key: cord-0793000-pv5fk920 authors: Mohamed, Mona A.; Eldin, Ghada M.G.; Ismail, Sani M.; Zine, Nadia; Elaissari, Abdelhamid; Jaffrezic-Renault, Nicole; Errachid, Abdelhamid title: Innovative electrochemical sensor for the precise determination of the new antiviral COVID-19 treatment Favipiravir in the presence of coadministered drugs date: 2021-05-28 journal: J Electroanal Chem (Lausanne) DOI: 10.1016/j.jelechem.2021.115422 sha: 56fc2a18f17df517b54b4bbb04853801a30094b9 doc_id: 793000 cord_uid: pv5fk920 Due the current pandemic of COVID-19, an urgent need is required for serious medical treatments of a huge number of patients. The world health organization (WHO) approved Favipiravir (FAV) as a medication for patients infected with corona virus. In the current study, we report the first simple electrochemical, greatly sensitive sensor using MnO2 -rGO nanocomposite for the accurate determination of Favipiravir (FAV). The developed sensor showed a high improvement in the electrochemical oxidation of FAV comparing to the unmodified screen-printed electrode (SPE). The suggested platform constituents and the electrochemical measurements parameters were studied. Under optimal experimental parameters, a current response to the concentration change of FAV was found to be in the linear range of 1.0x10-8 – 5.5x10-5 M at pH 7.0 with a limit of detection 0.11 µM and a quantification limit of 0.33 µM. The developed platform was confirmed by the precise analysis of FAV in real samples including dosage form and plasma. The developed platform can be applied in different fields of industry quality control and clinical analysis laboratories for the FAV determination. During the year 2020, the world faced the worst public-health crisis in past hundred years, COVID-19 pandemic. Coronaviruses are large genome viruses of the Nidovirales order, with a positivestrand RNA [1] . European and almost all countries have applied non-pharmaceutical involvements, like school closure and national lockdown that lead to huge economic crises [2] . Regardless of the major efforts to stop its spread, COVID-19 has affected considerable health and financial burden, stressing the urgent need for antiviral treatments [1] . Great efforts have been devoted to the development of an antiviral agent for the halt of the progression of this ailment. During the pandemic influenza in Japan 2014, Favipiravir (FAV) was approved for the treatment of that ailment which showed high potential for the in vitro activity against the acute respiratory syndrome coronavirus-2 [3] . FAV was first applied as a medication against COVID-19 in China-Wuhan, at the red zone of the pandemic origin. After that as the pandemic been in Europe, FAV got approval for emergency use in Italy, and currently has been in use in Japan, Russia, and many other countries around the globe including Egypt [4] . The main advantages of using FAV to treat a new indication, a process called "drug repurposing," are that FAV is available in high doses and the safety measurements have previously been conducted on a high patients number [5, 6] . Accordingly, the approved medical agent FAV has the potential to be rapidly used on a large scale and be used as a first line of protection to administer to suspect or contact cases during a pathogen lockdown [5] . Based on the above mentioned facts, there is urgent need to develop a sensitive, reliable, fast, low expensive analytical method to trace and determine FAV individuality and in the presence of coadministered drugs. By reviewing the previously published works regarding the determination of FAV, only few methods have been reported for the determination of FAV including HPLC method [7] , and spectrofluorometric method [8] . One electrochemical method has been reported for the single determination of FAV [9] . The MnO 2 nanomaterials have been used in different applications due to their high capacitance and low cost preparation; they are ecofriendly nanomaterials with an extraordinary stability in alkaline solutions [10] . By the incorporation of carbon with a high electrical conductivity, the conductivity of MnO 2 nanomaterials were further enhanced, reduce the equivalent resistance and charge-transfer resistance [10] [11] [12] . Graphene nanostructured materials have received great attention in the past recent years as these materials offer high conductivity, excellent mechanical characteristics, high chemical/thermal stability, with tremendous surface area [13] [14] [15] [16] . So, due to the urgent need to develop a fast, precise and sensitive strategy for the sensitive determination of FAV, we have fabricated the present electrochemical protocol. In this work, hydrothermal one-pot strategy was developed to prepare directly MnO 2 -rGO nanocomposite using graphene oxide (GO). To the best of our knowledge, there were no literature reporting the use of MnO 2 -rGO nanocomposite for the modification of screen-printing electrodes (SPE) for the electrochemical determination of FAV. The whole data and description of the used chemicals, apparatus, and methods are described in the electronic supplementary information (ESI) section S2. The structural morphology of the prepared MnO 2 -rGO nanomaterial is displayed in Figure 1A . TEM photo is used to examine the structural morphology of MnO 2 -rGO. TEM displays the structure of graphene with transparent layers and the manganese oxide distribution on its surface, (Fig. 1A) . The MnO 2 -rGO provided high surface area over the common graphite. The bulky particles of the graphite was exfoliated to layers with higher surface area. While the existence of MnO 2 nanoparticles with particle' diameter in the range of 30 to 85 nm offer much higher surface area that lead to improving the adsorptive affinity towards the FAV throughout the MnO 2 -rGO/SPE surface. Also, the EDX spectrum was utilized to examine the elemental configuration of the prepared material. Figure 1B shows the EDX of nanocomposite, indicating the presence of Mn, O, and C. The non-destructive method XRD is a beneficial tool in the description of MnO 2 . Inset in Figure 1B shows different peaks at 2θ 18. the MnO 2 nanoparticles that completely cover the reduced graphene sheets [24] . Next, the electrochemical characteristics of the developed platforms were depicted in 5. As can be seen in Figure 3A , the value of the current of the electrode rises due to the addition of GO, where the anodic peak appears at 1.25 V with a current value of 18.10 µA. After modification of the sensor with MnO 2 -rGO, the peak current increased to 25.14 µA at 1.14 V. Consequently, the successful application of MnO 2 -rGO for the determination of FAV enhanced the analytical signal, due to a higher electron transfer with high electrical conductivity. One of the important factors that affect the electrochemical process is the solution pH. Different pH values were tested using 5.5 × 10 -4 M FAV, Figure 3B . Upon varying the pH from 2.0 to 9.0, the FAV oxidation peak was shifted towards lower potentials values, i.e. more negative values, which might be explained as reduction-deprotonation of FAV [26] . The MnO 2 -rGO/SPE sensor showed high repeatability and reproducibility for FAV analysis. Figure S2 ). After the preliminary determination of FAV, the MnO 2 -rGO/SPE sensor was kept in the buffer (pH= 7.0) at 25 o C. The FAV electrochemical response was checked regularly over 4 weeks (Fig. S2 ). So, four sensors prepared in the same manner were tested in parallel (n=3). After four weeks, the final current decreased by 12% of the initial current value that proposes the sensor was rationally stable through the checking period. The high stability of the sensor can be gained because of the hydrophobic property of the graphene materials [28] [29] [30] , which prevents the formation of a water film on the sensor surface. Croscarmellose sodium, sodium lauryl sulphate, titanium dioxide, sodium dihydrogen orthophosphate (H 6 NaO 6 P), talc, castor oil, mannitol, cellulose, magnesium oxide, and povidone, were examined in order to check any change in the FAV electrochemical signal. Using 1.0 ×10 -5 M FAV in a pH 7.0 B.R. buffer (0.04 M) solution, each was added, and the magnitude of the anodic peak current was monitored. From the chosen potential interfering substances, none were found to interfere with the electroanalytical sensing of FAV. The tolerance limit was less than ± 5.0% for each interfering substance. Correspondingly, it was found that the use of 40-fold of inorganic ions (e.g. Mg 2+ , K + , Zn 2+ , Na + , Fe 3+ , Ca 2+ , Cl -, NO 3and SO 4 2-) did not affect the electrochemical responce, as shown in Figure S3 . In addition, the important commonly interfering materials in the biological fluids ascorbic acid The practicability of MnO 2 -rGO/SPE for the determination of FAV in real samples were tested using SWV technique. The standard addition method was used to evaluate the analytical performance of the sensor for FAV determination. The recovery experiment was presented in Table 1 , which confirm that, the MnO 2 -rGO/SPE is very sensible for the determination of low and high concentrations of FAV in different real samples. In the current study, we have described for the first time, the electrochemical determination of Furthermore, along with the excellent characteristics of high accuracy, sensitivity, and reproducibility, the developed sensor offers appropriate simple platform for the sensitive determination of FAV in the clinical work. -An electrochemical sensor using MnO 2 -rGO nanocomposite for the accurate determination of Favipiravir (FAV) is reported. -A current response to the concentration change of FAV was found to be in the linear range of 1.0x10 -8 -5.5x10 -5 M. -A limit of detection 9.0 x10 -9 M and a quantification limit of 2.9x10 -8 M were obtained. -The developed platform was applied for the analysis of FAV in real samples including dosage form and plasma. 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Ismail Contribution: investigation Nadia Zine Contribution: writing-original draft preparation Abdelhamid Elaissari Contribtion: conceptualization Nicole JAFFREZIC-RENAULT Contribution: writing-review and editing Abdelhamid ERRACHID Contribution: Funding acquisition The authors acknowledge the partial funding from KardiaTool, H2020, under the grant number 768686 and POC Allergies through the ERA PerMed program. Mona A. Mohamed thanks the French Embassy in Egypt for supporting this work. Campus France is acknowledged for financial support through PHC Imhotep # 46354WG.