by any means necessarily cor- respond to the so-called natural oleoresins, which consist for the main part of volatile oil and resin; but, in some cases, are products relatively poor in one or both of these constit- uents. Thus, for example, the oleoresin of capsicum contains little or no volatile oil and only a small amount of resin, while the oleoresin of parsely is practically free from resin. Furthermore, these preparations are not always liquid as is gen- erally stated. The oleoresin of lupulin, for instance, is of the consistence of a soft extract when prepared according to phar- macopoeial directions, and tends to become firmer with age owing to the transformation of the so-called soft into hard resin. The manner in which the oleoresins have been defined in the various text books and treatises on pharmacy is brought out by the following examples, which are representative of the periods corresponding to the different decennial revisions of the United States PJiarmacopoeia: "Oleoresinae — Their peculiarity is that they consist of principles which when extracted by means of ether, retain a liquid or semi-liquid state upon the evaporation of the menstruum, and at the same time have the property of self-preservation, differing in this respect from the fluid ex- tracts which require the presence of alcohol to prevent decomposition. They consist chiefly, as their name implies, of oil, whether fixed or volatile, holding resin and sometimes other active matter in solution.*' V. S. Disp. (1870), p. 1315. " Oleoresinae, Oleoresins — Mixtures of volatile oils with resins prepared by exhausting certain drugs containing both together, the menstruum be- ing usually ether which extracts both. The menstruum or solvent is evap- orated off, and the usually semi-liquid extract which remains constitutes the oleo-resin.*' Oldberg and Wall, C&mp. to the Z7. S. P. (1884), p. 721. **The oleoresins are official liquid preparations, consisting principally of natural oils and resins extracted from vegetable substances by per- colation with ethylic ether. The oleoresins were formerly classed with the fluid extracts, but they differ essentially from the latter: 1. They do not bear any uniform relation to the drug as fluid ex- tracts do, of gramme to cubic centimeter, — the yield of oleoresin obtained 14 DU MEZ— THE GALENICAL, OLEORESINS from the drug varying according to the proportion of oil and resin naturally present : 2. The menstruum used, ethylic ether, extracts principles which are often insoluble in alcohol or diluted alcohol, and vice versa. Oleoresin of Cubeb, for instance, is not identical with Fluid Extract of Cubeb: 3. They are without exception the most concentrated liquid prepara- tions of the drugs that are produced.^' Kemington, Pract. of Pharm. (1894), p. 433. ''Oleoresins are those substances obtained from vegetable medicines by means of ether (sometimes alcohol, etc.,) which consist principally of a fixed or volatile oil and a resin. In some cases the resin will be held in solution by the oil, while in other cases, it will be precipitated upon stand- ing and will require agitation to diffuse and suspend it in the oil. A third case occurs in which the oil and resin form a more or less perman- ent mixture, having the consistency of a very soft extract." King's Am. Disp. (1900), p. 1330. "Oleoresins are ethereal extracts of an oleoresinous nature, obtained from vegetable drugs by percolation with ether." Coblenz's EandbooJc of Pharm. (1902), p. 290. ' ' Oleoresins, Oleoresinae (Oleoresins, L. oleum, oil and resina, resin) — Natural solutions of resin in volatile oils, extracted by ether, acetone or alcohol." Culbreth, Mat. Med. (1906), p. 20. "The pharmaceutical oleoresins are liquid preparations of drugs con- taining volatile oil and resin, obtained by percolation of such drug with acetone, ether, or alcohol, and subsequent distillation of the solvent from the dissolved oleoresins." Arny, Prin. of Pharm. (1909), p. 259. "Solutions of this class represent the medicinal virtues of the drugs from which they are made, in a more concentrated form than is possible •in any other. They possess the power of self-preservation, and in this respect are superior to fluidextracts. Oleoresins consist chiefly of fixed or volatile oils associated with resin and other constituents; those of- ficially recognized, with one" exception, are all prepared, " et cetera. Caspari, Treat, on Pharm. (1916). p. 354. Drugs Used, Their Collection, Preservation, Etc. Since the oleoresins are characterized chiefly by their content of oil and resin (see definition above), it is evident that they may be prepared from many of the numerous vegetable drugs) 'of which these substances constitute an appreciable part. The number of such drugs, however, which has actually been used for this purpose, is comparatively small as is shown in the table which follows. The table also reveals the fact that nearly all of these drugs are derived from phenogamous plants and that they consist, as a rule, of those organs in which oils and resins are usually present in the greatest abundance. SOLVENTS USED 15 Tablk 2 — Drufis from which oleoresias have been prepared. Phenogams Alkanet (root) Cypripedium (rhizome) Pepo (seed) Anacardium (fruit) Eucalyptus (leaf) Pepper (fruit) Annatto (seed) Galan^al (rhizome) Pomegranate (root) Asarum (root) Ginger (rhizome) Ptelea (bark) Capsicum (fruit) Helenium (flower) Pyrelhrum (root) Cardamon (seed) Iris (rhizome) Sabal (fruit) Chenopodium (fruit) Kousso (flower) Santonica (unexp. flower) Clove (unexp. flower) Lobelia (seed) Savine (leaf) Conium (leaf) Lupulin (strobile) Senecio (root & herb) Croton (seed) Matico(leaf) Spiraea (herb) Cubeb (fruit) Mezereum (bark) Taxus (leaves) Parsley (fruit) Xanthoxylum (bark) Cryptogams Aspidium (rhizome) Ergot (sclerotium of Claviceps purpurea) Of the total immber of drugs enumerated above, seven have been utilized in the preparation of the oleoresins official in the United States Pharmacopoeia, namely : Aspidium Ginger Paisley Capsicum Lupulin Pepper Cubeb With respect to the collection (harvesting) of the foregoing and their preparation for use, there is little of a general nature to be said as the plants from which these drugs are obtained differ so widely in their habits. This subject will, therefore, not be given consideration here, but will be discussed in Part II under tlic treatment of the individual preparations. Solvents Used. At the present time, ether is the .solvent directed to be em- ployed in the preparation of the official oleoresins with the ex- ception of the oleoresin of cubeb which is prepared with alcohol. It will be recalled that the first of this class of preparations to make its appearance, namely, the Huile de Fougere ofPeschier, was also prepared with ether. In fact, ether appears to have been the only solvent^) given consideration in this connection by the early European investigators. * One animal drug, cantharides, has been utilized for the preparation of an ethereal extract. This preparation, which was official in the Belgian Pharmacopoeia of 1854, cannot properly be classed with the oleoresins since it contained no resin — the animal organism being free from constituents of this nature. 2 Buchner in 1826 experimented with alcohol in preparing the Extractum Filicis resinosum, while Brandes, in 1827, made use of a menstrum con- taining both alcohol and ether, namely the Liquor anodynus, for the same purpose. • Later, 1828, Dublanc and Oberdoerffer employed alcohol In th« preparation of the oleoresinous extract of cubeb. 1g DU MEZ— THE GALENICAL* OLJE30RESINS. With the introduction of the oleoresins into the United States PJiarmacopma of 1860, and their extensive use in this country,, a number of American pharmacists were lead to the conducting- of experiments, which had for their main object the discovery of a solvent less expensive and less dangerous to handle than ether. We must, however, note that prior to this time (1860) an at- tempt was made by Berjot, a Frenchman, to use carbon disul- phide for the purpose of preparing the Extrait olea-resineux de Cuhehe. Garot and Schaeuffele, in 1857, in a paper on Berjot 's preparation showed that nothing was gained by its use, as two and one-half times as much carbon disulphide as ether was re-' quired to extract the drug. Furthermore, the removal of the last traces of this solvent was a matter of considerable difficulty. The solvent which first appears to have suggested itself to American investigators was benzin as is indicated in the publi- cations of Procter, Maish, Trimble and others. The first ac- count of its use in this connection appeared in 1866, when Procter published his results on the preparation of the oleoresin of cubeb. The following table shows the relative value of alco- hol, benzin and ether for the extraction of cubeb as found by Procter. Table 3. — Yield of oleoresin of cubeb. Quantity of drugr Menstruum Total Yield grains 1000 Alcohol ... . grains 250 1000 170 1000 Ether '£19 While Procter could find no objection to the use of alcohol as a solvent in the preparation of this oleoresin, he advised against the use of benzin as he stated that it did not extract the cubebin completely. Simultaneously with the above publication of Procter, there appeared an account of a general method for preparing the oleoresins by Rittenhouse. The latter also worked with benzin, but employed it as a ''follow up" solvent after percolation had been partially completed with ether. He also experimented with glycerin and fusel oil, employing them in a similar manner. In 1872 Maish published a review of the experiments of A. H. SOLVENTS USED 17 Bolton and M. Koth. The latter of these two men conducted an investigation on the extraction of ginger and cubebs with benzin, the former also included capsicum in his series of ex- periments. These workers found that ether still extracted some non-volatile matter after the drugs had presumably been exhausted with benzin. Further, that, while the benzin oleore- sins were all soluble in ether, the ethereal uleoresins of cubeb and ginger were only partially soluble in benzin, thus confirming Procter 's work in 1866 on the oleoresin of cubeb. Henry Trimble was the next investigator^) to experiment to any considerable extent with benzin as a solvent. In his re- port to the Pennsylvania Pharmaceutical Association, in 1888, on commercial oleoresins, he stated that while benzin was in his opinion preferable to concentrated ether for the extraction of capsicum, it would not answer for the other official oleoresins. Following h a table showing the comparative extractive powers of ether and benzin as compiled by Trimble : Table 4 — Itelatixe extractive power of benzin and ether. Drugr Aspidium Capsicum, Cubeb . . . . Lupulin.. Pepper — Ginger — Yield witli etiier Percent. 6.51 19.5 21.26 60.59 8 79 3.97 Yield with benzin Percent 5.? 18.1-3 16.65 7.04 2.80 2.48 Results similar to the above with respect to the oleoresins of ginger were reported by Samuel J. Riegel in 1891. About this time George M. Beringer became interested in the preparation of the oleoresins, and in 1892, he published an ac- count of his researches, in which he had employed not only ether and benzin as extracting menstrua, but also the heretofore little used solvent, acetone. With respect to benzin, he ar- rived at the same conclusions as did Trimble, viz: that its use 1 In 1877, L. Wolff in an article entitled: The use of Petroleum Benzine! in Pharmacy, stated that benzin extracted none of the pungent resin from ginger, no cubebic acid from cubeb, no piperin from pepper and no san- tonin or resin from wormseed. 18 DU MEZ— THE GALENICAL. 0KE30RESINS is not permissable in the preparation of the official oleoresins^), except, perhaps in the case of capsicum, and then only under certain restrictions, namely: that percolation be terminated after 2 cubic centimeters of percolate are obtained for every gram of the drug, as upon further percolation, the oleoresin be- comes almost solid owing to the large increase of palmitin ex- tracted. In his experiments with acetone^) he found that, as with ether, the first portion of the percolate contained nearly all the medicinal ingredients of the drug. He, however, continued percolation until the drug was exhausted. The marc was then removed from the percolator, dried and re- percolated with stronger ether; but except in the case of capsicum no further extractive matter was obtained. The oleoresins were stated to be of excellent quality and the yield and properties were nearly the same as when ether was used. ■ He especially recommended the use of acetone in preparing the oleoresin of ginger, as he claimed that it was in every way equal to the preparation made with ether. Follow- ing is a table showing Beringer's results with acetone as com- pared with ether and benzin : Table 5 — Relative extractive values of acetone, ether and benzin. Yield to acetone Yield to ether Yield to benzin Drug U.S. P. method Complete exhaus- tion U. S. P. method Complete exhaus- tion U.S. P. metliod Complete exhaus- tion Percent. Percent. 18.00 25.00 25.00 24.10 21.75 5.57 71.00 24.00'^ 5.93to9.97 3 Per cent. Percent. Per cent. 16.18 21.00' Per cent. Capsicum 18.00' 17.32 25 00 Cubeb Cubeb Cubeb 1... Lupulin 70.80 Parsley 22.30 5.00 to 6.70 ' Two cubic centimeters of percolate were collected tor each grram of druer. '^Represents total extract from which 3 per cent, of wax precipitated, leaving 21.00 percent, of oleoresin. 3 Represents total extract whicii yielded 5.93 per cent, of oleoresin. ^ Pile (1867) confirms this statement in so far as it concerns the oleoresin of g-inger. He states that neither benzin nor ether completely extract ginger, but that alcohol is the best solvent for this purpose. 2 The acetone used by Beringer was procured from manufacturers of chloroform as the product obtained from the distillation of wood was found to consist largely of methyl alcohol and even higher boiling fraction.*?. ' SOLVENTS USED 19 From a comparison of the above data with those obtained by Trimble (See table 4), it would appear that acetone is equally as serviceable as ether in the preparation of the official oleo- resins. Such appears, also, to have been the opinion of the Re- vision Committee of the United States Pharmacopoeia of 1900, as the edition, which became official in 1905, directed that acetone be employed in the manufacture of those oleoresins which were formerly required to be prepared with ether.^ That this change was unsatisfactory is evidenced by the numerous comments on the subject occurring in the literature, and by the fact that ether is again directed to be used for this purpose in the ninth revised edition of the United States Fliarmacopoeia. To those unacquainted with the situation, the above action of the Revision Committee of 1910, might be taken to indicate that the matter of the proper solvent to be employed in the manu- facture of these preparations has been definitely settled and the superiority of ether in this respect firmly established. A close inspection of the preceding reports, along with other informa- tion of a similar nature occuring in the literature, would,, how- ever, appear to point out, that, as in the case of the oleoresin of cubeb, other solvents might be advantageously employed in the preparation of certain of these individuals. In this connection the use of benzin,^) or better, petroleum ether,^) in the prepara- tion of the oleoresins of capsicum and parsley fruit might be mentioned, or the employment of acetone in the preparation of the oleoresin of ginger..*) As further evidence of the possibil- ities along this line, attention is also called to the experiments of WoUenweber (1906) on the extraction of aspidium with ben- zene, and to the mention of chloroform^) and carbon tetra- chloride^) as solvents for the preparation of the oleoresins m general. The manner in which these solvents have been employed in ^ The most important factor in determining this change was probably the difference in cost of the two solvents at the time (1900), acetone being the cheaper. This statement is confirmed in a measure by the fact that now, since the price of ether has been reduced, owing to its preparation from denatured alcohol, it is again the solvent officially recognized. 2 See preceding reports by Trimble, Beringer and others. ^Hyers (1895) also made use of petroleum ether in extracting cubeb. *Idris (1898) stated that he found acetone, b. p. 65" C, to be the most suitable solvent for extracting ginger. «Dorvault, L'Officine (1898), p. 591. "Lucas, Practical Pharmacy (1908), p. 149. 20 I>U MEZ— THE GAUSNICAX. OLEORESINS. the preparation of the various oleoresins will be discussed in a general way under methods of preparation and in detail under individual oleoresins. Methods of Preparation The methods of preparing the oleoresins as outlined in the present edition of the United States PJiarmacopoeia may be stated in the following general way: extract the drug com- pletely^) by percolation, expose the percolate in a warm place until the solvent has completely evaporated and separate the remaining liquid portion from any deposited material. This is essentially the method of procedure given in most of the late editions of the foreign pharmacopoeias as well, notable excep- tions being the German and Japanese. In the two latter, the drug is directed to be exhausted by maceration instead of per- colation. In detail, the methods described in the United States Pharmacopoeia, as well as the foreign pharmacopoeias, differ somewhat Avith the particular oleoresin as will be brought out to some extent in the following discussion and more minutely under the separate treatment of each individual. It is perhaps needless to state that these methods are not of recent invention but have been gradually evolved from the numerous experiments conducted both in this country and abroad. The first of these experiments dates back to the year 1825, when Peschier prepared the Huile de Fougere Male, our pres- ent oleoresin of aspidium. In his description of the method of preparation, he directs that the male fern rhizomes be extracted with successive portions of ether, the decanted ethereal solu- tions mixed and evaporated at a gentle heat, and the remaining oily residue collected and preserved as the finished product. This is essentially the method which appeared in the early European pharmacopoeias as is shown in the following typical example taken from the Prussian Pharmacopoeia of 1830 : Agitate one ounce of powdered male fern root with successive portions of eight ounces of ether until the ether decants clear. Then mix the several portions and strain. Distill down to one-fourth of the volume and evaporate the remainder on a water bath to a thin yellowish-brown extract. 1 Percolation, in the extraction of capsicum is directed to be discontinued when eight hundred mills of percolate have been obtained. METHODS OF PREPARATION 21 An inspection of the above method brings out the fact that the decanted menstruum was directed to be clarified by the process of straining. Not only was a great deal of the solvent lost by evaporation in this procedure, but a very considerable amount remained adhering to the marc. While some of the latter was, in actual practice, removed by pressing the drug on the strainer with the hands, Mohr^) in commenting on the method stated that, inasmuch as three-fourths of the ether were ■often lost in these operations, it was useless to recover the re- mainder by evaporation. To overcome this loss to some extent, he suggested making these preparations in the winter when the low temperature would be less favorable for the volatilization of the solvent. As ether, at this time and for many years later, was a comparatively expensive solvent, it will become apparent that a change in the method was to be desired. The first decided departure^ from the above method of pro- cedure, which appears to have been given official recognition, is to be noticed in the Baden Pharmacopoeia of 1841. The method briefly stated is as follows : Mix the powdered male fern root with a sufficient quantity of ether to thoroughly moisten it. Then extract it in a EeaVsche Presse so connected with a receiving flask that none of the menstruum will be lost by evap- oration. A few years later, in 1846, there appeared a method in the Swedish Pharmacopceia which likewise included the process of displacement, viz: Macerate the male fern root, cut in small pieces, with ether and extract in a displacement apparatus.^ Then distill the ethereal solution to one- fourth of its volume and evaporate the remainder on a water bath to the consistence of a thin extract. Even with the use of a pressure percolator, so much ether was still lost through spontaneous evaporation and through ab- * Mohr, Redwood and Procter's Pharmacy (1849), p. 263. 2 Geiger, in 1827, employed the Real'sche Presse in the preparation of the Oleum Filicis Maris, our present oleoresin of aspidium. ' The apparatus employed for this purpose was most probably the Filtre- presse of Count Real or the Luft-presse of Dr. Romershausen, as both of these so-called presses were in general use at that time. In fact, both are mentioned in connection with the preparation of the extracta by the Prus- sian Pharmacopoeia as early as 1834. 22 DU MEZ— THE GALENICAL OLEORESINS sorption by the bag/) that, in operating with small quantities of the drug, the recovery of the remainder was scarcely worth the trouble. The recognition of these defects by Mohr lead him to construct (in 1847) a special form of apparatus for con- tinuous extraction with volatile solvents. However, while Mohr 's apparatus was a success from an economical standpoint,, there is no evidence to show that it was ever employed to any extent by the American pharmacist, although, Procter, the American editor of Kedwood's translation of Mohr's treatise on pharmacy, advocated its use in this connection in 1849. About this time (1846) Procter caused the American pharma- cists to become interested in this class of preparations by call- ing attention to his improvement upon Soubeiran's method (as suggested by Dublanc)^) for preparing the Extrait oleo-resineux de CuhehCf a preparation similar to our present oleoresin of cubeb. The following is the method as devised by Procter. "Take cubebs, in powder, one pound avoirdupois, and sulphuric ether a sufficient quantity, which is two and one-half to three pounds; intro- duce the powder into a displacer, insert the lower end into a bottle that fits it, add the ether carefully, and cover the top of the filter with a piece of wet bladder through which several pin holes have been made.' The flow should be very gradual and if too rapid, the filter should be partially closed with a cork. By attention to this point, much less ether will be required. The ethereal tincture should be introduced into a large retort^ heated by a water bath, and the receiver well refrigerated. The dis- tillation should not be hurried toward the last. When five-sixths of the ether have passed, it should be separated for use, and the evaporation be continued in the retort, observing to keep the temperature below 120®F, so as not to volatilize the volatile oil.'* A few years later (1850), this method (in essential detail) was given recognition by the United States Pharmacopma in connection with the preparation of the fluid extracts of cubeb and pepper, later known as the oleoresins of cubeb and pepper, respectively. For the purpose of better bringing out this » Mohr, Redwood and Procter's Pharmacy (1845), p. 263. ^Although Dublanc described a method for preparing the oleoreslnous extract of cubeb, similar to that of Soubeiran, in 1828, neither method is given consideration here as both differed to such an extent from the usual procedure that they had little or no influence on the development of the present process. «From the above description, it appears that the form of displacer used by Procter was the one described in Mohr, Redwood and Procter's Phar- macy, (1849), p. 270. METHODS OF PREPARATION 23 similarity, the following general statement of the pharmaeopoeial methods is also given : Take of the Drug, in powder, a poundj Ether a sufficient quantity. Put the drug into a percolator, and having packed it carefully, pour the ether gradually upon it until two pints of filtered liquid are ob- tained, then distill off by means of a water-bath, at a gentle heat, a pint and a half of the ether, and expose the residue in a shallow vessel, until the whole of the ether has evaporated. The methods in general as they were given in the United States Pharmacopoeia of 1860 differ from the above only in the quantity of drug and menstruum directed to be taken. Thus, twelve troy ounces of drug were directed to be subjected to per- colation with ether until twenty-four fluidounces of filtered liquid were obtained, "when eighteen fluidounces of the ether were to be removed by distillation. In the preparation of the oleoresin of ginger, however, the following method of procedure was given: "Take of Ginger, in fine powder, twelve troyounces; "Stronger ether twelve fluidounces; "Alcohol a sufficient quantity. "Put the ginger into a cylindrical percolator, press it firmly, and pour upon it the stronger ether. When this has been absorbed by the powder, add alcohol until twelve fluidounces of filtered liquid have passed. Ee- cover from this, by distillation on a water-bath, nine fluid-ounces of ether, and expose the residue in a capsule until the volatile part has evaporated.'^ That the Pharmaeopoeial Eevision Committee was informed of the work of Beral in this connection appears to be clearly evident, as it was he, who first suggested this procedure (1834), also, in the preparation of the oleoresin of ginger, then known as the Piperoide du Gingemhre. In 1866, Kittenhouse, commenting on the methods in gen- eral, which were given in the United States Pharmacopoeia of 1860, stated that about thirty-six fluid ounces of ether were re- quired to extract the drug when proceeding as officially directed. He, however, conceived the idea of reducing the amount of ether by a procedure similar to that employed in extracting the gin- ger rhizomes. Alcohol did not appeal to him as the proper * 'follow up" solvent for this purpose and he, therefore, con- ducted a series of experiments, in which he made use of benzin. 24 DU MEZ — THE GALENICAL. OLEORESINS. glycerin and fusel oil. finally devised by him : The following is the working formula ''Take any convenient quantity of the drug; for each ounce thus em- ployed, iy2 fluid ounces of ether, and 1 fluid ounce or q. s. of benzin. Pack the drug in a suitable apparatus, add the ether, and when it has ceased to pass, pour on the benzin in the proportion of one fluid ounce for eacli ounce of the drug employed or until as much percolate has been obtained as equals the amount of ether employed. Eeeover the ether by distilla- tion in the usual manner." The process of Rittenhouse does not appear to have received much attention as there is no subsequent mention of it to be found in the literature. During the meantime Procter continued his work on the oleo- resins and in the same year (1866), he pointed out that prac- tically all of the oleoresinous material was to be found in the first portions of the percolate, and that a considerable quantity of menstruum could be saved by discontinuing the operation be- fore the drug was completely exhausted. The following table compiled by Procter clearly brings out this point: Table 6 — Yield of oleoresin of cubeb to ether, alcohol and benzin . Quantity of cubeb Solvent Quantity of 1st percolate Yield of oleoresin Quantity of 2nrt percolate Yield of oleoresin Total yield grains 1000 Ether Alcohol Benzin grains 1000 grains 205 240 140 grains 1000 2000 grains 14 30 25 grains 219 250 170 The effect of Procter's work is noticed in the 1870 and 1880 editions of the United States PJiarmacopma. Thus, the Phar- macopoeia of 1870 directed that twenty instead of twenty-four fluidounces (as formerly required) of percolate be collected for every twelve troyounces of drug, while the Pharmacopoeia of 1880 required that only 150 parts of percolate be obtained for every 100 parts of drug taken. It should also be noted, that in the 1880 edition, the method of preparing the oleoresin of ginger was made to conform with that given for the other oleo- resins. METHODS OF PREPARATION 25 The United States Pharmacopoeia of 1890, directed, that, in the preparation of all of the official oleoresins, the drug be com- pletely exhausted by percolation with ether. The following directions for the preparation of the oleoresin of cubeb are typical of the methods given : * * Cubeb, in No. 30 powder, 500 Gm. ; ether a sufficient quantity. * ' Put the cubeb into a cylindrical glass percolator provided with a stop- cock, and arranged with a cover and receptacle suitable for volatile liquids. Press the drug firmly and percolate slowly with ether, added in suc- sive portions, until the drug is exhausted. Eecover the greater part of the ether, etc." The next edition of the United States Pharmacopoeia (1900) contained a number of changes with respect to the methods of preparing this class of galenicals. Two new solvents were in- troduced, namely, acetone and alcohol ; the method of procedure was modified in the case of the oleoresin of capsicum, and an ordinary percolator was directed to be used in the preparation of the oleoresin of cubeb. The following is a general state- ment of the manner in which the oleoresins of aspidium, ginger, lupulin and pepper were directed to be extracted. Introduce the powdered drug (degree of fineness specified) into a cylin- drical glass percolator, provided with a stop-cock, and arranged with a cover and receptacle suitable for volatile liquids. Pack the powder firmly, and percolate slowly with acetone, added in successive portions, until the drug is exhausted. The method of extracting the cubeb was stated as follows : Introduce the powdered cubeb (degree of fineness specified) into a cylindrical glass percolator, pack the powder firmly, and percolate slowly with alcohol, added in successive portions, until the cubeb is exhausted. The method described for the extraction of capsicum was similar in all respects to the first of the methods given above, except that percolation was directed to be discontinued when eight hundred cubic centimeters of percolate had been obtained. The above changes, except in the case of the oleoresin of cubeb^) must be attributed to the work of Beringer, an account of which was published in 1892. Not only did he advocate the use of acetone in these preparations, but he also pointed out ^ It will be recalled that Procter in 1866 suggested the use of alcohol in preparing the oleoresin of cubeb. See table 3, page 922. 26 r>U MEIZ— THE GALENICAL OLEORESINS the advantage of discontinuing percolation short of exhaustion in the case of capsicum. The ninth revised edition of the United States PJiarmacopoeia shows but one change in the method of preparing the oleoresins, viz: ether is directed to be used in those cases where acetone was employed in the preceding edition. From the foregoing discussion, it becomes apparent that the United States PJiarmacopoeia, even to the present edition, has consistently adhered to the process of simple percolation in ex- tracting the oleoresinous drugs. This condition not only ap- pears strange, in view of the fact that modern methods of operating with the volatile solvents, such as ether, make use of some form of continuous extraction apparatus; but is thought to show a lack of progress as well. Maish, in 1900, suggested the use of Soxhlet's apparatus for this purpose and pointed out its advantage, especially when operating with small quantities of drug. Reference is also made in this connection to similar forms of apparatus in most of the present day text-books on pharmacy. With reference to the preparation of the oleoresins on a com- mercial scale, there is good reason to doubt the employment of any of the heretofore mentioned methods. The method most likely in use at the present time is one similar to that offi- cial in the British PJiarmacopoeia of 1867. The latter, briefly stated, is as follows: Exhaust the powdered drug by percolation with alcohol, and distill the percolate until a soft extract is obtained. Treat this extract with suc- cessive portions of ether, mix the ethereal solutions and again distill off the solvent, when the residue will constitute the oleoresin. The advantage of this method lies in the fact that it requires the handling of comparatively small amounts of ether, and thereby lessens the danger incurred in working witK large quan- tities of this highly inflammable solvent. The disadvantage is that alcohol may not extract all of the eother-soluble material from the drug. In the preceding survey, only the official oleoresins and their methods of preparation have been considered. There is, how- ever, a number of preparations which have been classed as oleoresin, in Parrish's Treatise on Pharmacy, and King's American Dispensatory, although, they have never received of- APPARATUS EMPLOYED 27 licial recognition. They are the so-called Eclectic oleoresins ^nd are in general directed to be prepared in the following man- ner : Extract the drug by percolation with alcohol or ether and precipitate the oil and resin by pouring the alcoholic or ethereal tincture into water. Lastly, separate the product from the water by filtration. Among the preparations which have been made in this way are the following: oleoresin of iris (iridin), oleoresin of xanthoxylum, oleoresin of cardamon (oil of cardamon), oleo- resin of ergot, (oil of ergot) and oleoresin of parsley,^) (oil of parsley). In this connection, it should be pointed out that the fore- going are liquid preparations and do not constitute the so-called resinoids, which are solids, although prepared in a similar way. Apparatus Employed. Under the two preceding headlines, the preparation of the oleoresins has been discussed from the standpoint of the solvent employed in extracting the drug, and with respect to the method of procedure. There, is however, still another factor of inter- est which deserves consideration in this connection, namely: the form of apparatus made use of. It will be recalled that the first of this class of preparations to make its appearance, the oleoresin of aspidium, as originally prepared, required the use of nothing but a macerating jar, a cloth strainer and some sort of container, in which the colated liquid could be collected and exposed to the air to permit the evaporation of the solvent. Likewise, these were the utensils generally employed in the experimental stages of the prepara- tion of the other members of this class which became known at an early date. As soon, however, as the oleoresins became recognized as regular pharmaceutical commodities, the method of preparation as outlined above was found to be impractical owing to the complete loss of the solvent by evaporation. In adapting the same to commercial use, steps were, therefore, taken to recover as much of the latter as possible. For this purpose, some form of distilling apparatus was employed, pre- *This preparation should not be confused with the oleoresin of parsley as official in the present edition of the United States PharmacopoBia. 28 DU MEZ— THE GAUENICAL. OL.EORESINS. sumably, the retort and condenser. Even with this modifica- tion, however, a large part of the solvent was still lost in the operation of straining. About this time (1820 to 1840), the extraction of drugs by the process of downward displacement was attracting consider- able attention, and, as the pharmacist saw in this procedure a means of eliminating the operation of straining, it is not at all surprising that it should have received early application in the preparation of the oleoresins. In explanation of the method of procedure as followed at the time, it should be stated that it was in reality a process of percolation under pressure, and, as such, required the use of a special form of apparatus. Two such forms were already available at the time when the oleoresins became a subject for investigation, namely : the Filtre-Presse of Keal and the Luft-Presse of Romershausen. In fact, Geiger made use of the former in the preparation of the oleoresin of male fern as early as 1827. While these forms of pressure percolators eliminated the process of straining, their use, never- theless, appears to have been disadvantageous in certain other respects. For instance, the method of operation was rather cumbersome, and a considerable amount of solvent was absorbed by the cloth bag containing the powdered drug, thus rendering the apparatus of little value in working with small quantities of the latter. As a result of the early work with the pressure percolators, experimentation along this line was stimulated and it was soon shown that drugs could be completely extracted by simple per- colation under ordinary atmospheric pressures. The first evi- dence of the use of a simple percolator in the preparation of the oleoresins appears in Beral's account of his preparation of the Piperoide du Gingembre in 1834. Fifteen years later (1849), Procter, in an article on the oleoresinous ethereal ex- tracts, mentioned two forms of simple percolators, a conical percolator made of tin, and Gilbertson's displacement apparatus constructed of glass. Both of these were similar in essential detail to the percolators in general use at the present time. In fact, the United States Pharmacopoeia still directs that these pre- parations be made by simple percolation, a modified form of Gilbertson's displacement apparatus being specified for use in this connection. This condition seems strange, indeed, in view of the fact that modern methods of operating with volatile APPARATUS EMPLOYED 29 solvents, such as ether, make use of some form of continuous ex- traction apparatus. Such an apparatus was invented by Mohr in 1847 and its advantages in the preparation of the oleoresins pointed out by him at this time, and later, by Procter. An apparatus operat- ing on similar principles was described by Parrish in 1884 in his Treatise on Pharmacy. More recently Maish (1900) has sug- gested the use of the Soxhlet apparatus for the preparation of small quantities of oleoresins, while a number of other forms of continuous extraction apparatus have been mentioned in this connection in the various periodicals and text-books on phar- macy. The different forms of apparatus, which have been mentioned at various times in connection with the preparations of the oleo- resins, and the methods of operating with the same are described in detail in the following chronological list: Cadet, C. L. Filtre-presse de M. Real. Jour, de Pharm., 2, pp. 165 and 192; Repert. der Pharm. 2, p. 356. Fig. 1.) The body of the extraction apparatus A is made of tin, the top of which, being screwed on, can be remaved. It is 30 DU MEZ— THE GALENICAL OLEORESINS supported on a tripod. At D and D are two false bottoms be- tween which the material to be extracted is packed. Into the cpver of the apparatus, the pipe B, which may be 50 to 60 feet high, is fitted. The communication between B and A may be stopped by means of the stop cock C. The dish E under the tripod receives the percolate. Fig. 2.) The second figure is a modification of the first do- ing away with the long tube. The solvent is admitted to the space X by pouring it into the funnel E. The percolate is collected in the container G. The pressure is secured by filling the cast iron container A with mercury. After the apparatus C is charged with drug and solvent, the stop-cock H is closed and the pipe B also filled with mercury which then forces the menstruum through the firmly packed drug. Buchner, J. A. Beschreibung und Abbildung der von hausen erfundenen Luft-presse. Repert. der Pharm., 6, p. 316. Herrn Dr. 1819 Romers- '^. i^JPAarma^i^ ^ APPARATUS EMPLOYED 31 TaiM .£U The two twin cylinders B and C are mounted on the support A and are provided with covers 1 and 10. On the support, the diaphragm 3 is placed, covered with a straining cloth which is held in position by the diaphragm 4 which in turn is fastened by the clamp 5. A third diaphragm 6 is used to covef the sub- stance to be extracted. The two cylinders are united by the tube 7 provided with a stop-cock. The lower part of B is also provided with a stop-cock at S in order to allow the percolate to flow out at 9. The lower section of C is converted into an air tight compartment by the cover 11, which is provided with an opening and stopper at 12. The parts indicated by 13, 14, 15, 16, and 17 belong to the suction pump necessary to create a va- cuum. The suction pump is outside the cylinder and the per- colate is not allowed to collect underneath the percolator B, but is at once pumped in the reservoir C. Beindorff 1826 Mag. f. d. Pharm., 9, p. 185. [Geiger, Hanbuch d. Pharm. (1830), p. 142]. The cuts represent Beindorff 's modification of the Eeal and Romershausen extraction apparatus. It will be noticed that the apparatus in figure 6 is so mounted that it can be tipped 32 DU MEZ— THE GALENICAL OLEORESINS. at a convenient angle for filling and emptying. In figure 7, a more compact form of the apparatus is shown. In the latter, the long tube is replaced by an air pump. These forms of pressure percolators were mentioned in con- nection with the preparation of the oleoresins by Mohr (1854) in his Commentary on the Prussian PJiarmacopoeia. APPARATUS EMPLOYED Simonin Journ. de Pharm. et de Chim., 20, p. 128. 33 1834 It is thought that one of the above represents the form of per- colator made use of by Beral (1834) in his preparation of the Piperoide due Gingemhre. 34 DU MEZ— THE GALENICAL OLEORESINS Mohr 1847 Neuer Extractions Apparat fuer Weingeist und Aether. Arch, der Pharm., 100, p. 305. [Am. Journ. Pharm., 21, p. 117]. Fig- 78. Fig. 79. J e I •iii The apparatus consists of a two-necked Woulf 's bottle, figure 78 p, into the central mouth of which the metallic vessel R, figure 79, is fitted by means of a cork. The vessel R consists of a me- tallic cylinder a having a perforated strainer k near the bottom and terminating with a funnel neck, to admit of its being fitted into the Woulf 's bottle. This cylinder is surrounded by a second cylinder &, the space between them being intended to contain either hot or cold water. In the top of the inner cylin- der a, a slightly conical vessel c is made to fit air tight, as shown in the drawing. This vessel c is intended to be used as a con- densing apparatus, and for this purpose it is filled with cold water. From the second or lateral opening of the Woulf 's bot- tle, a glass or tin .tube d, figure 78, is carried to the upper part of the cylinder a, where it is inserted as shown in figure 80. The cold water in the vessel c is renewed through the pipe e which conducts it to the bottom, while the warm water runs off from the top through the pipe /, figure 79. Hot or cold water is re- newed to the space between the two cylinders R. by the tube funnel hy figure 78, and the water from this space overfiows inta g and is carried off together with that from /. The tube h is inserted through a perforated cork at i so that by turning the APPARATUS EMPLOYED 35 tube downwards, the water from the space between the cylin- ders can be run off. 1849 Mohr, Redwood and Procter 's Pharmacy, p. 270. This consists of a conical vessel A with a water joint rim at the top into which the cover fits. A tube D is ground to fit into the opening in the bottom, and over the end of this tube is placed a conical tube C, the lower end of which has several notches cut in it, so that the liquid can pass under when placed as shown in the drawing. The lower extremity of the vessel A is ground to fit into the mouth of the receiver B. The above apparatus was mentioned by Procter, in 1849, in his article on "the preparation of the oleoresinous ethereal ex- tracts. ' ' 1849 Mohr, Eedwood and Procter's Pharmacy, p. 272. A is an ordinary tin displacer, except that the rim c is soldered around the mouth, in such a manner as to form a water joint when the rim of the cover d is placed in it; a is a perforated diaphragm, e a tin tube open below and above. The latter is soldered to the lower diaphragm, through which it passes, while the upper diaphragm slips over it loosely. In using the dis- 36 I^U MEZ— THE GALENICAL OLEORESINS placer, the ingredients are introduced around the tube to a suitable height, the upper diaphragm put in its place, and menstruum poured on, the joint half filled with water and the lid inserted. The atmosphere of the bottle B communicates with that of A through the tube e. This form of percolator was mentioned by Procter (1849) in. his article on "The oleoresinous ethereal extracts." 1849 Mohr, Eedwood and Procter's Pharnmcy, p. 270. Figure A is a glass adapter, which is selected of suitable size. The lower extremity of this is partially stopped with a cork cut as represented in F. A layer of coarsely pounded glass is put over the cork, and above this a layer of clean sand, thus form- ing a strainer for arresting the passage of the solid particles of material to be acted upon. The end of the adapter is fitted, by means of a perforated cork, into the mouth of the bottle. A glass tube, one end of which is drawn to a capillary opening, is also fixed in the cork as shown at C so as to allow the air to escape out of the bottle as the liquid drops in. A piece of blad- der may be tied over the mouth of the vessel at A to prevent the evaporation of the solvent, but a few pin holes must be made in the bladder to admit of the ingress of air as the liquid passes into the receiver below. APPARATUS EMPLOYED 37 The above form of percolator was mentioned by Procter (1849) in his article entitled The Preparation of the Oleoresin- ous Ethereal Extracts. 1873 Utensilien zur Bereitung der aetherischen nnd weingeistig- aetherischen Extracte. Hager's Commentar zur Pharmakopoea Germanica, 1, p. 620. This consists of a cylinder hh fitted into a cork / which is in- serted into the neck of a flask or bottle g, aa is a cover which serves as a condenser. In the lower end of the cylinder && is a tin sieve plate ss in the center of which is a tin tube rr en- closed in a glass tube vv. The glass tube is held firmly in place by a cork at each end pp. The condenser aa has a conical shaped bottom N around the interior of which run two cor- rugated rings zz of tin. The space a, Fig. B, contains cold water which enters from the openings cc and flows out through 38 DU MEZ— THE GALENICAL OLEORESINS the tubes ee. As soon as the menstruum drops through color- less, the top aa is taken off and D put on in its place. It is also a condenser. The water flows in at a and off through &. The conical bottom K is so arranged that the condensed solvent drops from off the receiver i and is carried off into a flask through the outlet e. The space between vv and aa is filled with either hot or cold water. 1873 Utensilien zur Bereitung der aetherischen und weingeistig- aetherischen Extracte. Hagers Commentar zur Pharmakopoea Germanica, 1, p. 622. A displacement tube D with a wide mouth at its upper end is closed with a cork through which runs a thistle tube T. The lower end is pushed through a cork which fits tightly in a re- ceiving bottle R. The small glass tube I is for the purpose of letting the air escape from the receiver R. APPARATUS EMPLOYED ^9 1884 Parish's Treatise on Pharmacy, p. 755 A percolator of tinned copper is surrounded by a jacket of the same material ; the receiver is a copper vessel with two necks into one of which the percolator is secured, the other is connected with a pipe leading to the closed head of the percolator which is also jacketed ; on the other side of the head is a perforated plate 40 DU MEZ— THE GALENICAL OLEORESINS of tinned copper, which distribute^ the ether over the surface of the drug when it has been volatilized by placing the receiver in hot water. After the exhaustion of the drug, the receiver is removed, the lower orifice of the percolator closed, and the head well refrigerated; a stream of hot water is then passed into the jacket around the percolator, by which means the contained ether may be recovered. 1886 Kemington's Practice of Pharmacy 1886, p. 366. The apparatus consists of a cylindrical percolator fitted into the mouth of a receiving bottle with the aid of a cork. The upper part of the percolator being closed and a small opening left in the cork to allow the escape of air from the receiving bottle. A continuous extraction apparatus can be made of this per- colator by enclosing the upper part in a suitable case and pass- ing cold water between, arranging the apparatus like a Liebig's condenser. A glass tube is connected with the top of the perco- lator and the mouth of the bottle by rubber tube connections, APPARATUS EMPLOYED 41 and if the receiving bottle be placed in a water bath and the water gently heated, the ether will evaporate from the percolate, the vapors rising in the tube and condensing in the upper part of the percolator. Lewin R. Ein neuer Extractions Apparat, Arch, der Pharm., 215, p. 74. [Proc. A. Ph., 35, p. 12.] 1887 This apparatus is adapted for 1) continuous extraction with hot menstrua, 2) continuous extraction with cooled menstrua, 3) recovery of the menstrua from the finished extract by direct distillation. It is composed of three easily separable principle parts: C, the tinned copper still, B, the copper percolator, which is pro- vided with three movable sieve bottoms for the reception of 1) For continuous extraction with hot solvents, the vapors pass from the still C, in the tube 1, and enter through the tri- 42 DU MEZ— THE GALENICAL OLEORESINS faucet I, when in position a, through tube 4, into the percolator, the substance to be extracted. A is the condenser. B, penetrate the substance to be extracted, and condense. The percolate passes into the receiver and from this flows through the tri-faucet III in its position a, through the tube 7, again into the still, to repeat this course as long as it may be desir- able. To prevent pressure in the apparatus, the tube 2, is removed during this operation, and the tri-faucet II is placed in position a. This admits the vapor into the cooling worm, A, which thus forms a safety valve. 2) For the continuous extraction with cooled solvents, the vapors pass from the still C, into tube 1, and enter through the tri-faucet I, in its position h, through tube 2, into the cooling worm A, from this as a liquid through the tri-faucet II, in its position a, into the percolator, and so through the substance to be extracted into the still as before. 3) For the recovery of the solvent from the extract by direct distillation, the vapors pass from the still C, through tube 1, through the tri-faucet I, in its position h, through tube 2, into the cooler, A, through the tri-faucet II in its position h, into the exit tube 3, which latter may be lengthened at pleasure. Portions of the percolator may be removed from the receiver at pleasure through the tri-faucet III, in its position c, by the tubes 2 and 3. All of the tubes are connected or disconnected by good screw joints. Flueckiger, F. A. 1889 Ein zweckmaessiger Extraktionsapparat. Arch. d. Pharm., 227, p. 162. [Proc. Am. Pharm. Assoc, 37, p. 338]. The extraction tube A is provided at C with a diaphragm from the center of which a small tube or neck extends into the funnel D. The tube B F attached to the side, passes into a tubulure G, which is provided with an ordinary cork K by means of which communication through the tube B F, between the upper, and the lower portions of the apparatus may be cut off or established. Thus causing the condensed liquid to return through the drug when the communication is closed or allowing the liquid to be distilled off when it is open. APPARATUS EMPLOYED 43 Caspar! in his Treatise on Pharmacy (1916) describes the use of this apparatus in connection with the preparation of the oleo- resms. 1890 Szombazi Soxhlet's Extraction Apparatus. Dingier 's pol. Journ., 256, p. 461. [Zeitschrift f Anal. Chem., 19, p. 365.] Maish (1900) first suggested the use of this apparatus in the preparation of the oleoresins. 44 DU MEZ — THE GALENICAL OLEORESINS Alpers, William C. 1896 Oleoresinae. Merck's Rep., 5, p. 593. [Proc. Am. Pharm. Assoc, 45, p. 435.] The apparatus consists of a cylindrical percolator a. The upper end of the percolator is closed with a large cork b through which two holes have been bored — the one for receiving a bent glass tube c, the other for a small glass funnel d. The lower narrow end of the percolator is closed by a cork e through which a straight connecting glass cock / passes into another perforated cork g that closes the receiving bottle h. This cork contains a second perforation with a small bent glass tube i. The glass tubes and i are joined by means of a small piece of rubber tubing at k. 1902 Coblentz's Handbook of Phannacy, p. 290. (^ B A is a percolator with a stop cock C. It is inserted into a receiver B. The receiver B and percolator A are connected APPARATUS EMPLOYED 45 with a tube as shown in the figure for the purpose of equalizing the pressure as the apparatus is closed throughout. 1908 Brandel and Kremers, Percolation, p. 52. A is an ordinary conical percolator of such a size that it will not be more than two-thirds filled with the drug to be extracted. B is a round-bottom flask, containing a twice perforated stop- per, through one hole of which a glass tube connects the flask to the percolator. Through the second hole is inserted the glass tube C which also passes through the cork stopper in the top of the percolator. The end of the condenser D is also in- serted through this cork. All cork connections should be tightly sealed with gelatine. The above is the form of apparatus which was used in the laboratory in the preparation of the oleoresins when 500 grams or more of the drug were extracted. 46 DU MEZ— THE GALENICAL OLEORESINS Yield The yield of oleoresin is a variable quantity depending, first of all, upon the oleoresin content of the particular drug from which it is prepared. Thus, the oleoresin content of ginger is only about one-half that of the aspidium and one-fourth that of cubeb. Not, only, however, does the oleoresin content vary with the different drugs, but the drug, when of the same genus and species, may show a variation due to a number of in- fluences, such as the climate in which grown, time of harvest- ing, conditions under which stored, et cetera. As an illustra- tion of these influences, aspidium may be taken. The maxi- tnum yield of oleoresin, in this case, is obtained from the freshly ^dried Russian rhizomes collected in the month of September.^) ^Or, the case of ginger may be cited. In this instance, the African rhizomes harvested at maturity (usually in Feb- :ruary)^) give the largest amount of oleoresin. This character- istic will be taken up in detail under the treatment of the '^individual oleoresins. The other important factors in deter- mining the amount of oleoresin obtained, in general, are two in number, viz: the solvent employed in extracting the drug, and the method employed in operating with the same. Both of these factors have been dealt with in a general way under the two preceding headings. They will also be discussed more fully in connection with the individual preparations. Chemistry The Chemistry of the oleoresins per se has apparently re- ceived but little attention, except in the case of the oleoresin of aspidium. The latter has been the subject of numerous investigations and its chemistry is now under- stood fairly well. Some work has also been done toward de- termining the composition of the oleoresins of cubeb and lupulin, but our present knowledge of the chemistry of these preparations is still very indefinite. A very considerable amount of work has been done toward clearing up the chemistry of the drugs from which the oleo- resins are prepared, and it is from this source that we are 1 See tables of yield under the oleoresins of aspidium and ginger, re- spectively. PHYSICAL PROPERTIES 47 obliged to obtain what information we have concerning the composition of most of these preparations. It is for this rea- son that the chemistry of the drugs from which the oleoresins are prepared is given consideration in this monograph. See ^'Chemistry of the drug and its oleoresin" under the treatment of each individual oleoresin. Physical and Chemical Properties The determination of the physical and chemical properties of the galenical oleoresins in general does not appear to have been undertaken systematically in the past. While there are numerous references in the literature concerning color, odor, taste and consistence, there is no mention, except in connection with the oleoresins of* aspidium and cubeb, of the properties which we should naturally expect to find under a description of a class of preparations of this nature, viz: specific gravity, refractive index, acid number, saponification value, et cetera. This condition is surprising in view of the work which has been done along this line in connection with the natural pro- ducts of the same name. That cognizance is, however, being taken of the subject at the present time is evidenced in the comparatively recent work which has been done abroad on the oleoresin of aspidium. In the latter case, the methods usually employed in fixing the standards of similar natural products were applied, and with considerable success. A brief general dis- cussion of these properties as well as other characteristics, which have been mentioned in this connection, follows. Physical Properties Color: The color is a characteristic property of the individual mem- bers of this class of preparations. Considered with respect to a single member, it serves in some cases as a measure whereby the quality of the product may be roughly determined. Thus, a brown color in the oleoresin of aspidium indicates an inferior preparation, in the making of which old deteriorated rhizomes have been used, whereas, a deep green color is said to indicate adulteration with salts of copper. Likewise, a brown color in the oleoresin of cubeb warrants the opinion that ripe in- stead of unripe fruits have entered into its preparation. How- 48 DU MEZ — THE GALENICAL OLEORESINS ever, as the color of the individual preparations, when properly made, varies to a considerable extent, and as the description of exact shades is a difficult matter, this property as described in the literature is naturally somewhat indefinite. This subject will receive further consideration of the treatment of the in- dividual oleoresins. Odor: The oleoresins without exception possess distinct odors re- sembling in an intensified degree those of the drugs from which they are prepared. In general, this property offers a ready means of identifying these preparations. In specific instances,, it may also serve as an indication of the quality of the product. For example, a rancid odor in the case of the oleoresin of as- pidium is evidence of the use of old deteriorated rhizomes in its preparation or of undue exposure to the air while kept in storage. For similar reasons, the oleoresin of lupulin may have a disagreeable cheesy odor. Furthermore, unevaporated solvent, even when present in comparatively small amounts, may be most easily detected by this means. This property will be discussed in greater detail under the individual oleoresins. Taste: The taste of the individual oleoresins, like the odor, is a property acquired in an intensified degree from the drugs from which they are prepared. Likewise, this property also serves as an acid in the identification of these preparations. In addi- tion, however, it has been made the basis of a quantitative physiological test (^) for the determination of the quality of the oleoresins of capsicum and ginger. For a further discus- sion of this property, see the individual oleoresins. Consistence : The U. S. P. oleoresins, with the exception of the one pre- pared from lupulin, are liquids. The degree of fluidity, how- ever, varies with the individual under consideration, with the temperature and with certain other conditions, which will be dis- cussed in detail under the separate treatment of each indi- vidual. The oleoresin of lupulin is usually of the consistence of a very soft extract. * See under the oleoresins of capsicum and ginger respectively. PHYSICAL PROPERTIES 49 SoluhUity: The solubility of the different oleoresins naturally depends to a large extent on the solvent which was employed in their preparation. It does not, however, follow from this statement that, because an oleoresin was prepared with ether, it will al- ways be completely soluble in the same. Some of these prep- arations on standing undergo chemical changes with a result- ing change in solubility. For example, the oleoresin of aspi- dium forms a deposit on ageing, and the deposited material is practically insoluble in ether. As a rule, the oleoresins, when prepared with ether, form clear or slightly cloudy solutions with absolute alcohol, acetone and chloroform, whereas, they are only partially soluble in petroleum ether and carbon tetra- chloride. In the case of certain members of this class of preparations, this property has been of considerable value in detecting adul- terations or in the identification of the solvent which was em- ployed in their manufacture. For specific instances of the application in this connection, see under the oleoresins of aspi- dium and ginger. Specific gravity: The value of determining the specific gravity as an aid to standardizing the oleoresins appears to have been first noted by Procter. In 1866, he published data showing how this constant, in the case of the oleoresin of cubeb, varied with the solvent employed in its preparation, and further pointed out that a low specific gravity observed in the commercial product was, in one instance at least, an indication of the incomplete removal of the solvent, ether. Procter 's observations were as follows : Table 7. — The specific gravity of the oleoresin of cubeb. Drug Solvent Specific gravity Remarks Cubeb Alcohol Ether Benzin Ether at 76° P. 0,9850 0.9675 0.9325 0.9000 Prepared by Procter. Commercial sample containing ether» This work, however, appears to have received but little atten- tion as there is no further mention of the determination of this .50 DU MEZ— THE GALENICAL OLEORESINS constant in this connection in the literature until 1903. In that year, the English firm of Southall Brothers and Barclay pub- lished a statement in their Laboratory Reports, in which a stan- dard range for the specific gravity of the oleoresin of aspidium was given. Interest in the matter again seems to have waned and it was not until 1911, when Parry showed that the last named preparation was being extensively adulterated with castor oil, that the necessity for standardizing this preparation be- came apparent. The subject was then taken up in earnest, however, and in 1913, no less than four articles on the deter- mination of the physical and chemical constants of the oleo- resin of aspidium made their appearance. In each of these, the determination of the specific gravity was given some con- sideration. From the foregoing brief resume of the literature on this sub- ject, it becomes apparent that the determination of the ^ecific gravity as a factor in evaluating the oleoresins has received consideration in connection with but two of the official prepara- tions. Furthermore, that practical use has been made of this constant only in the case of the oleoresin of aspidium. The results obtained with respect to these two preparations, how- ever, are deemed to be of sufficient importance to warrant the determination of this constant in the case of the other members of this class of preparations. The manner in which this constant was determined by the above mentioned investigators does not become apparent from their work as reported in the literature. It is thought, how- ever, that an ordinary glass pycnometer and chemical balance were employed for this purpose. In the determinations made in the laboratory, a 10 cubic centimeter pycnometer was used, except in the case of the oleoresin of lupulin which was usually too thick to handle in this manner. For the determination of the specific gravity of the latter, a Nicholson's hydrometer was employed. All determinations were made at 25° C. The results as obtained in the laboratory and those reported elsewhere will be discussed in detail under the treatment of the individual oleoresins. Refractive index: The determination of the refractive index has received con- sideration only in connection with the standardization of the CHEMICAL. PROPERTIES 5J oleoresin of aspidium. In this case, it has proven to be of par- ticular value in detecting adulteration with castor oil as was first pointed out by Parry in 1911. Subsequent work by other investigators has not only confirmed Parry's observations, but has shown that in some instances a low refractive index may be an indication of a low filicin content due to natural causes^) as well. Since most of the other official oleoresins are sufficiently trans- parent to permit of the direct determination of this constant, it was thought that such determination might likewise prove to be of some aid in standardizing these preparations. That such an opinion has proven to be correct will be shown in connection with the discussion of this topic under the individual cases. For the determination of this constant in the laboratory, the Abbe refractometer was employed, all observations being made at 25° C. In those cases (the oleoresins of ginger and lupulin) where the color was too intense to permit of a direct determina- tion being made, the oleoresin was dissolved in an equal volume of castor oil and the refractive index computed from the follow- ing formula : njj (b) == 2nj^^ (a + b) — n^ (a) a = refractive index of castor oil. b= '' '' '' oleoresin. Chemical Properties Loss on Hearting : The oleoresins without exception lose weight on drying. This loss is usually referred to in the literature as the moisture con- tent. It has been determined by heating the preparation at 100 to 105° C. for a definite period of time, or until of con- stant weight. The fallacy of designating the loss of weight thus obtained as the moisture content becomes evident when we take into consideration the fact that these preparations con- tain volatile substances other than water, which would also be removed by heating to a temperature of 100° C. Indeed, the oily ^ The male fern rhizomes have been shown to vary in fllicin content due to the climatic conditions under which they were grown, time of harvesting, €t cetera. See under "Drug used, its collection, preservation, etc." 52 DU MEZ— THE GALENICAL OLEORESINS nature of these preparations exclude the presence of any great quantity of moisture. This statement has been borne out by laboratory experiments. Attempts to determine the moisture by means of the xylene^) method failed to reveal the presence of a measurable amount of water in any of the samples examined. The loss in weight is, therefore, due, ordinarily, to the removal of volatile oil and in exceptional cases to the removal of un- evaporated solvent. Such being the case, the determination of this constant serves as a means of measuring the amount of volatile oil naturally occurring in these preparations and as a means of detecting the presence of unevaporated solvent. The amount of weight lost by the oleoresins when deter- mined as stated above varies greatly with the individual members comprising this class of preparations. The oleoresin of cubeb which contains a comparatively large amount of volatile oil naturally sustains a comparatively great loss, while the oleoresin of capsicum which contains a small amount of volatile matter shows but a slight loss. There is noted a further variation in the case of each individual due to a variation in the amount of volatile matter naturally occurring in the drug from which the oleoresin was obtained, or to a variation in the conditions under which the individual was prepared. As an illustration, the oleoresin of cubeb may be cited. The volatile oil content of cubeb is stated to be 10 to 18 per cent. A much greater variation is, therefore, to be ex- pected in the oleoresin which represents only the alcohol soluble portion of the drug. With respect to the conditions under which the oleoresin of cubeb is prepared, observations in the laboratory have shown that the preparation will contain a larger amount of volatile oil when the solvent is allowed to evaporate spontaneously at room temperature, than when the same is re- moved by evaporation on a water bath. In most cases, the variation, due to the difference in solvent used in extracting the oleoresins, appears to be so slight as to be almost negligible. In the case of the oleoresin of pepper, however, there is a very no- ticeable difference. This is very likely due to the nature of the preparation, its viscosity making it difficult to remove the last traces of the less volatile solvents without the application of heat. 1 U. S. Dept. Agric, Forest Service, Circ. 134. CHEMICAL. PROPERTIES 53 In the determinations of this nature made in the laboratory, a, weighed amount of the oleoresin (about 2 grams) was heated in an electric oven at 100° C. for 3 hours, cooled in a desiccator and weighed, the difference in the two weights being taken as the loss. A more detailed consideration of this subject will be found under the treatment of the individual oleoresins. Ash Content: The determination of the ash content of the oleoresins is of special value in identifying the solvents which have been used in their preparation. Such determinations, made in this laboratory, also by the firm of Dieterich^) in Helfenberg, have shown that, while there is as a rule comparatively little dif- ference in the ash content of these preparations, when prepared with the same solvent, there is a marked variation in the case of each individual when different solvents are employed. The oleoresin of lupulin is an exception to this rule. Its ash con- tent varies to a considerable extent even when prepared with the same solvent. In addition to the above, the qualitative examination of the ash of commercial samples has revealed the fact that nearly all of them contain copper, due in most cases to the action of the free fatty acids on the utensils employed in their preparation* In some instances, the presence of the metal must be attributed to the addition of copper salts for the purpose of imparting the desired green color to preparations of inferior quality. See under the adulteration of the oleoresins of aspidium and cubeb, respectively. The ash content of the oleoresins examined in the laboratory was determined as directed by the last edition of the United States Pharmacopoeia under ''Determination of Ash or Non- volatile Matter,'* p. 589. Copper, when present, was identified by the blue color of the solution formed when the ash was dissolved in a few drops of hydrochloric acid, diluted with water, and ammonium hy- droxide solution added. ^ The firm of Dieterich has for a number of years determined the ash content of the oleoresins of aspidium and cubeb. A tabulation of the re- sults as obtained by this firm will be found under the separate treatment of these oleoresins. 54 I^U MEZ— THE GALENICAL OLEORESINS For a more detailed discussion of this subject, see under in- dividual oleoresins. Acid Number: Kremel in 1887 determined the acid numbers of the oleo- resins of aspidium and cubeb. Inasmuch, however, as he made- but one determination in each case, no conclusions can be drawn from his work. Similar determinations made in this laboratory on all of the official oleoresins show that this property varies, greatly depending on the particular individual under considera- tion. Furthermore, that no general statement can be made aa to -its value in fixing the standards of these preparations, but that it is of importance when considered in connection with individual cases as will be brought out later. For the manner in which this constant was determined in the laboratory, see the United States Pharmdcopoeia, ninth re- vision, (1916), p. 591. Saponification Value : The saponification values of the official oleoresins, as deter- mined in this laboratory and elsewhere,^) indicate that this property may be an important factor in fixing standards for these preparations. The results obtained by Parry, Harrison ;and Self, and others show that in the case of the oleoresin of aspidium, the saponification value varies directly as the filicin content, and is, therefore, useful as a check on the determina- tion of the latter. Considered in connection with such of these preparations as contain easily oxidizable substances, an abnor- mally high saponification value is very likely caused by an in- crease in the acid content due to the action of the oxygen of the air, and is thus an indication of an old product^) or of improper care in storing. As an example, the oleoresin of lupulin may be cited. In this case, a high saponification value signifies an old preparation or one that has been prepared from deteriorated drug.^) These factors, together with the influence of the solvent employed and the method of preparation on this property, will * Saponification values have only been determined in the past in the case of the oleoresin of aspidium and in one instance in the case of the oleoresin of cubeb. 2 See oleoresin of aspidium. 2 See oleoresin of lupulin. SPECIAL TESTS 55. be considered in greater detail under the treatment of the in- dividual members. The manner in which this constant was determined in the laboratory is described on p. 590 of the United States Phar- macopma, ninth revision. Iodine value: The determination of the iodine value as an aid to the standardization of the oleoresins appears to have been first em- ployed by the firm of Dieterich in Helfenberg in 1904, however^ only in the case of the oleoresin of aspidium. It has since re- ceived further practical application, in connection with the same preparation, by the English firm of Evans Sons, Lescher and Webb, while a number of similar determinations have been made by the author. The results^) obtained with respect to this preparation show that the iodine value varies directly as the filicin content, and, therefore, serves as another check on the determination of the latter constituent. With respect to the other official oleoresins, it may be stated that, as a general rule, the iodine value is high in the case of those preparations which contain a large amount of unsaturated constituents of ether fatty or volatile oil.^) Further than this,, it may be influenced largely by the nature of the other consti- tuents of these preparations and will be considered in detail in connection with the treatment of each individual. For the method employed in the laboratory in the determina- tion of this constant, see the United States Pha/rnmcopwia, ninth revision, p. 590. Special Tests While the different official oleoresins can, as a rule, be identi- fied without difficulty, the use of various adulterants in their preparation, through ignorance in some cases, or with willful intent on the part of unscrupulous manufacturers, has made it necessary to guard against this practice by making use of certain qualitative and quantitative tests. As will be brought out later, such tests have been applied principally to the pre- parations official in foreign countries, namely: the oleoresins * See under oleoresin of aspidium. ^ See under oleoresin of cubeb. 56 DU MEZ— THE GALENICAL. OLEORESINS of aspidium and cubeb. No tests of this, or, as a matter of fact, of any kind have been included in the United States Phar- macopoeia. It is thought, however, that if interest in these prep- arations could be awakened in this country, the need of sim- ilar precautions with respect to all of the official oleoresins would become apparent. Qualitative Tests: Inasmuch as the common physical properties, such as odor, taste and appearance, are very characteristic of the oleoresins, it is hardly necessary to resort to other means for their identi- fication. It appears, however, that the use of the so-called false cubebs in the preparation of the oleoresin of cubeb has made necessary a more certain method of identification. Such a method, based on the red color produced when concentrated sulphuric acid is added to the oleoresin prepared from the gen- uine fruit,^) has, therefore, been given in most of the late Eur- opean pharmacopoeias. Likewise, the use of other species of fern in the preparation of the oleoresin of aspidium caused a qualitative test for this preparation to be included in the late editions of the Austrian, Hungarian and Netherlands phar- macopoeias. For the details of these methods, see qualitative tests under the respective oleoresins. Quantitative Tests: On the whole, very little has been done in the past toward developing quantitative methods for the evaluation of the oleo- resins. This condition is perhaps due, for the main part, to an imperfect knowledge of the chemistry of most of these prepara- tions, as well as to the lack of exact information concerning the constituents of therapeutic value. In the case of the oleoresin of aspidium, however, the therapeutic value of the preparation has been shown to depend upon a number of acid constituents, the quantity present varying through natural and artificial causes. As a result, various methods^) for the determination of the total acid content have been devised and are in use at the present time, a modification of the original method of Fromme being officially recognized in the late edition of the British and Swiss ^ Dekker states that the so-called false cubebs give a yellow color with concentrated sulphuric acid. Pharm. Ztgr. (1912), 84, p. 845. 2 See under oleoresin of aspidium. SPECIAL, TESTS 57 pharmacopoeias. The only other work of this nature appears to have been done quite recently (1914) by the H. K. Mulford Co. in the standardization of the oleoresins of capsicum and ginger. This firm has devised a physiological method for this purpose based on the extreme pungency of these preparations, the highest dilutions in which these preparations (on the aver- age) are still perceptable to the taste being taken as standards. Experiments conducted in the laboratory in preparation for this monograph have shown, not only that there is an oppor- tunity for improving on some of the above mentioned methods, but that there is need for the development of quantitative meth- ods which may be applied to the other individuals of this class as well. With respect to the forepart of this statement, it Is thought that a gravimetric method for the estimation of the pungent priniciples (gingerol) in ginger would be an improve- ment over the physiological method of the Mulford Co. as per- sonal idiosyncrasy would thus be eliminated. Trials with the method of Garnett and Grier^) (for the estimation of gingerol in ginger) adapted to the oleoresin appear to indicate the cor- rectness of this opinion. In the case of the oleoresin of capsi- cum, however, the physiological method apparently offers the only practical course at the present time, in view of the fact that the active constituent, capsaicin, is present in such minute quantities that an accurate gravimetric determination would be a difficult matter. In considering the application of new methods, the work done in this laboratory on the oleoresin of pepper may be cited. Since the therapeutical value of this preparation is apparently due to its piperine content, a method for the quantitative de- termination of this constituent appeared to be desirable. With this object in view, the nitrogen present was determined by the Kjeldahl method and the piperine content computed therefrom. Some very interesting results were obtained.^) As to further possibilities along this line the determination of the apiol con- tent of the oleoresin of parsley, or the estimation of the quantity of total acid resins present in the oleoresin of cubeb may be- mentioned. * See under oleoresin of ginger. 2 See under oleoresin of pepper. 53 DU MEZ— THE GALENICAL OLEORESINS Adulterations The examination of commercial samples of the oleoresins has shown that they are all adulterated at times. With respect to most of these preparations, adulteration is thought to be acci- dental, 6. g. the presence of copper in nearly all samples due to the use of copper utensils in the manufacture of the same, or the use of ripe instead of unripe fruits in the preparation of the oleoresin of cubeb. In some cases, however, adulteration has been practiced with willful intention to defraud, as for example, the addition of fatty oils to the oleoresins of aspidium and cubeb. Other instances of this kind will be given con- sideration under the treatment of the individual oleoresins. PART II— INDIVIDUAL OLEORESINS OLBORESIN OP ASPIDIUM Synonyms Aceite de Helecho Macho, Sp. P. 1905. Aetheres pafran-Kivonat, Hung. P. 1880. Aetherhaltiges FarrenTcraut extract y Aust. P. 1844. Aetherisches Farrnkrautextract, Pruss. P. 1830. ; Aetherisches Farrnkrautwurzel Extract, Bad. P. 1841. AlvejuurieTcstrakti, Finn. P. 1914. , Balsamo de Helecho, Dorvault, L'Officine, Sp. Trans. 1879. Balsamum Filicis, Pareira, Mat. Med. 1854. Baum^ de Fougere, Dorvault, L' Officme, 1898. Braegne-Extract, Dan. Mil. P. 844. Bregnerod Extract, Nor. P. 1870. Bregnerodelcstralct, Nor. P. 1895. BregnerotekstraM, Nor. P. 1913. Estratto di Felce Maschio, Swiss. P. 1907. Estrato di Felce Maschio Etereo, Ital. P. 1902. Ethereal Extract of Male Fern, Journals. Extract of Male Fern, Jap. P. 1907. Extract van Mannetjes-Varen, Nethl. P. 1871. ■ * Extracto de Feto Macho, Port. P. 1876. Extracto de Feto Macho Ethereo, Port. P. 1876. Extracto Etereo Helecho, Sp. P. 1884. Extracto Ethereo de Helecho M t> Germany X.'i in X6. » (> 8.5 li ii France 0.0 .1 >k 0.0 1 Composed entirely of Osmunda rhizomes. It will be noticed that even the rhizomes purchased in Ger- many were not in good condition. As these rhizomes were ob- tained in January, they should have shown an internal green coloration had they consisted of the fresh stock harvested in the preceding autumn. From this, it appears that the German supply for exportation, at least, is not renewed yearly as it should be, but is allowed to accumulate and deteriorate. TJ. S. P. Text and Comments Thereon. Oleoresin of aspidium was admitted to the United States Pharmacopoeia in 1870 and has been official in all subsequent editions. 1870 Oleoresina Filicis Oleoresin of Fern Take of Male Fern,* in fine powder,^ twelve troy ounces; Ether* a suf- ficient quantity. Put the male fern into a cylindri- cal glass percolator, provided with a stop-cock, and arranged with cover and receptacle suitable for volatile liquids," press it firmly, and gradually pour ether upon it, until twenty-four fluidounces of liquid have slowly passed.' Recover' the greater part of the ether by distillation on a water- bath, and expose the residue, in a capsule, until the remaining ether has evaporated.' Lastly, keep the oleo- resin in a well-stopped bottle.' 68 DU MEZ— THE GALENICAL OLEORESINS 1880 Oleoresina Aspidii ■,' Oleoresin of Aspidium [Oleoresina Filicis, Pharm., 1870] Aspidium,* in No. 60 powder/ one ether by distillation on a water-bath, hundred parts 100. and expose the residue, in a capsule, Stronger Ether,* a sufficient quantity, until the remaining ether has evap- Put the aspidium into a cylindrical orated,* glass percolator, provided with a Keep the oleoresin in a well stopped cover and receptacle suitable for vola- bottle*. tile liquids,* press it firmly, and Note. Oleoresin of aspidium us- gradually pour stronger ether upon it, ually deposits, on standing, a granu- until one hundred and fifty (150) lar crystalline substance.** This should parts of liquid have slowly passed.' be thoroughly mixed with the liquid Recover' the greater part of the portion, before use." r 1890 Oleoresina Aspidii Oleoresin of Aspidium Aspidium,* recently' reduced to No. 60 of the ether from the percolate powder,* five hundred grams by distillation on a water-bath, and, 500 Gm. having transferred the residue to a Ether* a sufficient quantity. capsule, allow the remaining ether to Put the aspidium into a cylindrical evaporate spontaneously.' glass percolator, provided with a stop- Keep the oleoresin in a well-stop- cock, and arranged with cover and pered bottle.' receptacle suitable for volatile liquids." NOTE. Oleoresin of Aspidium Press the drug firmly, and percolate usually deposits, on standing, a gran- slowly with ether, added in succes- ular-crystalline substance.** This ■sive portions, until the drug is ex- should be thoroughly mixed with the hausted.* Eecover the greater part liquid portion before use.** OLBORESIN OF ASPIDIUM 69 1900 Oleoresina Aspidii Oleoresin of Aspidium Aspidium,* recently ' reduced to No. 40 powder/ five hundred grammes 500 Gra. Acetone,* a sufficient quantity. Introduce the Aspidium into a cy- lindrical glass percolator, provided with a stop-cock, and arranged with a cover and a receptacle suitable for volatile liquids." Pack the powder firmly and percolate slowly with ace- tone, added in successive portions, until the Aspidium is exhausted.' Eecover^ the greater part of the ace- tone from the percolate by distilla- tion on a water-bath, and, having transferred the residue to a dish, al- low the remaining acetone to evap- orate spontaneously in a warm place." Keep the oleoresin in a well-stoppered bottle." NOTE. Oleoresin of aspidium us- ually deposits, on standing, a granu- lar crystalline substance." This should be thoroughly mixed with the liquid portion before use." Average dose 2 Gm. (30 grains). 1910 Oleoresina Aspidii Oleoresin of Aspidium Oleores. Aspid. — Oleoresin of Male Fern Aspidium,^ recently' reduced to No. 40 powder,' five hundred grammes 500 Gm. Ether,* a sufficient quantity. Place the aspidium in a cylindrical glass percolator, provided with a stop-cock, and arranged with a cover and a receptacle suitable for volatile liquids.'' Pack the powder firmly, and percolate slowly with ether, added in successive portions, until the drug is exhausted." Eecover ' the greater part of the ether from the percolate by distilling on a water bath, and, having transferred the residue to a dish, allow the remaining ether to evaporate spontaneously in a warm place.* Keep the oleoresin in a well- stoppered bottle.' NOTE. — Oleoresin of Aspidium, on standing, usually deposits a granular crystalline substance." This should be thoroughly mixed with the liquid portion before use." Average Dose — Caution ! Single dose, once a day. Metric, 2 Gm. — Apothecaries, 30 grains. rjQ DU MEZ— THE GALENICAL. OLEORESINS 1.) The Pharmacopoeia of 1870 recognized but one species of fern (Aspidium Filix-mas) as the source of the official drug, hence, the directions : * ' Take of Male Fern, etc. ' ' In the sub- sequent editions, Aspidium marginale was also recognized as a cource of supply. In these editions, the drug is, therefore, referred to by the generic name, Aspidium. The species from which the official drug is obtained are now referred by botanists to the genus Dryopteris. See page 969 under "Drug used, its collection, preservation, etc." 2.) Owing to the fact that the drug deteriorates rapidly when in the powdered condition, the last three editions of the Pharmacopoeia have specified that the rhizomes be preserved whole and that they may be reduced to a powder shortly before using. For factors causing the deterioration of the drug, see under "Drug used, its collection, preservation, etc.'' 3.) In the last two editions of the Pharmacopoeia, it is di- rected that the drug be employed in the form of a moderately coarse powder (No. 40). In the previous editions, a fine pow- der (No. 60) was specified. The coarser powder posesses dis- tinct advantage in that it is better adapted to percolation and can be produced with a greater degree of uniformity. 4.) It will be observed that the pharmacopoeias of 1870, 1880 and 1890 directed that the drug be extracted with ether; that acetone was the menstruum specified in the Pharmacopoeia of 1900; and that ether is again directed to be used for this pur- pose by the present Pharmacopoeia. These changes appear to have been made for economic rea- sons as is evidenced in the following statement by Beringer (1916) : "In the Eighth Revision, acetone was directed in place of ether, because at that time the former was cheaper. As it is now permissable to use denatured alcohol in the manufacture of ether, that solvent is made so cheaply that it is again advan- tageous to use it in place of acetone. ' ' If the comparative cost of the two solvents was the factor which induced the Revision Committee to make the last change, it is indeed fortunate that ether was the cheaper inasmuch as it has proven to be the more desirable from a scientific standpoint as well. Acetone, although the official menstruum for the preparation of this oleoresin for more than a decade, does not appear to have been employed for this purpose to any considerable ex- OLEORESIN OF ASPIDIUM 71 tent by the manufacturer. This statement is based upon the examination of a number of commercial samples purchased at various times during the past ten years. While the reason for the above condition does not become apparent from the litera- ture, it is thought that it is to be attributed to the fact that acetone yields a product of inferior quality, rather than to the relatively low cost of ether. In support of this supposition, at- tention is called to the statement of Dunn (1909), who reports that it is necessary to purify the oleoresin made with acetone hy dissolving the same in ether, also, to the observations made in the laboratory. Experiments conducted in the laboratory have shown that the oleoresin, when prepared with acetone, is brown in color and always contains considerable deposited matter. While the greater bulk of the deposited material has the appearance of extractive matter and is very likely of no consequence from a therapeutical standpoint, portions of it answer to the descriptions of filixnigrin and filix acid, decomposition products of the therapeutically active constituents. The latter observation is in keeping with that of Kraft (1902), who found that filmaron, the most im- portant of the therapeutically active constituents, decomposes in acetone solution yielding the above mentioned decomposition products. It was also noted that the amount of deposited material increases much more rapidly in the preparations made with acetone than in those in which ether was used as the men- struum for extracting the drug. As previously stated, ether has proven to be the more sat- isfactory solvent for scientific as well as economic reasons. In fact it has been found to be superior to any of the solvents which have been experimented with in this connection, namely: benzin, benzene, chloroform and carbon disulphide. See Part I, page 921, under *' Solvents." At the present time, it is the sol- vent universally employed in the manufacture of the oleoresin, which is in itself a good reason for its adoption by the Pharma- copoeia. Furthermore, the product obtained with ether is perfectly homogenous and forms a deposit only after long standing, the constituents of therapeutic value evidently under- going no decomposition in ethereal solution. However, the quality of the preparation, even when ether is employed in ex- tracting the drug, is influenced to a certain extent by the purity of the solvent. ©2— S. A. L. 72 I5U MEZ— THE GALENICAL. OLEORESINS Alcohol and water appear to be the impurities which tend to exert a deleterious influence upon the finished product. Thus, Daccomo and Scoccianti (1896) observed that ether containing- a considerable amount of alcohol did not completely extract the therapeutically active constituents from the drug and that the oleoresin obtained was more prone to form a .deposit than when ether of a greater degree of purity was used. See also page 984 ander ''Yield of oleoresin." Similar effects were observed by the firm of Caesar and Loretz (1899.) The presence of water is so great a factor in promoting decomposition (hydrolysis?) that the German Pharmacopoeia (1910) directs that the rhizomes be preserved over freshly burned lime, a procedure which was recommended by Hager as early as 1871. Further evidence of the undesirability of the presence of water is to be found in the Norwegian (1913) and Finnish (1914) pharmacopoeias, which direct that the ethereal tincture be dried with anhydrous sodium sulphate or fused calcium chloride pre- vious to the removal of the solvent by distillation. 5.) For a description of the various forms of percolators designed for extraction with volatile solvents, see Part I under ''Apparatus used." 6.) All editions of the Pharmacopoeia, including the present,, direct that the drug be extracted by the process of simple per- colation even though the advantages of a continuous extraction apparatus in the handling of a volatile solvent like ether have been repeatedly pointed out. See Part 1 under "Solvents" and under "Apparatus used." Of special interest in this connection is the work of Matzdorif (1901), the results of which show that the therapeutically ac- tive constituents are not completely extracted by simple perco- lation as ordinarily carried out, but that complete extraction is effected in a comparatively short time with the use of a Soxh- let's apparatus. 7.) In connection with the recovery of the solvent by dis- tillation, attention is again directed to the deleterious effect of the presence of moisture and to the manner in which the same is directed to be removed by the Norwegian and Finnish phar- macopoeias. See above. Attention is also invited to the pharmacopoeial directions re- garding distillation, namely that it be conducted on a water OLEORESIN OF ASFIDIUM 73 bath. Inasmuch as Kraft (1902) states that filmaron melts at 60°C and undergoes decomposition at higher temperatures, it is thought that the pharmacopoeial directions should contain a. warning against exceeding this temperature during distilla- tion. 8.) The removal of a part of the solvent by spontaneous evaporation as directed by the Pharmacopoeia tends to operate against obtaining a uniform product as the time required to accomplish the same varies mth the temperature. If evapora- tion is allowed to proceed at a low temperature (winter tem- perature), the preparation will be exposed to the action of the air for a very considerable length of time and partial oxida- tion of some of the constituents will very likely result. The complete removal of the solvent can be accomplished much more rapidly by heating the preparation on a water bath, and without injury, if the temperature is kept below 60° C. By such a procedure, the above conditions are eliminated and a more uniform product will be obtained. 9.) The oleoresin should be kept in well-stoppered bottles as it becomes rancid on prolonged exposure to the air due to the hydrolysis and partial oxidation of the glycerides composing the fatty oil. 10.) For a discussion of the nature of the deposit which forms in the oleoresin on standing, see pages 992 and 1004 under ■''Constituents of therapeutic importance," and under ''Other properties. ' ' 11.) As to the propriety of the pharmacopoeial directions concerning the mixing of the deposit with the liquid portion before dispensing, there is some doubt. The question, however, is one which should be decided by the pharmacologist rather than the pharmacist and will, therefore, not be considered here. The use of an alkali, ammonia as suggested by Beringer (1892), for the purpose of facilitating the admixture of the pre- cipitate with the liquid portion should be condemned as a dan- gerous practice. The danger lies in the fact that the slightly soluble toxic constituents are converted into soluble compounds by union with the alkali and are thereby rendered readily ab- sorbable. Of further interest in this connection is the procedure recom- mended by Seifert (1881) and Kraemer (1884) for avoiding 74 DU MEZ— THE GALENICAL. OLEORESINS the formation of a deposit, namely: that the ethereal tincture be kept on hand and that the oleoresin be prepared therefrom just previous to dispensing. Yield The yield of oleoresin, when ether is the solvent employed in extracting the drug, is commonly stated to be 10 to 15 per cent, in the various dispensatories and American text-books on pharmacy. As a matter of fact, the amount of oleoresin actually obtained is about 7 to 10 per cent. (See the tables which fol- low.) When petroleum ether or benzene is used, the yield m slightly lower, as a rule, whereas, it is much higher (about 18 per cent.) when acetone is employed. These statements refer to the yield as found for the air dried drug. When the latter is dried at a temperature of 100 to 110° C, the percentage of oleoresin obtained will naturally be somewhat higher as is shown in the table immediately following. OLEORESIN OP ASPIDIUM 75 Table 10. — Yield of oleoresin as reported in the literature. Observer Yield of oleoresin to Date < 1 1 CO J Remarks 1826 von Esenbeck . Van Dyk Zeller Perct. Per ct. Perct. 5.63 7.30 Perct. Rhizomes harvested in 1827 37.5 32.0 August. Rhizomes harvested in 1828 Meylink 6.04 September. Winkler Haendess 15.6 Rhizomes harvested in 1829 8.85 8.33 12.87 7.80 8.20 8.50 10.30 12.40 11.50 14.00 6.51- 5.60 6.20 5.70 6.00 8.50 8.00 11.00 13.00 6.00 6.50 5.70 9.87 7.26 8.90 5.90 6.12 8.92 9.96 9.50 9.88 February. 1844 1851 Bock Peeled rhizomes dried at 1852 von der Marck 100° c. Portion of rhizomes having borne fronds the previous year. Portion of rhizome bearing fronds. Portion of rhizome to de- 1876 r Petrol. 1 Etlier 1 '-' 1 9.1 I velop fronds the next year. Rhizomes harvested in Kremel Trimble April. Dried at 110° C. Rhizomes harvested in July Dried at 110° C. Rhizomes harvested in Oc- 1887 29.0 tober. Dried at 110° C. 1888 J Benzin 1 5.9 1891 Nagrelwoort (i) Rhizomes harvested in July. 1889. Rhizomes harvested in September, 1889. Rhizomes harvested in October, 1889 Rhizomes harvested in December. Rhizomes harvested in February, 1890.^^ " " •' Rhizomes harvested in April. 1890. 1892 18.0 j Benzin 1 16.18 " Sherrard Whole Rhizomes. Bellingrodt . . . Peeled 1898 Rhizomes from "Rheinische Tiefebene (Calcar)." Rhizomes from "'Rheinische Tiefebene (Dinslaken)." Rhizomes from "Voreifel (Aachen.)" Rhizomes from "Hocheifel (Gerolstein.)" Rhizomes from "Taunus (Braubach.)" Rhizomes from Wester- wald auf Thonschiefer (Daaden.)" ^—^ ' Ed. Schmidt, Th&se pour I'Obtention Paris, 1903, p. 78. du DiplOme du Docteur I'UnlverslW 76 DU MEZ— THE GALENICAL. OLEORESINS Table 10.— Continued. Date 1902 1903 1905 1906 1906 Observer Bellingrodt— Con. Hausmann Buttin Schmidt. E.(») Dietrich Roder Wollenweber. Yield of oleoresin to Perct. Perct. Perct. 9.95 8.90 8.50 10.00 8.00 9.30 8.00 6.60 9.60 9.10 6.40 6.90 9.80 9.30 7.00 9.94 to 10.60 Up to 11.20 9.22 to 10.1 10.30 10.00 Per ct. Benzene ! 9.81 10.10 Petrol. Ether 9.5 Remarks Rhizomes from "Wester- wald auf Basalt boden (Daaden.)' Rhizomes from "Hansruclc (Simmern) ' Rhizomes from "St.Gallen, Switzerland." Rhizomes from "Bludenz (Vorarlberg)." Rhizomes from "Appenzell, Switzerland." Rhizomes from "Bierber- wier, Tyrol." Rhizomes harvested in spring:. Whole rhizomes from near Paris harvested in Sep- tember. Whole rhizomes from the Vosges JVIts. harvested in September. Whole rhizomes from the Jura Mts. harvested in September. Peeled rhizomes from the Vosges Mts. harvestsd in September. Whole rhizomes from near Paris harvested in Oc- tober. Whole rhizomes from the Vosg-es Mts. harvested in October. Whole rhizomes from the Jura Mts. harvested in October. Peeled rliizomes from the Vosges Mts. harvested in October. From air dried rhizomes. From rliizomes dried at 100° C. Yield obtained when the product was heated at 95° C for 2 hours, cooled in a desiccator & weighed . Air dried rhizomes extract- ed in a Soxh let's appar- atus. Exiccated rhizomes ex- tracted in a Soxhlet's apparatus. Air dried rhizomes extract- ed in a Soxhlet's appar- atus. Exiccated rhizomes ex- tracted in a Soxhlet's apparatus, 1. c, p. 110. OLBORESIN OF ASPIDIUM 77 Table 10. —Continued. Observer Yield of oleoresin to Date < 1 § < Si Other solvents Remarks 1908 Vanderkleed(i) Vanderkleed . . Perct. Perct. Per ct. Per ct. r Solvent? 6.68 \ 10.003 1 17.90 I 10.33 Reported as yield of oleo- resin. 1999 1911 Rosendahl. ... 10.00 12.50 11.50 9.50 11.60 8.80 7.90 8.30 7.70 9.70 8.60 7.50 7.00 10.90 9.40 to 9.70 Rhizomes harvested in Harrison & Self Riedel May. Rhizomes harvested in August. 1913 October. Rhizomes from "Harz." i» .< H t( .1 41 .4 " *' "Bayem" (k (( .1. ( "Schwarz- " "! wald, Wuert- f em berg." i "Mo&el, " *' ■{ Rhein- rPreussen." 914 " Vanderkleed . . i Solvent ? \ 6.85 to \ 10.12 Average yield of oleoresin is reported as 8. 23 per cent. ^ The high yield (1.79 per cent.) obtained in this instance is suggestive of the use of acetone as the menstruum for exhausting the drug. It may, how- ever, have been due to the extensive adulteration of the latter with the- rhizomes of Dryopteris spinuloaa. Rosendahl (1911) obtained 17.0 per cent., of oleoresin from the rhizomes of this species by extraction with ether. Table 11. — Yield of oleoresin obtained in the laboratory. Observer Yield of oleoresin to Date Alco- hol Ace- tone Ether Benzin Remarks 1909 DuMez & Baker Per ct. Per ct. 18.27 Per ct. 9.3 9.7 8.70 Per ct. Represents the yield using a Soxhlet's ex- traction apparatus. Represents the yield using a Soxhlet's ex- traction apparatus. Represents the yield using a Soxhlet's ex- traction apparatus. DuMez&Beedle.... 1910 DuMez &Netzel 43.33(1) 16.10 7.5 (i)The alcoholic extract was obtained by simple percolation. 78 DU MEZ— THE GALENICAL OLEORESINS An examination of the first of the foregoing tables reveals the fact that the yield is influenced to a very considerable extent by the condition of the drug from which the oleoresin is pre- pared. Thus, for instance, the amount obtained is less when the powdered whole rhizomes are used than when peeled rhizomes are employed. This is to be expected in view of the fact that the outer layers contain little that is soluble in the solvent (ether) usually made use of. It will also be noticed that na- tural causes, such as, locality in which the rhizomes are grown, and time of harvesting are important factors in this connec- tion. These influences will be brought out more clearly on an inspection of the following table which shows the results of this nature obtained by Ed. Schmidt. Table 12. — Effect of locality in which the rhizomes are gr0wn and the time of harvesting on the yield of oleoresin. Time of harvesting May June July Autrust Peptembet October . . . Peeled rhizomes from- Forest near Paris Per cent. 4.00 4.80 5.60 6.20 6.60 6.90 Vosges Mts. Per cent. 7.00 7.60 8.70 g.oo 9.60 9.80 Jura Mts. Per cent. 6.40 7.00 8.00 8.40 9.10 9.30 Whole rhizomes from— Vosges Mts. Per cent. 4.90 5.70 6.00 6.40 7.00 In addition to the comments already made with regard to the influence of the solvent on the yield, the observations of Dac- como and Sccocianti (1896) are of importance in this connec- tion. These investigators found that the amount of oleoresin obtained, when ether was employed for extracting the drug, de- pended to some extent on the purity of the former. Thus, ether, specific gravity 0.720 gave 10 per cent, of oleoresin, whereas, ether, specific gravity 0.756 yielded 17 per cent. It was further pointed out, however, that the greater yield was not desirable as in this case the preparation did not contain all of the therapeutically active constituents and in addition was more prone to form a deposit on standing. OLEORESIN OF ASPIDIUM 79 Chemistry of the Drug aTid Oleoresin. Tabulation of Constituents, A survey of the voluminous literature^ pertaining to the chemistry of the mak fern rhizome shows the constituents of pharmaceutical interest to be as follows: volatile oil, fatty oil, iilix acid, albaspidin, flavaspidic acid, aspidinol, flavaspidinin (phloraspin), filmaron, filixnigrin, chlorophyll, filix tannic acid, wax, sugar, starch and inorganic constituents. Of these sub- stances, the following have been identified in the oleoresin ob- tained by extracting the drug with ether: Volatile oil =* 0.40 to 0.45 per cent Fatty oiP 70.00 to 75.00 " '* Filix acid* 5.75 to 12.48 " '' Albaspidin'^ Av. 0.05 " '' Flavaspidic acid » " 2.50 " " Aspidinol » " 0.10 '' '* Flavaspidinin" ** O.IO " ** * Filmaron* " 5.00 " '' ^ The following have reported more or less complete analyses of the male fern rhizome or of the ethereal extract : Gebhardt, cited by Geiger, Mag. f. Pharm. (1824), 7, p. 38; Morin, Journ. de Pharm, et de Chim. (1824), 10, p. 223; Buchner, Rep. f. d. Pharm. (1827), 27, p. 337; Batso, TrommsdorfE's n. Journ. d. Pharm. (1827), 14, p. 294; Peschier, Ibid. (1828), 17, p. 9; Luck, Jahrb. f, prakt. Pharm. (1851), 14, p. 129 ; Bock, Arch. d. Pharm. (1851), 115, p. 257; Kruse, Ibid (1876), 209, p. 24; Daccomo, Annali di Chim et Farmak. (1887), 87, p. 69; Boehm, Arch. f. Exp. Path. u. Pharmak. (1896), 38, p. 35; Kraft, Schweiz. Wochenschr. f. Chem. u. Pharm. (1902), 40, p. 322. ' The percentage of volatile oil as given above has been computed on the basis of an average yield of 10 pr cent, of oleoresin. 3 The quantity of fatty oil present in the oleoresin has been shown to vary •with the strength of the ether employed in extracting the drug and with the degree to which the latter has been exhausted. These factors, however, are not sufficient to explain the large variation in oil content as found by various investigators. The variation is more probably due to the different methods employed in its estimation. Thus, Bock reports the presence of 42 per cent of fatty oil, Arch. d. Pharm. (1851), 115, p. 266; Kremel esti- mates it at 40 to 45 per cent, Pharm. Post d. Pharm. (1887), 20, p. 525; IVollenweber at 70 to 75 per cent. Arch. d. Pharm. (1906), 244. p. 467. * There is a very considerable difference in the filix acid content of the oleoresin as reported in the literature. This is due, principally, to the nat- ural variation in the filix acid content of the drug and to the different methods employed in its estimation. The limits as given above are those obtained by the method of Fromme and represent the percentage occuring In the oleoresin prepared from the better rhizomes. Under these conditions, Madsen found 5.8 to 12.1 per cent. Arch. f. Pharm. og. Chem. (1897), 54, p. 269; Gehe & Co., 5.78 to 11.32 per cent, Handels-Ber. (1897), p. 60; Bellingrodt, 5.75 to 10.75 per cent, Apoth. Ztg. (1898), 13, p. 869; Caesar and Loretz, 8.65 to 12.48 per cent, Geschaefts-Ber. (1901), p. 68. gQ DU MEZ— THE GALENICAL OLEORESINS Filixnigrin = " " 6.00 " " Chlorophyll • ' ' " Wax ' '' " Ash '' 3.50 to 5.00 '' " Occurrence and Description of Individual Constituents. Volatile oil.^ The volatile oil as described by Ehrenberg is a clear yellow liquid having a specific gravity of 0.85 to 0.86 at 15° C, and is stated by him to be composed principally of fatty acid esters of hexyl and octyl alcohol, the acids ranging from propionic to caproic. The quantity of essential oil present in the rhizomes is stated to vary with the seasons of the year, 0.04 to 0.045 per cent, being contained therein at the time of the year when the drug is- usually collected.^ Fatty oil}^ The fatty oil as obtained from the male fern rhizomes by extraction with ether and subsequent purification is stated by Katz^^ to be composed of the glyceryl esters of oleic^ palmitic, cerotic and butyric acids.^^ Filix acid^^ (Filiciny* Filix acid (CggHggOig) crystalizes » Kraft, Schweiz. Wochenschr. f. Chem. u. Pharm. (1902), 40. p. 323. •Bock, Arch. d. Pharm. (1851), 115, p. 266. T Kraft, 1. c, * The volatile oil as described above is that obtained from the rhizomes by steam distillation and in all probabilities differs somewhat from the same as it exists in the galenical oleoresin. » Ehrenberg reports the presence of volatile oil as follows : rhizomes gathered in April, 0.008 per cent; in June .025 per cent; in September, Octo- ber and November, 0.04 and 0.045 per cent. Arch. d. Pharm. (1893), 231, p. 345. 10 The fatty oil of male fern was probably first isolated by Luck. In 1851, he reported that the oily portion (filixoline) of the ethereal extract was a glyceride yielding filomysilsaeure and filixoUnsaeure upon saponifi- cation. Jahrb. f. prakt. Pharm. (1851), 22. p. 130. From Luck's description it is considered that these acids were in all probability butyric and oleic, respectively. "Arch. d. Pharm. (1898), 236, p. 655. " Butyric and oleic acids have also been identified by Farup in the fatty oil obtained from Aspidium Spinulosum. In addition a phytosterol, lino- linic, and probably isolinolinic acid are stated to have been detected. Arch, d. Pharm. (1904), 242, p. 17. "The term filixsaeure was first used by Luck to designate this constituent, Filix acid is the translation given above rather than the usual English form, filidc acid, to avoid confusion with the fiUcinsaeure of Boehm, a re- duction product of the former, Ann .d. Chem. (1899), 307, p. 249, or the Acidum fiUceum of Batso, a supposedly volatile acid which the latter isolated from the ethereal extract. Tromsdorff's n. Journ. d. Pharm. (1827), 14, p. 249. " Filicin is the term introduced by Poulsson to designate the crystalline form of filix acid as he was of the opinion that it also existed in the amor- OLEORESIN OF ASPIDIUM 81 in small yellow plates melting at 184 to 185° C. It is difficulty soluble in water, alcohol, and ether, quite readily soluble in ethyl acetate. According to Boehm,^^ its constitution^^ is prob- ably represented by the following structural formula : H0C|^ jIoh: H,C,COcL ]iC COH Filix acid has been found to be present in the male fern rhizome^^ in quantities varying from 0.268 to 2.159 per cent^ the variation in content depending principally upon the loca- tion in which the rhizomes are grown and on the time of har- vesting.^^ phous state. Arch. f. Exp. Path. u. Pharm. (1895), p. 357. The term is now usually employed to designate the mixture of acid substances obtained in the quantitative evaluation of the oleoresin. It should not be confused with the Filicina of Batso, supposedly an alkaloid isolated from the ethereal extract. 1. c. "Ann. d. Chem. (1901), 318, p. 256. !• The following investigators have contributed work on the constitution of fllix acid: Luck, Ann. d, Chem. (1845), 54, p 119; Jahrb. f. prakt. Pharm. (1851), 22, p. 129; Grabowski, Ann. d. Chem. (1867), 143, p. 279; Daccomo, Ber. d. deutsch. Chem. Gesell. (1888), 21, p. 2962; Gaz. Chim. Ital. (1895), 24, 1, p. 511 ; Ibid. (1896), 26, 2, p. 441 ; Paterno, Ber. d. deutsch. Chem. Gesell. (1889), 22, p. 463; SchifC, Ann. d. Chem. (1889), 253, p. 236; Poulsson, Arch. f. Exp. Path. u. Pharm. (1895), 35, p. 97; Boehm, Ibid. (1897), 38. p. 35; Ann. d. Chem. (1898, 302, p. 171. " Fllix acid has also been isolated by Hausmann from Athyrium Filix femma Roth. Arch. d. Pharm. (1899), 237. p. 556, and has been identified by Bowman in Aspidium rigidum Swartz. Am. J. Pharm. (1881), 53, p. 389.' "MatzdorfC, Apoth. Ztg. (1901), 16, p. 274. «2 DU MEZ— THE GAKENICAL OL.EORBSINS Alhaspidin}^ Albaspidin crystallizes in fine colorless needles melting at 147 to 148° C. It is readily soluble in ether, chloro- form and benzol, difficultly soluble in alcohol, acetone and ^glacial acetic acid. Its constitution is stated to be represented by one of the three following formulae :^^ ac cHi HOC H3C CH, X H3C CH, CO oc H,C.C0CI^ /^ V COH COCQH, COH CH, COH COH CH, Flavaspidic acid. Flavaspidic acid (C24H28O8) was first isolated from the ethereal extract by Boehm. It is stated to €xist in two forms (a and j8) which differ in their melting points, the a-fiavaspidic acid melting at 92° C and the ^-modification at 156 °C. The a-acid on heating is converted into the j8-acid ^» Albaspidin should not be confused with aspidin. Hausmann has shown the latter to be a constituent of Dryopteris spinulosa O. Kuntze, but that it Is not present in Dryopteris filix mas Schott. Arch. d. Fharm. (1899), 237, p. 544. *> Boehm, Arch. f. Exp. Path. u. Pharm. (1897), 38, p. 35; Ann. d. Chem. <1901), 318, p. 268. OLEORESIN OF ASPIDIUM 83 which may be crystallized from hot benzol or glacial acetic acid. The ^-form is converted into the a-modification on crystallizing the former from alcohol. The a-acid is thought to be the enol-, the /8-acid the keto-form. The structure is shown in the fol- lowing formulae :^^ c"» cocn^5 c H,C,CO COH CCH, HjCCOG CH, o(-F)ava5pidicAdd y3 f^ffavaspidkAdH COHJ Flavaspidic acid has been isolated from the male fern rhi- zome in quantities varying from 0.10 to 0.15 per cent.^^ Aspidinol. Aspidinol (CiaHigO^) crystallizes in small yel- lowish-white needles melting at 156 to 161 °C. It is difficultly soluble in petroleum ether and benzol, readily soluble in ether, alcohol, chloroform, carbon disulphide and acetone. The fol- lowing two formulae have been suggested by Boehm as repre- senting the structure of this compound :^^ CH. CH^ A p. HOCf ^^ \C0CH. HOC Voj HC^ V ^COCC.M> H,CX^OC V JcH COH COH Flavaspidinin.^* Flavaspidinin closely resembles flavaspidic « Boehm, Ann. d. Chem. (1901), 318, p. 253"; Ibid. (1903, 329, p. 310. 2* In addition to establishing the presence of flavaspidic acid in the male fern rhizome, Hausmann has also isolated this compound from Athyrium JF'ilix femina Roth, and Aspidium apinulosum Swartz. Arch. d. Pharm. (1899), 237, p. 556. 28 Arch. f. Exp. Path. u. Pharm. (1893), 33, p. 35; Ann. d. Chem. (1901), ■318, p. 245; Ibid. (1903), 329. p. 286. « Kraft. Schweiz. Wochenschr. f. Chem. u. Pharm. (1902), 40, p. 323. The "phloraspin" (C^^H^O^) of Boehm is probably identical with flavas- -pidinin. The pale yellow crystals obtained from the alcoholic solution melt at 211 "C, and are stated to be almost insoluble in ether, petroleum ether, benzene and carbon disulphide, but more readily soluble In acetone, chloro- torm, hot absolute alcohol, ethyl acetate, glacial acetic acid and boiling xylene. Ann. d. Chem. (1903), 329, p. 338. 84 DU MEZ— THE GALENICAL. OLBORESINS acid. It crystallizes from ethyl acetate in nearly colorless prisms melting at 199° C. It is soluble in methyl alcohol, dif- ficultly soluble in ether, carbon disulphide and alcohol, readily soluble in warm benzene, chloroform, ethyl acetate, acetone and amyl alcohol. Filmaron,^^ Filmaron (C^THggOis) is a light yellow, amor- phous powder melting at about 60° C. It is insoluble in water,, difficultly soluble in alcohol, methyl alcohol and petroleum ether^ readily soluble in acetone, chloroform, ether, ethyl, acetate,- benzene, carbon disulphide, carbon tetrachloride, amyl alcohol and glacial acetic acid. In acetone solution, at ordinary tem- peratures' or upon warming with alcohol, it gradually decom- poses into filix acid and filixnigrin. The following structural formula has been suggested by Kraft: COH Filixnigrin.^^ Filixnigrin is the term used by Kraft to desig- nate the mixture of brown to black amorphous decomposition, products of the foregoing constituents. These decomposition products differ from the mother substances in that they are in- soluble in petroleum ether. They have been isolated from the- etheral extract. To what extent they occur in the plant, if at all, has not been determined. Chlorophyll. The green coloring matter of the male fern rhizome and of the oleoresin prepared therefrom is generally^ conceded by the various investigators to be chlorophyll, al- » Kraft, 1. c. »« Kraft, I. c. OLBORESIN OF ASFIDIUM 85 though, no attempt appears to have been made to determine its composition. Work upon the pigments present in a closely related species of fern, Aspidium Filix femina Roth, has re- •sulted in the isolation of carrotin (CigHggO) and three aspi- ■diophylls, CaogHg^^OgaN, C24oH32o03iN2 and C2ioH34e048N2o " The amount of chlorophyll present in the rhizome varies with its age and with the season of the year.^^ Wax. The wax occurring in the male fern rhizome has not been studied from a chemical standpoint, although its presence in the ethereal extract was observed at a very early date.^^ Filix Tannic Acid.^^ ' Filix tannic acid (C41H48NO24) is a ^glucoside breaking down upon hydrolysis into hexose and a Tiiixture of reddish-brown compounds.^^ It is readily soluble in water and dilute alcohol. Filix tannic acid usually constitutes about 7 per cent, of the rhizome, as much as 7.8 per cent, having been isolated there- from.^^ Ash. Analyses^^ of the male fern rhizome have shown the ash to contain the basic elements, K, Na, Ca,. Mg, Al and Fe combined with the acid radicles CI', SO4'', PO/", SiOg'' and "'EhaLTd, Ann. Inst. Pasteur (1899), 13, p. 456. The more recent work of Willstaetter and his pupils on the chlorophylls isolated from more than 200 different plants belonging to numerous families indicates that mag- Tiesium is a constant consituent of the molecule, which is considered by them to be a methyl phytyl ester of the tricarboxylic acid, chlorophyllin, 'C3iH29N^Mg(COOH)3. Viewed in this light, the above formulae for the aspidiophylls are erroneous in that they contain no magnesium and express molecular weights which are much too high. Ann. d. Chem. (1908), 358, p. 267; Ibid. (1910), 378, p. 1. 2» Kruse has observed that the rhizomes collected in April and October :have a more intense green color than those gathered in July. Arch. d. Pharm. (1876), 209, p. 24. »Batso, Trommsdorff's n. Journ. d. Pharm. (1827), 14, p. 294; Peschier Ibid. (1828), 17, p. 5 and Bock, Arch. d. Pharm. (ISBi), 115, p. 266, report the presence of a stearin-like substance in the ethereal extract. Caesar and Loretz have observed that rhizomes rich in wax yield an -ethereal extract which is not fluid at the ordinary temperature. GecJiaefts Ber. (1897), p. 62. 30 In the light of our present knowledge concerning the chemistry of male fern, fllix tannic acid Is not considered to be a constituent of the oleoresin when prepared with ether. As its presence in the latter has been reported 1)y early investigators, the above description has been included here. See -analysis by Bock, Arch. d. Pharm. 1851, 115, p. 266. "Malin, Ann. d. Chem. (1867), 115, p. 276; Wollenweber, Arch. d. Pharm. <1906), 244, p. 480. 3' Wollenweber, 1. c. »3Bock, Arch. d. Pharm. (1851), 115, p. 257; Spies, Jahresb. d. Pharm. <1860), 20, p. 15. gg DU MEZ— THE GALENICAL OLEORESINS CO3''. Hell and Company^* report the presence of 0.0144 per cent, of copper. Sp'ies, however, was unable to detect the presence of either copper or manganese. The ash content of the dried rhizomes varies, about 2.0 to 3.0 per cent being the usual amount obtained.^^ Constituents of Therapeutic Importance The value of the oleoresin of aspidium as a teniafuge has at various times been attributed to either its filix acid^ or vola- tile oiP content. Comparatively recent pharmacological in-^ vestigation, ^ however, has shown that the property of expell- ing the tape worm is not due to a single constituent, but is shared by a number of the acid-like components, namely: filix acid, flavaspidic acid, albaspidin, aspidinol, flavaspidinin and filmaron. Of these substances, filmaron is the most active and is stated by Jacquet* and others to be the constituent of most importance therapeutically. The diminution in the therapeutic activity of the oleoresin on ageing has been found to be due to the breaking down of some of these constituents into compounds which are inert or less active as teniafuges. Of the decomposition products tested by Straub, phloroglucin, filicin acid and butyric acid were found to be non-toxic when administered to frogs.^ Filix acid on the other hand was found to be toxic. Its value as a teniafuge is, however, doubtful.* Physical Properties Color: The color of the oleoresin varies to a considerable extent depending principally on the condition of the drug from which it is prepared. It is described by various writers as being yellowish-green, green, dark green or greenish-brown. 34Pharm. Post (1894), 27, p. 168; Journ. de Pharm. et de Chim., 139, p. 493. ^ Bock gives the ash content of the air dried rhizomes as 2.13 per cent., Kruse as 1.90 to 2.2 and Spies as 2.74. For the exsicated rhizomes, the latter obtained 3.19 per cent. iPoulsson, Arch. f. Exp. Path. u. Pharmak. (1891), 29, p. 9. a Robert, Therap. Monatsch. (1893), p. 136. 8 Straub, Arch. f. Exp. Path. u. Pharmak. (1902), 48, pp. 1-47. * Therap. Monatsh. (1904), 18, p. 391. »Z. c. •Boehm, Arch. f. Exp. Path. u. Pharmak. (1897), 38, p. 35. OLEORESIN OF ASPIDIUM 8T When prepared from the freshly dried and powdered rhizomes gathered in the autumn/ it usually has an olive-green color when spread out in a thin layer on a white porcelain surface. A brownish-green color is an indication of the use of old de- teriorated drug^ in its preparation, whereas, a deep green color suggests adulteration with salts of copper or chlorophyll.^ The nature of the solvent employed in extracting the drug is also stated to have an influence on the color of the prepara- tion, the use of ether (specific gravity 0.720) yielding an oleo- resin of a green color, whereas, the color is brownish-green when ether (specific gravity 0.728) is employed.* Odor: The odor of the oleoresin is peculiar, like that of male fern. Taste: The preparation has a bitter, nauseous, subacrid taste. Consistence: The oleoresin when freshly prepared is homo- geneous and is of about the same degree of fiuidity as castor oil. It is variously stated as being of the consistence of syrup,, fresh honey or an oily extract. Solubility: The oleore'sin when prepared with ether forms clear or slightly cloudy solutions with acetone, ether, chloro- form and carbon disulphide.^ It is partially soluble in carbon: tetrachloride, benzene, methyl alcohol, ethyl alcohol (95 per cent.), glacial acetic acid and petroleum ether. The degree to which it is soluble in the last three solvents mentioned ha» been made the basis of tests for the detection of adulteration with castor oil. According to Hill (1913), not less than 8 volumes of the oleoresin should be soluble in 10 volumes of petroleum ether, a lesser degree of solubility indicating adulteration. Jehn and * The oleoresin prepared from rhizomes gathered in October is stated by Kruse (1876) to have a more intense green color than that prepared fronn rhizomes gathered in July. Caesar and Loretz in their Berichte for 1913 state the condition of the season in which the rhizomes are harvested has an influence on their color, which becomes evident in the oleoresin, e. g. the oleoresin, when prepared from the rhizomes gathered in a dry season, is often very dark green in color. 'Buchner (1826) found that when the drug was kept in an open container for more than a year a brown instead of a green colored oleoresin was ob- tained. ^Wepen and Lueders (1892), Beckurts and Peters (1893) and others. * Bellingrodt. (1898). •This statement holds good only for the freshly prepared oleoresin ancJ does not apply when the same contains deposited material. 88 DU MEZ— THE GALENICAL OLEORESINS Crato^ state that the presence of castor oil is indicated when more than 50 per cent, of the oleoresin is soluble in 95 per cent, alcohol. Solubility tests made in the laboratory with glacial acetic acid have shown that not over 10 per cent, by volume of the oleoresin is soluble in the latter, a greater degree of solubility indicating adulteration with castor oil. Specific gravity: Observations made in the laboratory show that the specific gravity should be above 1.000 when determined at 25 °C. This is in keeping with the findings of Parry (1911) and Hill (1913), respectively, even though their determinations were made at 15° C. It is also the standard given in the latei edition of the British Pharmacopoeia. A specific gravity of less than 1.000 usually indicates adulteration with castor oil or a preparation naturally low in filicin content. It may, how- ever, be due to the addition of chlorophyll as pointed out by Hill, or to the presence of unevaporated solvent. These de- tails, together with the effect produced by the use of different solvents in the extraction of the drug are brought out in the following tables: Table IJi. — Specific gravities of oleoresins prepared in the laboratory. Sample No. Date Observer Solvent Specific gravity 1 1910... 1916... DuMez&Netzel At25''C 1 166 2 Acetone 1 052 3 •• '♦ Ether 1 012 4 .4 l( • • Petrol ether 995 1 DuMez 1 048 2 Ether 1 000 1 •• :::::::::::::::::::::: Acetone 1.009 (2) 0.997 (») 2 Ether ^ Kommentar zum Arzneibuch ftier das deutsche Reich (1901), p. 258. 2 Same as 2 and 3 after having stood in the laboratory for 6 years. Both contained a heavy deposit which was not mixed with the liquid portion when the specific gravity was redetermined.. OLEORESIN OF ASPimUM 89 Table 14. — Specific gravities of commercial samples. Sample No. Date Observer Source Specific g-ravity 1 1911 1912 1913 1913 1913 1915 1916 Parry Notffiven At 15° C 0.973 (1) 2 0.973 (1) 3 " " 0.974 (') 4 " " 0.975 (1) 5 " '• 0.975 (») 6 •' >i 0.988 (') 1 2 Southall Bros. & Barclay. Bohrisch " 0.9745 (") 0.0800 (i> 3 4 " 1.0148 1.0200 5 • ' 1.0205 6 " 1.0231 1 Temp. ( ?) 0.9836(3) 2 0.9842 (*> 3 " " 0.9888 (») 4 " »' 1.0109 1 DuMez Manila. P.I At 25° C 0.977 (') 2 0.985 (i> 3 " United States .............. 0.9889 (i> 4 '* 1.001 5 " Germany 1.003 6 <■' 1.003 (») 7 „ UUnited States 1.008 {") 8 1.008 1 Harrison & Self Germany At 15° C 0.987 (♦> 2 V 0.997 3 «» 1.015 4 »• " 1.020 5 '« «• 1.029 6 " " 1.029 1 Hill Europe 0.9829 (3> 2 0.9850 3 '» »' 0.9921 4 " 1. 0.9944 5 " " 0.9980 c^y 6 »» '» 0.9980 (1) 7 " 0.9985 (1) 8 " 1.000 9 «• •' 1.000 10 '« »' 2.0006 (»> 11 " " 1.0036 12 " »« 1.0045 13 " •' 1.0065 14 »• " 1.0075 15 . . . . " Rngrland 1.0090 16 .4 1.0109 17 1« 1 0179 18 •' J. 0190 19 •' •' 1.0227 20 " England 1.0233 21 " Europe 1.0235 22 •» 1.0240 23 " •' 1.0249 1 Southall Bros. & Barclay. DuMez Not srlven 1.025 2 1.025 1 " 9985 2 " 1.0110 8 »« 1.021 4 " 1.023 5 »» 1.030 1 Sauibb & Sons At25°C 0.9808 O 2 Lilly &Co 0.9947 (') 3 . " Parlte Davis & Co 1 0103 4 " Steams & Co 1 0379 (') ^ Adulterated with castor oil. * Contained added chorophyll. ' Low in crude fllicin content. * Referred to as suspicious. * Contained ether. 90 DU MEZ— THE GALENICAL OLEORESINS Refractive index: A refractive index of not less than 1.490 at 40° C is required for this oleoresin by the late edition of the British Pharmacopoeia. This is in accordance with the observa- tions of Hill (1913). The statement by Parry (1911), that the refractive index should not be below 1.500 when deter- mined at 20 °C is confirmed by the results which were obtained by Harrison and Self (1913), and is more in conformity with the observations made in this laboratory at 25 °C. When the oleoresin is properly prepared, ether being the menstruum used, the refractive index appears to vary directly as the crude filicin content. A low refractive index, therefore, indicates a pre- paration naturally low in filicin content. With respeet to the commercial oleoresins, however, a low refractive index may also result from adulteration with castor oil or chlorophyll, or may be due to the presence of unevaporated solvent as is shown in the tables which follow: Table 15.— Refractive indices of laboratory preparations. Sample No. Date Observer Solvent Refractive index 1913 DuMez Harrison & Self. 1916 DuMez. Ether At 25° G 1.500 At20°C 1 4995 1 5018 1 5036 " 1.5088 1.5088 1.5102 1 5120 1.5122 1.5126 1 5145 1.5157 Acetone 1 500^ Ether 1.498' 1 These figures represent the refractive indices of oleoresins which had stood in the laboratory for six years. OLEORESIN OF ASPIDIUM 91 Table 16 — Refractive indices of commercial oleoresins. Sample No. Date Observer Source Refractive index 1 1011 1912 1913 1915 1916 Evans Sons.Lescher &Webb Parry Not stated At 15° C 1.484(3) 2 1.485 (») 3 4 .. 1.501 1.501 1 .. At 20° C 1.484(1) 2 " 1 484(1) 3 1.487 (') 4 »• 1 488 (') 5 " '• 1.4885 ( ) 6 •» 1 493(1) 1-16 Evans Sons,Le8cher&Webb Sou thai! Bros. & Barclay . DuMez ,4 At 15° C 1.507 to «• 1.509 1 .. At 20° C 1.4830(1) 2 •' 1.4840 (1) 3 1.5040 4 " 1.5055 5 »• 1.5065 € »• 1.5210(?) 1 England .... . At 25° C 1 484(1) 2 1 485 (1) 3 " Manila, P. I . 1.489 4 '• United States 1 490 5 •' 1.490 ^ 1.492 7 ■* England 1.493 8 '• Germany 1 494 1 Harrison & Self At 20° C 1.4910 (») 2 1 4944 3 " * * • ' 1.4984 4 •• '« 1.5055 5 .. •••• " 1.5080 f '• •• 1 5084 1 Hill Europe At 40° C 1,4823 (1) 2 1.4869(1) 3 '• 1 4874(1) 4 »* " 1.4880 5 '« 1.4909 6 " 1.4915 (') 7 «« 1.4920 8 England 1.4922 9 Europe 1.4925 10 1.4935 11 •• 1.4940 12 •« 1.4945 13 England 1.4960 14 1.4965 15 1.4980 16 1.4985 17 »• 1.4988 18 " 1 4990 19 '» 1.5006 20 • • " 1.5025 21 " 1.5036 1 7 Evans SonsXescher &Webb Southall Bros. & Barclay . Southall Bros. & Barclay . DuMez Not stated At 15° C 1 500 to 1.510 8 1.495 (•) 9 •• 1.497(3) 1.499 (S) At 2,5» C 1.4975 10 1 " 2 " 1.5115 1 '• 1.4976 2 •• 1.4983 3 •« 1.5000 4 •• 1.5001 5 «» 1.5020 1 Stearns & Co At 25° C 1.4953 (*) 2 Lilly&Co 1.4988 (*) 3 •' Squibb & Sons 1.4993 (*) 4 " Parke, Davis & Co 1.4998 1 Samples adulterated with castor oil. » Samples contained added chlorophyll. * Samples are referred to as being suspicious. 92 DU MBZ— THE GALENICAL. OL.EORESINS Chemical Properties. Loss in weight on heating: Hill (1913) stated that the oleo- resin when heated at 100 °C should not lose more than 6 per cent, of its weight, a greater loss indicating the presence of unevaporated solvent. The statement is confirmed by other data of this nature reported in the literature as well as by the results obtained in the laboratory as is shown in the tables which follow: Table 17 — Laboratory preparations — Loss in weight on heating. Sample No. Date Observer Solvent Per cent of loss on heating: 1 1887 1904 1916 Kremel Alcohol. At 100^ C 17 40 2 Ether 70 ] Dieterich 4 51 1 . DuMez Acetone At lio" 2 51C 2 Ether 2 37 OLEORESIN OF ASPIDIUM 93 Table 18 — . Commercial oleoresins — Loss in weight on heating. Sample No. Date Observer Source Per cent. of loss on heatinff 1 1891 1893 1894 1895 1896 1897 1901 1903 1904 1905 1913 •• 1914 1916 Dieterich Germany At 1()0° C 2.70 1 1.15 2 " 1.60 3 •' 1.75 1 '• 1.90 2 •♦ 2 32 ^ '• 3 65 1 4» 1.75 ■ 1 " 1.62 1 " 4.52 2 •• 4 72 1 " * * 5.23 1 •« 5 52 2 .. " 7.38 1 t< 2.96 2 .' 3.09 1 •• 5.06 2 " 7.51 Hill Europe 2 43 2 2.44 3 '• Eng'land 2.57 4 •• Europe 2.69 ^ " 3.55 R •• •« 3.63 7 «' »» 3 65 }j It '• 4.23 9 »• 4 40 10 .. • 4.57 11 '♦ 4.64 12 »» 4.84 13 •• England 5 03 14 .. • 5.22 15 •» 6.500 16 •' 6.52 (>) 17 »• •« 6 60(1) 18 " '• 6.68(1) 1 Unke Brtickner. Lampe & C5o Caesar & Loretz At l(X)tol05°C 3.20 2 .. . 3.25 3 •• Merck&Co 6.85 1 DuMez Parke, Davis & Co At 110° C 1.75 2 Stearns & Co 2.03 3 •• Lilly& Co 6.01 4 41 • ••• • Squibb & Sons 7.18(1) (') Unevaporated solvent (ether) was present. AsJi Content: The results of this nature reported in the lit- erature, as well as those obtaiined in the laboratory, indicate that the ash content of the oleoresin, when prepared with ether, seldom exceeds 0.50 per cent, which is the standard given in the Belgian and Spanish pharmacopoeias. With respect to the ^commercial samples examined in the laboratory, the high ash content obtained was due to the presence of copper, evidently a result of the use of copper utensils in the manufacture of these preparations. The results of the determinations made in the 94 DU MEZ— THH GALENICAL OLEORESINS laboratory and those reported in the literature are given in the tables which follow : Table 19. — A»li contents of laboratory preparations. Sample No. Date Observer Solvent Per cent of ash. 1 1904 1916 Dieterich Ether 36 1 DuMez : 0.26 2 31 Table 20 — Ash contents of commercial oleoresins. Sample No. Date Observer Source Per cent of ash Fereign con- stituents 1 1891 1893 1894 1895 1896 1897 1901 1903 1904 1905 1914 1916 Dieterich \\ ;; ::::■.::: Llnke ............ Germany 0.40 0.45 0.50 0.50 0.42 0.50 0.55 0.50 0.45 0.43 0.52 0.32 0.27 0.30 0.39 0.36 0.83 0.26 0.46 0.34 0.41 0.52 0.52 0.58 0.54(1) 0.80 0.82 1 2 «' 3 1 2 . ... 3 1 1 1 2 1 1 . .. 2 3 .... 1 2 " 1 " 2 »• 1 Brueckner, Lampe & Co . . Caesar & Loretz. . .... Copper 2 3 .... " Riedel •' 4 Merck&Co Lilly «& Co 1 DuMez Copper 2 Squibb & Sons 8 " Parke, Davis & Co •' 4 •' Stearns & Co »' (*) Contained unevaporated solvent — ether. Acid number: The acid numbers 82.2 and 82.7 were ob- tained for the oleoresins prepared in the laboratory. Inas- much, however, as these preparations were made six years previous to the time when the determinations were made, it is thought that the value of this constant would be somewhat lower for the oleoresin when freshly prepared. This state- ment is based on the assumption that the acidity of the prep- aration will increase on standing due to the partial hydrolysis- of the glycerides of the fatty acids and to the breaking down of the complex substances constituting the so-called crude filioin. OLEORESIN OF ASPIDIUM 95 In the case of the commercial samples, the acid numbers were found to vary as a rule in the same direction as the filicin content. It would appear, therefore, that the value obtained for this constant might serve as a check on the latter determina- tion. The results obtained in the determination of the acid numbers of the preparations examined in the laboratory and those reported by Kremel follow: Table 21.— Acid numbers of laboratory preparations. Sample No. Date Observer Solvent Acid number 1 1887 1916 Kr^mel Alcohol 23 Ether 50 to 70 1 DuMez 82.7(1) 2 Acetone.. 82 2(1) (1) These preparations were 6 years old when the acid number was de- termined. Table 22 Acid numbers of commercial oleoresins. Sample No. Date Observer Source Acid Number 1 1916 Du Mez Ptearns & Co 50 2 2 Squibb & Sons 65.90 n •• Lilly&Co 72 9 4 • » Parkp. Davis Ar Cn 87.8 (*) Contained ether. Saponification value: Determinations made by Parry in 1911 lead him to state that the saponification value of this prepara- tion should not be lower than 230, corresponding to a crude filicin content of not less than 22 per cent. The values obtained for this constant in the laboratory and those reported by Har- rison and Self agree, as a rule with this statement, when the minimum filicin content is taken as 20 per cent. A value of less than 230 in the case of commercial samples has been shown to be due in general to adulteration with castor oil. In a few instances, however, it is to be attributed to the presence of unevap orated solvent, or to a low filicin content due to the use of a poor quality of drug in the manufacture of the oleoresin. 96 DU MEZ— THE GALENICAL OLEORESINS The relatively high values obtained in the laboratory for the old preparations low in filicin content (16.0 and 16.27 per cent, respectively) is very likely due to the effect caused by the hydrolysis of the constituents of high molecular weight with the formation of acids of comparatively low molecular weight.^ The saponification values found for the preparations examined in the laboratory as well as those reported in the literature are given in the tables which follow: Table 23 — Saponification values of laboratory preparations. Sample No. Date Observer Solvent Saponifica- tion value 1887 1911 1913 1916 Ether 116 to 165 1-20 Parry van to 250 DuMez 208.8 Ether 229 3 Harrison & Self 225.0 227.0 •' " 236.5 " 248.0 " 248.9 •• 251 5 " " 252.0 " 254.5 '» •• 255 10 •• 259.0 11 " >> " * * 259 DuMez 245.2 (^) 2 Ether 246 4 (0 (*) Old preparations low in filicin content »See under "Chemistry of the drug and oleroesin/ OLEORESIN OF ASPIDIUM 97 Table 24 — Saponification values of commercial oleoresins. Sample No. Date. Observer. Source. Saponifica- tion value 1 1904 1911 1912 1913 1915 1916 Dieterich 204.4 2. 234 2 1 Evans Sons, Lescher & Webb 195.2 (1) 220 4 2 5 '« 248.8 1 Parry " 197.0 (» 2 200 (0 3 " '• 207.0 (0 208.0 (0 210.0 (" 4 " ;; 5 «' 6 " " 221.0 (1) 195.1 (0 204.6 (1) 235.4 1 Southall Bros. & Barclay. DuMez *' 2 \\ • 3 4 «» 241.0 5 •' 256.3 6 258 2 1 England 195.7 (0 200.3 (3) 202 4 0) 2 ... Manila,P.I 3 " 4 >. United States 206.7 (2) 208.7 (I) 5 " England % Germany 214.6 (3) 225.5 7.. % -i United States 240 5 1 Harrison & Self 205.0 (3) 213.0 2 .. .. 3 .i •••• " 218 4 . »' *» 223 5 '« 225.0 6 " " 237.0 1 Southall Bros. & Barclay. DuMez Not given 225.1 2 263.1 " 206.5 3 '• 236.0 3 " 250.0 4 253.1 5 •<■ 254 6 1 Stearns 2 Manila.?. I England 87.2 (») 3 ». 89.4 (1) 4 *» United States 94.4 5 it Germany 97.1 g " 98.3 (') 7 " Germany 100.2 8 '' United States 101.5 1 n Squibb & Sons 95. 3(') • 2 »' Stearns & Co 97.7 C') 3 .... '« Lillv& Co 98.2(») 4 " Parlie, Davis «fe Co 103.2 1 Adulterated with castor oil. 2 Low in crude fllicin content. ' Contained ether. Other Properties The oleoresin, when freshly prepared, is homogeneous, but upon standing, a deposit is formed therein as a result of the breaking down of some of its constituents. The precipitated OL.EORESIN OF ASPIDIUM 99 material has been identified by Boehm^ as crystalline filix acid and a wax-like substance. Kraft,^ in a later investigation, con- firmed the findings of Boehm insofar as they concerned the presence of filix acid. The wax-like material, however, he found to be composed of a number of substances, decomposi- tion products of the therapeutically active constituents, which he designated as filixnigrin. As the deposit has been found to be active^ in the expulsion of tapeworm, although in a much lesser degree than the oleoresin proper, the United States PJiar- macopocia directs that it be mixed with the liquid portion be- fore dispensing. Special Qualitative Tests A number of the European pharmacopoeias prescribe tests for the determination of the quality of this preparation. These tests are of two kinds, namely, those which have for their object the establishment of the presence of the constituents of thera- peutic value, i. e. the substances of an acid character known collectively as crude filicin, and those which serve to identify starch when present. The former are based on the fact that the above mentioned constituents of an acid character may be precipitated directly by means of certain solvents, or from alkaline solutions by means of acids. The following are the official tests of this nature : Tests for Filicin. Austrian Pharmacopoeia (1906) : Upon adding an excess of petroleum ether to the oleoresin dissolved in a small quantity of ethyl ether, a white precipitate should be produced. ' Netherlands Pharmacopceia (1905) : If 0.025 gram of the oleoresin dis- solved in 2 cubic centimeters of ether be shaken with 5 cubic centimeters of a saturated barium hydroxide solution and 5 cubic centimeters of water, the aqueous portion, when separated and filtered, should give a floccu- lent precipitate on being acidified with hydrochloric acid. Hungarian Pharmacopoeia (1909) : If 0.25 gram of the extract be dis- solved in 2 cubic centimeters of ether and shaken with 10 cubic centi- meters of lime water, the aqueous portion filtered and acidified with hydro- chloric acid, a copious white precipitate should be formed. ^Arch. f. exp. Path. u. Pharmak. (1897), 38, p. 85. 'Kraft (1902). 'Renter, Pharm. Ztg. (1891), 36. p. 245; Straub, Arch. f. exp Path u Pharmak. (1902), 48, p. 1. v. . . 100 ^U MEZ— THE GALENICAL OLEORBSINS The application of these tests in the laboratory has shown that they are of practically no value as an indication of the quality of the oleoresin, as preparations very low in crude filicin content give comparatively heavy precipitates when treated as described above. Furthermore, they do not serve as a means of identification as oleoresins prepared from the rhizomes of certain other species of fem^ behave in a similar manner when subjected to these conditions. Tests for Starch A test for the presence of starch has been included in those pharmacopoeias in which the oleoresin is directed to be pre- pared by the process of maceration, namely, the German and Japanese. In these instances, it serves as a means of distin- guishing between preparations which have been filtered as of- ficially directed and those which have been merely strained through cloth as is often the case. A similar test is also found in the pharmacopoeias of those countries (Hungary, Spain and Switzerland) in which this preparation is frequently made by maceration, although the official process is that of percolation. The test as officially recognized in the different countries is identical with that described in the German Pharmacopoeia. It is as follows: The oleoresin, when diluted by shaking with glycerin, should not show the presence of starch grains under the microscope. Experience in the application of this test to the preparations examined in the laboratory has shown that it is unsatisfac- tory when carried out as described above. The fault lies in the fact that the glycerin cannot be thoroughly mixed with the oleoresin by shaking. If mixing is effected by trituration in a mortar, the results are better, although there is consider- able danger in rupturing the starch grains by this procedure. In addition to the foregoing, special tests have been pro- posed for the detection of adulterants when present. They are as follows: *Bee under "Drug used. Its collection, preservation, etc' OLEORESIN OF ASPIDIUM IQl Tests for the Presence of the Oleoresin of Dryopteris Spinulosa. Hausmann found that the male fern of commerce frequently- contained large quantities of the rhizomes of Dryopteris spinv^ losa Kunze. He therefore devised a test for the detection of the use of the latter in the preparation of the oleoresin. It is based on the fact that the rhizomes of Dryopteris spinulosa Kunze contain aspidin, whereas those of the official species, Dryopteris Filixmas Schott do not. Eausmann's Method (1899): Dissolve a small amount of crude filicin* in as small a quantity of absolute ether as possible and set the solution aside in a desiccator. If aspidin is present, the thick solution will form a crystalline brine in a few hours, when the needle-like crystals of the former can easily be identified under the microscope. If aspidin is not present, the solution undergoes no change even on long standing except to deposit a granular substance. Tests for the Presence of Castor OH The tests for the presence of castor oil are based on the solubility of the oleoresin in various solvents and are discussed under the heading, ** Solubility. ' ' Tests for the Presence of Salts of Copper The tests for the presence of salts of copper involve an ex- amination of the ash of the oleoresin and are discussed under the general treatment of the subject, **Ash content/' Special Quantitative Tests. A great deal of work has been done with reference to the evaluation of this preparation, and as a result, a number of methods for the quantitative estimation of the constituents of therapeutic importance has been devised. The chemical meth- ods may be conveniently divided into two groups, the one includ- ing those methods which have for their object the quantitative determination of the filix acid; and the other comprising the methods in which the quantity of the total constituents of an acid character is determined. *See under "Special quantitative methods". 2Q2 DU MEZ— THE GALENICAL. OLEORESINS ■ ■ - " Methods for the Determination of Filix Acid. As the oleoresin was originally thought to owe its teniafuge properties to its filix acid content, the determination of this constituent naturally received consideration first. The nature of the methods devised for its estimation and their subsequent development is illustrated in the descriptions which follow : Method of Kremel (1887) : Place a weighed quantity (about 10 grains) of the oleoresin in a flask and macerate it successively with several portions of petroleum ether when the greater part will be dissolved leaving the filix acid as an insoluble residue. Collect the latter on a fiilter and wash with more petroleum ether. Then dissolve it while on the filter in hot alcohol, remove the latter by evaporation and again wash with petroleum ether to remove the last traces of fat. Finally dry and weigh. Method of Bocchi (1896) : * Dissolve 1 to 2 grams of the oleoresin in a small quantity of ether, place the solution in a separatory funnel and shake it with successive portions of lime water until the shakings become colorless and remain clear on the addition of acetic or hydrochloric acids. Filter the united lime water solutions into a separatory funnel and acidify with hydrochloric acid when a dirty yellow precipitate will form. Dis- solve the latter by shaking with carbon disulphide added in successive portions, unite the shakings, filter and remove the solvent by evaporation on a water bath. Dry and weigh the residue which is pure fili;x acid. Method of Kraft (1896): Add a solution composed of 2 grams of potassium carbonate, 40 grams of water and 60 grams of alcohol (95 per cent.) to 5 grams of the oleoresin in a suitable flask and shake for 15 minutes. Filter 83 grams of this liquid into a separatory tunnel, add 9 grams of dilute hydrochloric acid, 50 grams of ether and 35 grams of water and shake vigorously. After the mixture has separated draw off the lower hydro-alcoholie liquid and repeat the shaking, using 35 grams more of water. Separate the latter and run the remaining ethereal so- lution into a tared Erlenmeyer flask of 100 cubic centimeters capacity. Distill off the greater part of the ether and evaporate the remainder down to about 2 grams. Dissolve the dried mass in 1.5 grams of amyl alcohol and precipitate the filix acid by the addition of 30 cubic centimeters of methyl alcohol (5 cubic centimeters added at once and the remainder drop by drop.) Allow the precipitate and supernatant liquid to stand over night in a cool place, then collect the former on a tared filter and wash it with 15 cubic centimeters of methyl alcohol (use 3 portions of 5 cubic centimeters.) Finally, dry the precipitate at a temperature between 60° and 70 "C and weigh. The weight obtained will represent the filix acid contained in 4 grams of the oleoresin. ^The procedure as outlined above really grives the amount of total acid substances (crude filicin) present, but is described here as it was proposed by its originator as a method for the determination of the filix acid content OLEORESIN OF ASPIDIUM ^Q3 Original Method of Fromme (1896): Dissolve 1.5 to 2 grams of the «leoresin in 2 grams of ether, and thoroughly mix the solution in a porce- lain dish (diameter 8 to 10 centimeters) with 3 grams of calcined mag- nesia (or 8 grams of burned lime.) Allow the ether to evaporate com- pletely and triturate the remaining dry pulverent mass with water, added gradually until a thin brine is formed. Set the mixture aside until the magnesia has settled, then decant the supernatant aqueous portion on a •dry filter. Continue to repeat this operation, using fresh portions of water, until the filtrate no longer gives a precipitate when acidified with hydrochloric acid. Place the combined filtrates (usual weight 200 to 250 grams) in a separatory funnel, acidify with hydrochloric acid and shake out the precipitate with carbon disulphide added in successive portions (20, 10 and 10 cubic centimeters.) Filter the united carbon disulphide shakings into a round-bottom flask of 100 cubic centimeters capacity ^nd evaporate to dryness on a water bath. Dissolve the crude filix acid ob- tained in this manner in 10 drops of amyl alcohol, using a gentle heat if necessary, then add 10 cubic centimeters of methyl alcohol (added drop by drop at the beginning and later rapidly.) Set the liquid containing the crystals aside in a cool place for 12 hours, then collect the latter on a tared filter, and, after washing with several 5 cubic eentimener portions of methyl alcohol, dry at a temperature between 60° and 70 °C and weigh. Improved Method of Fromme (1897): Place 5 grams of the oleoresin, 30 grams of ether and 100 grams of a solution of barium hydroxide (1 per cent.) in a 200 cubic centimeter flask and shake for 5 minutes. Then run the mixture into a separatory funnel, and, after allowing it to stand for 10 to 15 minutes, run off into another separatory funnel 86 grams (cor- responding to 4 grams of the oleoresin) of the lower aqueous layer. Acidify by the addition of hydrochloric acid (25 to 30 drops) and shake out with ether (in 25, 15, 10 and 10 cubic centimeter portions.) Filter the combined ether washings into a 100 cubic centimeter flask and evapor- ate to dryness on a water bath. Dissolve the residue in 1 cubic centimeter of amyl alcohol by heating over a free flame and precipitate the pure filix acid with 30 cubic centimeters of methyl alcohol (added drop by drop until a permanent precipitate is produced, and the remainder at once.) After the liquid has stood quietly in a cool place for 10 to 12 hours, collect the precipitate on a tared filter, wash with methyl alcohol (two 5 cubic centimeter portions,) press the filter between porous plates, dry at an initial temperature of 40 °C and finally at 80 °C, and weigh. Stoder's Method (1901): Dissolve 5 grams of the oleoresin in 20 cubic centimeters of ether, add 100 cubic centimeters of a freshly prepared so- lution of barium hydroxide (2 per cent.) and shake the mixture fre- quently during 1 hour. After allowing the mixture to stand quietly for a short time, separate the lower aqueous layer by filtration. Collect 86 cubic centimeters of this portion (corresponding to 4 grams of the oleoresin) in a separatory funnel and acidify with 10 cubic centimeters of dilute hydrochloric acid. Shake out the resulting precipitate with three portions of ether (40, 30 and 20 cubic centimeters) added successively, unite the shakings and remove the solvent by distillation. Dissolve the 104 DU MEZ— THE GALENICAL OLEORESINS residue in 1 cubic centimeter of amyl alcohol, and, after the solution has stood in a cool place for 48 hours, add 15 cubic centimeters of methyl alcohol. After standing for 24 hours more, collect the precipitated filii acid on a filter, wash with 5 cubic centimeters of methyl alcohol, dry on a water bath and weigh. It will be noticed that the preceding methods, with the ex- ception of the one devised by Kremel, are very similar in gen- eral outline, practically the only difference being found in the procedure by which the crude filix acid is directed to be purified. This difference is of special importance, however, as the weight of the product finally obtained will naturally vary with the de- gree to which purification has been effected, and this in turn will cause the computed percentage to vary, as is shown in the following table : Table 'il .— Variation in filix, acid content due to the difference in the meth ods employed in its determination. Observer Per cent, of filix acid by the metliod of Date Bocchi Kraft Fromme (Original) Fromme (Improved) 1887 Gehe & Co Madsen 13.24 to S0.35 3.28 to 11.32 13.07 6.58 6.00 1897 12.10 1897 5.85 1898 Plzak 6.48 5.20 The above table shows further that the filix acid is obtained in the state of greatest purity when the improved method of Fromme is employed. And this method was usually given preference in the valuation of the oleoresin until it was dis- covered that the teniafuge properties were not due to the filix acid, alone, but were to be attributed in part to the presence of a number of other substances as well, compounds resembling acids to a certain extent in their chemical behavior. Methods for tJie determination of the Crude Filicin. With the above mentioned advance in our knowledge con- cerning the therapeutic constituents of this preparation, the methods for the determination of the filix acid lost their value and have since been superceded by those which have for their OLEORESIN OP ASFIDIUM 105 object the determination of the quantity of total active constit- uents (crude filicin) present. The methods which have been proposed for this purpose are as follows: Method of Bulle (1867) :"■ Add a liberal amount of water to a weighed portion of the oleoresin contained in a suitable flask and heat on a water bath at 40° to 50 °C. Add sufficient ammonia water to produce a strong odor of the same after vigorously shaking. Allow the mixture to stand in cold water for 3 or 4 hours and add 1/5 to i/4 of its volume of a sat- urated solution of salt, then filter. Wash the flask and filter with the salt solution, diluted with 6 parts water, until the filtrate no longer gives a precipitate with hydrochloric acid. Add dilute hydrochloric acid to the filtrate until precipitation is complete, collect the precipitate on a filter, wash and dry over sulphuric acid until of constant weight. Method of Daccomo and Sccocianti (1896) : ^ Dissolve 1 to 3 grams of the oleoresin in a small quantity of ether and shake the solution for % hour with an equal volume of an aqueous copper acetate solution. Allow the mixture to stand and separate, decant the ethereal liquid and collect the precipitate on a tared filter. Wash it successively with water, alco- hol and ether, then heat at 100°C until of constant weight. When dry 111.55 parts of the precipitate represent 100 parts, of filix acid. Method of Schmidt (1903) : ^ Place 5 grams of the oleoresin in a mortar and convert it to a coarse powder by triturating it with a sufficient quantity of calcined magnesia. Then add 250 cubic centimeters of water and thor- oughly mix. After the magnesia has settled, decant the aqueous portion on a filter. Repeat this operation twice using 150 cubic centimeters of water each time. Transfer the combined filtrate to a separatory funnel and add hydrochloric acid in sufficient quantity to produce complete pre- cipitation. Shake out the precipitate with ether, specific gravity 0.720 to 0.722, added in successive portions (100, 50 and 30 cubic centimeters.) After filtering the ethereal shakings, remove the solvent by distillation and dry the residue at 100*C. Method of Fromme (1905) : * Dissolve 5 grams of the extract in 30 grams of ether, add 100 grams of a saturated solution (3 per cent.) of barium hydroxide, and shake the mixture vigorously during several minutes. Transfer to a separator, and run 86 grams (4 grams of the extract) of the lower equeous layer into a flask of 200 cubic centimeters capacity. Add 2 grams of hydrochloric acid (25 per cent.) and shake out with 3 portions of ether, 25, 15, and 10 cubic centimeters. Separate the ether, and filter each portion successively through the same plain double filter into an 1 Cited by Doesterbehn (1898). 2 This procedure was proposed as a method for the estimation of the illix acid. As its nature and the results obtained In its application show that it is in reality a method for determining the total constituents of an acid •character, It has been included here. •The method proposed by Goris and VoisIn (1913) is almost identical with the above, the only difference being- that 2 to 3 grams of the oleoresin are taken instead of 5 grams as directed by Schmidt, *This is the method (but slightly modified) which is official in the British, Finnish and Swiss pharmacopceias. 106 DU MEZ— THE GALENICAL OLEORESINS Erlenmeyer flask of 200 cubic centimeters capacity which has been pre- viously weighed. Wash the filter with 10 cubic centimeters more of ether^ and finally distill off the ether and dry the residue at 100 °C. Weigh after allowing it to stand in a desiccator for half an hour. The weight multi- plied by 25 will give the percentage of crude filicin in the sample. The striking similarity in the above methods is quite ap- parent and needs no special mention. Attention, however, is invited to the principal point of difference, namely, the reagent employed for the purpose of rendering the constituents to be determined soluble in water. In the methods under considera- tion, ammonia water, magnesium oxide and barium hydroxide have been made use of. As the amount of crude filicin ob- tained has been shown to depend to a considerable extent upon which one of these reagents is employed, the difference in the results reported in the literature in this connection is readily accounted for. The importance of this factor is clearly brought out in the following data obtained by Hill : Table 28 — Influence of different alkalies on the percentage of crude filicin obtained. Alkali K2CO3 1 per cent KOH 6 per cent. KOH Mfir(OH)2) Ca(0H)2 Ba(0H)2 Per cent, of crude filicin 37.6 37.9 38.8 1S,6 20.0 21.6 These results would appear to indicate that potassium hy- droxide is the most efficient reagent for effecting a soluble com- bination of the constituents comprising the so-called crude filicin. The data, however, are misleading in that the strong- alkali combines with other material therapeutically inert, and thereby causes the results to be high. While there is no in- formation of a physiological nature at hand to substantiate the statement that barium hydroxide is the best reagent for this purpose, it is nevertheless, thought to be the most satisfactory from a chemical stand point at least. The method of Fromme^ in which the latter is directed to be used, was, therefore, em- ployed in the evaluation of the oleoresins examined in the laboratory. The results obtained in these analyses, together with those reported by other workers are given in the table which follows: OLEORESIN OF ASPIDIUM: 107 Table 29. — Crude filicin content of laboratory samples of the oleoresin determined hy Fromme's method. Sample No. Date Observer Solvent Crude filicin 1 1898 1899 1913 1914 1916 Bellincrnflt EtbPT- Percent. 18.20 2 . 18.96 3 • 19 82 4 20.38 5 ' 20.87 6 * t 21.76 7 ' 21.85 8 ^. • 24 32 1 Caesa Bohn DuMe Harri Linke DuMe 31.44» 2 27. 48^^ 1 sch 18.22 1 »z Ac Etl Ac( Etl Btone 13.79 2 20.37 1 son & Self 19.30 2 * 19.70 3.... . 21.50 S::::::::: " ' 21.90 3 " 24.10 6 •' 24.20 7 »» 24 50 8 " 24.70 9 •' 26.50 10.... 27.70 11 »' 28.0 1 19.30 2 z." 16. 00^ 2 ler 16.27 ' 1 Ether, specific gravity 0.720. =» Ether, specific gravity 0.728. ' Oleoresins which were prepared in 1910 and had deteriorated. Exam- ined shortly after being prepared, the ethereal oleoresin showed a crude filicin content of 26.35 per cent. From the foregoing, it is apparent that the crued filicin content is influenced^ by the age of the oleoresin as well as by the solvent which has been employed in its preparation. In the case of acetone, the low results obtained are not due to the in- complete extraction of the constituents to be determined, as might be inferred, but rather to the relatively large amount of total extractive matter obtained. It will be noticed that when the oleoresin is fresh and ether is the solvent which has been used in its preparation, the crude filicin content is usually above 20 per cent. This is in accordance with the require- ments of the British Pharmacopoeia and is thought to be a more reasonable standard than that adpoted by the Swiss, or the Finnish pharmacopoeias. The former requires a filicin content of 26 to 28 per cent, while the latter specifies a minimum con- tent of 26 per cent. This statement is further supported by the results obtained in the examination of commercial samples as is shown in the following compilation of such data : *For the effect of the condition of the rhizomes used on the crude filicin content, see under "Drui^ used, its collection, preservation, etc.'/ 108 DU MEZ — THE GALENICAL OLEORESINS Table 30. — Crude filicin content of commercial samples of the oleoresin determined by Fromme's method. Sample No. Date: Observer Source Crude fllicin 1 1901 1903 1911 1912 1913 1913 C. lesar & Loretz Prepared by the firm England Per cent. 21.40 2 3 26.15 27.37 4 5 28.17 30.00 6 30.12 7 8 30.80 30.92 1 27.08 2 4i 4» 28.22 3 28.78 4 14 (> 29.39 5 6 30.05 36 60 1 Evans Snns. T^ftsr>her & 26.30 2 Webb. ^^ 28.00 P E irry " 8.40 (1) 2 8.60 (1) 3 " " 8.80 (1) 4 " 44 9,00 (1) 5 " " 9.20 (1) 6 " '4 10.80 (1) Ito 16.. vans Sons. T^fisr'.her & 22.90 to 26.30 1 "... 2 Webb. South all Bros. & Barclay :; 6.09 0) 7.16 (0 3 4 26.04 28.76 1 B D E ohrlsch Germany 14.85 2 15.42 3 " 16.00 4 uMez " 24.00 1 Enjrland 8.79 2 United States 14.36 3 4' Germany England . . . 16.55 4 44 17.51 (») 5 " 20.32 6 44 United States 20.77 Ito 7 8 9 vans Sons, Lescher & Webb. Not given 21.3 to 25.30 15.60 0) 19.60 (0 10.... " 4. 4. 19.70 (0 G H H oris & Voisin Germany 13.61 to 19.00 7.13 to 24.00 France 20 60 to 22.13 1 13.70 2.. 19.10 3 4 '• " " 21.20 24.80 5 44 44 44 25.80 6 44 4. 44 28.10 (IS 11.60 },{ 13.20 )A 14.10 ^ ^ 1 ill 2 3 " 4 Not given 18.10 5 18.92 6 4. 44 19.30 7.. (4 44 20.22 8 44 20.67 9 44 44 21.57 10 44 44 21.60 11 44 22.00 12 [', i. 22.65 13 23.10 OLEORESIN OF ASPIDIUM 109 Table 30. —Continued. Sample No. 14 1913 15 16 " 17 '* 18 " 19 " 20 " 21 " 22 " 23 *' 1 1914 2 3 1 "mh" 2 3 '• 4 " 5 •' 1916 2 3 " 4 " Date Observer Hill. Linke Southall Bros. & Barclay DuMez . Source Not given. Merck & Co Brueckner, Lampe & Co. Caeser & Loretz Notgiven Stearns & Co Lilly & Co Squibb & Sons Parke, Davis & Co. Crude fllicin Percent. 23,72 23.75 24.50 24.55 25.15 25.27 27.10 27.82 28.10 29.75 20.40 21.67 27.22 20.40 21.60 24.20 24.60 27.70 7.79 (2) 17.57 19.04 22.66 1 These samples were adulterated with castor oil. 'Apparently an oleoresin from some species of fern other than Dry- opteris Mix-mas. In addition to the information gtiven in table No. 29, table No. 30 reveals the fact that a low filicin content in the com- mercial oleoresins is frequently due to adulteration with castor oil. Physiological Tests. In view of the difference in toxicity of the various constit- uents of the oleoresin with respect to the tapeworm, a physio- logical method for the evaluation of this preparation would ap- pear to be desirable. The method proposed for this purpose by Yagi indicates the possibilities along this line. However, as there is no available information regarding its application, aside from that given by the originator, no statement can be made concerning its practical value. A description of the method for conducting the test follows : Method of Yagi (1914): After thoroughly drying in a desiccator, ac- curately weigh 1 gram of the oleoresin and dissolve it in 25 cubic centi- meters of ether. Bring the therapeutically active constituents into aqueous solution by shaking the ethereal liquid with a saturated solution of magnesium hydroxide, using 50 cubic centimeters of the latter for every 110 DU MEZ— THE GALENICAL OLEORESINS cubic centimeter of the former. Filter and divide the filtrate into several parts. Prepare solutions of different dilution from these parts - by adding a measured amount of water to each. Then immerse 5 earthworms in each of these solutions and note the maximum dilution in which all 5 are killed. For computing the relative value of the preparation compare these re- sults with those obtained when using a standard solution prepared by dis- solving a weighed amount of filix acid, filmaron or albaspidin in water in the same manner as described above for the oleoresin. In the case of these standard solutions the limit of toxicity is given as follows: filmaron, 3 parts in 1,000,000; filix acid 4 parts in 1,000,000; albaspidin 1 part ia 100,000. Adulterations The efforts which have been made in recent years to stand- ardize this preparation have resulted in the discovery that the commercial article is very frequently adulterated, the latter being accomplished in a variety of ways. The method usually resorted to by unscrupulous manufac- turers in order to increase their profits consists of diluting the finished product with some comparatively cheap material. Castor oiP has generally been used for this purpose. In some cases, the oleoresin is prepared from deteriorated brown rhi- zomes and made to assume the green color of the official pre- paration by the addition of chlorophyll or salts of copper.^ Adulteration, however, is not limited to the addition of for- eign materials to the finished product, but may take place in the drug from which the oleoresin is prepared. The forms in which the drug may be contaminated are conveniently classed under three heads, viz.: (a) the substitution of old deteriorated rhizomes for the fresh material, (b) the admixture of chaff and dead stipe bases with the rhizomes, and (c) the admixture of rhizomes of unofficial species of fern with those of the official species. For a discussion of these conditions, see under ^'Drug used, its collection, preservation, etc." ^ Parry (1911) ; Evans Sons, Lescher and Webb (1911) ; and others, ^Weppen and Lueders (1892); Beckurts and Peters (1893); PendorfiC (1913) ; and others. A trace of copper is usually* present in the commercial product as a result of the use of copper utensils in the manufacture of the preparation. (See under "Ash"). OLEORESIN OF CAPSICUM HI OLEORBSIN OF CAPSICUM Sy7ionyms Aetherische SpunishpfefferextraTct, Nat. Disp. 1884. Capsicum,'' Chem. & Drugg. (1913), 82, p. 470. Capsicol, Vierteljahrschr. f. prakt. Pharm. (1873), 22, p. 507. Ethereal Extract of Capsicum, Am. Journ. Pharm. (1849), 21, p, 134. Extractum Capsici aethereum, Hirch, Univ. P. Ii90'2, No. 1905. Oleoresin of Bed Pepper, Stevens, Pharm. and Disp. (1909), p. 255. Oleoresina Capsici, U. S. P. 1910. Oleoresine de Capsique, U. S. Disp. 1907. SpanishpfefferextraTct, Nat. Disp. 1884. Spanishpfefer-Oelharz, Nat. Disp. 1884. History The oleoresin of capsicum appears to have been first prepared by Procter in 1849, and it was through his efforts that it was introduced into the United States Pharmacopma of 1860. Up to the present time, no such preparation appears in any of the foreign pharmacopoeias. A similar preparation known as capsi- ein has, however, been in use in Europe since 1873.^ Drug Used, Its Collection, Preservation, Etc. The drug directed to be used by the present edition of the United States PJiarmacopoeia is ''the dried ripe fruits of Capsi- cum fructescens Linne^ (Fam. Solanaceae), without the presence or admixture of more than 2 per cent, of stents, calyxes or other foreign matter." The preceding editions of the Pharmacopoeia since 1880 have specified the use of the species known as Capsi- cum fastigiatum Blume. The change is evidently due to the fact that the leading commercial varieties of Cayenne pepper are at the present time being received from Africa and Japan and ^For other uses of the term capsicin, see under "Chemistry of capsicum and its oleoresin." =* Buchheim states that capsicin (the ethereal extract of capsicum) was being prepared and sold by Merck of Darmstadt in 1873. Vierteljahrschr. f. prakt. Pharm. (1873), 22, p. 507. Capsicin, as found on the market in England, is stated to be indefinite in that it may be an alcoholic, a chloroformic, an ethereal or an acetone prep- aration. Chem. and Drugg. (1913), 82, p. 470. 3 This is also the species recognized by the French Pharmacopoeia. In the other European pharmacopoeias, in which this drug occurs, it is usually the the larger fruited variety, Capsicum annum, which is designated. 112 ^^ MEZ— THE GALENICAL. OL.EORESINS belong to the first mentioned species* which has also been known as Capsicum haccatum Veil. The fruit is plucked when ripe, exposed to the sun until dried, and then usually packed in suitable shape for market. It should be preserved in the whole condition in a cool place,^ and prefer- ably in a closed container as it is prone to become rancid owing to the large amount of fatty oil which it contains. U. S. P. Texts and Comments Thereon. The oleoresin has been official in the United States Phar- macopoeia for the past half century having been recognized for the first time in the edition of 1860. 1860 Oleoresina Capsici Oleoresin of Capsicum Take of Capsicum,* in fine powder,' distillation on a water-bath, eighteen twelve troy-ounces; fluid-ounces of ether," and expose the Ether ' a sufficient quantity. residue, in a capsule, until the re- Put the capsicum into a cylindrical maining ether kas evaporated. "^ percolator,* press it firmly, and grad- Lastly, remove, by straining, the fatty ually pour ether upon it until twenty- matter which separates on standing,* four fluid ounces of filtered liquid and keep the Oleoresin in a well-stop- have passed.' Eecover from this, by pered bottle." 1870 Oleoresina Capsici Oleoresin of Capsicum Take of Capsicum,* in fine powder,^ ounces of liquid have slowly passed.* twelve troyounces; Eecover the greater part of the ether Ether ^ a sufficient quantity. by distillation on a water -bath,' and Put the capsicum into a cylindrical expose the residue in a capsule, until percolator, provided with a stop-cock, the remaining ether has evaporated.'^ and arranged with cover and recep- Lastly, remove, by straining, the fatty taele suitable for volatile liquids,* matter which separates on standing,* press it firmly, and gradually pour and keep the Oleoresin in a well-stop- ether upon it, until twenty-four fluid pered bottle.*". *Tolman and Mitchell, Bull. 163, Bur. of Chem. (1913), p. 9. 'Brown, Bull. 150, Kentucky Agric. Exp. Sta. (1910), p. 131. OLEORESIN OF CAPSICUM 113 1880 Oleoresina Capsici Oleoresin of Capsicum Capsicum/ in No. 60 powder/ one residue, in a capsule, until the remain- Hundred parts 100 ing ether has evaporated/ Lastly, Stronger Ether,^ a sufficient quantity, pour off the liquid portion," transfer Put the capsicum into a cylindrical the remainder to a strainer, and, when percolator, provided with a cover and the separated fatty matter (which is receptacle suitable for volatile liquidflj* to be rejected) has been completely press it firmly, and gradually pour drained, mix all the liquid portions to- stronger ether upon it, until one hun- gether." dred and fifty (150) parts of liquid Keep the oleoresin in a well stop- have slowly passed.** Kecover the ped bottle." greater part of the ether by distilla- Preparation. Emplastrum Capsici. tion on a water-bath," and expose the 1890 Oleoresina Capsici Oleoresin of Capsicum Capsicum,* in No. 60 powder,^ five a water-bath," and, having transferred hundred grammes 500 Gm. the residue to a capsule, allow the re- Ether,^ a sufficient quantity. maining ether to evaporate spontan- Put the capsicum into a cylindrical eously.^ Then pour off the liquid por- glass percolator, provided with a stop- tion, transfer the remainder to a cock, and arranged with cover s^nd strainer, and, when the separated fatty receptacle suitable for volatile liquids,* matter (which is to be rejected) has Press the drug firmly, and percolate been completely drained, mix the li- slowly with ether, added in successive quid portions together.' portions, until the drug is exhausted.' Keep the oleoresin in a well-stop- Eecover the greater part of the ether pered bottle.", from the percolate by distillation on Preparation: Emplastrum Capsici. 114 DU MEZ— THE GALENICAL. OLEORESINS 1900 Oleoresina Capsici Oleoresin of Capsicum Capsicum/ in No. 40 powder,' -five hundred grammes 500 Gm. Acetone/ a sufficient quantity. Introduce the capsicum into a cylin- drical glass percolator, provided with a stop-cock, and arranged with a cover and a receptacle suitable for volatile liquids.* Pack the powder firmly, and percolate slowly with ace- tone, added in successive portions, until eight hundred cubic centimeters of percolate have been obtained." Recover the greater part of the ace- tone from the percolate by distilla- tion on a water-bath,* and, having transferred the residue to a dish, al- low the remaining acetone to evapor- ate spontaneously in a w^arm place.' Then pour off the liquid portion,* transfer the remainder to a glass fun- nel provided with a pledget of cotton, and when the separated fatty matter (which is to be rejected) has been completely drained, mix the liquid portions together.* Keep the oleo- resin in a well-stoppered bottle.^** Average dose. — 0.030 Gm. z=z 30 milligrammes (^ grain). 1910 Oleoresina Capsici Oleoresin of Capsicum Oleores. Capsic. Capsicum,^ in No. 40 powder* ^ive hundred grammes 500 Gm. Ether,' a sufficient quantity. Place the capsicum in a cylindrical glass percolator, provided with a stop- cock, and arranged with a cover and a receptacle suitable for volatile li- quids.* Pack the powder firmly and percolate slowly with ether, added in successive portions, until the perco- late measures eight hundred mils.^ Eecover the greater part of the ether from the percolate by distillation on a water-bath,« and, having transferred the residue to a dish, allow the re- maining ether to evaporate spontan- eously in a warm place.^ Then pour off the liquid portion,' transfer the remainder to a glass funnel provided with a pledget of cotton, and, when the separated fatty matter (which is to be rejected) has been completely drained, mix the liquid portions to- gether." Keep the oleoresin in a well- stoppered bottle." Preparation — Eplastrum Capsici. Average Dose. — Metric, 0.03 Gm. — Apothecaries, % grain. OLEORESIN OF CAPSICUM 115 1) For a description of the drug, see pag 1017 under ''Drug used, its collection, preservation, etc." 2) The editions of the Pharmacopoeia previous to that of 1900 directed that the drug be reduced to a fine powder (No. 60) for percolation. As a No. 40 powder has been found to be equally satisfactory for this purpose, the last two editions of the PharmacopcBia have specified the use of the coarser powder. 3) Ether is the solvent which is directed to be used in the ex- traction of the drug at the present time. Previous editions of the Pharmacopoeia, with the exception of that 1900, also, speci- fied the use of ether for this purpose. The use of acetone as di- rected by the Pharmacopoeia of 1900 was unsatisfactory as the large amount of extractive matter obtained caused the residue which remained upon the evaporation of the solvent to assume a semi-solid gelatinous form, and thus increased the difficulty of separating the liquid portion. Among the other solvents which have received considera- tion in this connection, benzin is worthy of mention. The re- ports of Maisch, Trimble and Beringer, respectively, (see part I, pages 923 and 924) indicate that it is a good solvent for the oleoresinous constituents of capsicum and that the pro- duct obtained is equal in quality to that yielded by ether. Experiments conducted in the laboratory confirm these ob- servations. The solvent used in the laboratory, however, was petroleum ether, boiling temp, 45 to 50° C, as the composition of ordinary commercial benzin varies to a considerable extent. 4) The Pharmacopoeia of 1860 directed that the extraction of the drug be carried out in an ordinary glass percolator. As a considerable amount of solvent was lost under these condi- tions, the subsequent editions of the Pharmacopoeia have specified that a form of percolator adapted to the use of vola- tile liquids be employed for this purpose. For a description of such forms, see Part I, under *' Apparatus used.'' 5.) Of interest in connection with the preparation of this oleoresin is the fact that the pharmacopoeial directions con- cerning the amount of percolate to be collected have been changed no less than three times. The first change appeared in the Pharmacopoeia of 1880, and was apparently instituted for economic reasons as the amount of percolate directed to 116 DU MEZ— THE GALENICAL. OLEOKBSINS be collected was reduced from approximately 2 cubic centi- meters for each gram of drug used (24 fluid ounces for 12 troy ounces of drug) to 1.5 cubic centimeters. In the succeeding edition of the Pharmacopoeia (edition of 1890), the second change was made, the directions being to continue percolation until the drug is exhausted. The third change occurs in the Pharmacopoeia of 1900, which directs that 1.6 cubic centi- meters of percolate be collected for each gram of drug taken. The reason for making the second change does not become apparent from the information at hand. The third change^ however, appears to have been instituted primarily for the purpose of reducing the amount of solid fats (mainly pal- mitin and stearin) extracted in order that the separation of the liquid portion constituting the oleoresin might be ac- complished more easily. In commenting further upon these changes, it is stated that, in the preparation of the oleoresin in the laboratory, no greater difficulty was experienced in the separation of the liquid portion when the amount of sold fats present was large than when the quantity present was relatively small. From this standpoint, therefore, the last change does not appear to have been warranted. For economic reasons, however, the change was desirable since at least twice as much ether was required for the complete exhaustion of the drug as is ordin- arily used when proceeding according to the directions given in the last edition of the Pharmacopoeia. It is thought that the present pharmacopoeial method could be still further improved through the use of some form of con- tinuous extraction apparatus for exhausting the drug. Not only would this procedure result in the saving of a large amount of solvent, but the time required to complete the preparation of the oleoresin would be considerably shortened. 6) The Pharmacopoeia of 1860 directed that only % of the menstruum contained in the percolate be recovered by distil- lation on a water bath. In all of the subsequent editions the directions are to recover the greater part of the solvent, no specific amount being mentioned. In this connection, it may be stated that the preparation will not be injured even if all of the solvent is recovered under the above conditions. In case this is done, however, it is necessary to use ether in re- OLEORESIN OF CAPSICUM ll7 moving the thick liquid from the flask so that no particular advantage is gained by such a procedure. 7) In all editions of the Pharmacopoeia in which this prepara- tion is official, it is directed that the last traces of solvent be allowed to evaporate spontaneously at room temperature. Since the complete removal of the solvent can be accomp- lished much more rapidly by heating the ethereal liquid on a water bath, and without injury to the finished product, it is thought that such a procedure would be a desirable improve- ment over the present pharmacopoeial method. 8-9) The liquid portion constituting the oleoresin is directed to be separated from the solid fats, which precipitate up- on the removal of the solvent, by decantation, and straining through a pledget of cotton. Experience has shown that this may be accomplished much more rapidly and satisfactorily by the aid of a force filter. By this procedure a more complete separation can be effected without washing the residue on the filter with a portion of the solvent as has been suggested by some and thus, the necessity of further exposure of the prep- aration to the air is done away with. With further reference to the removal of the solid fats, at- tention is called to the fact that the degree to which this is ac- complished depends upon the temperature at which the oper- ation is carried out. The preparation when made during the summer may be perfectly homogeneous at the time, but deposit fat during the winter. In order to secure a more uniform product, it is therefore, thought that the Pharmacopoeia should direct that the mixture be chilled to a definite tempera- ture previous to the separation of the liquid portion. 10) The oleoresin should be kept in well-stoppered bottles for the same reasons as are given in the comments on the oleoresin of aspidium. See page 979. Yield The average yield of oleoresin is usually about 15 to 18 per cent, when ether is the solvent employed in exhausting the drug. It is about the same when alcohol, acetone, petroleum ether, carbon disulphide or chloroform are used. In this con- nection, attention is called to the fact that the total amount of 118 DU MEZ— THE GALENICAL OLEORESINS extract obtained and the oleoresin are not identical, the latter consisting only of the oily, liquid portion of the former. Thus, it will be observed, upon examining the tables which follow, that the total amount of extract obtained with acetone may amount to 25 per cent, of the drug operated upon, whereas, the yield of oleoresin is only about 18 per cent. The factor which ap- pears to influence the yield to the greatest extent is the tem- perature at which the preparation is completed. This is due to the fact that the oleoresin is saturated with solid fats (principally palmitin) and, that these will be precipitated to a greater or lesser degree depending on the temperature at which the preparation is finally strained. The finished pro- duct will, therefore, contain a relatively small amount of these fats, and the yield will be correspondingly low when made dur- ing the cold winter months, whereas, the opposite will be the case when the oleoresin is prepared in the hot months of sum- mer. The following tables show the yield of oleoresin, as re- ported in the literature, likewise, that obtained in the labora- tory: OLEORESIN 0F .CAPSICUM 119 Table 31. — Yield of oleoresin as reported in the literature. Observer Yield of oleoresin to Date Alco- hol Ace- tone Ether Other solvents Remarks 1853 Bakes Perct 25.00 Per ct Per ct Percent. 888 Trimble 19.50 17.32 15.50 17.40 18.30 18.40 19.00 15.81 16.85 21.31 16.19 15.67 15.34 j Benzin 1 18.15 21.00 25.00 1892 18.00 25.00 Yield of oleoresin when pre- 1892 Sherrard, 28.00 paied b.v the U. S. P. method. Total yield of extract on com- plete exhaustion of the drug. Alpers 1896 Oleoresin from which deposited 1898 Wlnton, Ogden & Mitchell fat had been removed. Total ether extract from "Chilli Southall B10S.& Barclay Colorado." Total ether extract from Natal capsicum. Total ether extract from Ne- paul capsicum. Total ether extract from Zan- 1903 zibar capsicum. Capsicum minimum total .yield Vanderkleed to ether, sp. gv. Q.717. Capsicum annum total yield to 1905 j 9olvent(?) 19.40 to 23 90 J Benzin » 18.60 \ Petrol < Ether \ 16.40 \ Carbon X disulDhlde 1 16.70 j Chloroform ( 17.50 ether.sp.gr. 0.717. Reported as yield of oleoresin. 1905 Gerrard fAIco- Jhol 1 (905t) 126.40 18.20 The average yield of 8 samples is given as 18.13 per cent. 1 Patch i Represents yield of total ex- 1 tractive matter. J 1907 16.20 to 26.50 15.0 to 25.20 Total alcoholic extract. Re- 1908 sults obtained in the exam- ination of 10 samples of cap- sicum. Total alcoholic extract. 1908 Vanderkleed jSolvent(?) 1 11.59 to 18.35 14.34 to 17.95 j Benzene 1 14.00to 15.40 Reported as yield of oleoresin : 1909 Represents the yield from 3 samples of capsicum. 1910 Southall Bros. & Barclay Results obtained In the ex- traction of 5 samples of cap- sicum. 1910 Eldred 11.00 to 26.00 Ueported as yield of ether i9ia Vanderkleed J Solvent(?) \ 15.10 to 22.27 soluble oleoresin. The aver- erage yield obtained from 48 samples of capsicum Is given as 18.00 per cent. Reported as yield of oleoresin. Results obtained In extract- ing 7 samples of capsicum 120 DU MEZ— THE GALENICAL. OLEORESINS Table 31. — Yield of oleoresin as reported in the literature — Continued. Observer Yield of oleoresin to Date Alco- hol Ace- tone Ether Other solvents Remarks 1911 Vanderkleed— Continued. Johnson and Jolinson Per ct. Per ct. Per ct. Percent. \ Solvent (?) \ 14.70 \ 17.93 1 Reported as .yield of oleo- resin. 1912 16.00 to 19.00 J Reported as yield of ether ex- 1912 Vanderkleed J Solvent(?) (14.41 to 16.70 tract. Reporte( «« Ether 0.932 4 4. .. Benzine 0,925 1 DuMez Alcohol 0.926 2 Acetone 0.919 ■3 " Ether 0.925 4 " Petrol, ether 0.914 King's American Dispensatory (1900), p. 1331. 126 DU MEZ— THB GALENICAL OLiEORESINS Table 34 — Specific gravities of commercial oleoresins. Sample No. Date Observer Source Specific gravity 1 1916 DuMez Squibb «& Sons At 25° C 0.9101 2 Lilly «& Co 0.919 3 »i Sharp & Doiitne 0.928 * 1 taine d ether Refractive index: Determinations made in the laboratory show that the oleoresin should have a refractive index of about 1.47 when observed at 25° C. A refractive index lower than this was found to be due to the presence of unevaporated solvent. The solvent employed in extracting the drug or the variation in solid fat content appears to have very little influence, if any, on this constant. The results obtained in the laboratory in the examination of the oleoresin follow: Table ^6— Refractive indices of oleoresins prepared in the laboratory. Sample No. Date Observer Solvent Refractive index 1910 1916 DuMez & Netzel Alcohol At 25° C 1 463 2 1 477 '4 Ether 1 474 4 " Petrol, ether 1 47.5 DuMez Alcohol 1 473 2 1.473 »* Ether 1 474 »» Petrol, ether 1 472 Table 36 — Refractive indices of commercial oleoresins. Sample No. Date Observer Source Refractive index 1 1916 DuMez Lilly & Co At 25° C 1 472 2 1.473 3 '< Sauibb & Sons 1 467' * Contained ether. OLEORESIN OF CAPSICUM 127 Chemical Properties. Loss in weight on heating: Determinations made in the laboratory show that the oleoresin loses but little in weight on heating at 110 °C, a loss of but 0.42 to 2.13 per cent, having been observed for the preparation when free from solvent. The laboratory preparations as a rule showed a smaller loss than the commercial samples, which is very likely due to a difference in the temperature conditions under which the preparations were made. The results obtained in the determinations made in the laboratory are given in the following tables : Table ^1 —Laboratory preparations — loss in iceight on heating Sample No. Date Observer Solvent Per cent, of loss on heating 1 1916 DuMez Alcohol At 110° € 0.42 2 •• Acetone 52 3 Ether 0.88 4 . : Petrol, ether 0.68 5 " Alcohol 5.15' 6 .... Acetone 74 7 4( • Ether 2 09 8 " Benzine 1 01 Contained alcohol. Table 38. — Commercial oleoresins — loss in weigJit on heating. Sample No. Date Observer Source Per cent of loss on heating 1 1916 DuMez Sharp & Dohme . At 110° C 1 93 2 Lill.v& Co Squibb & Sons.. . 2.13 3 " 4 09 > * Contained ether. Ash Content: The determinations made in the laboratory show that the ash content of the oleoresin varies with the solvent employed in its preparation. When acetone was the solvent used, the amount of ash obtained did not exceed 0.26 per cent, whereas, the amount was only 0.09 to 0.12 per cent, when the oleoresin was prepared with ether. The variable results ob- tained in the examination of the commercial samples appear to 128 DU MEZ— THE GALENICAL. OLEORESINS indicate the use of different solvents in their preparation. The comparatively high value (0.40 per cent.) obtained in one case, however, may have been due to the copper present. The ash content of the samples examined in the laboratory is given in the tables which follow: Table 39 — AsJi contents of oleorsins prepared in the laboratory. Sample No. Date Observer Solvent Per cent, of ash 1 1916 DuMez Alcohol 0.39 2 Acetone 0.26 3 Ether Petrol, ether 0.09 4 »» 09 5 ;; 0.39 6 Acetone 0.24 7 " Ether 0.12 8 0.10 Tabe 40 — Ash contents of commercial oleoresins Sample No. Date Observer .Source Per cent, of ash Foreign constituents J 1916 DuMez Sauibb & Sons 0.091 0.40 0.30 2 Sharp & Dohme Lilly & Co Copper 3 " ^ Contained ether. Acid number: The acid numbers, when acetone, ether, or petroleum ether were used in the preparation of the oleoresin, were found to be 106.6, 103.8 and 105 respectively. When alcohol was employed for this purpose, the value obtained for this constant was considerably lower, being 93.5. With respect to the commercial samples examined, the acid number was in all cases found to be much lower. This is thought to be due, in two instances, to a low free acid content (principally pal- mitic acid) of the drug from which the oleoresins were pre- pared, or to the more complete removal of these acids in the separation of the deposited material. In the third case, it was caused, in part, at least, by the presence of unevaporated solvent. The acid numbers obtained for the preparations ex- amined in the laboratory are as of Hows: OLBORESIN OF CAPSICUM 129 Table 41- Acid numbers of oleoresins prepared in the laboratory. Sample No. Date Observer Solvent Acid number 1 2 3 4 1916 T)iiMp7 93.5 Acetone 106.6 ii Ether 103.8 .4 Petrol. Ether 105.0 Table 42 — Acid numbers of commercial oleoresins. 1 Contained ether. Sample No. Date Observer Source Acid , number 1 2 3 1916 DuMez Sauibb & Sons 30.81 Sharp &Dohme 60.3 it Lilly & Co 82.7 Saponification value: The saponification values obtained for the oleoresins prepared in the laboratory were above 200, as a rule, regardless of the nature of the solvent used in extracting the drug. The comparatively slight variations observed were very likely due to the difference in the degree to which the solid fats (principally palmitin) had been removed. This also accounts for the comparatively low values obtained for the commercial preparations. The exceptionally low value ob- tained for the sample from Squibb and Sons is to be attributed to the presence of unevaporated solvent. The values obtained for the preparations examined in the laboratory are given in. the tables which follow: Table 43 — Saponification values of oleoresins prepared in the laboratory. Sample No. Date Observer Solvent Saponifica.- tion value 1916 DuMez . Alcohol 203 5 Acetone 209.2 Ether 207 4 Petrol, ether 208.6 Alcohol 196 7 Acetone 202,8 •J Ether 206,9 Benzin 198 7 130 DU MEZ— THE GALENICAL OLEORESINS Table 44 — Saponification values of commercial oleoresins. Sample No. Date Observer Source Saponifica- tion value 1 1916 DuMez Squibb & Sons 193.4' 196 9 2 3 «■ Lilly & Co 198 3 * Contained ether. Iodine value: An iodine value of 122 to 123.9 was obtained for the oleoresins prepared in the laboratory using ether as the •extracting menstruum. Results very near the same were ob- tained when acetone or petroleum ether were the solvents used, whereas, the preparation when made with alcohol gave a lower value, 109.3 to 105.7. The principal cause^ for the variation in this constant (aside from the effect which the quality of the drug or the solvent may have thereon) as observed in the case of some of the laboratory preparations, as well as the commercial samples, is thought to be the difference in the degree to which the saturated fats (principally palmitin) have been removed. In the case of one of the commercial samples, however, the low iodine value is to be attributed to the presence of unevap- orated solvent. The results obtained in the determinations made in the laboratory together with those reported by Kebler for the total ether extract are given in the tables which follow: Table 45 — Iodine values of laboratory preparations. Sample No. Date Observer Solvent Iodine value \ 1913 1916 Keblera Ether 107. 2 \2%A 3 »• •« \2^ 2 4 •' •' 127.3 5 «' »« 132 6 " " 137.3 7 " 138 8-24 •' " 110.0 to 14-5.7 11.5.7 1 DuMez Alcohol 2 Acetone 125.2 8 " Ether 122.0 4 '• Petrol. Ether 123.7 1 «♦ Alcohol 109 3 2 '• Acetone 118.0 3 ♦» Ether 102 9 4 . ... »« Benzin 116 9 1 13. 69 to 23.60 3 Solvent (?) (16.49 to 24.34 f Petrol Ether 3.88 4.30 j 4.45 1 14.00 16.03 16.. 54 16.90 I 18.08 3 Sol vent (?) 1l8.42to 24.40 3 Solvent (?) ( 22.14 Petrol < Ether 4.66 to 8.78 1907 Blome Reported as yield of oleoresin 1907 Evans Sons, Lescher & Webb Vanderkleed .... Results obtained in the ex- traction of 5 samples of cubeb. ■ 1908 Reported as yield of oleoresin. 1909 Results obtained in the ex- traction of 4 samples of cubebs. Reported as j'ield of oleoresin. 1910 Southall Bros., & Barclay On subsPQuent extraction with Vanderkleed .... alcohol 3.40 to 5.66 per cent. of extractive matter was ob- tained. 1910 Reported as yield of oleoresin. 1911 Vanderkleed .... Results obtained in the ex- traction of 6 samples of cubebs. Reported as yield of oleoresin. 1911 Southall Bros. & Barclay The average yield of 5 samples of cubebs is griven as 6.95. 142 DU MEZ— THE GALENICAL OLEORESINS Table 47 — Yield of oleoresin as reported in the literature — Continued. Observer Yield of oleoresin to— Date Alco- hol Ace- tone Ether Other solvents Remarks 1912 Vanderkleed . . . . Per cent Per cent Per cent Per cent. J Solvent (?) 117.36 to 24.49 ' Solvent (?) he. 00 to 22.00 j Solvpnt(?) / 21.18 Alcohol and ■( ether 11.10 to 14.70 Reported as yield of oleoresin 1913 Dohme & Engel- hardt Results obtained in the ex- traction of 5 samples of cubebs. Reported as yield of oleoresin. 1913 Vanderkleed . . . . 1914 Riedel 1914 8.87 to 11.04 7.68 to 9.80 Results obtained in the ex- 1914 Scoville J Solvent (?) (18.1010 22.00 J Solvent(?) 113.90 to 19.80 traction of 6 samples of cubebs. Reported as an- hydrous extracts. Reported as yield of oleoresin. 1914 Vanderkleed .... Reported as yield of oleoresin. Results obtained in the ex- traction of 6 samples of cubebs. Table 48 — Yield of oleoresin as obtained in the laboratory. Observer Yield of oleoresin to— Date Alco- hol Ace- tone Ether Other solvents Remarks 1910 1916 DuMez & Netzel. DuMez Per cent 27.09 16.34 Per cent 26.07 16.76. Per cent 23.47 15.28 Percent. j Benzin 1 18.75 ( Petrol \ Ether 1 13.04 Represents the yield using a Soxhlet's extraction app., ex- cept in the case of alcohol. Represents the vield usingr s Soxhlet's extraction app.. ex- cept in the case of alcohol. OLEORBSIN OF CUBEB 143 Chemistry of the Drug and Oleoresin, Tabulation of Constituents. We are indebted principally to Bernatzik^ Schmidt^ and Schulze^ for definite information concerning the constituents of the cubeb fruit. According to these investigators, the con- stituents of importance from a pharmaceutical standpoint are as follows: volatile oil, fatty oil, fat, cubebin, cubebic acid, indifferent resin, coloring matter, starch, gum and inorganic substances. Inasmuch as an attempt to determine the compo- sition of the oleoresin does not appear to have been made since the identification of the above enumerated constitutents, a definite statement concerning its exact composition can not be given.* However, a knowledge of the physical properties of the constituents of the fruit warrants the statement that the following are present in the oleoresin when prepared with alco- hol or ether : Volatile oil Cubebin Coloring matter Fatty oil Cubebic acid (Acid resin) Ash Fat Eesin (Indifferent resin) Occurrence and Description of Individual Constituents Volatile Oil.^ The volatile oil of cubeb is a colorless or pale green, thick fluid possessing a burning, spicy, but not a bitter taste. Its specific gravity varies (0.915 to 0.937 at 15°C) de- pending on the age of the oil after distillation or the length of time that the fruits have been stored before obtaining the oil. It is strongly refractive and is laevogyrate, — 39.45° to iBuchner's n. Repert. f. d. Pharm. (1865), 14, p. 97. a Arch. d. Pharm. (1870), 191, p. 23. »Jhid. (1873, 202, p. 388. The following are among the early Investigators who have reported analy- ses of the fruit: Trommsdorff, Trommsdorff's n. Joum. der Pharm. (1811), 20, p. 69; Vauquelin, Journ. de Chim. Med. (1820), 21, p. 103; Taschenb. f. Scheidekuenst. (1822), p. 185; Monheim, Buchner's Repert. d. Pharm. (1833), 44, p. 199. *Vieth in an article on the relation between the chemical composition and therapeutic activity of various balsams states that Kubebenextrakt consists of terpenes (25 per cent.) resin acids (10 per cent.) and resins (25 per cent.) Verh. d. Ges. deutsch. Naturf. u. Aerzte (1905), 2, p. 364. •The above description is for the volatile oil obtained from the fruits by steam distillation and corresponds to the properties as observed by Schmidt, Arch. d. Pharm. (1870), 191, p. 18. 244 DU MEZ— THE GALENICAL OLEORESINS — 40.16°. Alcohol, ether, carbon disulphide, petroleum ether, chloroform and fatty oils dissolve it readily. The investigation of the composition of this oil has been undertaken by a number of workers.^ Oglialoro^ noted the presence of a small amount of a 1-terpene (pinene or camphene). Wallach^ isolated dipentene and cadinene. The presence of the latter has been confirmed by others.^ Cubeb camphor^'' has also been obtained from certain samples of the oil. It is a sesqui- terpene hydrate (C15H24H2O) which forms when the fruits are stored in a damp place or when the oil is exposed to a moist atmosphere. It separates out in the form of rhombic octahe- drons when the oil is cooled at a low temperature ( - 12 to -14° C) for some time. The yield of the oil is stated by Schimmel & Co.^^ to be from 10 to 18 per cent. A yield as low as 0.4 per cent, has been re- ported.^^ Schmidt obtained 14.215 per cent, from fresh cubebs and 13.041 per cent, from stored cubebs.^^ Fatty Oil. Schmidt^* describes the fatty oil as a thick, dark green liquid congealing at 0°C. It is stated to be slowly but completely soluble in cold alcohol, more soluble in hot alcohol, readily soluble in ether, chloroform, carbon disulphide and fatty oils. The yield as reported by the above investigator is 1.175 per cent, for fresh cubebs and 1.096 per cent, for fruits which have been stored for some time. "The earliest work on the constituents of the oil is that of Soubeiran and Capitaine, Ann. d. Chem. (1840), 34, p. 31. 'Gaz. Chim. Ital. (1875), 5, p. 497. •Ann. d. Chem. (1887), 238, p. 78. »Schaer and Wyss, Arch, d. Pharm. (1875), 206, p. 216; Umney, Pharm. Journ. (1895), 25, p. 951. "Blanchet and Sell, Ann. d. Chem. (1833), 6, p. 294; Winckler, Buchner's Repert. f. d. Pharm. (1833), 45, p. 397; Bernatzik, Buchner's n. Repert. f. d. Pharm. (1865), 14, p. 97; Schmidt, Ber. d. deutsch. chem. Ges. (1877), 10, p. 188. "Schimmel & Co., Ber. (1897), p. 14. "Busse reports the yield of volatile oil as obtained by various investi- gators as follows : Baumfe 5.3 per cent. Schoenwald 7.03 per cent. OberdoerfPer 12.5 per cent. Hager 0.4 per cent. Busse 15. per cent. Arch. d. Pharm. (1844), 89, p. 30. "Ibid. (1870), 191, p. 18. **Ihid., p. 34. ; . ', OLEORESIN OF CUBEB 145 Fat. Schmidt^^ obtained 0.511 per cent, of a semi-solid fat from fresh cubebs, 0.408 per cent, from old cubebs. It is stated to be of ointment-like consistence, melting at 30 to 32° C. Hot alcohol, ether, carbon disulphide, chloroform, benzene and petroleum ether dissolve it readily. It is reported to be insoluble in cold alcohol. Cuhehin}^ Cubebin crystallizes from alcohol in white, odor- less needles melting at 125 to 126°C (Schmidt), ^^ 132°C (Mameli).^^ The alcoholic solution has a bitter taste. It is only slightly soluble in cold alcohol, quite soluble in hot alcohol, readily soluble in ether, chloroform, carbon disulphide, glacial acetic acid, fatty and volatile oils. The chloroformic solution is laevogyrate. Concentrated sulphuric acid dissolves it with a purple violet color, a reaction which is used as test for the identity of the cubeb fruit and the oleoresin prepared therefrom. Cubebin was thought by Heldt^^ to be an oxidation product of the sesquiterpene constituent of the volatile oil, 2 C15H24 -f 18 P = C30H30O9 + 9 H2O. Later work on the determination of its structure, however, has shown this theory to be untenable. The following structural formulas have been brought forward to represent its composition. CCHiCHCK&Tf HC|^ A^.„ "< ^\ '\X. F.nn«lirt|it«t«tt"" « Ibid. "Monheim, Buchner's Repert. f. d. Pharm. (1833), 44, p. 199; Cassola, Journ. d. Chim. Med. (1834), 10, p. 685; Soubeiran and Capitaine, Journ. de Pharm. et de Chim. (1839), 25, p. 355; Ann. d. Chem. (1840), 34, p. 323; Steer, Buchner's Repert. f. d. Pharm. (1838), 11, p. 88; Ibid. (1840), 20, p. 119; Schuck, Buchner's n. Repert. f. d. Pharm. (1852), 1, p. 213; En&el- hardt, Ibid. (1854), 3, p. 1; Bernatzik, Ibid. (1865), 14, p. 97; Schmidt, Arch. d. Pharm. (1870), 191, p. 1; Weidel, W^ien. Akad. Ber. (1878), 74, p. 377. " I. c. "Chem. Ztg. (1908), 32, p. 46. "Arch, der Pharm. (1870), 191, p. 23. *>Monatsch. f. Chem. (1888), 9> p. 323. 146 ^U MEZ— THE GALENICAL OLEORESINS CH CH HC ^ C-(Qa(OH)J-C CH (21) Fonnula of Mameli Cubebin occurs in the fruit to the extent of about 2.5 per cent.^^ Ciihehic Acid. (Acid Resin) Cubebic acid, C13H14O71 (Schmidt) ,f C28H30O7H2O (Schulze),-* was first described by Bernatzik. It is a white, resinous mass melting at 56 °C (Schmidt), 45° C (Schulze) and becoming brown on exposure to the air. It shows only a weak acid reaction. Alcohol, ether, ammonia and the caustic alkalies dissolve it readily. There is a considerable variation in the cubebic acid content of the fruit as reported in the literature. Schmidt^^ obtained 0.96 per cent, from fresh cubebs and 1.16 per cent, from the fruit which had been stored. Bernatzik reports the presence of 3.458 per cent.^^ Resin. The so-called indifferent resin, CisHj^Os (Schmidt)^'' is a yellowish-brown, pulverulent mass readily soluble in alcohol and the caustic alkalies, but only slightly soluble in ether, chloro- form and carbon disulphide. The indifferent resin occurs in the fruit to the extent of about 3 per cent, on the average.^® Coloring Matter, Schmidt^^ isolated a brown amorphous sub- stance to which he attributes the brown color. This substance is stated to be soluble in dilute alcohol and solutions of the alka- ML C. "Monheim obtained 4.5 per cent, of a resin resembling piperine which he designated cuheMn. Buchner's Repert. f. d. Pharm. (1833), 44. p. 199. Schmidt reports the presence of 2.484 per cent, in fresh cubebs and 2.576 per cent, in cubebs kept in storage for some time. I. c. MZ. c. "Arch. d. Pharm. (1873), 202. p. 388. »I. c. "Buchner's n. Repert. f. d. Pharm. (1865), 14, p. 97. «l. .c » Schmidt observed the presence of 2.258 per cent .of indifferent resin in the fresh fruits, 2.968 per cent, in stored fruits, I. c. Bernatzik obtained 3.515 per cent, of this resin, I. c. »l. c. OLEORESIN OF CTJBEB 147 lies. The green color of the fatty oil as observed by the same investigator is stated to be due to chlorophyll. Asli. According to E. Schmidt, ^^ the ash of the cubeb fruit is composed of the basic elements, K, Ca, Mg, and Fe in combina- tion with the acid radicles CI', SO/', PO/", CO3" and SiOa'', also free SiOs- Cubeb fruits yield about 5.5 to 6.0 per cent, of ash.^^ Constituents of Therapeutic Importance. The value of the oleoresin of cubeb as a therapeutic agent is very probably due to its resin content. In addition to its diuretic action, the acid resin is said to render the urine feebly antiseptic and to act as an astringent.^ Cubebin has been shown to be physiologically inactive passing through the intestines unabsorbed.- The volatile oil is stated to act merely as a car- minative^ and its presence is even considered by some to be un- desirable* owing to its irritating action. Physical Properties Ash. According to E. Schmidt,^^ the ash of the cubeb fruit is directed by the United States Plmrmacopoeia has a grass-green color when spread out in a thin layer on a white porcelain sur- face. The commercial product, however, is often brownish-green or brown in color due to the use of the ripe fruit^ in its manu- facture. In such cases, the desired green color is sometimes im- parted to the preparation by the addition of copper salts.* Odor: The oleoresin has a strong aromatic odor like that of the crushed cubeb fruit. In fact, the odor is so strongly aro- matic that unevaporated solvent (alcohol), even when present in considerable amounts, cannot be detected by the sense of smell. so Arch. d. Pharm. (1870), 191, p. 11. "Schmidt obtained only 3.36 per cent of ash, I. c. Warnecke reports the yield of ash as 5.45 per cent. Pharm. Ztg. (1886), 31, p. 536. LaWall and Bradshaw give the ash content of two samples of cubeb as 5.70 and 6.10 per cent., respectively. Proc. A. Ph. A. (1910), 58, p. 751. ^Vieth, Med. Klin. (1905), p. 1276. •HefCter, Arch. f. Exp. Path. u. Pharm. (1895), 35, p. 871. « Heydenreich, Am. Journ. Pharm. (1868), 40, p. 42. *Bematzik, Buchner's neues Repert. (1865), 14, p. 97. » See under "Drug used, its collection, preservation, etc." •B6dall (1894). 148 DU MEZ— THE GALENICAL OLEORESINS Taste: The taste is bitter and somewhat spicy, like that of cubeb, only more pronounced. Consistence: The oleoresin is, as a rule, a rather thin liquid when compared with the other members of this class of prepara- tions. Its consistence, however, varies to a considerable extent owing to a difference in the volatile oil content.^ Some of the preparations examined in the laboratory were so thick that they could only be poured with difficulty. Solubility: The official preparation forms clear or slightly cloudy solutions with alcohol, acetone, ether, chloroform, carbon disulphide, and glacial acetic acid. It is almost completely soluble in petroleum ether. The solubility of the European product, which is usually prepared with a mixture consisting of equal parts of alcohol and ether, is about the same. Specific gravity: The oleoresins prepared in the laboratory in 1916 showed a specific gravity of 0.99 + at 25° C regardless of whether the solvent employed in extracting the drug was alcohol, acetone or ether. The uniformity is attributed to the fact that particular pains were taken to evaporate the solvent under the same conditions in each case, thereby insuring approximately the same volatile oil content for each of the finished prep- arations. The variation in specific gravity due to a difference in volatile oil content is shown in the data given for the first four of the laboratory preparations. The commercial samples examined also show a variation due to this influence, except, in the case of the low specific gravity observed by Procter, which was stated to be due to the presence of unevaporated solvent (ether). Tables illustrating these points follow: Table 49 — Specific gravities of laboratory preparations. Sample No. Date Observer Solvent Specific gravity 1 1866 1910 1916 Procter Alcohol At 76° F 0.985 2 Ether 0.967 3 «' Benzin 932 1 DuMez & Netzel Alcohol At 25° C 980 2 Acetone 0.994 3 ♦> Ether 985 1 DuMez Alcohol 1.049 (1) 0.994 2 3 •• Acetone Ether ... 999 4 •» 998 5 '• Petrol, ether 963 *A thick preparation containing only 4.71 per cent, of volatile matter. See under "Chemistry of the drug and the oleoresin". OLEORBSIN OF CUBEB 149 Table 50SpeciJlc gravities of commercial olcoresins. Sample No. Date Observer Source Specific gravity 1 . 1866 1916 At 76° F. 0.900 (»> 1 DuMez Lillv & Co At Z'y° C. 0.968 2 Squibb & Sons 0.969 3 »» Parke, Davis & Co Sharp & Dohme Stearns & Co 0.971 4 •' 0.975 5 •» ' 1.017 ^ Contained ether. Refractive index: The results obtained in the laboratory in- dicate that the refractive index of the oleoresin should be about 1.499 when determined at 25 °C. The solvent employed in ex- tracting the drug appears to have little influence on this con- stant, except in case petroleum ether is used, when it is slightly lower. The effect due to variation in volatile oil content is but slight as is shown in the tables which follow: Table 51. — Refractive indices of oleoresins 'pre'pared in the laboratory. Sample No. Date Observer Solvent Refractive index 1 1910 1916 DuMez & Netzel Alcohol A cetone At25°C 1.495 2 1.499 3 " Ether 1.499 1 DuMez Alcohol 1 .502 (>> 2 Alcohol 1 500 3 " Acetone ,... '.500 4 !!!!.!!!!!!!!!!!!!!! Ether 1.499 5 Petrol ether 1.495 (*) Low in volatile oil content. Table 52 — Refractive indices of commercial oleoresins. Sample No. Date Observer Source Refractive index 1 1916 DuMez Lilly & Co At 25° C 1.498 2 1.499 3 " Parice. Davis «& Co 1 499 4 " 1.499 5 " Stearns & Co 1 501 150 DU MEZ— THE GALENICAL. OLEORESINS Chemical Properties. Loss in weight on heating: An examination of the tables which follow shows that the oleoresin usually loses between 20 and 40 per cent, on heating at 100 to 110° C, the variation being due to the difference in the volatile oil content. The relatively small loss in weight observed in the case of four of the laboratory preparations is to be attributed to the removal of a part, or the whole, of the more volatile constituents of the essential oil in the process of evaporating the solvent. The com- paratively great loss noted for two of the commercial samples is thought to have been due to the presence of unevaporated solvent. The results obtained in the determinations made in the laboratory as well as those reported in the literature are given in the tables which follow : Table 53. — Laboratory preparations — loss in weight on heating. Sample No. Date Observer Solvent Per cent of loss on drying 1 1887 1916 Kremel Alcohol At 100° C 20.40 1 DuMez Alcohol At 110° C 23.06 ■2 Acet/Oiie 24 10 3 " Ether 25.88 4 *' ::. ..::.■;:::::: :::: Petrol ether 25 . 24 5 11.99 4 Xcerone 9-96 7 " Ether 8.81 8 Alcohol 4.71 Table 54 — Commercial oleoresins — loss in weight on heating. Sample No. Date 1893 1.S94 1895 1905 1916 Observer Source Per cent of loss on drying' 1 Dieterich At 100° C 32.70 1 31 OJ 1 i» 20 90 I «' 55.91(1) I DuMez Sharp & Dohme At 110° C 30 72 2 31.68 3 Parke. Davis & Co 37 03 4 Lilly & Co 44.21 (1) 5 Squibb & Sons 61.96 (') * Probably contained unevaporated solvent (alcohol). OLEORESIN OF CUBES 151 Ash content: The ash content of the oleoresin varies with the solvent employed in its preparation as is shown in the first of the tables which follow. The highest values were obtained for the official product, in the preparation of which alcohol was the solvent used. The camparatively low ash content ob- tained for the commercial samples examined, while suggesting the use of some other solvent in the manufacture of these preparations, is thought to have been due to the greater amount of volatile matter (essential oil) present. Although copper was detected in the ash of all of the commercial products, the quantities present were too small to effect the value of this constant to any considerable extent. The following tables give the ash content of the oleoresin as reported in the litera- ture and as determined in the laboratory: Tablb 55. — Ash contents of oleorexins prepared in the laboratory. Sample No. Date Observer Solvent Per cent of ash 1 1916 DuMez Alcohol Acet»jne Ether 45 0.20 " 0.13 •' 0.07 •• Alcohol 48 ^ '• 22 " Fther 15 8 '• Alcohol 51 Table 5G — Ash contents of commercial oleoresins. Sample No. Date Observer Source Percent, of ash Forelgrn crm- stituents 1893 1894 1895 1897 1905 1916 Dieterich . . . Du Mez ....... 50 0.52 0.47 0.10 0.87 21 (') 0.40 35 0.''9 (1) 0:37 •' •» 1 •' Squibb & Sons Copper 2 Sharpe & Dohme " Lilly & Co '• Stearns&Co >> * Unevaporated solvent (alcohol) probably present. Acid number: The acid numbers of the oleoresins prepared in the laboratory varied from 21.8 to 26.7, depending on the nature of the solvent employed in their preparation. The num- 152 DU MEZ— THE GALENICAL OLEORESINS / ber, 26.7, obtained in the case of the preparation made with alcohol agrees very well with that (26.2) obtained by Kremel for the oleoresin when prepared in a like manner. The low acid numbers obtained for the commercial samples are explained by the presence of relatively large amounts of volatile matter (generally essential oil, but unevaporated solvent in two cases) in these preparations, which has the effect of reducing the con- centration of the free acids. The values obtained for this constant follow: Table 57. — Acid numbers of laboratory preparations. Sample No. Date Observer Solvent Acid number 1 1887 1916 Kremel 26.2 2 Ether 31.2 1 DuMez . Alcohol 26 7 2 22.8 3 " Ether 22 2 4 21.8 Table 58 Acid numbers of commercial oleoresins. Sample No. Date Observer Source Acid number 1. 1916 DuMez Lilly «& Co 12.8(1) 2 SQuibb & Sons 13.4(1) 3.!..!.... " Stearns & Co 14.4 4 " Parke, Davis &Co Sharp & Dohme — 15.4 5 " 18.7 (>) Probably contained unevaporated solvent (alcohol), Saponification value: The saponification values obtained for the oleoresins prepared in the laboratory showed a slight variation due to the nature of the solvent used in extracting the drug as is shown in the first of the tables which follow. As a rule, however, the difference in the volatile oil content of the oleoresin, due to a variation in the conditions under which it has been prepared, is thought to be the principal factor in- fluencing the value of this constant, as is also brought out in the first table. In the examination of commercial samples, the presence of unevaporated solvent must be taken into considera- OLEOKBSIN OF CTJBEB 153 tion in this connection. The results obtained in the determina- tion of this constant in the laboratory follow: Table 59 — Saponification values of oleoresins prepared in the laboratory. Sample No. Date Observer Solvent Saponifica- tion value 1 1916 1' DuMez Alcohol Acetone 65.9 2 63.7 3 4« Ether 63.4 4 Petrol, ether 67.0 " Alcohol 63.9 2 57.9 3 t» Ether 59.5 1 105.9 (0 1 This preparation contained a relatively email amount of volatile matter (principally essential oil). See page 1056 under "Loss in Weight on Drying". Table 60. — Saponification values of commercial oleoresins. Sample No. Date Observer Source Saponifica- tion value 1 1916 DuMez Lillv& Co 48.5 (0 2 Parice. Davis & Co SQuibb & Sons 53.3 3. . " 49.3 {}) 4 i> • •• 55.0 5 •» Stearns & Co 65.9 i}) Unevaporated solvent (alcohol) probably present. Iodine value: Further observations are necessary before a definite statement can be made as to what the iodine value of this preparation should be. Determinations made in the labora- tory appear to indicate that it is influenced largely by the volatile oil content as those preparations which lost the greatest amount on drying usually gave the highest values for this con- stant. Apparent exceptions to this rule are to be found in the samples obtained from Lilly & Company and Squibb & Sons, respectively. In these cases, unevaporated solvent (alcohol) is thought to have been present, although, it could not be detected by the odor. The following tables show the values obtained for the preparations examined in the laboratory. 154 DU MEZ— THE GALENICAL OLEORESINS Table 61 — Iodine values of oleoresins prepared in tlie laboratory. Sample No. Date Observer Solvent Iodine value 1916 DuMez Alcohol 126 131.6 Ether 138.5 Petrol, ether Alcohol 141.8 130.0 113.2 Ether 115.6 J Alcohol 92.0 Table 62 — Iodine values of commercial oleoresins. Sample No. Date Observer Source Iodine value J 1916 DuMez Squibb & Sons 130.61 2 Lilly & Co 136.71 3 •» Parke, Davis & Co Sharp & Dohme 146.9 4 " 147.3 5 »• Stearns & Co 147.6 ^ Unevaporated solvent probably present. Ofher Properties. The oleoresin, upon long standing, forms a white deposit consisting of cubebin, indifferent resin, cubebic acid and thick- ened oil. As the greater part (80 per cent.)^ of this precipitated material consists of the therapeutically inert ciibebin,^ the United States PJiarniacopceia directs that it be removed before dispensing the preparation. Special Qualitative Tests. The methods which have been devised for the indentification of this oleoresin or as a test for its quality are based on the fact that characteristic color changes are produced when it is acted upon by certain acids. Sulphuric, sulphomolybdic^ and 1 Schmidt (1870). ^ See under "Constituents of therapeutic importance", ' Dieterich, in 1897, pointed out that sulphomolybdic acid might be used in place of sulphuric acid. The resulting color, however, was stated to be a cherry-red instead of a blood-red. OLEORBSIN OF CUBEB 155* hydrochloric^ acids have been made use of in this connection, the first mentioned being the reagent most generally employed. Attention was first called to the value of sulphuric acid in the identification of this preparation by Kremel in 1887. He,. however, reported nothing definite, merely stating that a car- mine-red color was produced when the ''strong'* acid and oleoresin were mixed. It was not until ten years later (1897), when the firm of Dieterich in Helfenberg published their method- of procedure, that this test assumed a definite form. The test as carried out by this firm is typical of those in use at the present time and is as follows: Upon mixing 0.01 gram of the oleoresin with 3 to 5 drops of concen- trated sulphuric acid, the mixture should assume an intense blood-red color." The fact that certain constituents of the cubeb fruit, namely,, cubebin, the acid resin (cubebic acid) and the indifferent resin, formed red colored mixtures with sulphuric acid was noted by Schmidt in 1870. These observations have been confirmed in this laboratory in so far as they pertain to the production of a red color. It was further noted, however, that the shade of red varies with the particular constituent under consideration, the cubebin giving rise to a mixture which is brownish-red in •color, whereas, the color is bright red (carmine-red) in the case of the acid or indifferent resin. As all of the above mentioned constituents are normally present in the oleoresin, the particular shade of red (blood-red) obtained in this test must be due to- the blending of the colors produced by the action of the acid' on the several constituents, and cannot be caused by the action of the acid on the cubebin, alone, as is usually reported in the literature. As the shade of red obtained will naturally vary with the relative quantities of the several constituents present, this test not only serves as a means of identification, but is also of value in determining roughly the quality of the preparation as well.* Thus, a bright red color obtained by the action of the acid may 1 Test of Gluecksmann. See the following pages. 2 The so-called false cubebs give a dirty brown color when triturated with concentrated sulphuric acid, hence, we may expect the oleoresin prepared therefrom to form a mixture of a similar color. See Pharm Ztg. (1912)^ 84, p. 845. * B^dall (1894) observed that the oleoresins possessing a green color gave a more intense red with sulphuric aeid that those which were brown in color. 156 DU MEZ— THE GALENICAL. OLEORESINS be taken as an indication of the presence of relatively large amounts of the therapeutically active resins, while a dark shade of red implies that the cubebin content is exceptionally large or that the resins are present in comparatively small amounts. The test of Gluecksmann (1912) in which hydrochloric acid is the reagent made use of, appears to be based on the presence of cubebin.^ It is carried out as follows: Dissolve a small quantity (a trace) of the oleoresin in concentrated acetic acid and dilute with the latter until the solution shows scarcely any color. Heat to boiling and add 5 drops of a 35 per cent, solution of hydrochloric acid to a 5 cubic centimeter portion. A faint yellowish-brown color should appear immediately. Upon standing quietly, the color should change in 2 to 4 hours to a brownish-violet, and then to a violet blue, after which it should gradually disappear. While the foregoing may prove to be a test of considerable worth in the identification of the oleoresin, the length of time required for its completion would appear to be a drawback to its general application. The tests of this nature prescribed by the various phar- macopoeias all involve the use of sulphuric acid. As will be- come apparent in the following description of these methods, the color specified differs to a considerable extent. This may "be due, as already pointed out, to a variation in the relative quantities of the reacting constituents, or, as has been further observed in the laboratory, to the strength of the acid employed. A very slight dilution with water will cause the color to change from red to purple. The following are the tests prescribed by the different pharmacopoeias: Austrian Pharmacopoeia (1906) : The oleoresin should give a red color on being triturated with concentrated sulphuric acid. French Pharmacopoeia (1908) : The oleoresin should give a purple-red -color with concentrated sulphuric acid. Swiss Pharmacopoeia (1907) : If 0.01 to 0.02 grams of the oleoresin are mixed with a few drops of concentrated sulphuric acid, an intense brownish-red color should be produced. Upon diluting with a little water, The color should change to a rose and upon further dilution, it should disappear. Hungarian Pharmacopoeia (1909) : A drop of concentrated sulphuric * This assumption is made in view of the fact that the closely related •compounds, coniferyl alcohol and syringenin, give similar color reactions 'With hydrochloric acid. See Euler, Die Pflanzenchemie (1908), Vol. I, p. 87. OLEORESIN OF CUBES 157 acid added to a drop of the oleoresin spread out in a thin layer on a white porcelain surface should produce a blood -red mixture. German Pharmacopoeia (1910) : If 1 cubic centimeter of a mixture of 4 parts of concentrated sulphuric acid and 1 part of water is poured over 1 drop of the oleoresin, a red color should be produced. Upon diluting the mixture with water the color should disappear. Special Quantitative Tests. Apparently but one attempt has been made to develope a method for the quantitative determination of the constituents of therapeutic importance in this preparation, the same having" been made by Kremel in 1887. As no work of this nature was done on the oleoresin in the laboratory, and, as there is no further information on this subject in the literature, a state- ment cannot be made as to the value of this method. However,, as a suggestion of what might be accomplished in this direction, a description of the method is included here. It is as follows : KremeVs Method for the Estimation of Cuhehic Acid (1887) : Dissolve 3 to 5 grams of the oleoresin in 4 times the quantity of alcohol (90 per cent.), filter the solution and add alternately to the filtrate an alcoholic solution of calcium chloride and ammonia water until a distinct cloudi- ness appears. Set the liquid aside for a day or two to allow the cal- cium salt of cubebic acid to crystallize. Then, collect the precipitate on a filter, wash successively with alcohol (90 per cent.) and ether, dry at lOO'C and weigh. Compute the weight of the cubebic acid using the formula, C H O Ca, for the calcium salt. According to the results obtained by Kremel, the oleoresin prepared with ether shsowed a cubebic acid content of 2.35 per cent., while the same when prepared with alcohol gave 5.75 per cent, of cubebic acid. Adulterations, Willful adulteration of this preparation does not appear to be practiced very extensively, although, the occassional use of fixed oils^ or salts of copper^ for this purpose has been reported ' Schneider and Suess, Handkommentar zum Arzneibuch fuer das deutsche Reich (1902), p. 376. »B6dall (1894). A trace of copper is usually present in the commercial preparations as a result of the use of copper utensils in their manufacture. (See under "Ash".) ^58 ^U MEZ— THE GALENICAL. OLEORESINS in the literature. On the other hand, accidental adulteration ■effected through the use of ripe instead of unripe fruits in the preparation of the oleoresin is thought to be quite general. «(See under ''Drug used, its collection, preservation, etc.") OLEORESIN OF GINGER Synonyms Aetherisches Ingwerextrdkt, Nat. Stand. Disp. 1884. Ethereal Extract of Ginger, King's Am. Disp., (1900), p. 1336. Extractum Zingiheris aetJiereum, Hirsh, Univ. P. 1902, No. 1320. Extractum Zingiberis aethereum, King's Am. Disp. (1900), P. 1336. Gingerin, Chem. and Drugg. (1913), 82, p. 470. Gingerine, Am. Journ. Pharm. (1898), 70 p. 466. Oleoresina Zingiberis, U. S. P. 1910. jQl^oresine de Gingemhre, U. S. Disp. 1907. Piperoide du Gingerribre, B§ral, 1834. .Piperoid of Ginger, U. S. Disp. 1865. Zingiberin, U. S. Disp. 1907. History The oleoresin of ginger was prepared in 1834 by Beral, a ^Frenchman, but was apparently first brought to the notice of American pharmacists by Proctor in 1849. It was intro- duced into the United States PJiarmacopma in 1860 and is still official at the present time. While the oleoresin has never been officially recognized abroad, a similar preparation is said ito be used extensively in England under the name of gingerin.^ Drug Used, Its Collection, Preservation, Etc. For this drug, the present pharmacopoeial definition is as follows: "The dried rhizomes oi Zingiber officinale Jioscoe (Fam. Zingiber aceae,) the outer cortical layers of which are often either partially or completely removed. Preserve it in tightly-closed containers, adding a few drops of chloroform or carbon tetrachloride, from time to time, to prevent attacks by insects.'^ The official drug has also been described in the literature under the following botanical synonyms: Amomum Zingiber Linne, and Zingiber Zingiber (Linne) Rusby. * Gingerin is stated to be the extract obtained upon evaporating off the •alcohol from the tincture of. ginger. Chem. & Drugg, (1913), 82, p. 470. OLEORESIN OF GINGER 159 The rhizomes as they are found on the market occur in a variety of forms characteristic of the source from which they are obtained. In view of this fact, the Pharmacopoeia recog- nizes six different commercial varieties, namely : Jamaica ginger, African ginger, Calcutta ginger, Calicut ginger, Cochin ginger and Japanese ginger. These commercial forms differ to a considerable extent, not only through natural causes, but also through a difference in the conditions under which they are harvested and prepared for the market. As a rule the rhizomes are dug after the stems have withered, January or February, when one or more years old. Experience has shown the oleoresin content to be the greatest at this period of the year.^ They are then washed in boiling water to pre- vent germination, dried rapidly in the sun, and as such con- stitute, what is known as black, coated, or unscraped ginger. In other cases, after treatment with boiling water, a part or the whole of the epidermis is removed, the rhizomes dried, and bleached with sulphur fumes, chlorinated lime, milk of lime or gypsum. This constitutes the so-called, white, uncoated, scraped, race or hard ginger. ^ In commenting on the relative values of these various forms of ginger in the preparation of the oleoresin, it should be stated, first of all, that the yield of oleoresin is influenced to the largest extent by habitat, African ginger giving the maximum yield.® Secondly, the extent to which the rhizomes have been decorticated is an important factor, as the outer corky layer contains none of the oleoresinous material. These factors will be more fully discussed under yield. To what degree, if at all, the process of so-called bleaching effects the yield or quality of oleoresin does not become apparent from the literature. It is thought, however, that a heavy coating of gypsum, for instance, would tend to considerably reduce the percentage of oleoresin ob- tainable. * Hooper, Fharm. Joum. (1912), 89, p. 391. ' Culbreth, Mat. Med. and Pharmacol. (1917), p. 130. » See reference under "Yield of oleoresin". 160 DU MEZ— THE GALENICAL. OL.EORESINS V. S. P. Text and Comments Thereon. The oleoresin of ginger first became official in the Pharmaco- poeia of 1860. It has remained official throughout all of the? subsequent editions. 1860 Oleoresina Zingiberis Oleoresin of Ginger Take of ginger/ in fine powder,* alcohol until twelve fluidounces ^ of twelve troyounces; filtered liquid have passed. Eecover Stronger Ether ^ twelve fluidounces; from this, by distillation on a water- Alcohol* a sufficient quantity. bath, nine fluidounces of ether,' and Put the ginger into a cylindrical expose the residue, in a capsule, until percolator," press it firmly, and pour the volatile part has evaporated.* upon it the stronger ether." When this Lastly keep the oleoresin in a well- has been absorbed by the powder, add stopped bottle." 1870 Oleoresina Oleoresin Take of ginger,* in fine powder,* twelve troyounces; Stronger Ether' twelve fluidounces; Alcohol* a sufficient quantity. Put the ginger into a cylindrical percolator, provided with a stop-cock, and arranged with a cover and recep- tacle suitable for volatile liquids,' press it firmly, and pour upon it the Zingiberis of Gringer stronger ether.* When this has been, absorbed by the powder, add alcohol until twelve fluidounces of liquid have slowly passed.' Eecover from thia the greater part of the ether by distilla- tion on a water-bath,' and expose the residue, in a capsule, until the volatile part has evaporated.* Lastly, keep the oleoresin in a well-stopped bottle.*" 1880 Oleoresina Oleoresin Ginger,* in No. 60 powder,* one hun- dred (100) parts 100 Stronger Ether,' a sufficient quantity. Put the ginger into a cylindrical percolator, provided with a cover and receptacle suitable for volatile liquids," press it firmly, and gradually pour stronger ether upon it, until one hun- dred and fifty (150) parts of the Zingiberis of Ginger liquid have slowly passed, or until the Ginger is exhausted.' Eecover the greater part of the ether by distilla- tion on a water-bath,' and expose the residue, in a capsule, until the remain- ing ether has evaporated.' Keep the oleoresin in a well-stopped bottle." OLEORBSIN OF GINGER 1890 Oleoresina Zingiberis Oleoresin of Ginger Ginger/ in No. 60 powder,^ five hun- portions, until the drug is exhausted.* dred grammes 500 Gm. Eeeover the greater part of the ether Ether,^ a sufficient quantity. from the percolate by distillation on Put the ginger into a cylindrical a water-bath,» and, having transferred glass percolator, provided with a stop- the residue to a capsule, allow the re- cock, and arranged with cover and maining ether to evaporate spontaa- receptacle suitable for volatile liquids." eously." Press the drug firmly, and percolate Keep the oleoresin in a well-stop- slowly with ether, added in successive pered bottle.^" 1900 >; Oleoresina Zingiberis ' Oleoresin of Ginger Ginger,* in No. 60 powder,' five hun- is exhausted.^ Eeeover the greater dred grammes 500 Gm. part of the acetone from the percolate Acetone,^ a sufficient quantity. by distillation on a water-bath,« and, Introduce the ginger into a cylindri- having transferred the residue to a cal glass percolator, provided with a dish, allow the remaining acetone to* stop-cock, and arranged with a cover evaporate spontaneously in a warmi and a receptacle suitable for volatile place.* Keep the oleoresin in a well- liquids." Pack the powder firmly, and stoppered bottle." percolate slowly with acetone, added Average dose. — 0.030 Gm. = 3(r in successive portions, until the ginger milligrammes (% grain.) 1910 Oleoresina Zingiberis Oleoresin of Ginger Oleores. Zingib. Ginger,* in No. 60 powder,'' five hun- hausted.' Eeeover the greater part dred grammes 500 Gm. of the ether from the percolate bj Ether,' a sufficient quantity. distillation, on a water-bath,* and, Place the ginger in a cylindrical having transferred the residue to a glass percolator, provided with a stop- dish, allow the remaining ether to cock and arranged with cover and a evaporate spontaneously in a warm receptacle suitable for volatile liquids." place.* Keep the oleoresin in a well- Pack the powder firmly, and perco- stopped bottle.** late slowly with, ether, added in sue- Average dose. — Metric, 0.03 Gm.^ eessive portions, until the drug is ex- Apothecaries, % grain. 162 ^^ MEZ— THE GALENICAL. OL.EORESINS 1) For a description of the different commercial varieties of the official drug, see page 1065 under ''Drug used, its collection, preservation, etc." 2) As starch, in the shape of fine granules, constitutes about 20 per cent, of the ginger rhizome, the latter can only be ob- tained in the form of a uniformly fine powder by reducing the other tissues to a corresponding degree of fineness. It is for this reason and for' the purpose of insuring the complete breaking up of all of the small resin cells that the Pharma- •copoeia directs that the drug be reduced to a No. 60 powder. 3-4) Ether is the solvent which appears to be best adapted to the preparation of this oleoresin in that it completely extracts the pungent principles from the drug and yields a product containing a minimum amount of undesirable extractive mat- ter. According to Garnett and Grier (1909) acetone, which "was directed to be used by the Pharmacopoeia of 1900, does not completely exhaust ginger, even when a Soxlet's appara- tus is used. It is, therefore, fortunate that the present Phar- macopoeia again specifies that ether be used for this purpose. In the earlier editions of the Pharmacopoeia (editions of 1860 and 1870), alcohol was directed to be used as a "follow lip" solvent to replace the ether with which percolation was begun. This procedure was abandoned in 1880 for reasons which will be discussed later. 5) Since 1870, the Pharmacopoeia has directed that percola- tion be carried out in a special form of percolater adapted to the use of volatile liquids. For a description of such forms, see Part I under ''Apparatus used." 6-7) The method of extracting the drug as outlined in the earlier editions of the Pharmacopoeia, the editions of 1860 and 1870, was essentially the same as suggested by Beral in 1834. See Part I, page 929. From' a practical standpoint, this method possessed distinct advantages, especially at the time when it was adopted, in that a considerable saving in the cost of the preparation of the oleoresin was effected through the use of alcohol as a "follow up" solvent for replacing the relatively expensive ether. The method, however, was not entirely sat- isfactory as the finished product contained a considerable amount of undesirable extractive matter owing to the greater •solvent properties of the alcohol. Another disadvantage lay OLEORESIN OF GINGER 153 in the fact that a relatively large amount of volatile oil was lost in the removal of the solvent. The present edition of the Pharmacopoeia directs that the drug be completely exhausted by simple percolation with ether. Here, as in the case of the oleoresin of capsicum, the extraction of the drug with the aid of some form of continu- ous extraction apparatus would effect a considerable saving in solvent and without injury to the finished product. 8-9) With respect to the removal of the solvent from the per- colate, the present edition of the Pharmacopoeia directs that this be accomplished in greater part by distillation on a water bath and that the remainder be allowed to evaporate spon- taneously in a warm place, a procedure similar to that de- scribed in the earlier editions. For reasons, identical with those given in the comments on the oleoresin of cubeb (see page 1045), it is thought that the pharmacopoeial directions should include specific statements with reference to the amount of solvent to be recovered by distillation and the tem- perature at which the remainder is to be removed in order to insure greater uniformity in the product obtained. 10) Upon exposure to the air, a portion of the volatile oil con- tained in the oleoresin is altered (resinified) or lost through evaporation. The preparation should, therefore, be kept in well-stoppered bottles. Yield With respect to the solvents, alcohol (95 per cent.), acetone and ether, the yield of oleoresin, in the case of ginger, varies in magnitude in the order in which the solvents are mentioned. For these menstrua, a minimum yield of 2.57 per cent has been reported while the maximum yield has been stated to be as high as 11.1 per cent. . When petroleum ether is the solvent used, the yield is much lower, being only about one-half that obtained in the preceding cases. In this connection, the source of the rhizomes is a factor of first importance. Thus, it has been found that Jamaica ginger usually gives the smallest yield and African ginger the highest, while Cochin ginger occupies an intermediate position in this respect. These facts will be brought out more clearly in the tables which follow. -^Q^ DU MEZ— THE GALENICAL. OLEORESINS The yield of oleoresin is further influenced by the degree to which the rhizomes have been deprived of the outer corky layer, and, in the case of bleaching, to the manner in which the latter was accomplished. "With respect to this statement, the yield, in the case of the unbleached ginger, will be the greatest when decortication is complete. When the rhizomes have been bleached, in addition to being partially or wholly decorticated, the influence of the latter, may be diminished, in part at least, by the process employed in accomplishing the f onner. Thus, if gypsum or lime have been used for this purpose, the weight of the insoluble material in the rhizomes will be considerably in- creased, which will have the effect of reducing the percentage yield of oleoresin. These points are also brought out in the tables which follow. OLEORESIN OF GINGER 165 Table 63. — Yield of oleoreain as reported in the literature. Date 1834 Observer Yield of oleoresin to— Alco- hol Ace- tone Ether Other solvents Remarks B6ral Per ct. Per ct. Per ct. 5.20 3.29 4.96 8.06 3.58 Per cent. 1879 .Tamaica ginger. Cochin *' .Tones 1886 3.38 fAlco- 1 hoi |( sp. 1 gr. 1 0.82) \ 5.00 1 4.80 1 6.65 6 57 6.17 I 7.00 1888 Siggnis Jamaica ginger, unbleached. '* *' , bleached Trimble (limed) East Indian ginger. African ginger. 18S8 3.97 i Benzin 1 2.48 3 Benzin 1 2.50 1891 Rlegel 5.00 8.00 Jamaica ginger, unbleached. East Indian ginger, epidermis Sherrard 8.00 3.85 4.72 5.20 5.40 1892 removed. Beringer 1892 5.57 1893 Dyer and Gilbard Davis 3.00 to 5.20 4.30 to 4.84 5.75 to 6.27 5.50 5.00 4.33 6.33 2.57 to 6.41 2.97 to 4.60 Upon subsequent extraction 1895 with alcohol 0.80 to 1.50 per cent, of material was ob- tained. Jamaica ginger. African " 1896 I Methyl \ alcohol \ 6.50 1S97 Glass and Thresh .Jamaica ginger. r Alco- hol (90 per cent.) 3.94to 5.61 3.41to ,5.67 4.91to 6.74 5.4110 6.51 5.14to 6.61 5.14to 16.47 Cochin African IdOl Jamaica ginger, whole. Ballard •Jamaica ginger, ground. Cochin ginger, whole. Cochin ginger, ground. African ginger, whole. African ginger, ground. 1903 3.75 6.33 fEth'r (Sp. gr. -! 0.717) 1 4.76 1 6 04 111.09 Tahiti ginger. Southall Bros, & Barclay Ivory Coast ginger. 1903 r Alco- hol (90 J per Icent) 4 35 4.57 I 9.93 Jamaica ginger. Cochin African 166 I^U MEZ— THE GALENICAL OLEORESINS Table 63. — Yield of oleoresin as reported in the literature — Continued. Observer Yield of oleoresin to— Date Alco- hol Ace- tone Ether Other solvents Remarks 1908 Vanderkleed .... Per ct. Per ct. Per ct. Per cent I Solvent (?) \ 5.58 / 9.55 j Solvent(?) 1 3.14 to 6.91 8.20 9.03 Reported as yield of oleoresin. 1909 Vanderkleed .... Represents tlie yield from 16 1909 Vanderkleed .... samples of Jamaica ginger. Reported as oleoresin. Vanderkleed .... 1909 Patch 3.70 to 6.20 1910 Vanderkleed .... r Solvent(?) 5.63 6.31 10.12 3.40 to 6.60 j 7.12 to 9.48 1 3.44 to 6.64 1 6.85 to 11.10 I \ Jamaica ginger. Reported as ( yield of oleoresin. Vanderkleed African ginger. Reported as 1911 yield of oleoresin. Jamaica ginger. Reported as Vanderkleed.... yield of oleoresin. African ginger, Repoi'ted as 1912 yield of oleoresin. Patch yield of oleoresin. African ginger. Reported as 1912 3.30 to 6.00 6.40 8.30 4.23 yield of oleoresin. Jamaica ginger. 1912 Hooper Young rhizomes harvested in Patch December. Rhizomes harvested in Feb- 1913 ruary . Average yield of 9 samples of 1913 Vanderkleed j SolventC?) 1 3.10 to 5.75 S Solvent(?) 1 6.85 to 9.92 J SolventC?) 1 2.81 to 5.24 ginger. Reported as yield of oleoresin. 1913 Vanderkleed . . . . Results obtained in extract- ing 37 samples of Jamaica ginger. Results obtained in extracting 1913 Engelhard t 17 samples of African ginger. Results obtained in extracting 1914 Rlppetoe 4.98 5.50 6.20 6.23 2.79 4 97 5.31 5.45 8 samples of Jamaica ginger. Jamaica ginger. Vanderkleed . . . . African ginger. 1914 S Solvent(?) 1 5.06 9.00 3.93 7.99 8.90 Average yield of 3 samples of Vanderkleed Jamaica ginger. Average yield of 3 samples of 1915 African ginger. Yield of Jamaica ginger. " African ginger. OLEORESIN OF GINGER 167 Table 6L — Yield of oleoredn as obtained in the laboratory. Yield of oleoresin Date Observer Alco- hol Ace- tone Ether Other solvents Remarks 1909 DuMez & Arnold DuMez & Netzel. DuMez Per ct. 6.60 6.33 6.28 Per ct. 5.62 5.49 Per ct. 5.30 5.00 4.92 Per cent Represents yield using a Soxh- lei's extraction app.^ except- 1910 1916 Henzin 2.57 Petrol, ether 3.15 in the case of alcohol. (^) Represents yield usinj? a Soxh- let's extraction app. . except in the case of alcohol. Represents yield using a Soxh-^ let's extraction app., except in the case of alcohol. 1 Jamaica ginger was the variety of the drug used in all cases. When alcohol was the solvent employed, the process of extraction was that of simple percolation. Chemistry of the Drug and Oleoresin. Tabulation of Constituents, The chemistry of the constituents of ginger is still incomplete in many details, although, it has been the subject of a number of investigations.^ In the light of our present knowledge, the fol- lowing may be said to comprise the constituents ol importance to the pharmacist: volatile oil, gingerol, resins, fat, wax, gum, sugar, starch and inorganic matter. Thresh^ has identified the following in the oleoresin prepared by extracting the rhizomes with ether : Volatile Oil Gingerol Eesin Fat Wax Ash Occurrence and Description of Individual Constituents. Volatile Oil.^ The volatile oil or so-called essence of ginger is described by Thresh* as being a pale straw colored limpid »Morin, Journ. de Pharm. et de Chim. (1823), 9, p. 25$; Thresh, Pharm. Journ. (1879), 39, p. 171; Jones, Chem. & Drugg. (1886), 28, p. 413; Gane, Pharm. Journ. (1892), 51, p. 802; Balland, Journ. Pharm. Chim. (1903), 18, p. 248; Reich, Zeitschr. Unters. Nahr. u. Genussm. (1907), 14, p. 549. M. c. "The description of the volatile oil as given above is for the product ob- tained from the rhizomes by steam distillation. The oil as it exists in the oleoresin prepared from the rhizomes by extraction with a solvent will un- doubtedly differ somewhat. *Pharm. Journ. (1881), 41, p. 198; Tear-Book of Pharm. (1881). 18. p. 39S. 168 ^^ MEZ— THE GALENICAL OLEORESINS fluid with a somewhat camphoraceous odor and an aromatic, but not a pungent taste. It is laevogyrate (-25 to 50°) and has a specific gravity of 0.875 to 0.886. It is soluble in strong alcohol, petroleum ether, carbon disulphide, benzene, turpentine and glacial acetic acid. The principal constituent of the oil, a sesquiterpene, gingerene or zingiberene, (C15H24) was first definitely described by von Soden and Rojahn^ in 1900. Accord- ing to Semmler and Becker,^ it is a monocyclic butadiene having the -following structure : CH CH. H,C f y Y H.C k A" A"' ¥ I CH, The former investigators also identified d-camphene and phellan- drene^ in the lower boiling fractions. In addition to these hy- drocarbons, Schimmel & Company® have reported the presence of citral, cineol, borneol and probably geraniol, and Dodge^ the presence of an aldehyde of the probable formula, n-CglligCHO. The volatile oil has been found to be present in the rhizomes in varying quantities depending on their age before harvesting, the methods of curing and their geographical source.^*' Ac- •Pharm. Ztgr. (1900), 45. p. 414. •Ber. d. deutsch. chem. Gesell. (1913), 46, p. 1814. T Schimmel & Co. Semi-Ann. Rep. (1905), II, p. 38. ' Phellandrene and d-caniphene were identified in the oil by Bertram and Walbaum in 1894. Journ. f. prakt. Chem. (1894), 49, p. 18. •Chem. Abs. (1912), 6, 3, p. 2976; Orlg. Com. 8th Intern. Congr. Appl. Chem, 6 p. 77. *» Gane reports the presence of volatile oil in ginger as follows : Jamaica 0.64 per cent., Cochin 1.35 per cent., African 1.615 per cent, Fijian 1.45 per cent. Pharm. Journ. (1892), 51, p. 802. Thresh obtained 0.75 per cent, of oil from Jamaica ginger, 1.35 per cent, from Cochin and 1.61 per cent, from African. Pharm. Journ. (1879), 39, p.l. 191. Haensel states that he obtained only 1.072 per cent, of volatile oil from. Jamaica ginger, whereas other sorts yielded from 2 to 3 per cent. Pharm. Ztg. (1903), 48, p. 58. Bennet found 0.20 to 0.90 per cent, of oil in Jamaica ginger, Pharm. Journ. (1901), 66, p. 522. Reich gives the following as the volatile oil content of various sorts of OLEORESIN OF GINGER 169 cording to Cripps and Brown a ''good ginger" will yield from 2.24 to 3.48 per cent.^^ Gingerol. Gingerol or zingiberoP^ is the constituent or mix- ture of constituents to which ginger is said to owe its pungency. It is a colorless, odorless, viscid fluid possessing an extreme pungency. Its exact composition has not been determined, the most recent investigations indicating that it is a mixture of phenols.^^ It is readily soluble in strong alcohol, carbon disul- phide, benzol and oil of turpentine, but only slightly soluble in petroleum ether. Gingerol is present in the rhizomes in amounts varying from 0.6 to 1.82 per cent.^* Resins. The resins of ginger have been isolated and described ; by Thresh.^ ^ This investigator recognizes four individuals with respect to their physical properties and their behavior toward acids and alkalies, viz : a neutral resin, an a-resin, a jS-resin and a y-resin. The neutral resin is stated to be a black, pitch-like substance; soluble in ether, alcohol, benzene and oil of turpentine, but in- soluble in petroleum ether and carbon disulphide. The a-resin is a soft, but brittle substance soluble in ether> and alcohol, but insoluble in the remainder of the above men- tioned solvents. The /8-resin is also soft and brittle, but is soluble in all of the above solvents. The y-resin is firmer in consistence and is soluble in ether, alcohol and petroleum ether. The total resin content of the rhizomes varies to a considerable • ginger: Cochin 1.38 per cent., Japan 1.38 per cent, Bengal 1.6 per cent», African 2.54 per cent. Zeitschr. Unters. Nahr. u. Genussm. (1907), 1^, p. 549. "Analyst (1909), 34, p. 519. "The term gingerol was first used by Thresh in 1884 to designate the pungent principle of ginger. Year-Book of Pharm. (1884), 21, p. 516. Zingiberol is evidently a modification of the above, the idea being to bring the nomenclature in closer conformity with the name of the botanical source — Zingiheris officinale Roscoe. "Garnet and Grier, Year-Book of Fharm. (1907), 44, p. 441, " Thresh obtained gingerol in the following quantities : Jamaica ginger 0.66 per cent.. Cochin 0.60 per cent., African 1.45 per cent. Pharm. Joum. (1879), 39, p. 193. Gane reports the presence of the following percentages: Jamaica 0.84 per^ cent., Cochin 0.60 per cent., African 1.45 per cent., Fijian 1.82 per cent. Pharm. Joum. (1892), 51, p. 802. "Pharm. Journ. (1879), 39, p. 193. X70 ^U MEZ— THE GALENICAL OLEORESINS extent and appears to depend principally on their geographical source. The minimum yield (1.18 per cent.) has been obtained from Jamaica ginger, the maximum yield (4.47 per cent.) from the Fijian rhizome.^^ Fat and Wax. Little or no work has been done toward de- termining the composition of the fat or wax in ginger. The two substances, combined, are stated to constitute 0.70 to 1.225 per cent, of the rhizome.^'^. Ash. The qualitative examination of the ash of ginger has been undertaken by Thresh,^^ who reports the presence of the basic elements : K, Ca, Mg, Mn,^^ and Fe combined with H2CO3 and H3PO4. The ash of African ginger is stated to contain the largest amount of manganese. The ash content^^ of the whole rhizome appears to be in- fluenced but little by the locality from which obtained, 3.0 to5.5 per cent, being conservative limits for the usual commercial var- ieties. Peeling^^ appears to decrease the amount of ash while bleaching^- (liming) increases it. Constituents of Therapeutic Importance. The physiological action of the oleoresin of ginger was at one time thought to be due to the resin content, but the work of Thresh^ has shown the pungency to be the property of the phenolic constituents known collectively as gingerol. The car- " Thresh reports the total resin content of g-inger as follows : Jamaica 1.18 per cent, Cochin 1.815 per cent., African 3.775 per cent., Pliarm. Journ, (1879), 39, p. 173. Gane noted the presence of the following percentages : Jamaica g-inger 1.76 per cent.. Cochin 1.815 per cent., African 3.775 per cent., Fijian 4.475 per c^nt. Pharm. Journ. (1892), 51, p. 802. " The combined fat and wax present in g-inger is stated by Thresh to be as follows: Jamaica 0.70 per cent., Cochin 1.205 per cent., African 1.225 per ■cent. I. c. Gane found the following amounts: Jamaica ginger 0.92 per cent., Cochin 1.20 per cent., African 1.225 per cent., Bengal 0.86 per cent., L. C. "Pharm. Journ. (1879), 29 pp. 174 and 193. "See also Flueckiger, Ihid. (1872), 32, p. 208. *> C. Richardson. Bull. 13, Dept Agr. Washing-ton, 1887; Gane, Pharm. Journ. (1892), 51, p. 802; Liverseeg-e, Vierteljahresschr. Nahrungs-u. Genussm. (1896), 11, p. 353; Glass, Pharm. Journ. (1897), 58, p. 245; Bennet, Ibid. (1901, 66. p. 522. »Winton, Ogden and Mitchell obtained 3.66 to 4.06 per cent, of ash for un- peeled and unbleached Cochin ginger, 3.36 per cent, for the same when peeled and bleached. Rep. Conn. Agr. Exp. Sta. (1898), p. 202; (1899), p. 102. 22 Davis reports 5.20 per cent, of ash for unbleached Jamaica ginger, 6. 55 per cent, for the bleached. Fharm. Journ. (1895), 54, p. 472. » Tear-Book of Pharm. (1884), 21, p. 516. OLEORESIN OF GINGER 171 minative action of the preparation must also be attributed in part to the volatile oil contained therein. Physical Properties. Color: The oleoresins examined in the laboratory were ob- served to be rather dark brown in color when spread out in thin layers on a white porcelain surface. This property, however, is reported to vary somewhat with the variety and condition of the ginger used in making the preparation. When African ginger is employed, the oleoresin is stated to be dark brown in color, whereas, uncoated Jamaica ginger is said to yield a preparation comparatively light in color.^ Odor: The oleoresin, when prepared according to the official process, has the full aroma of ginger, the quality of which is stated to be influenced largely by the variety of ginger used.^ Taste: The preparation has the sharp pungency and flavor of ginger. This property, like the odor, is stated to vary with the variety of ginger used, Jamaica ginger yielding the product with the best flavor.^ Consistence: The oleoresin is a thick liquid, being of about the consistence of molasses, as a rule, but varying somewhat with the variety of the ginger used in its preparation. The fluidity is said to be the greatest when prepared from Jamaica ginger and the least when made from the African variety.'* Solubility: The oleoresin is soluble in absolute alcohol, ace- tone, ether, chloroform, and glacial acetic acid. It is partially soluble in petroleum ether, the extent of its solubility depend- ing on the solvent used in its preparation as is shown in the fol- lowing table: Table 65 — Solubility of the oleoresin in petroleum ether. 9ol S »» Sharp & Dohme 14 1 Contained ether. Saponification value: Saponification values of 103.4 to 110.4 were obtained for the oleoresin when prepared with 176 DU MEZ— THE GALENICAL OLEORESINS acetone. For the preparation in which ether was employed as a menstruum in extracting the drug, a saponification value of 102.9 was obtained. The comparatively low values obtained for the commercial samples examined are to be accounted for by the fact that in all cases, they contained nearly twice as much volatile matter (presumably essential oil) as the laboratory preparations. The values found for this constant are given in the tables which follow. Table 85 — Saponification values of oleoresins prepared in the laboratory. Sample , No. Date Observer Solvent Saponifica- tion value 1 1916 DuMez Alcohol 119 4 2 103.4 110 4 3 «» 4, " • •• • 105.7 « »» Ether 102 9 5 •' Petrol, ether 78.1 Table 86 — Saponification values of commercial oleoresins. Sample No. Date Observer Source Saponifica- tion value 1 1916 DuMez Sharp & Dohme 94.1 2.. .. SQuibi)& Sons 98.41 3 " Lillv& Co 89.9 * Contained a trace of ether. Iodine value: Iodine values of 122.4 to 124.1 were ob- tained for the oleoresin when prepared with acetone. The preparations made with alcohol or ether gave values very near the same, whereas, the value of this constant was some- what higher (126.9) when petroleum ether was the solvent em- ployed. With respect to the commercial samples, the values found were lower in all cases. In one instance, this was due to the presence of unevaporated solvent, while, in the other cases it is to be attributed to the relatively large amount of volatile matter (essential oil) present. The iodine values found for the preparations examined in the laboratory follow. OLEORESIN OF GINGER 177 Table 87. — Iodine values of oUoresins prepared in the laboratory. Sample No. Date Observer Solvent Iodine value 1 1916 122.3 2 Acetone 122 4 3 »' 111.5 1 4 " " 124.1 5 Ether 121.1 6 " Petrol, ether .. 126.9 Tlie drug in this instance was extracted by simple percolation. TabLiE 88. — Iodine values of commercial oleoresins. Sample No. Date Observer Source Iodine value 1 1916 DuMez ?quibb&9ons 104. 2> 2 Lilly & Co 109.9 3 " Sharp & Dohme 112 * Contained ether. Special Qualitative Tests. Most of the qualitative methods which have been mentioned in connection with the standardization of this preparation are of the nature of tests for the detection of adulterations. The oleo- resin of capsicum^ is the adulterant which appears to have re- ceived special attention, several methods for detecting its pres- ence having been reported. Tests for the Presence of the Oleoresin of Capsicum La Wall, in 1910, pointed out the necessity of a test for the presence of the oleoresin of capsicum as he had observed that many of the commercial samples of the oleoresin of ginger used in the preparation of ginger ale extracts were adulterated with this substance. At the same time, he also described a method whereby this form of adulteration might be detected. His method is almost identical with that of Garnett and Grier pub- lished in 1907, both being based on the destruction of the 1 While the oleoresin of capsicum per se may occassionally be added to the finished product, it Is thought that the adulteration is usually accomplished ^y mixing capsicum with the ginger previous to the extraction of the oleoresin. 178 I^U MEZ— THE GALENICAL OLEORESINS pungent principles ( ginger ol) of the oleoresin of ginger with alkalies, whereby the pungent principle (capsiciri) of the oleo- resin of capsicum remains unaltered. As it was subsequently found that the pungent principles of the former were not com- pletely destroyed by this treatment, Nelson proposed a modi- fication of the above methods, in which he makes use of manganese dioxide for completing the disintegration of these constituents. Full descriptions of these methods follow : Method of Garnett and Grier (1907) : Digest 1 gram of the oleoresin for 15 minutes on a water bath with a small quantity of caustic alkali dissolved in alcohol. Evaporate the solution to remove the alcohol and make the residue faintly acid with hydrochloric acid. Transfer the liquid to a test tube and shake it with 5 cubic centimeters of ether which have previously been used to rinse the dish. Allow the mixture to stand quietly and then taste the separated ethereal layer. If sharply pungent, adultera- tion with capsicum is indicated. Method of La Wall (1910) : Add 10 cubic centimeters of half -normal alcoholic potassium hydroxide solution to 1 gram of the oleoresin contained in a shallow porcelain dish and evaporate to dryness on a water bath. Dis- solve the residue in 50 cubic centimeters of water and transfer the solution to a separatory funnel. Add 20 cubic centimeters of ether and shake vigor- ously. After allowing the mixture to stand until the ether has separated, run the latter off on a watch glass and expose it until the solvent has all evaporated. The residue should have a warm camphoraceous taste. A sharp pungent taste indicates adulteration with capsicum. Method of Nelson (1902) :' Add 10 cubic centimeters of double-normal alcoholic potassium hydroxide solution to one gram of the oleoresin contained in a porcelain dish and evaporate on a steam bath. Add about 0.1 gram of powdered manganese dioxide and 5 to 10 cubic centimeters of water, and continue heating for about 20 minutes, or until all of the volatile oil has been expelled. Cool, acidify with dilute sulphuric acid and extract at once with petroleum ether. Evaporate the petroleum ether solution in a small crucible, keeping the residue within as small an area as possible. When all of the solvent has evaporated, apply the tongue to the residue, being careful to keep the material on the tip. If capsicum is present, the char- acteristic burning sensation will soon be felt. The latter is the method which was employed in making the test in the laboratory. In no case, however, was capsicum de- tected in the samples examined. « Journ. Indust. and Eng. Chem. (1910), 2, p. 419. OLEORESIN OF GINGER 119 Special Quantitative Tests. While tlie matter of determining the quality of the unadulter- ated product has apparently received but little attention, two distinct methods have, nevertheless, been made use of in its evaluation. They are the methods of Garnett and Grier for the determination of the gingerol content, and the physiological test employed by the H. K. Mulford Company. Methods for the Estimation of the Gingerol Content. The only method of an analytical nature which has been sug- gested for the quantitative evaluation of this oleoresin is based on the fact that the pungent principles, gingerol, are more readily soluble in 60 per cent alcohol, than in petroleum ether, A description of the manner in which this assay is carried out follows. Method of Garnett and Grier (1909): Dissolve the gingerol by boiling about 1 gram of the oleoresin with several portions of petroleum ether^ filter the solutions thus obtained and remove the solvent bj evaporation on a water bath. Dissolve the residue in alcohol (60 per cent.) added in three separate portions, shake the united alcoholic solutions with a small amount of petroleum ether to remove traces of fat and remove the alcohol from the hydro-alcoholic portion by evaporation. Shake the residual liquid with 3 portions of ether added successively, filter the combined shakinga into a tared flask, remove the ether by evaporation on a water bath, dry at 100°C and weigh. In the final shaking out, carbon disulphide or chloro- form may be used in place of the ether. The use of this method in the laboratory has shown that it gives fairly constant results, and, as it is easily carried out, it should prove to be of practical value. The results obtained in the examination of oleoresin s prepared in the laboratory and those obtained from commercial sources are given in the fol- lowing tables : Table 89 — Gingerol content of oleoresins prepared in the laboratory. Sample No. Date Observer Solvent Gingerol content 1 1916 DuMez Alcohol Percent. 27 2 2 Acetx)ne 23.2 3 " Ether 27.5 4 " Petrol ether . 43 9 ISO DU MEZ— THE GALENICAL OLEORESINS Table 90 — Oingerol content of commercial oleoresins. Sample No. Date Observer Source Gingerol content 1 1916 DuMez Li lly «Sz; Co Per cent. 19.5 12 Sharp & Dobme 24.0 Z " flQuibt) & Sons 28.2 The first of the preceding tables shows that the gingerol con- tent varies with the solvent employed in the preparation of the oleoresin. Further, that this variation is not in inverse ratio to the yield of oleoresin obtained as might be expected, but is •exceptionally low in the case of acetone due to the fact that it is a difficult matter to completely exhaust the drug when the lat- ter is the solvent used. The low gingerol content of two of the commercial samples as shown in the second table, points to the use of acetone in their preparation. A similar effect might, however, be produced when ether or alcohol are employed if the ginger used is of poor quality (low in gingerol content,) or if percolation is termin- ated before complete exhaustion of the drug has taken place. The oleoresin obtained from Squibb and Sons is stated to have been prepared with ether, which statement is confirmed by the result obtained in the determination of the gingerol content as is also shown in the second table. Physiological Tests. The H. K. Mulford Company reports the use of a physiologi- -cal test for determining the quality of this oleoresin. As an arbitrary standard, the firm has taken a preparation which is pungent to the taste in a maximum dilution of 1 to 20,000'. While there is no information, at hand to indicate what solvent was employed as the diluent, experience in the laboratory has shown that dilute alcohol (50 per cent.) may be used for this purpose. After vigorously shaking the oleoresin with alco- "hol, the resulting solution should preferably be filtered before applying to the tongue. AlUiough no extensive series of ex- periments were made with this test in the laboratory, the results obtained would appear to indicate that the above standard is rather low as the pungency in the preparations examined was OLEORESIN OF LUPIILIN lg% easily perceptible in dilutions of 1 to 30,000. In view of the fact that personal idiosyncrasy must be a factor in applying this- test, the use of the previously described method for the estima- tion of the gingerol content is thought to be more preferable for use in this connection. Adulterations There is no evidence to show that the oleoresin as prepared for pharmaceutical use is adulterated. La Wall,^ however, states that the commercial article used in the manufacture of ginger ale frequently contains oleoresin of capsicum. A trace of copper was found in most of the commercial samples examined. See under **Ash content." Oleoresin of Lupulin Synonyms Aetherisches Lwpulinextrdkt, Nat. Disp. 1879. Extractum Lupulini, Hirsh, Univ. P. 1902, No. 1222. Extractum Lupulini aethereum, Nat. Disp. 1879. Oleoresina Lupulinae, U. S. P. 1860. Oleoresina Lupulini, U. S. P. 1880. Oleoresine de Lupuline, U. S. Disp. 1907. Ethereal Extract of Lupulin, King's Am. Disp. (1900), p. 1333. History The first mention of the oleoresin of lupulin which could be f ound in pharmaceutical literature appeared in Procter 's article, '^ Formulae for fluid extracts in reference to their more general adoption in the next Pharmacopoeia," published in 1859.. Procter's oleoresin was in reality an ethereal extract, ether hav- ing been the menstruum employed in exhausting the drug. In this connection, it is interesting to note that the extract prepared with the use of alcohol had previously been brought to the notice of the American pharmacist by Livermore in 1853, while the attention of the European pharmacist had been directed ta the same by Planche as early as 1823. The oleoresin was first admitted to the United States Pharmacopoeia in 1860, in which it remained official for more than half a century, having been 1 La Wall (1910). 282 ^U MEZ— THE GALENICAL. OLEORESINS omitted from the present revised edition. It has never re- 2 Acetone 84 1 3 ., Ether Benzin 80.1 4 79 7 * Contained unevaporated solvent. Table 102 — Acid numbers of commercial oleoresins. Sample No. Date Observer Source Acid number 1 1916 DuMez Lillv& Co 61.7 2 85.5 3 " .*Quibb&Sons 78 4' * Contained ether. Saponification value: Saponification values ranging from 223.4 to 239.6 were obtained for the oleoresins prepared in the laboratory, the variation being due, very likely, to the nature of the solvent employed in extracting the drug. The values found 196 DU MEZ— THE GALENICAL OLEORESINS for the commercial preparations were somewhat lower, due, in two eases, to the presence of unevaporated solvent. In the third instance, the low saponification value obtained was very probably due to a difference in the quality of the lupulin from which the oleoresin was extracted. The results obtained in the examina- tion of laboratory and commercial preparations follow. Table 103 — Saponification values of oleoresins prepared in the laboratory. Sample No. Date Observer Solvent Saponifica- tion value 1 1916 DuMez 223.4 > 2 Acetone . 239 6 3 '« Ether 230 8 4 •» Benzin 227 4 1 Contained ether. Table 104 — Saponification values of commercial oleoresins. Sample No. Date Observer Source Saponifica- tion value 1 1916 DuMez Lilly & Co 158. 8* 2 220.0 3 •• Squibb & Sons 223.3" 2 Probably contained unevaporated solvent (alcohol). * Contained ether. Iodine value: The oleoresin, when prepared with acetone, ether, or benzin, was found to have an iodine value varying from 94.7 to 96.2. When alcohol was the solvent employed in its preparation, the value obtained was considerably lower, namely, 82.05. A comparison of thse values with those found for the commercial samples indicates that alcohol is sometimes used in their preparation. The extrernely low value obtained for the oleoresin of Lilly & Co. is to be attributed to the pres- ence of unevaporated solvent (alcohol) as well as to the effect produced by its use as a menstruum. The iodine values ob- tained for the preparations examined in the laboratory are given in tihe tables which follow. OLEORESIN OF PARSLEY FRUIT 197 Table 105 — Iodine values of oleoresins prepared in the laboratory. 9 ana pie No. Date Observer Solvent Iodine, value 1... 1916 DuAIez . Alcohol 82.05' 2 Acetone 96.2 3 •' Ether 94.7 4 " Benzin., 95.7 Alcohol was present. Table 106 — Iodine values of commercial oleoresins. Sample No. Date Observer Source Iodine value J 1916 DuMe/ Lilly Alcohol was probably present. ' The odor of ether was noticeable. Adulterations, Adulteration effected through the use of old deteriorated drug in the iiiaimfacture of this preparation has been noted. See under ''Drug used, its collection, preservation, etc." The presence of copper was detected in all of the commercial samples examined. See under "Ash content." OLEORESIN OF PARSLEY FRUIT Synonyms Aetherisches PetersilieextraTct. Culbreth, Mat. Med. (1917), p. 42S. Green Apiol,"- Brit. Pharm. Cod. 1907. Oil of Parsley, Parrish. Treat, on Phar. (1867), p. 757. Oleoresina Petroselini, U. S. P. 1910. Oleoresine de Persil, Culbreth, Mat. Med. (1917), p. 428. Liquid Apiol, Brit. Phann. Cod. 1907. * "Green apiol" is stated to be an alcoholic extract of the parsley fruit ; "yellow apiol." the product obtained on treating- this extract with animal charcoal, or upon saponifying the same with lead oxide ; and "white apiol" the volatile oil obtained on distilling the extract with steam. Brit, and Col. Drugg. (1910), 58, p. 235. The compound, Cj^Hj^O^, spoken of in chemical literature as apiol is known commercially as crystalline apiol. Brit. Fharm. Cod. (1907), p. 112. 198 I^U MEZ— THE GALENICAL OLEORESINS History. The oleoresin of parsley appears to have come into existence through the attempts which were made to discover a simple method for the preparation of the so-called ''apiol" of Homolle and Joret,^ which was first brought to the attention of the phar- macist in 1855. The first mention of the oleoresin, insofar as could be determined with the information at hand, is to be found in Parrish's Treatise on Pharmacy published in 1867. Since that time, the preparation, or one of a similar nature, has been on the market under the name of "green apiol" or ''liquid apiol,'' but was never given official recognition until the ap- pearance of the present edition of the United States PJiar- macopoeia. Drug Used, Its Collection, Preservation, Etc. In the present edition of the United States Pharmacopoeia, parsley fruit is defined as follows: ''The dried ripe fruit of Petroselinum sativum Hoffman (Fam. Umhelliferae), without the presence or admixture of more than 5 per cent, of foreign seeds or other matter. Preserve Parsley Fruit carefully in tightly-closed containers protected from light." The plant from which the fruit is obtained has also been known under the following botanical synonyms: Carum Petroselinum Benth. and Hook., and Apium Petroselinum Linne. Parsley is an annual herb commonly cultivated in the gar- dens of Europe and America. The fruit ripens in the fall, when it is gathered, dried and preserved for domestic use or shipped to market. The fruit as found in the market shows no marked difference in appearance regardless of its source. However, it is known to differ in its chemical composition. Thus, the fruits grown in Germany contain apiol as the principal constituent of therapeutic importance, whereas, those grown in France contain mj-risticin.^ The volatile oil content also appears to vary with the source as Flueckiger^ states that the ^ The "apiol" of Homolle and Joret is stated to be the product which re- mains unsaponified when the ether or chloroform soluble portion of the alco- holic extract of parsley fruit is heated with litharge. Journ. de Pharm. et de Chim. (1855), 28, p. 212. 2 See under "Chemistry of parsley fruit". * Pharmakognosie des Pflanzenreichs (1891), p. 938. OLEORESIN OF PARSLEY FRUIT 199 fruits grown in Norway have an exceptionally strong odor. Both of the foregoing variations in the composition of the drug would naturally be imparted in an increased degree to the oleoresins prepared therefrom. As the chemistry of the American fruit does not appear to have been studied, its value in this connection cannot be said to be definitely established. There is good reason, however, to believe that the oleoresins made in this country, in part at least, are prepared from home grown fruits.^ The large amount of fixed and volatile oils present in these fruits requires that they be preserved in tightly closed con- tainers protected from the light. Z7. S. P. Text and Comments Thereon, The oleoresin was given official recognition for the first time by being admitted to the late edition of the United States Phar- macopoeia (edition of 1910). 1910 Oleoresina Petroselini Oleoresin of Parsley Fruit Oleores. Petrosel. — Liquid Apiol Parsley Fruit,* in No. 60 powder,' tillation on a water-bath,* and, hav five hundred grammes ....500 Gm. ing transferred the residue to a dish. Ether,' a sufflcient quantity. remove the remaining ether by spon Place the parsley fruit in a cylin- taneous evaporation in a warm place drical glass percolator provided with a stirring frequently.' Allow the oleo stop-cock and arranged with a cover resin to stand without agitation for and a receptacle suitable for volatile four or five days, decant the clear liquids.* Pack the powder firmly, liquid portion from any solid residue,' and percolate slowly with ether, and preserve it in well-stoppered bot- added in successive portions until the ties.' drug is exhausted." Eecover the Average Dose. — Metric, 0.5 mil — greater portion of the ether by dis- Apothecaries, 8 minims. 1) For a description of the drug, see page 1104 under *'Drug used, its collection, preservation, etc.'' 2) The Pharmacopoeia directs that the fruit be reduced to a ^ Joseph K. Janks in his book on spices states thati parsley is being grown in thli country. Jos. K. Janks, Spices, New York (1915), p. 69. Oulbreth on page 428 of the 1917 edition of his work on Materia Medica also refen to the cultivation of parsley in the United States. 2Q(^ DU MEZ— THE GALENICAL OLEORESINS No. 60 power for percolation. Owing to the large fatty oil content, this degree of fineness is difficult to attain, and, as experiments conducted in the laboratory indicate that a No. 40 powder is equally satisfactory for this purpose, it appears that a change to this effect in the pharmacopooeial directions is desirable. 3) Ether is the solvent directed by the Pharmacopoeia to be used for the extraction of the substances constituting the oleo- resin. Observations made in the laboratory indicate that other solvents may also be employed for this purpose without in any way detracting from the value of the finished product. Thus, acetone and petroleum ether were found to yield pro- ducts almost identical with that obtained by the use of ether. The latter is to be preferred to benzin as suggested by Bering- er (1892) since its composition is more constant. Alcohol which is used commercially in the preparation of some of the so-called liquid apiols dissolves a considerable amount of col- oring matter and other inert substances and, therefore, yields a product of inferior quality. 4) For a description of the various forms of percolators which have been designed to meet the specifications of the Pharma- copoeia, see Part I under "Apparatus used". 5) The pharmacopoeial directions governing the extraction of the oleoresinous material are to slowly percolate the drug with ether, added in successive portions, until complete exhaustion has been effected. Here again, the use of some form of contin- uous extraction apparatus would appear to be an improve- ment over the present method. 6-7) For comments on this step in the pharmacopoeial method of preparation, see under comments on the oleoresin of cubeb. 8) Upon the complete removal of the solvent from the perco- late, the residual oily liquid deposits a small amount of waxy matter which the Pharmacopoeia directs shall be removed by decantation. When either is the solvent used in extracting the drug, this deposit amounts to less than 1 per cent of the oleoresin, while the percentage is somewhat greater, about 1.5 per cent when acetone is used. The deposit resulting when benzin was the solvent employed was found by Beringer to be equal to about 3 per cent. 9) The oleoresin should be kept in well-stoppered bottles as OLEORESIN OF PARSLEY FRUIT 201 it loses volatile oil upon exposure to the air, and as the glycer- ides are prone to undergo partial decomposition due to the ac- tion of the moisture and oxygen. Yield. The information at hand is not sufficient to permit of a state- ment being made as to what the average yield of oleoresin should be in this case. The results obtained in the laboratory and those reported by Beringer show that it is at least 24 per cent., when ether or acetone are the solvents employed in ex- tracting the drug, whereas those reported by Vanderkleed would appear to indicate that the yield is much lower. The available information of this nature is given in the following tables : Table 107 — Yield of oleoresin as reported in the literature. Observer Yield of Oleoresin to— Date Alco- hol Ace- tone Ether Other Solvents Remarks 1892.. Beringer Per cent. Per cent. 24.0 Per cent. Per cent. Benzin 19.3 Solvent (?) 11.40 13.04 14.70 The total yield of 1913 Vanderkleed . . . extractive mat- ter to benzin is given as 22.3 per cent, which in- cludes 3 percent, of deposited wax. Reported as yield of oleoresin. " Table 108 — Yield of oleoresin as obtained in the laboratory. Observer Yield of oleoresin to— Date Alco- hol Ace- tone Ether Other • sol- vents Remarks 1916 DuMez Per ct. Perct. 28.89 Perct, 29.17 Perct. Represents the yield using a Soxhlet's Extraction App. 2Q2 DU MEZ— THE GALENICAL. OLEORESINS Chemistry of the Drug and Oleoresin. Enumeration of Constituents. The following are the known constituents of parsley fruit which may be considered of pharmaceutical interest ; volatile oil, fatty oil, apiin, and inorganic substances. While analyses of the oleoresin have not been reported, the first two named constitu- ents of the fruit, together with a small amount of inorganic matter, very likely represent this preparation when made by extracting the drug with ether, as apiin is stated to be insoluble in this solvent. Occurrence and Description of Individual Constituents. Volatile Oil} The volatile oil of parsley fruit is described as a colorless or yellowish, thick liquid having a specific gravity of 1.03 to 1.10 at 15 °C. The angle of rotation in a 100 milli- meter tube is given as -5° to -10°. It is soluble in alcohol, ether, chloroform and petroleum ether. On cooling or shaking with water, it precipitates apiol.^ The composition of the oil varies with the locality in which the fruit is grown. The principal constituent of the oil dis- tilled from the fruit grown in Germany is apiol. Myristicin is present only in very small quantities.' It is stated that the apiol content is often so great that the oil is a semi-solid at or- dinary temperatures. In the French oil, myristicin predom- inates, while apiol, together with allyltetramethoxybenzene, is present in small amount.* The constitution of these compounds is represented by the following formulas: *The following- list comprises the more important references to the earlier literature on the volatile oil: Bley, TrommsdorfC's neues Joum. (1827), 14, p. 134; Bolle, Arch, der Pharm. (1829), 29, p. 168; Blanchet and Sell, Ann. der Chem. (1833), 6, p. 301; Loewig and W^eidmann, Ibid. (1839), 32, p. 283; von Gerichten, Ber. der. deutsch. chem. Ges. (1876), 9, pp. 258 and 1477. aSchimmel & Co., Ber. (1906), p. 95. "Thorns, Ber. der deutsch. chem. Ges. (1903), 36, p. 3451; Ihid (1908), 41, p. 2753; Chevalier, Bull. sci. pharmacologique (1910), 17, p. 128; Chem. Abs. (1911). 5, p. 1490. *Ibid. Also, Bignami and Testoni, Gaz. Chim. ital. (1900), 30, p. 240. OLEORESIN OF PARSLEY FRUIT 203 Apiol is a crystalline solid possessing in a strong degree the odor of parsley. Its melting point is 30 °C and the boiling point 294° C* Eykman^ gives the specific gravity at 14° C as 1.176, and the refractive index [n]D as 1.538. It is soluble in alcohol, ether, chloroform and oils. It also dissolves in con- centrated sulphuric acid, the solutron formed being blood-red in color. Myristicin is a liquid possessing but little odor. It does not solidify even when cooled to a comparatively low temperature. Semmler^^ gives the specific gravity as 1.141 at 25° C. Its solubility is similar to that of apiol. In addition to the foregoing, Thoms^^ reports the presence of the following in both, the German and French oils : 1-pinene, phenols and palmitic acid. Semmler^^ reports the volatile oil content of parsley fruit to be 2 to 6 per cent. Fatty X)il}^ The fatty oil of parsley fruit is a greenish yellow mobile liquid. It is soluble in a mixture of alcohol and ether, in ether, chloroform and carbon disulphide. A sample from Schimmel & Co., examined by von Gerichten and Koehler,^* 'Eykman, Ber. der. deutsch. chem. Ges. (1890), 23, p. 862; Thorns, IMd. 1903, 36, p. 174. •Thorns. Chem. Ztg. (1903). 27, p. 938. T Thorns. Ber. der. deutsch. chem. Ges. (1908), 41, p. 2761. •Ciamician and Silber, IJyid. (1888), 21, p. 1632. •I. c. »»Semmler, Die aetherische Oele (1907). 4. p. 168. ^ Arbeiten axis d. Pharm. Inst., Univ. Berlin (1909), 6, p. 190. " Semmler, Die aetherische Oele (1907), 4. p. 173. " Grimme obtained 16.7 per cent, of a red-brown oil having the following properties: specific gravity at 15° C, 0.9243 ; refractive index at 35" C, 1.4778 ; saponification value, 176.5 ; iodine value, 109.6 ; acid value, 3.4 ; unsaponifl- able matter, 2.18 per cent. He was unable to obtain a test for the presence of phytosterin in the unsaponifiable residue. Pharm, Centralh. (1911), 52, p. 663. "Ber. der. deutsch. chem. Ges. (1909), 42. p. 1638. 204 ^U MEZ— THE GALENICAL OLEORESINS showed the following properties: specific gravity at 15°C, 0.972; refractive index at 40°C, 1.4624; saponification value, 190.9; iodine value, 80.07. The saponifiable portion of the oil was found to be com- posed of the glyceryl esters of oleic, palmitic, stearic and petroselinic acids. The latter is stated to be isomeric with oleic acid. From the unsaponifiable residue, Matthes and Heintz^^ isolated a hydrocarbon, C20H40, to which they gave the name petrosilan; also, myricyl alcohol and a mixture giving a test for phytosterin. The average fatty oil content of the fruit is probably about 20 per cent.^^ Apiin.^'^ Apiin (C27H30O1G) is a glucoside. Its melting point is stated to be 228 °C. On hydrolysis, it yields a sugar and apigenin (trioxyflavon) C15H10O5. It is soluble in hot alcohol or water, insoluble in ether, and therefore, it is not likely to be present in the oleoresin. Ash. Available information concerning the constituents of the ash of parsley fruit is limited to the anaylsis of Rump,^* who reports the presence of the basic elements, K Ca, Mg and Fe in combination with the acids, HCl, H2SO4, H3PO4, H2CO3 and H2Si03, also, some free SiOo. The ash content^® of parsley fruit is about 6.50 to 7.00 per cent. Commercial samples sometimes show a higher percentage of ash due to contamination with foreign matter.-^ Constituents of Therapeutic Importance. The oleoresin of parsley fruit is said to be used chiefly as an emmenagogue. Such being the case, its therapeutical value is undoubtedly due to the volatile oil which it contains as both apioP and myristicin,- constituents of the essential oil, have i^Ber. der. pharm. Ges. (1909), 19, p. 325. 1^ Rump, obtained 22 per cent, of fatty oil. Buchner's Repert. f. d. Fharm. (1836), 6, p. 6. Grimme gives the yield as 16.7 per cent. 1. c. "von Gerichten, Ber. der deutsoh. chem. Ges. (1876), 9, p. 1121. "Buchner's Repert. f. d. Pharm. (1836), 56. p. 26. 1® Rump gives the ash content as 6.5 per cent. Ibid. Warnecke reports the percentage of ash as 7.04. Pharm. Ztg. (1886), 31. p. 53 6. *• La Wall and Bradshaw report two commercial samples of parsley fruit yielding 6.61 and 9.10 per cent, of ash, respectively. Proc. A. Ph. A. (1910), 58, p. 752. ^Heffter, Arch. f. exp. Path. u. Pharmak. (1895), 35, p. 365. Chevalier Bull. Sci. pharmacologique, 17, pp. 128-131. 2Juerss, Schimmel & Co., Ber, (1904), p. 159. OLEORESIN OF PARSLEY FRUIT 205 been shown to be severe intestinal irritants. The activity of the volatile oil may be further accounted for by the presence of terpenes as these compounds are also known to be irritants.* PJiysical Properties Color: When spread out in a thin layer on a while porcelain surface, the oleoresin was observed to be greenish-yellow in color. The so-called fluid apiols of commerce, preparations made with alcohol, are of a comparatively deep green color. Odar: The oleoresin has the agreeable aromatic odor of parsley. Taste: The taste is spicy like that of the drug from which it is prepared. Consistence: The oleoresin is a rather thin liquid, being of about the consistence of olive oil. Solubility: The official preparation is soluble in acetone, ether, chloroform, carbon disulphide and petroleum ether. It is almost insoluble in alcohol or water. Specific gravity: The specific gravities of the oleoresins pre- pared in the laboratory were found to be 0.937 and 0.940 at 25° C. In the making of these preparations ether and acetone, respec- tively, were employed as menstrua for extracting the drug. The specific gravity of the only commercial sample, conforming in its general properties to the official product, was observed to be about the same, i. e. 0.943. In the case of the other commercial products, the greater density is thought to be due to the use of alcohol in their preparation.^ The results for the determina- tions made in the laboratory follow. Table 109 — Specific gravities of oleoresins prepared in the laboratory. Sample No. Date Observer Solvent specific gravity I 1916 Du Me7 Acetone At25° C 0.940 2 Ether 0.937 sKehrer, Arch. f. Gyn. (1910), 90. p. 169. ^ This statement is also based on the dark green color of the preparations and the fact that alcohol is the solvent mentiond in the literature in con- nection with the preparation of the so-called fluid apiols. See under "His- tory" of the oleoresin. 206 DU MEZ— THE GALENICAL OLEORESINS Table 110 — Specific gravities of commercial oleoresins. Sample No. Date Observer Source Specific erravity 1 1916 DuMez Sharp & Dohme At 25° C 0.943 2 SQuibb & Sons 0.984' 3 " Merck& Co 1.0082 ^Apiol, fluid, — Squibb. 2 Apiol, fluid, green, — Merck. Refractive index: Observations made in the laboratory in- dicate that the oleoresin should have a refractive index of about 1.477 at 25° C, when ether or acetone are employed in the extraction of the drug. A result almost identical with the preceding was obtained for the only commercial sample ex- amined. The refractive indices observed in the case of the so-called liquid apiols were somewhat higher, due very likely to the use of alcohol in their preparation. The data given in the following tables illustrate these points. Table 111 — Refractive indices of oleoresins prepared in the laboratory. Sample No. Date Observer Solvent Refractlre index 1 1916 DuMez Acetone At 25° C 1 477 2 Ether 1.477 Table 112 — Refractive indices of commercial oleoresins. Sample No. Date Observer Source Refractive index 1 1916 DuMez Sharp & Dohme At 25° C 1.475 2 Sauibb & Sons 1 486' 3 ♦• Merck & Co 1 1488* 1 Apiol, Fluid— Squibb. * Apiol, Fluid, Green, — Merck. OLEORESIN OF PARSLEY FRUIT 207 Ckemical Properties. Loss in weight on heating: The oleoresins prepared in the laboratory, using ether and acetone as menstrua for exhausting the drug, lost 7.87 and 7.92 per cent, of their weight, respec- tively, on heating at 110°C. In the case of the only com- mercial sample examined, the loss was about one-half as great due very likely to a smaller amount of volatile matter (essential oil) being contained in the drug from which the lat- ter was prepared. The results obtained are given in the tables which follow. Table 113 — Laboratory preparations — loss in weight on heating. Sample No. Date 1916 Observer DuMez Solvent Acetone Ether... Percent, of loss on heatlncr At 100° C 7.92 7.87 Table 114 — Commercial oleoresins — loss in weight on heating. Sample No. Date Observer Source Per cent, of loss on heating 1 1916 DuMez Sharp & Dohme At 110° C 8.35 Asli content: The results obtained in the determination of the ash content of the oleoresins examined in the laboratory are given in the tables which follow. Aside from the fact that the amount of ash obtained varied with the solvent used in the making of the preparations, the only items of importance brought out by these results are that ether was evidently em- ployed in the manufacture of the commercial product and that the latter contained copper. Table 115 — Ash contents of oleoresins prepared in the laboratory. Sample No. Date Observer Solvent Per cent, of ash 1 1916 DuMez 0.18 0.09 2 F.thAT 208 DU MEZ— THE GALENICAL, OLEORESINS Table 116 — Ash contents of commercial oleoresins. Sample NO. Date Observer Source Percent, of ash Foreign con- stituents 1 1916 DuMez Sharp & Dohme 0.09 Copper Acid number: The acid numbers obtained for the oleoresins prepared with acetone and ether were found to be 9.3 and 9.2, respectively, indicating that the difference in the nature of the two solvents has but little influence on the value of this con- stant. The high value found for the sample obtained from Sharp & Dohme is thought to be due to the hydrolysis of some of the glycerides, and, therefore, to indicate an old preparation, or one that has been prepared from old deteriorated drug. The acid numbers obtained for the oleoresins examined, also those found for the so-called liquid apiols, are given in the tables which follow. Table 117 — Acid numbers of oleoresins prepared in the laboratory. Sample No. Date Observer Solvent Acid number 1 1916 DuMez Acetone 9 3 2 Ether 9.2 Table 118 — Acid numbers of commercial preparations. Sample No. Date: Observer Source Acid number I 1916 DuMez Merck & Co 12.11 2 Sharp & Dohme 50.5 3 n Squibb & Sons 58.5' ^Apiol, Fluid, Green. Saponification value: The saponification values of the oleo- resins prepared in the laboratory, using ether and acetone as menstrua for extracting the drug, were found to be 158.5 and 165.6, respectively. The high value (181.6) obtained for Sharp OLEORESIN OF PARSLEY FRUIT 209 & Dohme's preparation is thought to be due to the presence of a relatively large amount of the glyceride of petroselinic acid, which is stated by von Gerichten to have a saponification value of 191.2. See under ''Chemistry of the drug and oleoresin." Tables showing the saponification values of the preparations examined in the laboratory follow. For comparison with the foregoing data, the values obtained for the so-called liquid apiols have also been included in these tables. Table 119 — Saponification values of oleoresins prepared in the laboratory. Sample No. Date Observer Solvent Saponi6ca- tion value 1 1916 DuMez Acetone 165 6 2 Ether 158.5 Table 120 — Saponification values of commercial preparations. Sample No. Date Observer Source Saponifica- tion value I 1916 DuMez Mpfck &Co 108.51 S::::::::: Sauibb & Sons 126.7''' 45 " Sharp & Dohme 181.6 ^ Apiol, Fluid, Green, — Merck. 2Apiol, Fluid,— Squibb. Iodine value: The iodine values as found for the oleoresins prepared in the laboratory are given in the first of the tables which follow. It will be observed that there is a considerable difference in these values due to the nature of the solvent em- ployed in extracting the drug. The low iodine value observed for the preparation made by Sharp & Dohme is to be attributed to the partial oxidation of the unsaturated glycerides. For comparison, the iodine values of two samples of so-called ^'liquid apiols "( preparations made with alcohol) have been included in the tables which follow. 210 DU MEZ— THE GALENICAL OLBORESINS Table 121 — Iodine values of oleoresins prepared in the laJ)oratoru, Sample No. Date Observer Solrent Iodine value 1 1916 DuMez Acetone 132.5 2 Ether 12?. 9 Table 122 — Iodine values of commercial preparations. Sample No. Date Observer Source Iodine value 1 1916 DuMez Sharp & Dohme 110.6 2 Sfiuibb & Sons 123.3 1 3 '» Merck & Co 130.2 « 1 Labeled "Apiol-Fluid." 2 Labeled Apiol, Fluid, Green. Adulterations. A trace of copper was found to be present in the commercial samples examined. See under "Ash content.'' OLEORESIN OF PEPPER Synonyms Aetherisches Pfefferextralct, Nat. Disp. 1884. Ethereal Extract of Black Pepper, King's Am. Disp. 1900. Extractum Piperis, Hirsh, Univ. P. 1902, No. 1244. Extr actum Piperis Fluidum, U. S. P. 1850. Fluid Extract of BlacTc Pepper, U. S. P. 1850. Oil of BlacTc Pepper, King's Am. Disp. 1900. Oleoresina Piperis, U. S. P. 1900. OUoresine de Poivre noir, U. S. Disp. 1907. History. The oleoresin of pepper appears to have been first obtained as a by-product^ in the preparation of piperine. Thus, Dr. Meli in France as early as 1825, reported having obtained the so-called ''oil of black pepper'' as a residue on separating the piperine from the alcoholic extract of the drug. The first notice of its use as a therapeutic agent apparently came from >Jourdan, Univ. P, (1832), p. 84f OLEORESIN OF PEPPER 211 America as Carpenter, in 1829, in an article on Peruvian bark, refers to its use by Dr. Chapman of Philadelphia in connec- tion with the administration of quinine. The oleoresin prepared with ether became official in the United States Pharmacopoeia in 1850 under the title Extractum Piperis Fluidum. In the 1860 edition, the name was changed to Oleoresina Piperis, under which title, it is still official at the present time. Neither this preparation nor one of a similar nature has ever been given of- ficial recognition abroad. Drug Used, Its Collection, Preservation, Etc. According to the present edition of the United States PJiar- macopoeia, the drug recognized is ''the dried, unripe fruit of Piper nigrum Linne (Fam. Piperaceae), without the presence or admixture of more than two per cent of stems or other for- eign matter. ' ' It has also occassionally been referred to under the botanical synonyms. Piper trioicum Roxb. As becomes apparent from the foregoing, only the unripe fruits should be used. As the fruit reaches maturity, the chlorophyll content diminishes and it becomes less pungent.* A variation in the chlorophyll would naturally effect the prop- erties of the oleoresin prepared therefrom, while a difference in piperine content would have no significance in this connec- tion as only a small portion of the total piperine (to which pep- per owes its pungency)^ remains in solution in the oleoresin, the greater part being precipitated upon the ermoval of the sol- vent. Pepper, as it occurs on the market, consists of a number of commercial varieties, viz: Malabar, Cochin, Penang, Singapore, Siam and others.^ The quality of these varieties is ordinarily governed by weight, the Malabar being the heaviest. The Penang, however, is stated to be the most pungent. The man- ner in which either of these qualities effect the oleoresin does not appear to have been determined. While the Pharmacopoeia makes no provisions for the preservation of this drug, its volatile oil content necessitates the use of closed containers. iFlueckiger, Pharmakognosie des Pflanzenreiches (1891), p. 913. 'Kayser, Chem. Centralb. (1888), 59, p. 261. ■Jos. K. Janks, Spices, New York, (1915), p. 10. -212 I^U MEZ— THE GALENICAL, OLEORESINS JJ. S. p. Text and Comments Thereon. The oleoresin of pepper has been official in the United States Pharmacopoeia since 1850, when it was recognized under the title of Extractum Piperis Fluidum. 1850 Extractum Piperis Fluidum Fluid Extract of Black Pepper Take of Black Pepper/ in powder,^ heat, apint and a half of ether," and a pounds expose the residue in a shallow ves- Ether,^ a sufficient quantity. sel, until the whole of the ether has Put the powder into a percolator,* evaporated,^ and the deposition of and pour ether gradually upon it until piperin in crystals, has ceased. Lastly, two pints of filtered liquor are ob- separate the piperin by expression tained." From this distill off, by through a cloth,* and keep the liquid means of a water-bath, at a gentle portion. 1860 Oleoresina Piperis Oleoresin of Black Pepper Extractum Piperis Fluidum, Pharm., 1850 Take of Black Pepper,^ in fine pow- eighteen fluidounces of ether,* and der,2 twelve troyounces; expose the residue, in a capsule, until Ether,' a sufficient quantity. the remaining ether has evaporated,^ Put the Black Pepper into a cylin- and the deposition of piperin in cry- drical percolator,* press it firmly, and stals has ceased. Lastly, separate gradually pour ether upon it until the oleoresin from the piperin by ex- twenty-four fluidounces of filtered pression through a muslin strainer,' liquid have passed." Recover from and keep it in a well-stopped bottle.' this, by distillation on a water-bath. OLEORESIN OF PEPPER 2ia 1870 Oleoresina Piperis Oleoresin of Black Pepper Take of Black Pepper/ in fine pow- der,' twelve troy ounces; Ether,^ a suificient quantity. Put the Black Pepper into a cylin- Recover the greater part of the ether by distillation on a water-bath,* and expose the residue, in a capsule, until the remaining ether has evaporated,' drical percolator provided with a and the deposition of piperin in crys- stop-cock, and arranged with cover tals has ceased. Lastly, separate the and receptacle suitable for volatile oleoresin from the piperin by expres- liquids,* press it firmly, and gradually sion through a muslin strainer,* and pour ether upon it, until twenty fluid keep it in a well-stopped bottle.' ounces of liquid have slowly passed.' 1880 Oleoresina Piperis Oleoresin of Pepper Pepper,^ in No. 60 powder,' one hun- greater part of the ether by distilla- dred parts 100 tion on a water-bath,* and expose the Stronger Ether,' a sufficient quantity, residue, in a capsule, until the re- Put the pepper into a cylindrical maining ether has evaporated,' and percolator, provided with a cover and the deposition of piperine, in crystals, receptacle suitable for volatile liquids,* has ceased. Lastly, separate the press it firmly, and gradually pour oleoresin from the piperine by ex- stronger ether upon it, until one hun- pression through a muslin strainer.' dred and fifty (150) parts of liquid Keep the oleoresin in a well-stopped have slowly passed.' Recover the bottle.' 1890 Oleoresina Piperis Oleoresin of Pepper Pepper,^ in No. 60 powder,' five hun- from the percolate by distillation on a dred grammes 500 Gm. water-bath,* and, having transferred Ether,^ a sufficient quantity. the residue to a capsule, set this aside Put the pepper into a cylindrical until the remaining ether has evapor- glass percolator, provided with a stop- ated,^ and the deposition of crystals of cock, and arranged with a cover and piperine has ceased. Lastly, sepa- receptaele for volatile liquids.'* Press rate the oleoresin from the piperin by the drug firmly, and percolate slowly expression through a muslin strainer.' with ether, added in successive por- Keep the oleoresin in a well-stop- tions, until the drug is exhausted." pered bottle.' Recover the greater part of the ether 214 E>U MEZ— THE GALENICAL OLEORESINS 1900 Oleoresina Piperis Oleoresin of Pepper Pepper/ in No. 40 powder/ -five hun- distillation on a water-bath,' and, dred grammes 500. Gm. having transferred the residue to a Acetone/ a sufficient quantity. dish, set this aside in a warm place, Introduce the pepper into a cylin- until the remaining acetone has evap- drical glass percolator, provided with orated,'' and the deposition of crystals a stop-cock, and arranged with a cover of piperin has ceased. Lastly, sepa- and a receptacle for volatile liquids.* rate the oleoresin from the piperin by Pack the powder firmly, and percolate straining through purified cotton.' slowly with acetone, added in succes- Keep the oleoresin in a well-stoppered sive portions, until the pepper is ex- bottle.* hausted." Kecover the greater part Average dose. — 0.030 Gm. :=30 mil- of the acetone from the percolate by ligrammes (^ grain). 1910 Oleoresina Piperis Oleoresin of Pepper Olcores. Piper. Pepper,* in No. 40 powder,* -five hun- tillation on a water-bath,* and, hav- dred grammes 500. Gm. ing transferred the residue to a dish, Ether,^ a sufficient quantity. set this aside in a warm place until Place the pepper in a cylindrical the remaining ether has evaporated,' glass percolator, provided with a stop- and the deposition of piperine has cock, and arranged with a cover and ceased. Lastly, separate the oleo- s. receptacle for volatile liquids.* resin from the piperine by straining Pack the powder firmly, and perco- through purified cotton.' Keep the late slowly with ether, added in sue- oleoresin in a well-stopped bottle.' cessive portions until the drug is ex- Average Dose. — Metric, 0.03 Gm. — hausted.' Kecover the greater part of Apothecaries, ^2 grain, the ether from the percolate by dis- 1) For a description of the official drug, see page 1117 under ^'Drug used, its collection, preservation, etc." 2) The last two editions of the Pharmacopoeia have specified that the drug be in the form of a No. 40 powder for percolation. Previous editions, with the exception of that of 1850, in which the degree of .fineness was not stated, required that a fine OLEORESIN OF PEPPER 215 powder (No. 60) be used for this purpose. The coarser powder possesses the advantages of being more readily pro- duced and of being better adapted to the rapid exhaustion of the drug. 3) The solvents which have been experimented- with in the preparation of this oleoresin are alcohol, ether, acetone, ben- zin and petroleum ether. Of these, ether has proven to be the most satisfactory and is the solvent specified for this purpose by the present Pharmacopoeia. Acetone, which was directed to be used by the Pharmacopoeia of 1900, like alcohol, is un- satisfactory as the large amount of extractive matter obtained interferes with the separation of the piperine. Benzin or pe- troleum ether, on the other hand, dissolves piperine but slightly and, therefore, yield a product low in piperine con- tent. See tables on page 1134. 4) For a description of percolators adapted to the use of volatile liquids, as specified for use in this connection by the Pharmacopoeia, see Part I under ''Apparatus used." 5) With respect to the manner of exhausting the drug, it is thought that the process of continuous extraction would be a distinct improvement over the present pharmacopoeial method. The reasons for this statement have already been given in the comments of the preceding oleoresins and need not be re- peated here. 6-7) As this oleoresin does not appear to undergo any notice- able changes upon exposure to the air, except to lose a small amount of volatile oil, the conditions under which the solvent is removed from the percolate are not as important as in the case of the other oleoresins. The time necessary to complete the preparation, however, can be considerably shortened if the operation is completed at the temperature of the water bath, for which reason, this procedure is thought to be justi- fied. 8) The Pharmacopoeia directs that the mixture obtained on evaporating the solvent from the percolate be allowed to stand until the deposition of the piperine is complete and that the latter then be separated from the liquid portion by straining through purified cotton. The object to be attained in allow- ing the piperine to deposit is not understood as it has been found in actual practice that the liquid portion. does not sep- 21 g DU MEZ— THE GALENICAL, OLEORESINS arate as a rule, but that the whole sets to form a semi-solid mass owing to the large amount of piperine present. The means by which the separation of the piperine was accomp- lished in the laboratory appears to be more rational and is as follows: the mixture was heated on the water bath until the portion constituting the oleoresin was quite fluid when it was filtered through cotton with the aid of a suction pump. The piperine which deposited from the filtered oleoresin on cool- ing was finally separated by decantation. 9) As the oleoresin loses volatile oil on exposure to the air,, it should be kept in well-stoppered bottles. Yield. The yield of oleoresin to acetone or ether is about 4.5 to 6.5 per cent. With petroleum ether, a yield of 3.2 per cent, was ob- tained in the laboratory. Aside from the effect which the solvent has upon the amount of the oleoresin obtained, the temperature at which the piperin is separated is a factor to be considered. The higher the temperature at which this is accomplished, the greater the amount of piperine remaining in solution and the greater the yield of finished product, and visa versa. In the tables which follow, the yield of total extract is fre- quently reported as oleoresin. These reports should not be confused with those pertaining to the official preparation, which consists of the liquid portion only, the precipitated piperine and other insoluble material having been removed. Data of this kind have been included here for the sake of comparison with results of a like nature obtained in the laboratory and in order to point out the erroneousness of such reports. OLEORESIN OF PEPPER 217 Table 123 — Yield of oleoresin as reported in the literature. Observer Yield of oleoresin to- Date Alco- hol Ace- tone Ether Other solvents 1888 Trimble Per ct. Per ct. Perct. 8.79 Per cent. J Benzin 1 2.80 J Represents total 1892 Bei iii^er 9.97 5.93 yield of extract- tive matter. Sherrard 5.00 to 6.70 8.84 9.64 5.50 8.70 10 15 10.04 10.87 12.88 Yield of oleoresin. .....1 Reported as yield Ballard ... . f of" oleoresin (' ) 1903 Patch , . ) liidies. Total ex- tract. Pepper from Gua- deloupe. Total extiacL. 1913 coa.stof Daliomey. Total extract. Enifelhardt I Represents total ::::::: ::::::::::i » Solvent (?)... . 1 9.20 ] 10.60 1 11.00 f 12.50 J yield of extract. ,. Reported as yield (1) Undoubtedly represents total extract. Table 124 — Yield of oleoresin as obtained in the laboratory. Observer Yield of oleore.sin to— Date Alco- hol \ce- tone Ether Pptrol. ether. Remarks 1916 Du Mez Per ct. 11.10 5.32 Per ct. lO.fiS 5.09 Per nt. 10.42 4.44 Perct. 7.14 3.20 Repre-ents. total ex- tract. Rei resents the por- tion (iecaiitod and waslied from the de- posited piperine. 21g DU MEZ— THE GALENICAL. OLEORESINS Chemistry of the Drug and Oleoresin. Tabulation of Constituents. The chemistry of black pepper has been the subject of a number of investigations^ conducted during the past century. As a result of these investigations, the presence of the follow- ing substances of pharmaceutical interest has been established: volatile oil, piperine, resin, starch, coloring matter and inor- ganic constituents. In addition to the foregoing, the presence of fatty oil, piperidine and methyl pyrroline has been reported. The following are stated by Kayser and others^ to be present in the oleoresin when prepared with ether: Eesin Volatile Oil Coloring Matter Fatty Oil Ash Piperine Occurrence of Description of Individual Constituents. Volatile Oil:^ According to the report of Schimmel and Company,* the volatile oil of pepper is a colorless or yellowish- green liquid, having a phellandrene-like odor. At 15°C, the specific gravity is given as 0.88 to 0.905 and the angle of ro- tation in a 100 millimeter tube as -5° 2' to -[-2° 27'. It is stated to be soluble in 15 parts of alcohol (90 per cent). Early attempts to determine the composition of the oil were made by Dumas,^ and Soubeiran and Capitaine.® In 1887, Eberhardt^ isolated a 1-terpene which he failed, however, to * Among those who have reported more or less complete analyses of pepper the following may be mentioned: Pelletier, Ann. de Chim. et de Phys. (1821), 16, p. 337; Luca, Tschenb. f. Scheidekiinstl. u. Apoth. (1822), 43, p. 81; H. ROttger, Arch. f. Hygiene (1886), 4, p. 183; Richardson, U. S. Dept. of Agric. Bull. No. 13, (1887), p. 206; Johnstone, Chem. News (1888), 58, p. 235; Kayser, Chem. Centralb. (1888). 59, p.261 ; V^eigle, Apoth. Ztg. (1893), 8, p. 468; Hebebrand, Zeitschr. Unters. Nahr. u. Genussm. (1896), p. 345; Winton, Ogden and Mitchell, Ann. Rep. Conn. Exp. Sta. (1898), p. 198; Balland, Journ. de Pharm. et de Chim. (1903), 157, p. 296. 2 Kayser, Weigle, Balland, I. c. 3 The description of the oil as here given is for that obtained from the fruit by distillation with steam. * Schimmel & Co., Semi-Ann. Rep., Oct. 1893, p. 34. »Ann. d. Chem. (1835), 15, p. 159; Journ. f. prakt. Chem. (1835), 4, p. 434. "Journ. de Pharm. et de Chim. (1840), 26, p; 83. 'Arch, der Pharm. (1887), 225, p. 515. OLEORESIN OF PEPPER 219^ identify. Schimmel and Company* have reported the presence of phellandrene and cadinene. From 0.70 to 2.2 per cent, of volatile oil has been obtained from the fruits by steam distillation.® Piperine}^ Piperine (C17H19NO3) was first isolated by Oersted in 1819.^^ It is a weak base crystallizing from alcohol in colorless, shining, four sided prisms, the melting point of which is 128 to 129 °C. It is slightly soluble in boiling water, readily soluble in alcohol, ether, chloroform, benzene and volatile oils, slightly soluble in petroleum ether. When acted upon by solutions of the alkalies, it is hydrolyzed breaking down into piperidine and piperic acid. Its constitution is represented* by the following structural formula :^^ H. H, -O N COCH:CH CH:CH. ^ C H H H, H, H H The quantity of piperine present in the fruit of black pepper as obtained on the market varies to a considerable extent. This variation is very probably due in greater part to natural causes, such as the age of the fruit before harvesting, climatic condi- tions under which grown, et cetera}^ The yield is variously stated as being from 4.05 to 13.02 per cent.^* *i. c. »A yield of 0.7 to 1.69 per cent, of volatile oil is reported by C. H. Rich- ardson I. c. W. Johnstone obtained 0.98 to 1.87 per cent. Analyst (1889), 14, p. 41. G. Teyxeira and B. Ferrucio give the yield as 1.4 per cent. Bull. Chim. Fharm. (1900), 38. p. 534; Chem. Centralb. (1900), 71, p. 736. Schim- mel & Co. (1. c.) report the yield as 1.3 to 2.2 per cent. wRochleder, Ann. d. Chem. (1845), 54, p. 255; Babo and Keller, Journ. f. prakt. Chem. (1857), 72, p. 53; Rugheimer, Ber. d. deutsch. chem. Ges. (1882), 15. p. 1390. "Schweitz. Med. Journ. (1819), 29, p. 80; Buchner, Repert. f. die Pharm.. (1820). 10, p. 127. "Ladenburg- and Scholtz, Ber. d. deutsch. chem. Ges. (1894), 27, p. 2958. " Caseneuve and Caillot report the piperine content to be as follows : Sumatra. 8.10 per cent; Singapore, 9.15 per cent; Fenang, 5.24 per cent. Z. c.. G. Graff gives the following percentages of ether soluble nitrogenous matter as piperine: Java, 5.85 to 9.5 per cent.; Lampong, 5.13 to 7.09 p^r cent.; Penang, 9.12 to 9.42 per cent; Saigon, 6.16 per cent.; Singapore, 11.08 per cent. Zeitschr. f. offentl. Chem. (1908), 14, p. 425. "W. Johnstone obtained 5.21 to 13.03 per cent of piperine from nine samples of black pepper, I. c. C. Heisch gives the yield as 4.05 to 9.38 per cent. Analyst (1886), 11. p. 186. F. Stevenson reports the presence of 7.14 per cent, or piperine. Ihid. 12^ p. 144. 220 ^U MEZ— THE GALENICAL OLEORESINS Resin. The presence of 1.25 to 2.08 per cent, of resin in black pepper has been reported.^^ Buchheim/® the only in- vestigator who appears to have attempted to isolate the same in sufficient purity to determine its composition, states that it Is a condensation product of piperidine with an acid, to which lie gives the name Chavicinsaure. He assigns the name Chavicin to this compound, and describes it as a yellowish-brown mass ■soluble in alcohol, ether, petroleum ether and the other com- mon solvents. Coloring Matter. The green coloring matter in pepper is ■stated to be chlorophyll.^^ The brown coloring matter observed in the ethereal or alcoholic extracts has not been identified. Fatty Oil}^ The presence of a fatty oil in black pepper must be considered doubtful at the present time. Hirsch^^ states that •a microscopical examination of the fruit revealed the presence of a fatty oil in the endosperm. Kayser,^° Weigle,^^ and others mention fatty oil as one of the constituents. None of these investigators, however, appear to have isolated the oil in a pure state or to have described it in detail. Ditzler,^^ who made this matter the subject of a special investigation, concluded that glycerides were absent. Likewise, Gerock^^ could obtain no fat from white pepper. Piperidine. "^^ Piperidine has been named as a constituent of black pepper by Johnstone,^^ who found the average content of nine samples to be 0.56 per cent. Kayser^® disputes the find- ings of Johnstone and states that the base obtained by distilla- tion is ammonia. ^' Teyxeira and Ferruoio grive the resin content as 1.25 per cent., F. Stevenson as 1.44 per cent. I. c. F. Blyth reports the presence of 1.7 to 2.08 per cent. Foods. Their Com- position and Analysis (1903). p. 496. "Buchner's n. Repert. f. Pharm. (1876), 25 p. 335; Pharm. Journ. 1876, 36. p. 315. "Arthur Meyer, Das Chlorophyllkorn, Leipzig (1883), p. 2. "In the literature on food chemistry, the non-volatile ether extract is Aisuolly spoken of as fat or fatty oil. See "Wanton, Ogden and Mitchell, 1. c. ^® Flueckiger, Pharmako gnosis des Pflanzenreiches (1891), p. 914. ^' I. c. 217. c. «Arch. d. Pharm. (1886), 224, p. 103. 2J Ihid. 2* As piperidine is one of the products obtained when piperine ia hydrolysed, It is quite probable that it is not a normal constituent of the fruit but is 'formed when the powdered material is subjected to distillation. 2* I. c. 2« I. c. OLEORESIN OF PEPPER 221 Piperidine is a colorless limpid liquid having a specific gravity of 0.8591 at 25 °C, and boiling at 106.3 °C." It m stated to have an odor resembling both, that of ammonia and pepper. It is a powerful base behaving generally like am- monia in its action on the metallic bases. It is soluble in all proportions in alcohol or water. It has the following struc- tural formula.^®. Methyl-Pyrroline. Pictet and Court-*^ report the occurrence^ of 0.01 per cent of methyl-pyrroline in black pepper obtained from Singapore. The exact constitution has not been deter- mined, but the authors are of the opinion that it is a C-methyl pyrroline represented by one of the following formulas: Ash. The basic elements, K, Na, Mg, Ca, Fe and Mn, com- bined with the acids, HCl, H3PO4, H2SO4, HgSiOg are the com- ponents of the ash of black pepper as determined by Rottger**' and others.^^ The average ash content of black pepper is stated by Blyth^^ 2^Ferkin, Chem. Soc. Journ. (1889), 55, p. 699. 28Hofmann, Ber. der. deutsch. chem. Ges. (1879), 12, p. 985; Koenigs, Ibid., p. 2341; Ladenburg, Ibid. (1885), 18, pp. 2956 and 3100. *» Pictet states that he was able to isolate pyrrolidine and N-methyl pyrro- line from various leaves by steam distillation after treatment with sodiuno carbonate. He is of the opinion that the methyl pyrrolines undergo re- arrangement forming pyridine and quinoline rings, thus giving rise to the- more complex alkaloids. Arch. Sci. Phys. Nat. (1905), 19, p. 329; Ber. d- deutsch. chem. Ges. (1907), 40, p. 3771. "Arch. Hyg. (1886), 4, p. 183. „ »Blyth, Chem. News (1874), 30, p. 170. «2 Ibid. ,"222 DU MEZ— THE GALENICAL, OLEORESINS to be 4.845 per cent. As high as 8.99 per cent, has been re- ported.^^. Constituents of Therapeutic Importance The oleoresin of pepper is said to be used chiefly in the South, where it is administered with quinine in the treatment of ''in- termittent fever." Its value in this connection is accounted for by the presence of piperine which has been shown to be an :active antiperiodic.^ Piperdine and methyl pyrroline, if pres- ent, would impart similar properties,^ while the composition of the contained volatile oil w^ould indicate a carminative action. PJiysical Properties Color: The color of the oleoresin, when the latter was spread out in a thin layer on a white porcelain surface, was observed to be a greenish-brown, closely resembling that of the oleoresin of cubeb when prepared from the ripe fruits. The so-called oil of black pepper, sometimes sold as a substitute for the official oleoresin, is stated to be considerably darker in color due to the removal of the greater part of the volatile oil. Odor: The odor, while slight, resembles that of ground pepper. Taste: The taste is sharp and spicy, the sharpness becom- ing more noticeable after the oleoresin has been retained in the mouth for a short time. Consistence: The oleoresin is a thick, sticky liquid which •can only be poured with difficulty. The fluidity is greatly in- creased by heating the preparation on a water bath. Solubility: The oleoresin is completely soluble in alcohol, ether, acetone, chloroform, carbon disulphide and glacial acetic acid. It is only partially soluble in petroleum ether and is insoluble in water. Specific gravity: The specific gravity of the oleoresin is fairly constant, only, when similar conditions with respect to "Heish reports the ash content of 8 samples of black pepper to be from 4.35 to 8.99 per cent. Analyst (1886), 11, p. 186. Others who have reported on the ash content of pepper are Bergman, Zeitschr. f. Analyt. Chem. (1882), ^1, p. 535, and von Raumer, Zeitschr. angew. Chem. (1893), p. 453. ^Wood, Therapeutics, Principles and Practice, (1908), p. 482. ^Tunnicllffe and Rosenheim, Centralbl. f. Physiol. (1902), 16, p. 93. OLEORESIN OF PEPPER 223 temperature have been observed during the separation of the precipitated piperine. A comparatively slight difference in tem- perature causes a considerable variation in the amount of the latter constituent retained in solution, which results in a cor- responding variation in the specific gravity of the finished pro- duct. This effect is further ncviced in connection with the menstruum employed in extracting the drug, e. g. petroleum ether which is a poor solvent for piperine yields an oleoresin relatively low in specific gravity. With respect to the com- mercial samples examined, a low specific gravity was, in one in- stance, found to be due to the presence of unevaporated solvent. The tables which follow show the specific gravity of the samples examined in the laboratory. Table 125 — Specific gravities of oleoresins prepared in the laboratory. Sample No. Date Observer Solvent Specific gravity 1 1916 DuMez Alcohol At 25° C 1.069 2 1.083 3 •♦ Ether 1.056 4 •• Petrol, ether 981 Table 126 — Specific gravities of commercial oleoresins. Sample No. Date Observer Source Specific gravity 1 1916 DuMez Squibb & Sons At 25° C 0.985' 2 Sharp & Dohme 1.061 The odor of ether was very noticeable. Refractive index: The refractive index of this preparation as observed in the laboratory was not constant, varying from 1.521 to 1.696. From an inspection of the first of the tables which follow, it would appear that this variation was a result of the influence of the solvent employed in extracting the drug. While the solvent undoubtedly exerts an influence in this con- nection, it does so indirectly, that is, through its effect on the piperine content.^ The latter, however, is also influenced by * See discussions under "Piperine content" and "Yield of oleoresin, spectively. 224 DU MEZ— THE GALENICAL OLEORESINS the temperature at which the preparation is finished — the tem- perature at which the liquid oily portion, which constitutes the official oleoresin, is separated from the deposited material, in- cluding the excess of piperine. In the case of commercial samples, the piperine content and, therefore, the refractive in- dex may also be affected by the presence of unevaporated solvent. The results obtained in the laboratory in the deter- mination of this property are given in the tables which follow. Table 127 — Refractive indices of oleoresins prepared in the laboratory. Sample No. Date Observer Solvent Refractive index 1 1916 DuMez Alcohol At 25° C 1 =559 2 .. . Acetone . 1 696 3 " Ether 1 562 4 " Petrol, ether 1 521 Table 128 — Refractive indices of commercial oleoresins. Sample No, Date Observer Source Refractive index 1 1916 DuMez Squibb & Sons Sharp & Dohme At 25° C 1.501(a) 1 560 2 . . (a) Contained ether. Chemical Properties. Loss in iveiglit 071 Jieating: A loss in weight varying fromi 9.49 to 11.52 per cent, was obtained for the laboratory prepara- tions, when heated at 110° C, showing that the nature of the solvent employed in extracting the drug has but little influence on this property. With respect to the commercial samples ex- amined, the loss was much greater, being as high as 32.64 per cent, in one case. The comparatively great loss in the latter instance was due to the presence of unevaporated solvent (ether.) The results obtained in the determination of this constant in the laboratory follow. OLEORESIN OF PEPPER 225 Table 129 — Laboratory preparations — loss in weight on heating. Sample No. Date Observer Solvent Per cent, of loss on heatingr 1 1916 DuMez ,.. Alcohol At 110° C 10.34 2 Acetone Ether Petrol, ether 11.52 3 '« 10.91 4 ti 9.49 Table 130 — Commercial oleoresins—loss in weight on heating-.. Sample No. Date Observer Source Per cent, of] loss on heatin«r 1 1916 DuMez At llO^C 17.52 2 Sauibb & Sons 32.64» ^ Unevaporated solvent (ether) was present. Ash content: The ash determinations made on the oleoresinsi prepared in the laboratory show that the solvent employed ini their preparation is the chief factor influencing the results ob- tained. The official product, in the making of which ether was: the solvent used, yielded 0.11 per cent, of ash, which was about, the percentage yield obtained for one of the commercial samples; examined. The other commercial oleoresin gave 0.29 per cent, of ash indicating the use of acetone in its preparation. Both samples contained copper, apparently, however, in quantities too small to noticeably affect the weight of the ash. The re- sults of the determinations made in the laboratory follow:. Table 131 — Ash contents of oleoresins prepared in the laJ>oratorvi Sample No. Date Observer Solvent Per cent of asli J 1916 DuMez Alcohol O.fS 0.32 O.ll 0.05 2 Acetone 8 •' Ether ..'.'..'.'.*.* 4 •» Petrol, ether 226 DU MEZ— THE GALENICAL OLEORESINS Table 132 — Ash content of commercial oleoresins. Sample No. Date Observer Source Per eent. of ash Foreign constituents 1 1916 DuMez Squibb & Sons... Sharp & Dohme.. 0.12 (a) 0.29 Copper 2 * Contained ether. Acid number: The acid number of the oleoresin when pre- pared with alcohol, acetone or ether was found to be about 19. In the case of the two commercial samples examined, however, the values obtained differed to a considerable extent, being 19.2 in one instance and 27.5 in the other. As the preparation represented by the first number contained considerable unevap- orated solvent, this difference can be accounted for in part. The high values obtained for the commercial samples are thought to be due to their relatively low piperine content or to a partial decomposition of the resin. The values obtained for this con- stant in the laboratory follow. Table 133 — Acid numbers of oleoresins prepared in the laboratory. Sample No. Date Observer Solvent Acid number J 1916 DuMez Alcohol . . 19.2 2 19.0 3 »• Ether 18 9 4 •t Pfitrnl.-fithfir 15.1 Table 134 — Acid numbers of commercial oleoresins. Sample No. Date Observer Source Acid number 1 1916 DuMez Sauibb & Sons 19.2 (a) 2 Sharp & Dohme 27 5 (a) Contained ether. Saponification value: As will be observed in an inspection of the first of the tables which follow, the saponification value of the oleoresin varies with the solvent employed in its prepara- tion. This appears to be due principally to the effect which the nature of the solvent has upon the piperine content of the OLEORESIN OF PEPPER 227 finished product, e.. g. the piperine content of the preparation made with acetone was found to be 54.36 per cent and the saponification value 88.6, while the oleoresin when prepared with petroleum ether, contained only 15.06 per cent, of piperine and gave a saponification value of 109.5. Other influences, besides the nature of the solvent, affecting the piperine content may likewise produce a variation in the saponification value, e. g. the temperature at which the preparation is made and the presence of unevaporated solvent in the finished product. The latter may also have a direct infiuence. The saponification values as found for the oleoresins examined in the laboratory are given in the following tables. Table 135 — Saponification values of oleoresins prepared in the laboratory. Sample No. Date Observer Solvent SaDonlflca- tion value 1 1916 DuMez Alcohol 63 7 2 74 9 3 •« Ether 83 5 4 •• Petrol, ether 86 8 Table 136 — Saponification values of commercial oleoresins. Sample No. Date Observer Source Saponifica- tion value 1 1916 DuMez Sharp & Dohme 66.3 2 Saulbb & Sons 73 7(a) (a) Contained ether. Iodine value: Iodine values ranging from 88.6 to 95.4 were obtained for this oleoresin when acetone, alcohol or ether were the solvents employed in its preparation. This variation is due to the difference in the piperine content of these oleo- resins as a result of operating under different conditions of temperature when preparing the same, as well as to the nature of the solvent. In addition to these influences, the presence of unevaporated solvent must also be taken into consideration in the case of the commercial samples, as is indicated by the values given in the following tables. 228 ^U MEZ— THE GALENICAL OLEORESINS Table 137 — Iodine values of oleoresins prepared in the laboratory. Sample No. Date Observer Solvent Iodine value 1 1916 DuMez Alcohol Act'tone 90.0 2 88.6 3 .» * ■ Eiher Petrol. -elher 95.4 4 '• 109.5 Table 138 — Iodine values of commercial oleoresins. Sample No. Date 1916 Observer DuMez. Scource Sharp & Dohme. Stiuibb & Sons... Iodine value 83.7 89.9 (a) (a) Contained ether. Special Quantitative Tests. At the present time, there does not appear to be a method in use for the evaluation of this oleoresin. As its therapeutic properties are due, in greater part at least, to its piperine con- tent,^ a quantitative method for the estimation ot this con- stituent appears to offer the best means of determining its quality. Method for the Estimation of the Pipeline Content. In the laboratory, the amount of piperine present was com- puted from the nitrogen content of the oleoresin, the latter being determined by the Gunning-Arnold^ method. The re- sults obtained are given in the following tables: Table 139 — Piperine content of oleoresins prepared in the laboratory. Sample No. Date Observer Solvent Piperine content 1 1916 DuMez Alcohol Per cent. 47.0 2 Acetone 54.3 8 «» Ether 51.3 4 •« Fetrol, ether 15 1 1 See under "Constituents of therapeutic importance.' 'Bull. No. 107. Bur. of Chem. (1912), p. 162. BIBLIOGRAPHY 229 Table 140 — Piperine content of commercial samples. Sample No. Date Observer Source Piperine content 1 1916 DuMez Sharp & Dohme Per cent. 27.3 2 Squibb & Sons 33.8 The laboratory samples were prepared and tested during the warm months of summer, which accounts for the high piperine content. A very considerable amount of the latter precipitated out during the colder months which followed. It is, therefore, thought that the results obtained in the case of the commercial products are the more typical. Adulterations. Copper was found to be present in all of the commercial samples examined. See under ''Ash content.'* Bibliography. Planche 1823 Von den pharmaceutischen Zubereitungen des Lupulins. Mag. f. Pharm., 1, p. 183. [Trommsdorff's n. Journ. d. Pharm., 7, p. 345.] A method for preparing the alcoholic tincture of lupulin is given. It is further stated that an extract similar in all respects to the resin said to have been isolated by Ives results when the alcohol is removed from the tincture by evaporation. Geiger, Ph. L. 1824 Versuche fiber die chemische Zusammensetzung der Wurzel des maennlichen Parrenkrauts, Polypodium (Aspidium, NepJi- r odium) Filix Mas. Mag. f. Pharm., 7, p. 38. The article is a review of Morin's analysis of the rhizome of male fern with a note pointing out that Morin was not the first investigator to make such an analysis, but that Gebhardt had already published an analysis of the same in 1821 in an inaugural dissertation delivered at Kiel. Gebhardt is stated to have used ether for extracting the "oil." 230 I^U MEZ— THE GALENICAL. OLEORESINS Morin 1824 Sur la composition chimique de la racine de fougere male, Polypodium filix mas Linn. Journ. de Pharm. et de Chim., 10, p. 223. [Mag. f. Pharm., 7, p. 38.] In making a chemical examination of the male fern rhizomes, the author used the method of selective solvents. Upon extracting with ether, as the first solvent, and subsequently evaporating of the ether, a thick green fatty oil was obtained. The author considers this fatty substance the active principle. Meli 1825 Nene Erfahrungen und Beobachtungen ueber die Art, das Alkaloid und das seharfe Oel des Pfeffers zu gewinnen. Trommsdorff's n. J. d. Pharm., 11, p. 174. [Bull, de scien. math., phys. et chim., 1825, p. 191.] It is stated that more than an ounce and a half of piperine and about four ounces of a sharp tasting oil were obtained from three pounds of black pepper by extraction with alcohol. Peschier, Ch. 1825 Oel des maennlichen Farrenkrauts (Aspidium Filix Mas), ein sehr vorzuegliches und sicheres Mittel gegen den Bandwurm. Biblioth. univers., Nov. 1825, p. 205. [Mag. f. Pharm., 13, p. 188.] The so called oil, Euile de Fougere Mdle, is directed to be prepared by extracting the powdered male fern rhizomes with ether and subsequently re- moving the ether by warming gently. Buchner, A. 1826 Extractum Filicis maris resinosum. Repert f. d. Pharm., 23, p. 433. The preparation of this extract by means of alcohol instead of ether is recommended. The product thus obtained is spoken of as an Extractum resinosum. The Kuile de Fougere of Peschier is spoken of as the harz- haltiges Oel. A chemical analysis of the extrpiCt is also given. von Esenbeck, Nees 1826 Farrnkrautwurzelextrakt. Arch. d. Pharm., 19, p. 153. The extract is reported to have been prepared by the process of macera- tion, ether being the solvent employed. Four ounces of rhizomes gathered in August gave 108 grains of extract. BIBLIOGRAPHY 231 1827 Verhandlungen des pharmaceutischen Vereins in Wuertem- berg. Eepert. f. d. Pharm., 26, p. 441. Zeller is stated to have prepared the Extractum radicis Filicis maris resinosum according to the method suggested by Buchnerj extraction with alcohol. The extract obtained in this manner from rhizomes gathered in September amounted to 30 per cent, of the air dried drug. Batso, Y. 1827 Dissertatio inaugur. chemica de Aspidio filice mare Quam cons, et auctor. praes et direct, etc., pro summis in scient. et arte chemica honor, et doct. laurrite cappess. in miivers. vindobon. publ. erudit, disq. snbmittit Valentinus Batso, N. H. Debreczino Bibariensis p. 37, 8. Vindobonae, typis Antonii Pichler. 1826. [Trommsdorff's n. Journ. d. Pharm., 14, 2, p. 249.] In addition to oil, resin and fatty wax, the author finds a free acid and an alkaloid in the ethereal extract of male fern. He calls the acid Acidum filiceum and the alkaloid Filicina. He attributes the activity of the extract to these two substances. Brandes, R. * 1827 Ueber das Extractum oleo-resinosum Filicis. Arch d. Pharm., 21, p. 253. The physical properties of the extracts obtained by extracting male fern rhizome with ether and with Liquor anodynus, respectively, are de- scribed. Buchner, A. 1827 Zur medicinischen und chemischen Geschichte der Filix mas. Repert. f. d. Pharm., 27, p. 337. The author speaks of the ethereal extract of male fern as the Extractum oleoso-resinosum Filicis maris. It is stated to contain a volatile oil, a green fatty oil, a fatty wax, a brown resin and a volatile acid (probably acetic acid.) Van Dyk 1827 Ueber das Oleum Filicis maris. Arch. d. Pharm., 22, p. 141. Two ounces of powdered male fern rhizome gave 70 grains of ethereal extract, while 8 ounces of the rhizome yielded 3 ounces of extractive matter 232 DU MEZ— THE GALENICAL OLEORESINS to alcohol. The extract prepared with ether is stated to be dark olive- ;green in color and of the consistence of honey, that prepared with alcohol .•greenish-brown in color and much thicker. Oeiger, Ph. L. 1827 Analytische Versuche mit der Wurzel des maennlichen Parrenkrauts und Darstellung des Gels (01. Filicis Maris) ^us derselben. Mag. f. Pharm., 17, p. 78. The ethereal extract when prepared from green rhizome, by extraction with ether in a Bealsche Presse is said to be a yellowish-green oily sub- stance. An analysis of this extract showed the presence of 30 per cent, of resin- ous material soluble in alcohol, 50 per cent, of a fixed oil and a considerable amount of volatile substances. TiUoy 1827 Bereitungsart des Oels des maennlichen Farrenkrauts. Journ. de Chim. med., 3, p. 154. [Geiger's Mag. f. Pharm., 18, p. 157.] The so-called oil of male fern is directed to be prepared by extracting the rhizome with alcohol. The alcoholic liquor thus obtained is treated with lead subacetate, filtered, and the solvent removed by distillation. The resulting oil is further purified by dissolving in ether and evaporating. Dublanc, H. 1828 Extrait oleoresineux de Cubebe. Journ. de Pharm. et de Chim., 14, p. 41. The author's method for preparing the oleoresinous extract consists in distilling off the volatile oil with water, exhausting the dried marc with alcohol, evaporating off the alcohol, and mixing the residue so obtained with the volatile oil. Meylink 1828 Ueber das Extractum oleo resinosum Filicis. Arch. d. Pharm., 25, p. 243. Two ounces of the powdered male fern rhizome are reported to have yielded 58 grains of a dark green, oily extract to ether. Oberdoerffer 1826 Ueber die Darstellung des Cubeben Extracts. Arch. d. Apoth. Ver., 24, p. 178. In the method of preparation, the oil is first obtained by steam distilla- tion, the marc remaining in the still, after drying, is then extracted with BIBLIOGRAPHY 233 alcohol. The residue remaining after removing the alcohol by evapora* tion is mixed with the volatile oil, this mixture constituting the so-called extract. Peschier, Ch. 1828 Ueber mehrere schon frueher erschienene Analysen der Farrenkrautwurzel (Aspidium filix mas L.) und neber die Gewinnnng seines harzigen Oels. Trommsdorff's n. Journ. d. Pharm., 17, p. 5. The vermifuge properties of male fern are said to be due to its ol6o- resine (oelliars) content. This the author prepares by extracting the drug with ether and subsequently evaporating the solvent, (p. 8.) It is further stated that this oleosesine remains perfectly homogenous after months if prepared from freshly gathered rhizomes, but deposits a white granular substance when old rhizomes are used (p. 9.) According to the author's analysis the oleoresine consists of a volatile aromatic oil, a fatty oil, resin, stearin, green and red coloring materials, acetic and gallic acids. Winkler, F. L. 1828 Einige Worte ueber die Bereitung des 01. Filic. Maris. Geiger's Mag. f. Pharm., 22, p. 48. The ''oil" extracted with ether is said to be a mixture of oil, resin and oxidized tannin. Twelve ounces of rhizomes gathered in February yielded 15 drachms of extract. Two drachms of this extract yielded 43 grains of fatty oil. Allard 1829 • Note sur rhuile de fougere. Journ. de Pharm. et de Chim., 21, p. 292. The powdered rhizome of the male fern is directed to be extracted with alcohol and the alcoholic extract after evaporating off the solvent, washed with water. The extract is then further purified by solution in ether and subsequent evaporation. Carpenter, G. W. 1829 Observations and Experiments on Peruvian Bark. Silliman's Am. Journ., 16, p. 28. [Buchner's Repert f. d. Pharm., 34, p. 446.] . In the discussion of the therapeutic uses of the various constituents of Peruvian bark, it is stated that Dr. Chapman of Philadelphia prescribed piperin and oil of pepper in combination with quinine. The oil of pep- per is said to be the more active therapeutically, one drop of oil being equivalent to three grains of piperin (p. 39.) 234f DU MEZ— THE GALENICAL OLEORESINS Haendess 1^29 Ueber 01. filicis maris. Arch. d. Pharm., 28, p. 212. Four ounces of powdered male fern rhizomes gave 170 grains of ethereal extract. Upon treating this ethereal extract with alcohol, 20 grains were dissolved leaving a residue of 150 grains. The extract first obtained was of a brownish color, after treating with alcohol it assumed a beautiful green color. Voget 1829 Notiz ueber 01. filicis maris. Arch. d. Pharm., 30, p. 104. According to the author's method of preparing the Oleum filicis maris, the powdered male fern rhizome is first extracted with water. After dry- ing the drug is then extracted with ether. Twenty-eight grains of a brownish-green extract were obtained from 9 drachms of the marc. Schuppmann 1830 Extractum resinosum Seminis Cynae. Buchner's Repert. f. d. Pharm., 35, p. 430. The extract is directed to be prepared by macerating 4 ounces of the coarsly powdered seed with 16 ounces of ether for 3 or 4 days, decanting the liquid portion and evaporating to remove the solvent. Beral 1834 Du principe du gingembre, et formules de plusieurs com- poses pharmaceutiques dont il est la base medicamenteuse. Journ. de Chim. med., Pharm. et Tox., 10, p. 289. The product obtained by extracting ginger with ether is designated Fiperoide du Gingemhre. It is directed to be prepared by extracting in a percolator 4 ounces of ginger with 6 ounces of ether, the rate of flow being so regulated that the operation will consume not less than 2 hours. It is stated that 5 scruples of piperoide were obtained in this manner, and that € scruples can be obtained if the residual ether is forced out by subse- quent percolation with alcohol (40°). The piperoide is 'reported to be soluble in ether, anhydrous alcohol and oils. • 1838 Extrait Oleo-Resineaux de Cubebe, Journ. de Chim. med., Pharm. et Tox., 14, p. 366. It is stated that Hausman prepared the oleoresinous extract of cubebs by macerating the powdered drug with ether (625 grams of ether to 250 grams of drug), then decanting and evaporating the ethereal solution to remove the solvent. BIBLIOGRAPHY 235 Hornung 1844 Pharmaceutisch-Chemische Mittheilungen. Arch. d. Pharm., 89, p. 34. Three ounces of fresh, powdered rhizomes of male fern, treated with 3 ouncs of ether in a Verdraengungsapparat, are reported to have yielded 2 drachms of extract. Luck, E. 1845 Ueber einige Bestandtheile der Eadicis Filicis. Ann. d. Chem., 54, p. 119. Upon standing, the ethereal extract deposits a granular substance which can be obtained quite pure by pouring off the supernatant oily layer and washing the deposit rapidly with ether. The washed precipitate, dis- solved in ether, crystallizes, upon evaporation, in rhombic leaflets, m. p. 160°C, insoluble in alcohol or water. The crystals were not obtained in a suflScient degree of purity to determine their chemical constitution. Procter, Wm., Jr. 1846 On the Ethereal Extract of Cubebs. Am. Journ. Pharm., 18, p. 167. [Pharm. Jonm., 6, p. 319.] At Dr. Goddard 's request, Procter prepared a * ' true oleoresin ' ' of cubebs by extracting the drug with ether. This method is regarded by him as a great improvement over the method of Soubeiran. Bell 1846 Oleoresinous Extract of Cubebs. Pharm. Journ., 6, p. 319. The report includes a reprint of Procter's paper on the ethereal ex- tract of cubebs and remarks by Ure, at whose request the preparation was made and by whom it is stated to have been used with success. A yield of 15 to 20 per cent, of oleoresin was obtained. Procter, Wm., Jr. 1849 Remarks on oleoresinous ethereal extracts, their preparation and the advantages they offer to the medical practitioner. Am. Journ. Pharm., 21, p. 114. A method for the preparation of the following ethereal extracts is given: capsicum, chenopodium, semen contra, ginger, cardamom and pellitory. (p. 116.) Several forms of apparatus, including a tin percolator, Mohr's apparatus for extracting with ether and Gilbertson's diplacement appara- tus are also described as being useful in this connection. ?36 DU MEZ — THE GALENICAL OLEORESINS Bock, H. 1851 Analyse der Wurzel nnd des Wedels von Filix mas. Arch. d. Pharm., 115, p. 257. [Am. Jonrn. Pharm., 24, p. 61.] The powdered rhizomes were extracted with ether, specific gravity 0.720. By this means, 2000 grains of the powder are reported to have yielded 257.4 grains of an oily extract which was found to be composed of volatile oil, tannic acid, resin, fatty oil stearin and chlorophyll. The author recommends preparing the oleoresin from fresh rhizomes as he states that the greater part of the volatile oil is lost upon drying and the fatty oil tends to become rancid. Lncke, E. 1851 Ueber einige Bestandtheile der Wurzel von Aspidium Filix mas. Jahrb. f. prakt. Pharm., 22, p. 130. [Arch. d. Pharm., 119, p. 178 ; Journ. de Pharm. et de Chim., 54, p. 476.] A crystalline substance resembling the Filicin obtained by Trommsdorff eight years previous was isolated from the ethereal extract. The author calls it Filixsaeure and assigns it the formula C20H15O9 It is further stated that extracts prepared with ether contain no tannic acid or sugar, but filix acid, pteritannic acid and fatty oil are present. Upon being saponi- fied, the oil yielded Filixolinsaeure (C42H40O4 + H O) and Filosmylsaeure. Von der Marck, W. 1852 Ueber Verfaelschnng der Radicis Filicis maris. Arch. d. Pharm., 120, p. 87. The botanical characteristics of other than the official species are enumerated and the manner in which they differ from those of male fern pointed out. With respect to the male fern rhizomes, the author gives the following information: rhizomes gathered in September are the most active as they contain the greatest amount of oil. In the preparation of the extract, only that portion of the rhizome having borne fronds in the year collected, should be taken. The following results were obtained using different parts of the rhizome: 1.) Extract from portion of rhizome which had borne fronds the previous year. Yield 7.8% of a brownish-green extract. 2.) Extract from portion bearing fronds during year collected. Yield 8.2% of a beautiful green extract. 3») Extract from portion which will develop fronds the coming year. Yield, 8.5% of a beautiful green extract. BIBLIOGRAPHY 237 Schuck, F. 1852 Ueber Cubebin Buchner's n. Repert. f. d. Pharm., 1, p. 213. [Jahresb. d. Pharm., 12, p. 34.] Cubebin is stated to be slowly deposited from the ethereal extract of cubeb upon standing. The extract prepared from 17 ounces of cubeb gave 15 grains of cubebin. Bakes, W. C. 1853 Extract of Capsicum. Am. Journ. Pharm., 25, p. 513. The extract was prepared at the request of a physician. Dilute alcohol was employed for exhausting the drug. Eight ounces of Capsicum yielded two ounces of extract. It is stated that a simple ointment which acts as a rubiafacient in 20 minutes may be prepared by mixing one drachm of this extract with 1 ounce of simple cerate. Livermore 1853 Extract of Lupulin. Am. Journ. Pharm., 25, p. 294. The extract is directed to be prepared by maceration, using alcohol as the solvent. Sixty-six per cent, of extractive matter was obtained by this treatment. Garot and Schaeuffele 1857 Rapport sur le produit oleo-resineux de cubebe obtenu a Taide du sulfure de carbone. Journ. de Phai-m. et de Chim., 65, p. 368. The article is on the experimental preparation of the oleoresin of cubebs with carbon disulphide. This solvent is proven to be worthless for this purpose on account of the large amount necessary for extracting the drug and on account of the difficulty in removing it by evaporation. Landerer, X. Ueber Cubebinum. Arch. d. Pharm., 139, p. 302. The so-called cubebin was obtained in the preparation of Extractum Cubebarum oleoso-resinosum, for which a mixture of ether and alcohol was used. Upon standing in a cool place, needle-like crystals adhering in groups were noticed. These crystals were soluble in warm alcohol and gave a carmine red color with sulphuric acid. 238 DU MEZ— THE GALENICAL OLEORESINS Procter, Wm., Jr. 1859 Formulae for the fluid extracts in reference to their more general adoption in the next pharmacopoeia. Proc. A. Ph. A., 8, p. 265. [Am. Journ. Pharm., 31, p. 548.] It is suggested that the preparations made by extracting drugs with ether be designated as Oleoresinae in the next pharmacopoeia. Methods for preparing the following oleoresins are described: " Oleoresina Cardamom^ Oleoresina CaropJiylli, Oleoresina Cuhelae, Oleoresina Filicis maris, Oleo- resina LupuUnae, Oleoresina Piperis Nigri, Oleoresina Pyrethri, Oleoresina Satinae, Oleoresina xanthoxyli and Oleoresina Zingiieris.'* Girtle 1863 Extractum Cubebarum oleoresinosum. Pharm. Centralh., 3, p. 608. [Canstatt's Jahresber., 23, p. 178.] The preparation is an aqueous-alcoholic-ethereal extract with which the volatile oil, previously obtained by distillation, has been incorporated. It is said to represent the therapeutic properties of the entire drug. It is also stated that this preparation is not identical with the Extr. Cub. oleoso- resinosum of Landerer (1857.) Parrish, E. 1864 On Capsicum. Proc. A. Ph. A., 12, p. 262. [Jahresb. 1 Pharm. 1, p. 68.] In discussing the constituents of capsicum, Parrish refers to the ethereal extract as the oleoresin. Bernatzik, W. 1865 Chemische Untersuchung der Cubeben mit besonderer Beruecksichtigung der Wirkungsweise ihrer wesentlichen Bestandtheile. Buchner's Repert. f. d. Pharm., 14, p. 97. [Arch. Pharm., 179, p. 123.] The article is a comprehensive discussion of the constituents of cubebs and their physiological and therapeutic action. Based on the results of clinical experiments, it was concluded that the desired therapeutic principle is the resinous constituent and that the volatile oil, cubeb camphor and cubebin are practically of no therapeutic value. A method for preparing the Extractum Cubeharum resinosum, in ^vhich cubebs freed from the volatile oil are extracted with alcohol, is given (p. 139.) BIBLIOGRAPHY 239 1866 Procter, Wm., Jr. Note on Oleoresina Cubebae. Am. Journ. Pharm., 38, p. 210. [Pharm. Journ., 25, p. 620.] The author reports the results obtained in the extraction of cubebs with ether, alcohol and benzine. The yield of oleoresin obtained was as fol- lows: ether, 21.9 per cent., alcohol, 27 per cent, benzine, 16.5 per cent, (p. 212). The use of benzine in the preparation of this oleoresin is not recommended as it does not extract the cubebin completely. Rittenhouse, H. N. 1866 On Substitutes for Ether and Alcohol in the Preparation of the Official Oleoresins. Proc. A. Ph. A., 14, p. 208. [Am. Journ. Pharm., 38, p. 24.] The feasibility of displacing the ether remaining in the exhausted drug with benzine, glycerine or water is discussed. From experiments conducted along this line, it was concluded that benzine would be the most preferable for this purpose. A working formula in which benzine is used to this end is described. Cubebs and ginger were the drugs employed in the experiments. Paul, C. 1867 Sur I'extrait oleoresineux de cubebe. Journ. de Pharm., et de Chim., 84, p. 197. The extract is directed to be prepared by treating the powdered drug successively with water, alcohol and ether. The extract so prepared iSi said to contain all of the medicinal principles of the original drug. Pile • 1867 On the preparation of Oleoresins with benzine. Proc. A. Ph. A., 15, p. 94. One pound of cubebs percolated with 2 pounds of light benzine, specific gravity 86°, Beaume, is stated to have yielded a trifle over 5 per cent, of oleoresin of a pale ash color. It is further stated that neither benzine nor ether completely exhaust ginger, but that alcohol is a much better solvent for this purpose. Heydenreich, F. V. 1868 On Cubebin and the Diuretic Principle of Cubebs. Am. Journ. Pharm., 40, p. 42. Eighty ounces of cubebs yielded, when extracted with ether, 19 ounces of oleoresin or nearly 24 per cent. The results obtained in the administration of cubebin, the volatile oil and the soft resin are given. 240 ^^ MEZ— THE GALENICAL OLEORESINS Rump, C. ' 1869 Extractum Lupulini aethereum. Arch. d. Pharm., 189, p. 232. [Jahresb. d. Pharm., 4, p. 39.] The extract of lupulin is directed to be prepared hj macerating the fresh drug with ether, decanting and evaporating the ethereal solution to the consistence of a thin syrup. Squibb, E. 1869 Keport of the Committee on the Pharmacopoeia. Proc. A. Ph. A., 17, p. 298. The process of repercolation is stated to be well adopted to the prep- aration of the oleoresins and that it materially lessens their cost. Lefort, M. J. 1870 Memoire sur les extraits sulfocarboniques, et sur leur emploi dans la preparation des huiles medicinales. Journ. de Pharm., 90, pp. 102-110. In considering the methods of medicating oils, the author proposes pre- paring the extract of the leaves of Conium maculatum by exhausting the drug with carbon disulphide and subsequently removing the solvent by evaporation. Hager, 1871 Zur Bereitung des Extractum Filicis aethereum. Pharm. Centralh., 12, p. 457. [Am. Journ. Pharm., 44, p. 104.] It is stated that, if the rhizomes are dried over burned lime previous to extraction, and anhydrous ether (Sp. gr. below 0.723) used as the ex- tracting solvent, the oleoresin does not deposit on standing but remains perfectly clear. Maiseh, J. M. 1872 On the use of Petroleum-Benzine in Making Oleoresins. Am. Journ. Pharm. 44, p. 208. [Pharm. Journ., 31, p. 968; Proc. A. Ph. A., 21, p. 138; Year-Book of Pharm., 10, p. 328.] Petroleum benzine, sp. gr. 0.700, is stated to have been used to advantage in the preparation of the oleoresins of capsicum, cubeb and ginger, but. the author regards the use of this solvent in the place of ether as inad- missable until it has been proven that the proximate principles not ex- tracted by th(B benzine are medicinally inert. BIBLIOGRAPHY 241 Buchheim 1873 Fructus Capsici. Vierteljahresschr, f. prakt. Pharm., 22, p. 507. [Proc. A. Ph. A., 22, p. 106.] The capsicin sold by the firm of E. Merck is stated to be the ethereal extract of the capsicum fruit. Kemington, J. P. 1873 On the Use of Petroleum Benzin for Extracting Oleo- resinous Drugs. Proc. A. Ph. A., 21, p. 592. It is stated that benzin does not extract all of the diuretic principles from buchu and that its use for extracting the oleoresinous drugs is limited on account of its inflammability and great volatility. Patterson, J. 1875 Aspidium marginale, Wildenow. Am. Journ. Pharm., 47, p. 292. The ethereal extract compared very favorably in appearance, taste and color with the best German oleoresin of male fern which could be obtained upon the market. An acid resembling the filicic acid of Luck was isolated therefrom. Kruse 1876 Versuch einer vergleichenden Analyse der in den Monaten April, Juli und October 1874, in der Umgegend Wolmars gesam- melten Radicis filics maris. Arch. d. Pharm., 209, p. 24. The results obtained in the analyses of rhizomes gathered during the months of April, July and October are tabulated. The rhizomes gathered in April and October were found to have a more intensive green color and stronger odor than those gathered in July. The rhizomes gathered in April and July yielded a yellow colored extract while those gathered in October gave a beautiful green colored product. Griffin, L. F. 1877 Preparations of Cubebs. Am. Journ. Pharm., 49, p. 552. The author found that cubebs yielded 16.5 per cent, of oil and resin to gasoline, while the wax and cubebin were not extracted. He, therefore, concludes that gasoline is adapted to the making of a good oleoresin of cubebs. 242 DU MEZ— THE GALENICAL OLEORESINS Wolfe, L. 1877 On the use of Petroleum Benzin in Pharmacy. Am. Journ. Pharm., 49, p. 1. It is stated that benzin does not extract any of the pungent resins from ginger, no cubebic acid from cubebs, no piperin from pepper, and no santonin or resin from wormseed. Cressler, C. H. ' 1878 On Aspidium marginale, Swartz. Am. Journ. Pharm., 50, p. 290. The author prepared an oleoresin from what he thought was male fern, but later proved to be Aspidium marginale. According to his report, it proved effective in expelling tapeworm. Rohn, E. 1878 Recovering Ether in the Preparation of the Ethereal Extracts. Schweiz. Worchenschr. f . Chem. u. Pharm., — , p. — [Year- Book Pharm., 16, p. 250.] The author recommends mixing the exhausted drug with water and then heating the mixture over a direct flame up to 60° C, when the ether remaining in the marc distills over. In this manner three kilos of ether are stated to have been recovered from eight to ten kilos of male fern used in the preparation of the extract. Kennedy, . 1879 Aspidium marginale. Am. Journ. Pharm., 51, p. 382. Favorable results in the expulsion of taenia by the administration of oleoresin of Aspidium marginale a'*© reported. Thresh 1879 Proximate Analysis of the Rhizome (Dried and Decorti- cated) of Zingiber Officinalis and Comparative Examination of Typical Specimens of Commercial Gingers. Pharm. Journ., 39, pp. 171 and 191. The yield of ether extract is given as follows: Jamaica ginger, 3.29 per sent., Cochin, 4.965 per cent., African, 8.065 per cent. It is further stated that twice as much ether is required to exhaust the African ginger as it is necessary in the case of the other sorts (p. 191.) BIBLIOGRAPHY 24$ Bowman, J. ' 1881 Aspidium rigidum. Am. JoTirn. Pharm., 53, p. 389. [Pharm. Journ. 12, p. 263.] A crystalline substance thought to be identical with the Filixsaeure of Luck was obtained from the ethereal extract of Aspidium rigidum. Seifert, 0. * 1881 Einiges ueber Bandwurmkuren. Wien. Med. Wochenschr., 31, p. 1364. [Centralb. f. klin, Med. 3, p. 1884.] The author contends that the extract should be prepared from the peeled fresh drug gathered in May or October as drying causes the loss of a greater part of the volatile oil. The ether should not be evaporated until just before the extract is to be dispensed. Maisch, J. M. 1883 Comparison of Galenical Preparations of the United States and German Pharmacopoeias. Am. Journ. Pharm., 55, p. 398. In the preparation of oleoresin of cubebs, the German Pharmacopceia directs that a mixture of equal parts of ether and alcohol be used as a menstruum^ while the Z7. S. Pharmacopoeia directs that ether alone be used. In the preparation of oleoresin of aspidium, the solvents are the same (ether) but the German Pharmacopoeia directs that the oleoresin be pre- pared by maceration instead of percolation as in the Z7. S. Piiarma^opodia, Kramer 1884 Extractum filicis maris. Pharm. Centralh., 25, p. 578. The fresh rhizomes gathered in May or October, are directed to be ex- tracted with, ether containing a little alcohol. The tincture thus obtained is to be preserved in a cool place and the oleoresin prepared therefrom immediately before dispensing. Berenger-Feraud 1886 Valeur taenifuge de la fougere de Normandy. Journ. de Pharm. et de Chim., 14, p. 321. [Arch. d. Pharm., 224, p. 134.] The author states that the rhizomes gathered in Normandy have scarcely any action while those gathered in the Vosges or Jura mountainB are very active as taeniafuges. ^44 ^U MEZ— THE GALENICAL OLEORESINS Jones, E. W. 1886 Amount of Starch in Ginger. Chem. & Drugg., 28, p. 413. [Arch. d. Pharm., 224, p. 769.] The yield of ethereal extract is given as 3.58 per cent., of alcoholic extract :-as 3.38 per cent. 1887 Extractum Cubebarum aethereum. Gehe & Co. Handels -Ber. Sept., 1887, p. 50. It is stated that, upon long standing, the extract of cubebs deposits a crystalline substance. The firm, therefore, cannot guarantee that the •extract will remain clear. Kremel, A. 1887 Notizen zur Pruefung der Arzneimittel. Pharm. Post, 20, p. 521. [Archiv. d. Pharm., 225, p. 880.J Methods for the identification and evaluation of the ethereal extract of cubebs are presented. The chemical constants of both the alcoholic and ethereal extracts are tabulated (p. 522.) Analytical data on the alcoholic and ethereal extract of male fern are also given (p. 523.) Lippincott, C. P. 1887 What Are the uses of Benzine and the Lighter Petroleum Products in Pharmacy? Proc. Penn. Pharm. Assoc, 10, p. 156. The six official oleoresins were prepared using "benzole" as the ex- iiausting menstruum. Keefer, C. D. 1888 Aspidium marginale, Willdenow. Am. Journ. Pharm., 60, p. 230. The author states that the ethereal extract of the rhizomes of Aspidium marginale contains 0.61 per cent, of resin, and chlorophyll. Filicic acid could not be identified. :Siggnis, F. M. 1888 Comparative value of commercial gingers. Am. Journ. Pharm., 60, p. 278. The following percentages of resin were obtained on extracting ginger U MEZ— THE GALENICAL OLEORESINS 1904 Extractum Filicis. Caesar and Loretz, Geschaefts-Ber., Sept. 1904, p. 77. It is stated that for years the firm has placed upon the market under their name an extract of male fern containing not less than 29 per cent. of crude filicin. Dieterich 1904 Ueber Extractum Filicis, D. A. IV. Helfenberger Ann., 1904, p. 182. The results obtained in the examination of 3 samples of the extract of male fern are tabulated. The results include the per cent, of ' ' moisture ' ' and ash, and the iodine and saponification values. 1905 Extractum Filicis. Caesar and Loretz, Geschaefts-Ber., Sept. 1905, p. 7. It is stated that, although the year's crop of male fern is poor, the firm guarantees a crude filicin content of 28 per cent, for their extract, (p. 71.) Promme's method for estimating the crude filicin content is given (p. 85.) 1905 Ueber die wirksamen Bestandtheile des Famwurzel- extrakts. Pharm. Ztg., 50, p. 651. The work of Boehm, also thai of Kraft, is commented on, special ref- erence being made to Filmaron isolated from the extract by the latter. 1905 The Newer Remedies. Am. Drugg. & Pharm. Rec, 46, p. 135. Capsolin which is recommended as a substitute for mustard papers, is said to consist of a mixture of oleoresin of capsicum, the oils of turpentine, cajuput and croton, with an ointment base. It is manufactured and marketed by Parke, Davis & Co., Detroit. 1905 The New U. S. P., Changes in Composition and Strength. Drug Topics, 20, p. 210. [Am. Journ. Pharm., 78, p. 412.] The new edition of the U. S, P. specifies acetone as the solvent for making all of the oleoresins with the exception of oleoresin of cubebs, which BIBLIOGRAPHY 263 is prepared with alcohol. It is stated that manufacturers have long since seen the folly of employing an expensive solvent like ether, and the adoption of acetone for this purpose is a recognition of commercial phar- maceutical advances, (p. 214.) Dieterich 1905 Extracta spissa et sicca. Helfenberger Ann., 1905, p. 159. A sample of the ethereal extract of cubeb, D. A. IV, showed a "mois- ture" content of 55.91 per cent, and an ash content of 0.87 per cent, (p. 160.) A sample of extract of maje fern D. A. IV, gave a *' moisture" content of 5.06 per cent., an ash content of 0.46 per cent, and yielded 23.22 per cent, of crude filicin (p. 161.) Dieterich 1905 Khizoma Zingiberis. Helfenberger Ann., 1905, p. 131. The following percentages of extract were obtained by exhausting ginger with different solvents, evaporating the latter and dryiag the residue at lOO'C: 1) One part alcohol, 8 parts water — 7.86 per cent. 2) Sixty-eight per cent, alcohol — 4.88 per cent. 3) Ninety per cent, alcohol — 2.79 per cent. Dieterich , * 1905 Rhizoma Filicis. Helfenberger Ann., 1905, p. 130. During the year, a number of lots of male fern rhizomes were examined. The air-dried rhizomes yielded 9.94 to 10.60 per cent, of ethereal extract. The rhizomes when dried at lOO^C yilded as high as 11.20 per cent, to the same solvent. Francis, J. M. 1905 The New Pharmacopoeia: A Detailed Commentary on the Eighth Revision of the U. S. P. Bull, of Pharm., 19, p. 317. [Am. Joum. Pharm., 78, p. 412.] Under acetone, it is stated that oleoresins prepared with this solvent will separate in two layers on standing owing to the fact that this ketone pos- sesses in a measure the combined solvent properties of both alcohol and ether. 264 ^^ MEZ— THE GALENICAL. OLEORESINS Vanderkleed, C. E. 1905 Report of the Committee on Adulterations. Proe. Peixna. Pharm. Assoc., 28, p. 47. Eight assays of capsicum gave 9.4 to 23.9 per cent, of oleoresin, the average being 18.13 per cent. The standard for a good drug is stated to be 15 per cent. Vieth, H. 1905 Ueber die Beziehung zwischen chemischer Zusammenset- zung und medizinisclier Wirkung einiger Balsamika. Verh. d. Ges. deutsch. Naturf. u. Aerzte, 2, p. 364. [Jah- resber. d. Pharm., 66, p. 13.] Kubetenextrakt is reported to consist of terpenes (65 per cent.), resin acids (10 per cent.), and resins (25 per cent.) 1906 Apiolin Merck's Ann. Eep., 20, p. 34. Apiolin is the raw ethereal oil obtained from the seed of Petroselinum sativum or from Apiol viride by extraction with a suitable solvent. It is a yellow fluid, sp. gr. 1.25 to 1.135, boiling at 280 to 300*C. 1906 Extractum Filieis. Caesar and Loretz, Geschaefts-Ber., Sept. 1906, pp. 82 and 99. The firm reports that the crude filicin content of the extract obtained from the current year's crop of male fern averages 27 per cent. (p. 82). Fromme's method for estimating the crude filicin is given (p. 99). Naylor, A. H. 1906 Progress in pharmacapoeias : drugs and their constituents* Year-Book of Pharm., 43, p. 204. It is stated that in the present state of our knowledge, neither Daccpmo and Scoccianti 's, Kraft's nor Stoeder's process for the quantitative esti- mation of filicic acid is a measure of the anthelmintic value of the ex- tract of male fern. BIBLIOGRAPHY 265 Roeder, Ph. 1906 Ehizoma Filicis. Jahresb. d. Pharm., 41, p. 46. The author states that the rhizomes of Aspidium filix mas should give at most 3 per cent, of ash and should yield at least 8 per cent, of extractive matter to ether, allowing the latter to evaporate spontaneously and then heating for 2 hours at 95 "C, cooling in a desiccator and weighing. Three samples of rhizomes gave 2.52 to 2.92 per cent, of ash, respectively, and 9.22 to 10.1 per cent, of ether-soluble extract. WoUenweber, W. 1906 Ueber Filixgerbsaeure. Arch. d. Pharm., 244, p. 466. In connection with his work on the tannic acid in the male fern rhizomes, "the author presents the results obtained in extracting the drug in a Soxh- let's apparatus with various solvents, ether, benzol, and petroleum ether. At the end of six hours, extraction was found to be practically complete in all cases. The yield obtained in each case is given as follows; ether, 10.0 per cent., benzol, 9.06 per cent., petroleum ether, 9.08 per cent. Extraction with alcohol of varying strength yielded extractive matter in the following quantities: alcohol (90 per cent.), 20.0 per cent., alcohol (96 per cent.), 16.6 per cent. The fixed oil content of the ethereal extract is stated to be 70 to 75 per cent. 1907 Cubebs. Evans Sons Lescher & Webb, Analyt. Notes, 1, p. 21. The oleoresin extracted by ether from four samples of cubebs amounted to (1) 22.08, (2) 22.6, (3) 21.13 and (4) 22.8 per cent., respectively. Blome, W. H. 1907 Cubeba. Proc. Mich. Pharm. Assoc, 1907, p. 68. [Bull. Hygienic Lab., No. 63, p. 225.] Five samples of cubeb are reported which assayed from 18.85 to 26.88 per cent, of oleoresin. 266 DU MBZ— THE GALENICAL OLEORESINS Van der Harst, J. C. 1907 Lupulin. Pharm. AVeekbl., 44, p. 1506. [Bull. Hygienic Lab., No. 63, p. 301.] Two samples of lupulin were found to contain 52 and 65 per cent, of ether-soluble matter, respectively. Patch, E. L. 1907 Report of Committee on Drug Market. Proc. Am. Pharm. Assoc, 55, p. 314. The samples of capsicum examined yielded from 16.2 to 26.5 per cent, of alcoholic extract (p. 324.) Smith, 0. W. 1907 Galenicals of the U. S. P. VIII. Proc. Mo. Pharm. Assoc, 29, p. 132. The author is of the opinion that the oleoresin of eubeb might well have been included in the class made with acetone, as the drug yields but little on subsequent extraction with alcohol. Alcohol on the other hand is /Open to the objection that its boiling point is so high that a considerable loss of volatile substances from the cubeb occurs when the solvent ia evaporated (p. 134.) 1908 Extractum Filicis. Caesar and Loretz, Geschaefts-Ber., Sept. 1908, pp. 76 and 99. It is stated that for years the firm has estimated the crude filicin con- tent of the extract of male fern and marketed a standard product contain- ing 28 per cent, of this constituent as required by the Swiss PharmacopcEia, VI, (p. 76.) Fromme's method for estimating the crude filicin is given (p. 99.) Dohme and Engelhardt 1908 Purity of some official and non-official drugs and chemicals. Proc Am. Pharm., Assoc, 56, p. 814. A sample of lupulin yielding only 56 per cent, of ether-soluble matter is reported (p. 817.) BIBLIOGRAPHY 267 Patch, E. L. 1908 Report of Committee on Drug Market. Proc. Am. Pharm. Assoc., 56, p. 765. The different samples of capsicum examined yielded from 15 to 25.2 per cent, of alcoholic extract (p. 768.) Spaeth, Eduard 1908 Die chemische und mikroskopische Untersuchung der Gewiirze und deren Berurteilung. Pharm. Centralh., 49, p. 581. The paper discusses the characteristics of several commercial varieties of ginger and the composition of the drug. The quantity of material extracted by ether, alcohol, petroleum ether and methyl alcohol is given. Vanderkleed, C. E. 1908 Report of Committee on Adulteration. Proc. Penna. Pharm. Assoc, 31, p. 65. Three samples of capsicum yielded from 11.59 to 18.35 per cent, of oleo- resin; four samples of cubebs, 16.39 to 23.6 per cent; two samples of ginger, 5.58 to 9.55 per cent; three samples of male fern, 6.68 to 17.9 per cent., average 10.002 per cent. (p. 88.) 1909 Pharmacy Committee's Report. Chem. & Drugg., 74, p. 288. The Committee of Reference in Pharmacy asserts that cubebs should yield not less than 20 per cent, of oleoresin to ether, sp. gr. not over 0.720. (p. 292.) 1909 Extractum Filicis. Caesar and Loretz, Geschaefts-Ber. Sept. 1909, pp. 67 and 84. A crude filicin content of 28 per cent, is guaranteed by the firm for the new lot of extract of male fern (p. 67.) Fromme's method for the estimation of the crude filicin is given (p. 84.) 1909 Apiol. Evans Sons Lescher & Webb, Analyt. Notes, 4, p. 11. A sample of apiol of French manufacture examined by the firm is re- ported as having been liquid and green in color. It yielded 40 per cent, of 268 DU MEZ— THE GALENICAL OLEORESINS Its bulk to steam distillation. It is^ therefore, thought that the sample was prepared by the extraction of parsley fruits with a suitable light solvent. ' Bernegau, L. H. 1909 Report of the Committee on Adulteration. Proe. Penna. Pharm. Assoc, 32, p. 119. Ten samples of lupulin examined yielded from 34 to 65.8 per cent, of ether-soluble matter (p. 125.) Dohme and Engelhardt 1909 Purity of some official and non-official drugs and chemicals. Proc. A. Ph. A., Assoc, 57, p. 713. * Three samples of lupulin examined were low in ether-soluble matter yielding but 47.50, and 43 per cent., respectively (p. 716.) Dunn, J. A. 1909 Suggested Modifications of U. S. P. and N. F. Formulas. Proc A. Ph. A., 57, p. 942. It is stated that the oleoresin of male fern prepared by the TJ. S. P. method, using acetone, contains so much undesirable extractive matter that it is necessary to purify it by dissolving in ether. It is suggested that it might be worth while to consider whether the U. S. P. should not go back to the use of ether (p. 949.) Parson, W. A. 1909 Report of the Committee on Adulteration. Proc Penna. Pharm. Assoc, 32, p. 119. Three samples of lupulin yielded 66.1 and 54 per cent, of ether-soluble matter, respectively (p. 125.) Patch, E. L. 1909 Report of Committee on Drug Market. Proc A. Ph. A., 57, p. 721. The alcoholic extract from specimens of ginger examined varied from 3.7 to 6.2 per cent. (p. 739.) BIBLIOGRAPHY 269 Vanderkeed, C. A. 1909 Report of the Committee on Adulteration. Proc. Penna. Pharm., Assoc., 32, p. 119. Samples of capsicum, cubebs, ginger, and male fern examined are re- ported to have yielded oleoresin as follows: five samples of capsicum, 14.34 to 17.95 per cent; four samples of cubebs, 16.49 to 24.34 per cent; sixteen samples of Jamaica ginger, 3.142 to 6.91 per cent; two samples of African ginger, 8.2 and 9.036 per cent; one sample of male fern, 10.33 per cent, (p. 129.) i9ia Extr actum Filicis. Caesar and Loretz, Jahres-Ber., Sept. 1910, p. 90. Fromme's method for the estimation of crude filicin is given. 1910 Cubebs. Southall Bros. & Barclay, Lab. Rep., 17, p. 11. Eight samples of cubebs, when extracted with petroleum spirits, yielded from 3.88 to 18.08 per cent, of extractive matter. The same samples on- subsequent extraction with alcohol (90 per cent.) yielded from 3.4 to 5.6(ii per cent, of extractive matter. 1910 Capsicum. Southall Bros. & Barclay, Lab. Rep., 17, p. 8. Two samples of capsicum (B. P. C.) yielded 15.4 and 14.0 per cent., respectively, of extract to benzol. Dohme and Engelhardt 1910 The new Hungarian Pharmacopoeia. Proc. Am. Pharm. Assoc, 58, p. 1168. The extraction of male fern with ether, as directed in the Ph. Hung. Ill, instead of acetone as in the U. S. P., VIII, is thought to be desirable since the latter is liable to extract substances which might produce injurioni after effects (p. 1179.) It is further stated that the yield of ether extract as given in the Hun- garian Pharmacopoeia is 8 per cent. (p. 1184.) nfQ DU MEZ— THE GALENICAL OLEORESINS Eldred, F. R. 1910 Some data obtained in the examination of official substances. Proc. A. Ph. A., 58, p. 889. Forty-eight lots of capsicum were examined. The yield of ether-soluble oleoresin, when the latter was dried for one hour on a water bath, was found to vary from 11 to 26 per cent., the average 18 per cent. (p.891.) Gane, E. H. 1910 Pharmacopoeial notes and comments. Drug Topics, 25, p. 212. It is stated that a good sample of cubebs should yield 20 per cent, of ether-soluble extract. Gane and Webster 1910 Pharmacopoeial notes and comments. Drug Topics, 25, p. Aspidium is stated to be one of the most useful of drugs when carefully collected and preserved, but that much of the rhizome is inert and is ob- tained from any old species of fern. It is said to be falling into disuse on this account. It is thought that the observance of more care in the collection of the drug and the preparation of the oleoresin would restore •its popularity as an anthelmintic. La Wall, C. H. 1910 Some suggested standards and changes, for the U. S. P. Am. Joum. Pharm., 82, p. 21. The author asserts that a test for capsicum should be included in the U. S. P. requirements for the oleoresin of ginger as many commercial samples used in making ginger ale extracts contain oleoresin of capsicum and these occasionally find their way into the pharmaceutical trade. A method for the detection of capsicum in the oleoresin of ginger based on the neutralization of the pungent principle of the ginger with potassium hydroxide is described (p. 25.) Vanderkleed, C. E. 1910 Report of the Committee on Adulterations. Proc. Penna. Pharm. Assoc, 33, p. 131. Seven samples of capsicum yielded from 15.10 to 22.27 per cent, of oleoresin; one sample of African ginger 10.12 per cent; two samples of Jamaica ginger 5.636 and 6.316 per cent., respectively (p. 147.) BIBLIOGRAPHY 271 1911 Extractum Filicis. Caesar and Loretz Jahres.-Ber., Aug. 1911, pp. 76 and 105. Eegret is expressed in that the Ph. Germ. V. has not included an assay for oleoresin of aspidium. The crude filicin content is thought to be a satisfactory indication of the value of this preparation. A filicin con- tent of 27 per cent, is guaranteed by the firm for the new lot of the ex- tract prepared by them (p. 76.) Fromme's method of estimating the crude filicin is given (p. 105.) 1911 Male fern extract. Evans Sons Lescher & Webb, Analyt. Notes, 6, p. 48. Five samples of male fern extract were tested. Two were found to be adulterated with castor oil (55 to 70 per cent.) The Kraft and the Swiss pharmacopoeial methods for evaluating the extracts are discussed and the results obtained in each case, along with other physical and chemical constants, are tabulated. 1911 Cubebs. Southall Bros. & Barclay Lab. Rep., 19, p. 9. Five samples of cubebs yielded from 4.66 to 8.78 per cent, of extract to petroleum spirit, the average being 6.95 per cent. : 1911 Insect Powder. Southall Bros. & Barclay, Lab. Rep., 19, p. 10. Two samples of insect powder yielded 8.28 and 7.57 per cent, of oleo resin when tested by Durant's method. One sample of Japanese insect flowers yielded 13.98 per cent, of oleo- resin of an orange brown color. 1911 Oil of male fern. Brit. & Col. Drugg., 60, p. 388. In this article, it is stated that parcels of the extract of male fern are being condemned in London as they have been found to contain large quantities of castor oil. Suspicion was first aroused through the low selling price of some 272 DU MEZ — THE GALENICAL. OLEORESINS of the extracts.- The adulterated extract was being sold for 4s per pound while reliable manufacturers would not quote prices below 5 s 6 d per pound. 1911 Ext. Filicis maris. Chem. & Drugg., 79, p. 749 and 798. This editorial commenting on Parry's observation, that extract of male fern is commonly adulterated with castor oil, calls attention to the testj* given in the Netherlands and Swiss pharmacopoeias. Bernegau, L. H. 1911 Keport of the Committee on Adulterations. Proc. Penna. Pharm. Assoc. 34, p. 117. Three lots of lupulin tested 58.9, 57.7 and 62.1 per cent, soluble in ether (p. 125.) Beythien, Hemple & Others 1911 Kurze Mitteilungen aus der Praxis des Chemischen Unter- siichungsamtes der Stadt Dresden. Zeitschr. Unters. Nahr. u. Genussm., 21, p. 666. A table is presented showing the ash content and extract content of a number of samples of ginger (p. 668.) According to Eeich the volatile ether extract content varied from 0.80 to 4.02 per cent., the non volatile from 1.66 to 6.93 per cent; the alcoholic extract from 1.33 to 4.08 per cent; the petroleum ether extract from 1.14 to 4.49 per cent; and the methyl alcohol extract from 4.40 to 12.53 per cent. Deane, Harold 1911 Oleoresina Capsici, B. P. C. Pharm. Journ., 87, p. 804. The author criticises the British Pharmaceutical Codex with respect to the title Oleoresina Capsioi. He is of the opinion that the preparation has no right to the name oleoresin, as it corresponds more closely to the product sold as capsicin or soluble capsicin for the use of pill makers and mineral water manufacturers. Francis, J. M. 1911 Report of the Committee on Adulterations. Proc. Penna. Pharm. Assoc, 34, p. 117. Only one of eight lots of lupulin examined failed to exceed the required 60 per cent, of ether-soluble matter (p. 125.) , BIBLIOGRAPHY 273 Glueeksmann, G. 1911 Ueber eine neue Identitaetsreaktion des Extractum Cube- barum. Pharm. Praxis, 1911, p. 98. [Apoth.-Ztg., 27, p. 334.] A test in which hydrochloric acid is used fo^ producing a color reaction is described in detail. Parry, E. J. 1911 Extract of male fern. Pharm. Journ. 87, p. 778. [Chem. & Drugg., 79, p. 860; Am. Journ. Pharm., 84, p. 136; Apoth-Ztg., 26, p. 1046.] The author reports on the examination of commercial extracts of male fern and finds that the greater part are undoubtedly adulterated with from 30 to 60 per cent, of castor oil. The physical and chemical constants of the commercial samples and of genuine extracts are tabulated for com- parison. Pearson, W. A. 1911 Report of the Committee on Adulterations. Proc. Penna. Pharm. Assoc, 34, p. 126. [Bull. A. Ph. A., 6, p. 346.] The author reports that two lots of oleoresin of aspidium were rejected because they were not green in color. Rosendahl, H. V. 1911 Fern rhizomes, yield of extract and relative activity of. Year-Book of Pharm., 48, p. 286. [Apoth.-Ztg., 26, p. 588 ; Svensk. farmac. Tidsk., 1911, p. 85.] The yield of ethereal extract obtained from various species of ferm harvested during different months of the year was found to be as follows: Aspidium filix mas Dryopteris spinulosa Dryopteris dliatata Fteris aquUina Athyrium filix femina Aspidium alpestris Two grams of the extract of Dryopteris dilataia are stated to be thera- peutically equivalent to 8 to 10 grams of the extract of Aspidium filix maa or four grams of the extract of Dryopteris spinulosa. May August October Per cent. Per cent. Per cent. — 12.5 11.0 — 17.0 — 10.0 — — 2.0 — — 0.9 0.7 __ «_ >274 I5U MEZ— THE GALENICAL OLEORESINS Vanderkleed, C. E. 1911 Eeport of the Committee on Adulterations. Proc. Penna. Pharm. Assoc., 34, p. 117. Two samples of capsicum are reported to have yielded 14.7 to 17.93 per ^ent., respectively, of oleoresin; one sample of subebs, 22.14 per cent; eleven samples of African ginger, 7.128 to 9.484 per cent; and eight samples of Jamaica ginger, 3.4 to 6.6 per cent. (p. 132.) 1912 Extractum Filicis. Caesar and Loretz, Jahres-Ber., Sept. 1912, p. 128. The firm's method for estimating the crude filicin is given. 1912 Capsicine. Evans Sons Lescher & Webb, Anaylt. Notes, 7, p. 18. Five samples of capsicvne examined were all entirely soluble in 10 vol- lunes of 90 per cent, alcohol. 1912 Male fern extract. Evans Sons Lescher & Webb, Analyt. Notes, 7, p. 51. Sixteen samples of male fern extract examined in 1912 were free from castor oil and of satisfactory purity. They showed a refractive index of 1.507 to 1.509 at 15''C, and gave a filicin content of 22.9 to 26.3 per cent., when assayed according to the method given in the Swiss Pharmacopoeia. 1912 Capsicum. Johnson & Johnson, Lab. Notes, 1912, p. 14. The yield of ether extract obtained from capsicum is reported to have varied from 16 to 19 per cent. 1912 Cheap extract of male fern found badly adulterated. Merck's Eeport, 21, p. 29 [Apothecary, 24, p. 14.] A sample of cheap extract of male fern examined by Merck was found to be adulterated with 25 per cent, of castor oil, and to contain only 8 per cent, of crude filicin. BIBLIOGRAPHY 275 1912 Male fern extract. Southall Bros., & Barclay, Lab. Kep., 20, p. 15. The statement of Parry that much of the male fern extract is adulterated is confirmed. The physical and chemical constants obtained in the ex- amination of six commercial extracts are tabulated. Dohme and Engelhardt 1912 Drug quality during the period 1906-1911. Journ. A. Ph. A., 1, p. 99. It is stated that there was hardly any variation in the percentage of oleoresin in the samples of cubebs examined during the last six years, (p. 101.) Goris and Voisin 1912 The determination of the ether extract of male fern, and the unification of the methods of analysis. Bull. Sci. Pharmacolog., 19, p. 705, [Pharm. Ztg., 58, p. 129; Journ. 90, p. 81; Year-Book of Pharm., 50, p. 337.] It is stated that the method of the Swiss Codex gives values for crude filicin which are about 30 per cent, too high owing to the solubility of the ether solution in ' the solution of barium hydroxide. If the ether be driven off by heating to 50 °C before filtering, the results will be com- parable with those obtained by the magnesia methods. Hooper, D. 1912 Notes on Indian drugs. Pharm. Journ. 89, p. 391. The examination of the rhizomes of Indian ginger, with reference to de- termining the relationship between maturity and oleoresin content, showed that young rhizomes develop oleoresin as they are allowed to grow. Those gathered in December yielded 6.4 per cent, of extract to alcohol (90 per cent.), while those gathered in February gave 8.3 per cent. Upon washing the extracts with water, the remaining insoluble residue amounted to 3.0 per cent, and 3.5 per cent., respectively. Some of the more mature rhizomes gave as high as 11.8 per cent, of alcoholic extract or 8.1 per cent, of washed resin. Patch, E. L. 1912 Report of the Committee on Drug Market. Journ. A. Ph. A., 1, p. 499. Eight samples of Jamaica ginger gave from 3.3 to 6.0 per cent, of alco- holic extract (p. 500.) 276 DU MEZ— THE GALENICAL OLEORESINS V'anderkleed, C. E. 1912 Report of Committee on Drug Market. Proe. Penna. Pharm. Assoc., 35, p. 165. The assay of 4 samples of capsicum showed the oleoresin content to ba from 14.41 to 16.7 per cent; five samples of cubebs yielded 1.735 to 24.49 per cent, of oleoresin; seventeen samples of Jamaica ginger, 3.444 to 6.b'4<> per cent; ten samples of African ginger, 6.85 to 11.10 per cent (p. 179.) 1913 Miscellaneous Inquiries. • Chem. & Drugg., 82, p. 470. Gingerin is stated to be the extract obtained upon evaporating the tinc- ture of ginger. It is said to vary with the variety of ginger used in the preparation of the tincture. Capsicin is stated to be commercially indefinite. It may be a strong alco- holic extract, an ethereal, a chloroformic or an acetone preparation. The accepted capsicin of commerce, however, is the oleoresin prepared with ether. 1913 Die Methoden zur Wertbestimmung des Filixextrakts. Pharm. Ztg., 58, p. 129. The methods of Goris and Voisin, and E. Schmidt for the evaluation of the extract of male fern are discussed. 1913 Extractum Filicis. Caesar and Loretz, Jahres.-Ber., Sept. 1913, pp. 98 and 106. Four samples of extract of male fern prepared by the firm showed a crude filicin content of 32.64, 23.7, 28.15 and 30.4 per cent., respectively, (p. 98.) The firm guarantees the filicin content of their extract to be 27 per cent. 1913 Male fern extract. Evans Sons Lescher & Webb, Analyt. Notes, 8, p. 44. [Year- Book of Pharm., 51, p. 244.] Seven samples of extract of male fern examined during the year showed a filicin content of 21.3 to 25.3 per cent, and a refractive index of 1.5 to 1.51. Three eamples were impure or suspicious. They showed a refractive index of 1.495, 1,497 and 1.499, and a filicin content of 15.6, 19.6 and 19.7 per cent., respectively. BIBLIOGRAPHY 277 1913 Male fern extract. Southall Bros., & Barclay, Lab. Rep., 21, p. 14. The analytical data obtained in the examination of two commercial samples of the extract of male fern are given. Bohrisch, P. 1913 Ueber Extractum Filicis. Pharm. Ztg., 58, p. 601. [Chem. Abs. 8, p. 206.] A comprehensive review of the constituents and the methods of evaluat- ing the extract of male fern is given. Four samples of commercial extracts in bulk were examined for density and crude filicin content. The findings for density were 0.9888, 0.9842, 0.9836 and 1.0109; for crude filicin 14.85; 15.42, 16.00 and 24.00 per cent. The same tests for five samples of the extract in capsules showed: density, 0.9824, not determined, 1.0135, 1.0255 and 0.9910; crude filicin, 15.02, 23.42, 26.77, 27.72 and 14.45 per cent. Dobme and Engelhardt ' 1913 Cubebs. Oil, Paint and Drug Rep., 83, p. 55. The quantities of oleoresin obtained from cubebs ranged between 16 and 22 per cent. DuMez, A. G. 1913 The physical and chemical properties of the oleoresin of As- pidium with respect to the detection of adulterations. Philippine Journ. of Sc, 8, Sec. B., p. 523. The methods of adulterating the oleoresin are discussed in detail The physical and chemical constants of samples prepared in the laboratory and those obtained from various commercial sourcee are presented with the idea of indicating to what extent they may be relied upon in detecting a deteriorated or adulterated product. Engelhardt, H. 1913 Purity of chemicals and drugs. Journ. A. Ph. A., 2, p. 163. Four samples of black pepper are reported to have yielded 10.6, If^.S, 9.2 and 11 per cent., respectively, of oleoresin; six samples of capsicum, 13.1, 41.8, 15.26, 15,8, 11.3 and 11 per cent; cubebs from 18 to 25 per cent; Jamaica ginger from 2.81 to 5.24 per cent; lupulin, eight samples out of twelve, less than 60 per cent; three samples of parsley seed. 14.7, 11.4 and 13.04 per cent. (pp. 164 and 165.) 278 I^U MEZ — THE GALENICAL OLEORESINS Gane, E. H. 1913 Report of Committee on Drug Market, August, 1912. Journ. A. Ph. A., 2, p. 677. Four lots of lupulin gave 44.94 to 65.5 per cent, of ether-soluble material,. (p. 681.) Harrison and Self. 1913 Analytical constants of extract of male fern. Chem. & Drugg. 83, p. 182. [ Year-Book of Pharm., 50, p. 494 ; Pharm. Journ. 91, p. 128 ; Pharm. Ztg., 58, p. 643.] The analytical constants of genuine and commercial extracts of mala fern are tabulated. The authors do not approve of the standards sug- gested by Parry. Hm, C. A. 1913 Analytical notes on extract of male fern. Chem. & Drugg., 83, p. 181. [Pharm. Ztg., 58, p. 643.] The analytical constants of 23 samples of extract of male fern are discussed and tabulated. The chemical and physical constants of the oily portion are also given for comparison with those of castor oil. One com- mercial sample is reported to have contained 59 per cent, of the latter. Osborne, Oliver F. 1913 A last plea for a useful Pharmacopoeia. Journ. Am. Med. Assoc, 60, p. 1427. Among the ''useless" preparations adopted by the Committee of Re- vision, the author includes the oleoresins of lupulin and parsley seed^ (p. 1429.) Parry, E. J. 1913 Extract of male fern. Chem. & Drugg., 83, p. 231. The author confirms the results which he published in an earlier paper. Patch, E. L. 1913 Report of the Committee on Drug Market. Journ. A. Ph. A., 2, p. 1081. The percentage of alcoholic extract obtained from the drugs tested is reported as follows: BIBLIOGRAPHY 279^ Capsicum, four samples, 19 to 24 per cent; ginger, nine samples, 5.2, 5.7, 4.2, 4.0, 4.5, 4.9, 3.5, 4.8 and 4.3 per cent. pp. 1088 and 1094. The yield of ether extract reported by Kebler is as follows: Fifty-three samples, lupulin, 63.96 to 77..82 per cent; black pepper three lots, 10.04, 10.87 and 12.88 per cent; red pepper, eight samples, 13.0, 10.6, 14.7, 18.91, 13.12, 10.4, 13.25 and 14.7 per cent. The iodine^ values for the same were 132, 138, 123.4, 107, 127.3, 25.2 and 137.3. Seventeen other samples yielded from 11.22 to 20.77 per cent. The iodine value of these varied from 110 to 145.7 (pp. 1098 and 1101.) Umney, J. C. 1913 What is capsicin? Pharm. Journ., 91, p. 594. Capsicin is stated to be a synonym for Oleo-Besin of Capsicum of the B. P. Codex, and, is made by extracting capsicum with 60 per cent. alcohoL and subsequently evaporating off the solvent. It should not be con- fused with the preparations made with strong alcohol (90 per cent.)^ ether or acetone. Vanderkleed, C. E. 1913 Report of the Committee on Drug Market. Proc. Penna. Pharm. Assoc, 36, p. 77. Thirty-seven samples of Jamaica ginger are reported to have yielded 3.10 to 5.75 per cent, of oleoresin; seventeen samples of African ginger,, 6.85 to 9.92 per cent; seven samples of capsicum, 13.1 to 18.1 per cent;, one sample of cubebs, 21.8 per cent. Yagi, S. 1913 Physiologische Wertbestimmung von Filixsubstanzen nnd' Filixextrakten. Zeitschr, f. d. ges. exp. Med., 3, p. 64. [Therap. Monatsch.,. 1914, p. 443; Apoth-Ztg., 29, p. 544.] A method in which earth worms are used for the purpose of testing the- relative activity of extract of male fern and its constituents is described. 1914 Untersuchung der offizinellen vegetablischen Drogen. Riedel's Ber. 58, p. 29. The samples of cubebs examined are reported as having yielded 11.1 to- 14.7 per cent, of extract soluble in ether 1 part and alcohol 1 part (p. 31.) The alcohol extract obtained from capsicum varied from 31.9 to 35.3- per cent. (p. 32.) The samples of aspidium examined gave 9.4 to 9.7 per cent, of ether- soluble extract. DU MEZ— THE GALENICAL. OLEORESINS 1914' Ueber Gelatinkapsel-Fabrikate. RiedePs Ber. 58, p. 45. [Apoth.-Ztg., 29, p. 310.] Capsules from only two manufacturers contained extract of male fern of which the crude filicin content was higher than 20 per cent. The ex- tract of male fern in capsules from four other sources showed a filicin content of from 8.57" to 16.02 per cent. (p. 48.) 1914 Extractum Filicis. Caesar and Loretz, Jahres-Ber., Oct., pp. 23, 37, and 96. The method of S. Yagi for the physiological standardization of the extract of male fern is stated to be too cumbersome for practical use. (p. 23.) Extracts prepared in the laboratory showed the following crude filicin content, 25.48, 24.85, 29.7, 26.04, 26.0, 35.58, 27.35 and 33.79 per cent, (p. 37.) It is further stated that the yield of ether extract, after evaporating on & water bath at 60 °C to constant weight and drying in a desiccator for half an hour, should be about 15 to 18 per cent. (p. 96.) 1914 United States Pharmacopoeia Ninth Kevision. Abstracts of proposed changes with new standards and descriptions. Journ. A. Ph. A., 3, pp. 524 and 1573. [Year-Book of Pharm., 52, p. 324.] It is stated that the former solvent, acetone, is to be changed to ether in the following: Oleoresina Aspidii, Oleoresina Capsici, Oleoresina Zingiheris and Oleoresina Piperis. (p. 551.) Directions are also given for the preparation of Oleoresina Petroselini (p. 573.) Bohrisch, P. 1914 Ueber verschiedene verbessemngbeduerftige Artikel des Deutschen Arzneibuches V. Apoth.-Ztg., 29, p. 901. It ih stated that a large portion of the extract of male fern made in Ger- many shows a crude filicin content of less than 15 per cent., while the Swls^ Pharmacopoeia requires a content of 26 to 28 per cent. The author, therefore, thinks it desirable that a method for the estimation of the crude filicin in this preparation be given in the German PharmacopcBia. 6IBLJOGRAPSY 281 E'we, G. E. 1^14 Report of Committee on Drug Market. Proc. Penna. Pharm. Assoc, 37, p. 125. The author reports as follows on the oleoresins examined: Four samples of oleoresin of capsicum were found to be pungent m dilutions of 1 to 150,000, the arbitrary standard of H. K. MulforcT Company. Seven samples of oleoresin of ginger were pungent to the taste in dilutions of 1 to 20,000, the arbitrary standard of H. K. Mulford Company. Oiie lot of oleoresin of cubeb contained the waxy deposit which the U. S. P. directs should be rejected. One lot of oleoresin of say palmetto, ''U. S. P." contained 15 per cent, of water which separated on standing. It also contained a large amount of insoluble matter (p. 152.) Linke, H. 1914 Ergebnisse, Beobachtungen und Betrachtungen bei der Untersuchung unserer Arzneimittel. Apoth.-Ztg., 30, pp. 606 and 628. The results obtained in the examination of extract of male fern, in bulk and in capsules, obtained from various sources are tabulated. Especially the extract marketed in capsules was found to be low in filicin content. Patch, E. L. 1914 Report of Committee on Quality of Medicinal Products. Journ. A. Ph. A., 3, p. 1283. A sample of oleoresin of capsicum examined is reported as having been? found to be insoluble in ether, only slightly soluble in alcohol and almost completely soluble in water (p. 1298.) Rippetoe, J. R. 1914 The examination of some drugs with special reference to* the anhydrous alcohol and ether extracts, and ash. Am. Journ. Pharm., 86, p. 435. Four samples of capsicum are reported as having yielded 17.02 to 24.46" per cent, of extract to alcohol, and 16.49 to 17.88 per cent to ether, (p. 437.) Six samples of cubebs gave 8.87 to 11.04 per cent, of alcoholic extract^ and 7.68 to 9.80 per cent, of ethereal extract, (p. 438.) Two samples of Jamaica ginger yielded 4.98 to 5.5 per cent, of extractive matter to alcohol, and 2.79 to 4.97 per cent, to ether. Two samples of African ginger yielded 6.20 to 6.23 per cent, to alcohol, and 5.3 to 5.45- per cent, to ether, (p. 439.) Three samples of lupulin yielded 32.49, 55.18 and 57.06 per cent.,, respectively, of ethereal extract, (p. 440.) 282 ^U MEZ— THE GALENICAL. OL.EORESINS Scoville, W. L. 1914 Report of Committee on Quality of Medicinal Products. Joura. A. Ph. A., 3, p. 1283. It is stated that the samples of cubebs examined during the year gave from 18.1 to 22 per cent, of oleoresin, (p. 1287.) Vanderkleed, C. E. 1914 Report of Committees on Drug Market. Proc. Penna. Pharm. Assoc, 37, p. 125. On page 160, analytical data obtained from the laboratory of H. K. Mulford Company are reported showing the following yield of oleoresin for capsicum, cubebs and ginger: Capsicum (15 samples) Cubebs (6 samples) African ginger (3 samples) Jamaica ginger (3 samples) Male fern (4 samples) Lowest Highest Yield, Yield Average. Per cent. Per cent. Per cent 13.0 18.0 16.0 13.9 19.8 16.9 8.50 9.61 9.0 4.33 5.75 5.06 6.85 10.12 8.23 1915 Male fern extract. Southall Bros. & Barclay, Ann. Rep., 22 and 23, p. 17. The filicin content of five samples of extract of male fern examined is reported as having varied from, 20.4 to 27.7 per cent., the specific gravity from 0.9885 to 1.030. Olickman, L. H. 1915 Report of Committee on Drug Market. Proc. Penna. Pharm. Assoc, 38, p. 138. Ten lots of lupulin examined are reported to have yielded the following percentages of ether-soluble matter: 55.5, 55.0, 57.1, 58.6, 54.7, 55.3, 44.2, €9.2, and 68.2, (p. 149.) Yanderkleed, C. E. 1915 Report of Committee on Drug Market. Proc. Penna. Pharm. Assoc, 38, p. 138. On page 155, the following data concerning the yield of oleoresin are BIBLIOGRAPHY 283 reported as having been obtained from the analytical laboratory of H. K. Mulford Company. Lowest Highest Yield. Yield. Average. Per cent. Per cent. Per cent. Capsicum (6 samples) 13.85 20.84 16.65 African ginger (2 samples) 7.99 8.90 8.44 Jamaica ginger (1 sample) 3.93 3.93 3.93 Beringer, G. M. 1916 The reasons for some of the changes in the formulas of galeni- cals made in the ninth revision of the United States Pharma- copoeia. Journ. A. Ph. A., vol. 5, No. 12, p. 1390. It is stated that acetone was the menstruum directed to be used in the preparation of the oleoresins by U. S. P., eighth revision, on account of cheapness. It is further stated that, since permission has been obtained to use denatured alcohol in the manufacture of ether, the cost of the latter has been reduced to such an extent that it has again become advantageous to use it in place of acetone. Hence, its use in the new Pharmacopoeia. 284 DU MEZ— THE GALENICAL OLEORESINS INDEX TO BIBLIOGEAPHY Oleoresin of Aspidium 1891. Kuersten, R. 1824. Geiger, Ph. L. 1891. Poulsson, E. 1824. Morin 1891. Raymon 1826. Buchner, A. 1891. Eeuter, Ludwig 1826. Von Esenbeck, Nees 1892. Beringer, G. M. 1826. Peschier, Ch. 1892. Duhourcau 1827. Batso, V. 1892. Kobert 1827. Brandes, E. 1892. Sherrard, C. 0. 1827. Buchner, A. 1892. Weppen & Lueders 1827. Van Dyk 1892. Dieterich 1827. Geiger, Ph. L. 1893. Bechurts & Peters 1827. Tilloy 1893. Dieterich 1827. Zeller 1893. Gehe & Co. 1828. Meylink 1894. Poulsson, E. 1828. Peschier, Ch. 1894. Dieterich 1828. Winkler, F. L. 1894. Hell & Co. 1829. Allard 1895. Van Aubel 1829. Haendess 1895. Boehm, R. 1829. Voget 1895. Dieterich 1844. Hornung ' 1896. Bocchi, I. 1845. Luck 1896. Daccomo and Scoccianti 1851. Bock 1896. Dieterich 1851. Luck, E. 1896. Kraft, F. 1852. von der Marck 1896. Caesar and Loretz 1859. Procter, Wm., Jr. 1897. Boehm, R. 1861. Pavesi 1897. Candussio 1871. Hager 1897. Lauren, W. 1875. Patterson, J. 1897. Madsen, H. P. 1876. Kruse 1897. Caesar and Loretz 1878. Cressler, C. H. 1897. Dieterich 1878. Rohn, E. 1897. Gehe & Co. 1879. Kennedy 1897. Chem. C^tralb. 1881. Bowman, J. 1898. Bellingrodt, Fr. 1881. Seifert, 0. 1898. Dieterich, Karl 1883. Maish, J. M. 1898. Duesterbehn, F. 1884. Kramer 1898. Katz, Julius 1886. Berenger-Feraud 1898. Lefils 1887. Kremel, A. 1898. Miehle, Feodor 1888. Keefer, C. D. 1898. Plzak, F. 1888. Trimble, H. 1898. Caesar & Loretz 1889. Greenwalt, W. G. 1898. Gehe & Co. 1891. Dieterich 1898. Pharm. Centralh. BIBLIOQRAPHY 285 Oleoresin of Aspidium. — Con. Oleoresin of Aspidium. — Con. 1899. Hausmann, A. 1912. Caesar & Loretz 1899. Am. Drugg. & Pharm. Eec. 1912. Evans Sons Lescher & Webb 1899. Caesar & Loretz 1912. Merck's Eep. 1900. Caesar and Loretz 1912. Southall Bros. & Barclay 1900. Geh€ & Co. 1913. Bohrisch, P. 1901. Linda, O. 1913. Du Mez, A. G. 1901. Matzdorff, M. 1913. Goris & Voisin 1901. Schmidt, M. E. 1913. Harrison and Self 1901. Stoeder 1913. Hill, C. A. 1901. Caesar and Loretz 1913. Parry, E. J. 1901. Dieterich 1913. Yagi, E. 1902. Buttin, L. 1913. Caesar and Loretz 1902. Kraft, F. 1913. Evans Sons Lescher & Webb 1902. Caesar and Loretz 1913. Southall Bros. & Barclay 1903. Pendorff, 0. 1914. Bohrisch, P. 1903. Schmidt, E. 1914. Linke, H. 1903. Caesar and Loretz 1914. Vanderkleed, C. E. 1903. Dieterich 1914. Caesar & Loretz 1903. Southall Bros. & Barclay 1914. Journ. A. Ph. A. 1904. Caesar and Loretz 1914. Riedel's Ber. 1904. Dieterich 1915. Sherman, H. B. 1905. Kiezka, M. 1915. Southall Bros. & Barclay. 1905. Pharm. Ztg. 1905. Caesar and Loretz Oleoresin of Capsicum 1905. Dieterich 1849. Procter, Wm. Jr. 1906. Naylor, A. H 1853. Bakes, W. C. 1906. Eoeder, Ph. 1864. Parrish, E. 1906. Wollenweber, W. 1872. Maish, J. M. 1906. Apoth.-Ztg. 1873. Bucheim 1906. Caesar & Loretz 1888. Trimble, H. 1908. Caesar and Loretz 1892. Sherrad, C. C. 1908. Vanderkleed, C. E. 1898. Winton, Ogden and MitchelL 1909. Dunn, J. A. 1903. Beythien 1909. Vanderkleed, C. E. 1903. Southall Bros. & Barclay 1909. Caesar & Loretz 1905. Vanderkleed, C. E. 1910. Dohme & Engelhardt 1905. Am. Drugg. & Pharm. Rec. 1910. Gandini, V. 1907. Patch, E. L. 1910. Gane & Webster 1908. Patch, E. L. 1910. Caesar & Loretz 1908. Vanderkleed, C. E. 1911. Parry, E. J. 1909. Vanderkleed, C. E. 1911. Pearson, W. A. 1910. Brown, L. A. 1911. Rosendahl, H. V. 1910. Eldred, F. R. 1911. Chem, & Drng. 1910. Southall Bros. & Barclay 1911. Brit. & Col. Drugg. 1910. Vanderkleed, C. E. 1911. Caesar & Loretz 1911. Deane, Harold 1911. Evans Sons Lescher & Webb 1911. Vanderkleed, C. E. 1912. Roberts, H. G. 1912. Vanderkleed, C. E. 286 DU MEZ— THE GALENICAL OLEORESINS Oleoresin of Capsicum. — Con. 1913. Chem. & Drugg. 1913. Engelhardt, H. 1913. Patch, E. L. 1912. Evans Sons Lescher & Webb 1912. Johnson & Johnson 1913. Unmey, J. C. 1913. Vanderkleed, C. E. 1914. Patch, E. L. 1914. Rippetoe, J. R. 1914. Vanderkleed, C. E. 1914. Journ. A. Ph. A. 1914. Riedel's Ber. 1915. Vanderkleed, C. E. Oleoresin of Cube!) 1828. Dublane, H. 1828. Oberdoerffer 1838. Hausmann 1846. Bell 1846. Procter, Wm., Jr. 1857. Garot and Schaeuffele 1857. Landerer, X. 1859. Procter, Wm., Jr. 1863. Girtle 1865. Bernatzik, W. 1866. Procter, Wm., Jr. 1866. Rittenhouse, H. N. 1867. Paul, C. 1867. Pile 1868. Heydenreich, F. V. 1872. Maish, J. M. 1877. Griffin, L. P. 1877. WolflF, L. 1883. Maish, J. M. 1887. Kremel, A. ' 1887. Gehe & Co. 1888. Trimble, H. 1892. Sherrard, C. C. 1893. Dieterich 1894. Bedall 1894. Hell & Co. 1895. Hyers, P. 1895. Dieterich ^ 1895. Gehe & Co. 1905. Vieth, R. 1905. Dieterich -?? t • - Oleoresin of Cubeb. — Con. 1907. Blome, W. H. 1907. Smith, A. W. 1907. Evans Sons Lescher & Webb 1908. Vanderkleed, C. E. 1909. Vanderkleed, C. E. 1909. Chem. & Drugg. 1910. Gane, E. H. 1910. Vanderkleed, C. E. 1910. Southall Bros. & Barclay 1911. Southall Bros. & Barclay 1911. Vanderkleed, C. E. 1912. Dohme & Engelhardt ' 1912. Gluecksmann, G. 1912. Vanderkleed, C. B. 1913. Dohme & Engelhardt 1913. Vanderkleed, C. E. 1914. Maines and Gardner 1914. Rippetoe, J. R. 1914. Scoville, W. L. 1914. Vanderkleed, C. E. 1914. Journ. A. Ph. A. 1914. Riedel'B Ber. Oleoresin of Ginger 1834. Beral 1849. Procter, Wm., Jr. 1859. Procter, Wm., Jr. 1866. Rittenhouse, H. N. 1867. Pile 1872. Maish, J. M. 1877. Wolflf, L. 1879. Thresh 1886. Jones, E. W. : 1888. Trimble, H. 1891. Riegel, S. J. 1892. Sherrard, C. C. 1893. Dyer and Gilbard 1895. Davis, R. G. 1896. Liverseege 1897. Glass and Thresh 1901. Bennet 1903. Ballard 1903. Southall Bros. & Barclay 1905. Helfenberger Ann. 1908. Spaeth, Eduard 1908. Vanderkleed, C. E. 1909. Patch, E. L. BIBLJOGRAPHT 287 Oleoresin of Ginger. — Con. 1909. Vanderkleed, C. E. 1910. La Wall, C. H. 1910. Vanderkleed, C. E. 1911. Beythien, Hemple & Others 1911. Vanderkleed, C. E. 1912. Hooper, D. 1912. Patch, E. L. 1912. Vanderkleed, C. E. 1913. Engelhardt, H. • 1913. Patch. E. L. 1913. Vanderkleed, C. E. 1913. Chem. & Drugg. 1914. Eippetoe, J. K. 1914. Vanderkleed, C. E. 1914. Journ. A. Ph. A. 1915. Vanderkleed, C. E. Oleoresin 1825. 1829. 1859. 1877. 1888. 1892. 1903. 1913. 1913. 1913. 1914. of Pepper Meli Carpenter, G. W. Procter, Wm. Jr. Wolff, L. Trimble, H. Sherrard, C. C. Ballard La Wall, C. H. Engelhardt, H. Patch, E. L. Journ. A. Ph. A. Oleoresin of Lupulin 1823. Planche 1853. Livermore 1859. Procter, Wm. Jr. 1869. Kump, C. 1888. Trimble, H. 1892. Sherrard, C. C. 1907. Van der Harst, J. C. 1908. Dohme & Engelhardt 1909. Bernegau, L. H. 1909. Dohme & Engelhardt 1909. Parson, W. A. 1911. Bernegau, L. H. 1911. Francis, J. H. 1913. Gane, E. H. 1913. Engelhardt, H. 1913. Osborne, 0. T, 1913. Patch, E. L. 1914. Eippetoe, J. E. 1915. Glickman, L. H. Oleoresin of Parsley Fruit 1877. Wolff, L. 1892. Beringer, G. M. 1906. Merck's Ann. Eep. 1909. Evans Sons, Lescher & Webb 1913. Engelhardt, H. 1913. Osborne, O. P. 1914. Jonm. A. Ph. A. Oleoresin of AlTcanet Boot 1892. Gehe & Co. Oleoresin of Annatto ! 1895. Gehe & Co. Oleoresin of Cardamom Seed 1849. Procter, Wm., Jr. 1859. " '« <' Oleoresin of Chenopodvum 1849. Procter, Wm., Jr. 1877. Wolff, L. Oleoresin of Clove 1849. Procter, Wm., Jr. Oleoresin of Coni/um Leaves 1870. Lefort, M. J. Oleoresin of Pepo 1890. Minner, L. A. Oleoresin of Pyrethrum 1849. Procter, Wm., Jr. 1859. ** *' " 1902. Southall Bros, and Bardaj 1911. ** *' " ** Oleoresin of Santonica 1830. Schuppmann 1849. Procter, Wm., Jr. 1877. Wolff, L. •288 DU MEZ— THE GALENICAL. OLEORESINS Oleoresin of Savine ' 1849. Procter, Wm., Jr. Oleoresin of Saw Palmetto 1914. E'we, G. E. Oleoresin of Xanthoxylum 1849. Procter, Wm., Jr. Oleoresins (General) 1869. Squibb, E. 1873. Remington, J. P. 1887. Lippincott, C. P. 1900. Maish, H. C. 1905. Francis, J. M. 1905. Drug Topics 1916. Beringer, G. M. C-UIDS Information of the encyclopaedic dictionary type is being edited and distributed on the card plan. The following cards are now ready: 1. 2. 3. 4. 5. 6. 8. 9. 10. 11. 12. 13. 14. 15. 1(]. 17. IS. 19. 20. 21. 22. 23. 24. 25. 26. Anaesthesin Drug vT. O. Schlotterbeck (Biography) J. O. Schlotterbeck (Original Publications) J. O. Schlotterbeck (Miscellaneous Writings, views) Liquor* Potassii Arsenitis, U. S. P. 1890 Linogen Linoliment Linoval Parogen (um) Penetrole Petrogen Petrolatum Saponatum Petroliment Petroxolin (um) Valselol Valsol Vasapon Vascosan Vaselon Vaseloxyne Vasenol Vasogen(um) Vasol Vasoliment (um) Vasopolent (^um ) Vasoval Book Re- Additioual cards are in the hands of the printer. Price: Individual cards 0.05 each In lots of 10 or more . 25 Extra duplicates *.''.'. q ! 02 each