Voltammetric Determination of Favipiravir Used as an Antiviral Drug for the Treatment of Covid‐19 at Pencil Graphite Electrode

Teslime Erşan; Didem Giray Dilgin; Elif Kumrulu; Umur Kumrulu; Yusuf Dilgin

doi:10.1002/elan.202200295

. 2022 Nov 16:10.1002/elan.202200295. Online ahead of print. doi: 10.1002/elan.202200295

Voltammetric Determination of Favipiravir Used as an Antiviral Drug for the Treatment of Covid‐19 at Pencil Graphite Electrode

Teslime Erşan ¹, Didem Giray Dilgin ², Elif Kumrulu ³, Umur Kumrulu ³, Yusuf Dilgin ^1,^✉

PMCID: PMC9874810 PMID: 36712592

Abstract

This work describes the sensitive voltammetric determination of favipiravir (FAV) based on its reduction for the first time with a low‐cost and disposable pencil graphite electrode (PGE). In addition, the determination of FAV was also performed based on its oxidation. Differential pulse (DP) voltammograms recorded in 0.5 M H₂SO₄ for the reduction of FAV show that peak currents increase linearly in the range of 1.0 to 600.0 μM with a limit of detection of 0.35 μM. The acceptable recovery values (98.9–106.0 %) obtained from a pharmaceutical tablet, real human urine, and artificial blood serum samples spiked with FAV confirm the high accuracy of the proposed method.

Keywords: COVID-19, Favipiravir, Pencil graphite electrode, Differential Pulse Voltammetry

1. Introduction

The new type of coronavirus (SARS‐CoV‐2 also known as COVID‐19), which was first seen in Wuhan, China in December 2019, has continued its impact on the world and new variants such as Delta, Omicron, and Ba.2–5 have been emerging. The World Health Organization (WHO) on March 11^th, 2020 declared that the COVID‐19 outbreak is a global pandemic [1], and more than 594 million cases and more than 6.4 million deaths have been reported by the WHO on August 23^th, 2022 [2]. It is estimated that more people are infected and have died than those reported. Generally, people infected with COVID‐19 experience symptoms such as high fever, fatigue, weakness, dry cough, and lymphopenia, resulting in viral pneumonia in severely ill patients [3]. In most cases, severe respiratory failure, multiple organ failure, acute respiratory distress syndrome, shock, arrhythmias, heart failure, renal failure, and death have occurred [3, 4, 5].

Important progress has been made with vaccine studies to fight against COVID‐19, as well as intensive studies have been carried out on the drugs used by infected people. Unfortunately, any specific drug has not been developed for the treatment of COVID‐19, a large and enveloped RNA virus with crown‐shaped protrusions. However, a few currently available anti‐viral drugs with approved efficacy and safety against other viruses have been tested for the treatment of COVID‐19. Although two new anti‐viral drugs (molnupiravir and nirmatrelvir+ritonavir) have been recently approved for COVID‐19 treatments [6, 7], one of the most effective antiviral drugs widely used in the early days of COVID‐19 is Favipiravir (FAV) [8, 9]. SARS COV‐2, which contains an RNA polymerase enzyme, performs virus replication as well as RNA replication. Here, as in other RNA viruses, FAV is converted to the ribofuranosyl triphosphate derivative by host enzymes, and thus it selectively and strongly inhibits RNA‐dependent RNA polymerase in COVID‐19 [10].

FAV was developed for antiviral activity against the influenza virus by Toyama Chemical Company in Japan by modification of a pyrazine analog. To treat acute respiratory syndrome coronavirus 2 infections due to pandemic influenza virus, FAV was approved for medical use in Japan in 2014 [11]. FAV (6‐fluoro‐3‐hydroxypyrazine‐2‐carboxamide or 6‐fluoro‐3‐oxo‐3,4‐dihydropyrazine‐2‐carboxamide) is a pyrazine derivative and it has been easily synthesized using different routes, including the substitution of aminocarbonyl, hydroxy, and fluor groups to the pyrazine ring at positions of 2, 3, and 6, respectively [12].

The development of sensitive, accurate, and reliable analytical methods with low cost is required to trace and determine this important drug, which has become more important today in different matrices such as biological fluids and pharmaceutical preparations. Literature surveying shows that various analytical methods based on the use of UV‐Vis spectrophotometry [13], spectrofluorimetry [14, 15, 16], chromatography [13, 16, 17, 18, 19, 20, 21, 22, 23], and electrochemical techniques [24, 25, 26, 27, 28, 29, 30] have been developed to determine FAV in pharmaceutical tablets and biological matrices such as urine and human plasma. Among them, electrochemical sensors have been broadly used in pharmaceutical analysis because electrochemical methods have some advantages such as low cost, miniaturization, portability, fast response, acceptable sensitivity, high accuracy, precision, and selectivity, ease of operation, and allowing the use of green solutions such as aqueous buffer solutions instead of toxic organic solvents [24, 31, 32]. In this context, the first electrochemical study on FAV determination was reported by Şentürk et al. using a cathodically pretreated boron‐doped diamond electrode (CPT‐BDDE) [24]. Then, electrochemical FAV determination was carried out based on its oxidation at different electrodes such as gold/silver core‐shell nanoparticles (Au@Ag CSNPs) with conductive polymer poly (3,4‐ethylene dioxythiophene) polystyrene sulfonate (PEDOT : PSS) and functionalized multi carbon nanotubes (F‐MWCNTs) on a glassy carbon electrode (GCE) [33], MnO₂‐reduced graphene oxide nanocomposite modified screen‐printed electrode [29]; ionic liquid crystals (ILCs)‐carbon nanotubes (CNTs) modified electrode [26] and diamond nanoparticle modified carbon paste electrode [27]. However, our literature search shows that no voltammetric study based on FAV has not yet been reported using not only pencil graphite electrode (PGE) but also reduction of FAV. This electrode has many advantages over other solid electrodes, such as disposability, extremely low cost, commercially readily available, mechanical rigidity, ease of modification, no long‐time and hard polishing steps, and providing a renewable surface [34, 35, 36, 37, 38]. Therefore, PGEs have been extensively used in the electrochemical determination of many pharmaceutical compounds [39, 40, 41, 42, 43].

In this study, the voltammetric behavior and determination of FAV have been performed in detail at PGE for the first time. Although a few types of electrodes have been reported for determination of FAV as mentioned above, they are very expensive and require long‐time and hard polishing or long‐time and tedious preparation steps. On the other hand, only the electrochemical oxidation of FAV has been studied at these previously reported electrodes. However, in this study, the reduction of FAV in addition to its oxidation was studied, and the mechanisms for both were elucidated. Therefore, the fact that the differential pulse (DP) voltammetric determination of both the oxidation and reduction of FAV was performed at disposable and low‐cost PGE for the first time constitutes the novelty side of the study.

2. Materials and Method

2.1. Chemicals and Apparatus

The chemicals and apparatus used in this study are given in the Supplementary Information file. A stock solution of FAV (0.01 M) was prepared by dissolving 15.71 mg of FAV with methanol and then its dilution to 10 mL with methanol.

2.2. Electrochemical Studies

The first electrochemical studies were performed by recording cyclic voltammograms (CVs) of 5.0×10⁻⁴ M FAV by applying two different potential scan ranges (from 0 to +1.3 V and from 0 to −1.0 or −1.3 V) in 0.10 M H₂SO₄, 0.10 M HCl, and the Britton Robinson buffer solution (BRBS) containing 0.10 M KCl with varying pH in the range from 2.0 to 10.0 at a scan rate of 50 mV/s. CVs of FAV were separately recorded dependent on scan rates varying between 10 to 1000 mV s⁻¹ in 0.10 M H₂SO₄ for cathodic direction and pH 5.0 BRBS containing 0.10 M KCl for anodic direction.

In the following electrochemical study, DP voltammetric experiments were performed for the voltammetric determination of FAV. The DP voltammograms were also recorded dependent on pH change by applying potential scanning to both cathodic and anodic directions at PGE. Parameters used in DPV mode such as pulse amplitude (P_am), pulse time (P_t), and step potential (E_step) were optimized by recording DP voltammograms of 1.0×10⁻⁴ M and 5.0×10⁻⁴ M FAV for both its reduction and oxidation in the 0.50 M H₂SO₄ and pH 5.0 BRBS containing 0.10 M KCl, respectively. Then, DP voltammograms of FAV were recorded based on the increasing concentration of FAV in the range from 1.0 to 1000 μM in 0.50 M H₂SO₄ for reduction and pH 5.0 BRBS containing 0.10 M KCl for oxidation under optimized conditions. In all experiments, highly pure Ar was purged from the supporting electrolyte for 5 min.

2.3. Preparation of Samples

Three different samples (pharmaceutical tablets, artificial human serum, and real urine) were used to see the feasibility of the proposed method. A commercial pharmaceutical tablet containing 200.0 mg FAV was purchased from a local pharmacy. An artificial human serum sample was prepared according to the literature[44] and real urine was obtained from a healthy volunteer. A real urine sample was immediately used after 10 min of centrifugation.

The FAV in the pharmaceutical tablet was determined directly by DP voltammetry using the standard addition method. Also, a known amount of FAV was spiked into the pharmaceutical tablet, artificial human serum, and real urine samples, and then recovery studies in these samples were performed by recording the standard addition DP voltammograms. In this context, ten pharmaceutical tablets were weighed and grounded in an agate mortar until fine homogenous powders were obtained. An amount of homogenized powder weighed to be equivalent to 500 μM FAV was dissolved in 10 mL of methanol. After approximately 10 min of sonication, the final solution was diluted with methanol in a 50 mL volumetric flask. An aliquot volume of this sample was transferred to the appropriate supporting electrolytes used separately for reduction and oxidation, and DP voltammograms were recorded based on standard addition. In addition, a pharmaceutical solution including about 0.12 mM FAV was spiked as 0.10‐, 0.15‐, and 0.20‐mM FAV, and recovery studies were performed for each spiked sample by recording standard addition DP voltammograms.

The artificial human serum and the real urine samples were spiked by the addition of known volumes of stock FAV (10⁻² M) solution such that the final concentration of FAV in the samples would be 10, 25, and 50 μM. Then 0.50 M H₂SO₄ and pH 5.0 BRBS containing 0.10 M KCl were prepared from these spiked samples to use as supporting electrolytes for the reduction ad oxidation of FAV respectively. After the addition of 5 mL of spiked samples prepared with H₂SO₄ and BRBS to the electrochemical cell, the standard addition DP voltammograms for reduction and oxidation were individually recorded, similar to the pharmaceutical tablet mentioned above.

3. Results and Discussion

3.1. Voltammetric Behavior of FAV

3.1.1. The Effect of pH

To see the peaks of both oxidation and reduction of FAV at disposable PGE, CVs of FAV (1.0×10⁻⁴ M and 5.0×10⁻⁴ M for reduction and oxidation, respectively) were recorded based on both supporting electrolyte types (H₂SO₄, HCl, and BRBS), and varying pH between 2.0 and 10.0 for the same supporting electrolyte (BRBS) at a constant scan rate of 50 mV/s. The cathodic and anodic directions were individually scanned in the potential range from 0 to −1.0 or −1.3 V and from 0.5 to 1.5 V, respectively. The CVs given in Figures S1A and S2A show that a single‐well‐shaped irreversible peak was observed for both reduction and oxidation at unmodified PGE. The peak potential of cathodic and anodic peaks shifted to more negative potential values by increasing the pH of BRBS containing 0.10 M KCl. According to the graphs of peak current versus supporting electrolyte and pH obtained from evaluating CVs (Figure S1B and Figure S2B), the supporting electrolytes which the maximum current was obtained, were found to be 0.10 M H₂SO₄ and pH 5.0 BRBS for the reduction and oxidation of FAV, respectively. In addition, the fact that the following voltammetric studies will be carried out at a more positive potential for the cathodic peak and a more negative potential for the anodic peak supports the selection of these electrolytes.

The curves of the potential values of the anodic and cathodic peaks versus pH are given in Figure1. These figures show that the potential of the cathodic peak decreases linearly with increasing pH in the range from 2.0 to 10.0 (Figure 1A), while anodic peak potential decreases linearly with pH between 2.0 and 5.0 and is stable between 5.0 and 10.0 (Figure 1B). The slopes of the linear parts of these curves are found to be −72.2 mV/pH for reduction and 51.3 mV/pH for oxidation of FAV, respectively, which are close to the theoretical Nernstian slope value of 59.2 mV/pH. This indicates the participation of equal numbers of protons and electrons for the irreversible oxidation and reduction of FAV at unmodified PGE. In addition, the pK_a value of FAV can be estimated from Figure 1B because peak potential remained stable between pH 6.0 and 10.0 for the group involved in the electrochemical oxidation process. The point where the linear descending and the horizontal parts of the curve intersect corresponds to a value of approximately 5.1, which gives the pK_a value of FAV. The reporting of a similar pK_a value for FAV in the literature supports the result obtained in this study [24, 45, 46, 47]. In particular, a recently published study reported that the pKa value of FAV was determined chromatographically as 5.03[47].

Plots of peak potentials of reduction (A) and oxidation (B) of FAV versus pH.

3.1.2. The Effect of Scan Rate

In the following cyclic voltammetric study, the effect of scan rate on the potential and current of reduction/oxidation peaks of FAV was investigated. In this regard, the CVs of FAV (1.0×10⁻⁴ M and 5.0×10⁻⁴ M for reduction and oxidation, respectively) were individually recorded at scan rates varying in the range from 10 to 1000 mV s⁻¹ in 0.10 M H₂SO₄ and pH 5.0 BRBS for reduction and oxidation, respectively (Figures 2A and 3A). The reduction and oxidation potentials shifted to more negative and positive directions with increasing scan rate for reduction and oxidation, respectively, while peak currents of both of them increased linearly with the increasing square root of scan rate (Figure 2B and 3B). These results reflect that both oxidation and reduction of FAV at PGE occur as irreversible by a diffusion‐controlled process. Linear curves of logarithmic peak current versus logarithmic scan rate have slope values of 0.43 and 0.51 for reduction (Figure 2C) and oxidation (Figure 3C) respectively. These slope values also indicate the diffusion‐controlled process in both reduction and oxidation of FAV, because the ideal slope was reported as 0.5 for the diffusion‐controlled process[48]. The curves of logaritmic scan rate versus Ep(mV) were also given in Figures 2D and 3D for reduction and oxidation respectively.

Cyclic Voltammograms of FAV (1.0×10⁻⁴ M) at PGE based on its reduction in 0.10 M H₂SO₄ at varying scan rates (B). Plots of peak current vs. square root of scan rate (B), log current vs. log scan rate (C), and peak potential vs. log scan rate (D).

Cyclic Voltammograms of (5.0×10⁻⁴ M) at PGE based on its oxidation in pH 5.0 BRBS containing 0.10 M KCl at varying scan rates (B). Plots of peak current vs. square root of scan rate (B), log current vs. log scan rate (C), and peak potential vs. log scan rate (D).

3.1.3. Reduction and Oxidation Mechanism of FAV

Reduction: It was reported that pyrazines can show three different electrochemical behaviors: i) reversible‐substituted pyrazines with electron‐withdrawing groups; ii) reversible under certain conditions‐substituted pyrazines with electron‐donating groups; and iii) irreversible under all conditions[49]. Pristine pyrazine itself belongs to the first group in which it is reversibly reduced to protonated 1,4‐dihydropyrazine by accepting two electrons and three protons. Its reversibility was decreased by the substitution of electron ‐withdrawing or ‐donating groups, and the reversibility can change based on electrode type and supporting electrolyte used [50, 51]. The CVs show that the reduction of FAV is included in the third category because the pyrazine ring in the FAV molecule was substituted with three different groups, which led to an irreversible reduction of FAV. In the literature, reduction mechanisms with two electrons and two protons at different pH media have been proposed for a pyrazine derivative, (2‐hydroxy‐3‐phenyl‐6‐methyl pyrazine) substituted with ‐OH, ‐CH₃, and ‐phenyl [49]. Based on this information, similarly, the reduction mechanism for FAV with 2e⁻ and 2H⁺ can be proposed as given in Figure 4. According to this mechanism, either neutral FAV or its protonated form formed in the strong acidic medium can give an enol‐keto tautomeric reaction and then they reduced to un‐protonated or protonated 1,4‐dihydropyrazine. The linear variation of the peak potential change versus pH between pH 2.0 and 10.0 with a slope of −72.2 mV/pH, as shown in Figure 1A demonstrates that FAV is reduced with an equal number of protons and electrons. This proves that FAV is reduced to 1,4‐dihydropyrazine with 2e⁻ and 2H⁺.

Reduction and oxidation mechanism of FAV at PGE.

Oxidation: The oxidation mechanism of FAV is also shown in Figure 4. According to this mechanism, both neutral and protonated FAV molecules are oxidized to a phenoxy radical by donating an electron and a H⁺. The phenoxy radical is delocalized to the nitrogen atom and then the radical on nitrogen is neutralized with the cationic −NH group for acidic FAV or by accepting a H⁺ for neutral FAV. The linear variation of the peak potential change versus pH between pH 2.0 and 5.0 with a slope of −51.3 mV/pH, as shown in Figure 1B demonstrates that FAV oxidized with an equal number of protons and electrons. This proves that FAV is oxidized to the phenoxy radical with one e⁻ and one H⁺. The fact that the potential remains constant after pH 5.0 as shown in Figure 1B can be explained by the dominance of the basic form after pH>pK_a(5.1). Thus, the peak potential is pH‐independent and only one electron oxidation of FAV takes place.

3.2. Optimization Studies for Differential Pulse Voltammetric Determination of FAV

Although electrolyte type and pH were optimized for the reduction and oxidation of FAV with CV studies, these optimizations were also repeated for DP voltammetric studies to precisely select the medium in which the maximum current was observed. Figure S3A shows the DP voltammograms of reduction of 1.0×10⁻⁴ M FAV in different supporting electrolytes (BRBS, PBS, ACBS, HCl, and H₂SO₄) with varying pHs. The maximum peak current was obtained from acidic supporting electrolytes. Moreover, the effect of the ionic strength of the acidic medium (H₂SO₄), where the best response was obtained, was also studied, and 0.50 M H₂SO₄ was chosen as the optimum supporting electrolyte for the reduction of FAV. On the other hand, the oxidation peak current of FAV (5.0×10⁻⁴ M) was found to be very stable between pH 4.0 and 8.0 BRBS containing 0.10 M KCl and it decreased in the strong acidic media (Figure S4A). In the following studies, pH 5.0 BRBS containing 0.10 M KCl was used as the optimum supporting electrolyte for the oxidation of FAV.

Then, optimization studies of parameters such as pulse amplitude (P_amp), pulse time (P_t), and potential step (E_step) were carried out. DP voltammograms of 1.0×10⁻⁴ M FAV dependent on each optimization parameter recorded in 0.50 M H₂SO₄ for reduction and pH 5.0 BRBS containing 0.10 M KCl for oxidation are given in Figures S5 and S6, respectively. Curves of the peak current versus each parameter (Figure S5 for reduction and Figure S6 for oxidation) show that the highest peak currents were obtained when the values of 120 mV, 1.0 ms, and 8 mV for reduction, and 120 mV, 3.0 ms, and 8 mV for oxidation were used as P_amp, P_t, and E_step, respectively.

DP voltammograms of FAV scanned towards the cathodic direction at varying concentrations in the range of 1.0 to 1000.0 μM under optimized conditions (P_am=120 mV, P_t: 1 ms, E_step: 6 mV, and scan rate: 25 mV/s). Dynamic range and calibration curves.

DP voltammograms of FAV scanned towards the anodic direction at varying concentrations in the range of 5.0 to 1000.0 μM under optimized conditions (P_am=120 mV, P_t: 3 ms, E_step: 6 mV, and scan rate: 25 mV/s). Dynamic range and calibration curves.

3.3. Analytical Performance Studies

To determine the analytical figures of the merits of the proposed electrode, DP voltammetric responses of FAV were recorded at PGE under optimized conditions. DP voltammograms of FAV were recorded depending on its increasing concentration and related dynamic ranges, and calibration curves were given in Figure 5 and 6 for reduction and oxidation, respectively. Figure 5 shows that the reduction peaks of FAV linearly increased in the range from 1.0 to 600.0 μM (I(μA)=1.320[FAV](μM)+ 0.9553 and R²=0.9992) while the oxidation peaks of FAV have two linear ranges: i) 5.0–200.0 μM (I(μA)=0.6263[FAV](μM)+3.460 and R²=0.9930) and ii) 200.0–600.0 μM (I(μA)=0.3357[FAV](μM)+57.53 and R²=0.9926). Limit of detection (LOD) values based on 3×σ/m (σ: the standard deviation of blank and m: the slope of calibration curve) and sensitivities were found to be 0.35 μM and 8302 μA mM⁻¹ cm⁻² for reduction and 1.55 μM and 3939 μA mM⁻¹ cm⁻² for oxidation, respectively. It is concluded that the sensitivity of reduction is twice that of oxidation. The precision of the proposed DP voltammetric method for both the reduction and oxidation was evaluated by recording DP voltammograms of FAV at three individual PGEs, yielding three different calibration curves. The RSD values of the slopes of calibration curves for the reduction and oxidation were found to be 3.45 and 5.13 %, respectively. These results indicate that the proposed electrode has very high repeatability for both reduction and oxidation of FAV. All the studied validation parameters were determined by the guidelines of the International Conference on Harmonization (ICH) [52] for the method validation (Table 1).

Table 1.

Validation parameters of the proposed method.

Parameters	Reduction of FAV	Oxidation of FAV
Linearity range (μM)	1.0–600.0	5.0–200.0 (1^st linear segment) 200.0–600.0 (2^nd linear segment)
Slope (μA/μM)	1.32	0.626 0.336
Standard error (SE) of slope	0.09	0.019 0.017
Intercept (μA)	0.955	3.46 57.5
Standard error (SE) of intercept	0.1	0.46 7.3
Coefficient of determination (R²)	0.9992	0.9930 0.9926
LOD (μM)	0.35	1.55 –
LOQ (μM)	1.15	5.11
%Mean recovery±%RSD	100.5±1.7	100.3±1.9 99.8±1.3

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In the literature, various types of modified electrodes have been proposed for the voltammetric determination of FAV based on only its oxidation. A comparison of the analytical performance of the proposed methods with these electrodes is given in Table 2. It can be seen that the sensitivities of oxidation and especially reduction of FAV at PGE are competitive with those at previously reported electrodes. In addition, linear ranges obtained from PGE are found to be wider than those from these electrodes. Although some electrodes are more sensitive than PGE for FAV determination, PGE has some advantages over these electrodes, such as low cost, disposability, commercial availability, no time‐consuming preparation, and hard cleaning procedures.

Table 2.

Comparison of analytical parameters for FAV determination of the proposed electrode with previously reported electrodes.

Electrode	Method	The type of response	LR (μM)	LOD (μM)	Sensitivity (μA mM⁻¹ cm⁻²)	Ref.
CPT‐BDDE	SW stripping voltammetry at pH 8.0 BRBS in the CTAB	Oxidation of FAV	0.064–0.64 0.64–130	0.018 0.15	1330	[24]
MnO₂‐rGO/SPE	SWV at pH 7.0 BRBS	Oxidation of FAV	0.01–55	9×10⁻³	2.52	[29]
Au@Ag CSNPs/ PEDOT : PSS/F‐MWCNTs/GCE	DPV at pH 4.0 BRBS	Oxidation of FAV	0.005–0.009 and 0.009–2.0	4.6×10⁻⁴	216.4	[25]
Diamond NPs/CPE	AdsDPV* AdsSWV** at pH 3.0 PBS	Oxidation of FAV	0.2–1.0 and 1.0–5.0* 0.8–6.0**	4.83×10⁻³* 0.244**	1.35 and 4.87* 2.05**	[27]
MoS₂@MIP/GCE	DPV: Decreasing peak current of ferro/ferri cyanides after incubation of FAV on MIP electrode	Oxidation of Ferro/ferri cyanides	1.0×10⁻⁵–1.0×10⁻¹	2×10⁻⁶	–	[28]
GCE	AdsSWV** at pH 10.0 BRBS in the SDS	Oxidation	6.4–640	1.7	–	[30]
PGE	DPV	Oxidation	5.0–200.0 200.0–600.0	1.55	3939 2111	This Study
PGE	DPV	Reduction	1.0–600.0	0.35	8302	This Study

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3.4. Interference Studies

The effect of some potentially interfering compounds on the peak current of FAV was investigated by recording DP voltammograms of 1.0×10⁻⁴ M or 5.0×10⁻⁴ M FAV based on both reduction and oxidation in the presence of up to 500 times the maximum of the studied compounds or ions. Considering the change of the current below 10 % as an evaluation criterion, it was seen that i) most of the simple sugar molecules (glucose, mannose, galactose, sucrose), urea, and studied ions (Ca²⁺, Mg²⁺, Zn²⁺, K⁺, Na⁺, Cl⁻, NO₃ ⁻, SO₄ ²⁻), ii) ascorbic acid and dopamine, iii) Cu²⁺, and iv) uric acid did not show any interference effect on the reduction current of FAV at 1 : 500, 1 : 250, 1 : 10, and 1 : 1 ratios of FAV:interfering compound respectively (Table S1). DP voltammograms of 1.0×10⁻⁴ M FAV in the presence of ascorbic acid and dopamine and DP voltammograms of 1.0×10⁻⁵ M FAV in the presence of uric acid were given at Figure S7 for concentrations of each interfering compound where interference was not observed for both oxidation and reduction. The most important difference in the effect of the studied interfering compounds on the oxidation of FAV compared to the reduction of FAV is that the tolerance limit of ascorbic acid and dopamine decreased up to a ratio of 1 : 5. These results show that FAV can be selectively determined in various types of matrices, including those compounds.

3.5. Real Sample Analysis

The practical applicability of the PGE was tested for FAV determination in commercial pharmaceutical tablets, human urine, and artificial blood serum samples. The FAV amount in the pharmaceutical tablet was analyzed by the standard addition method as mentioned in the experimental section. The FAV content was found to be 215 mg/tablet, which is very close to the declared value of 200 mg FAV/tablet by a pharmaceutical company. Moreover, FAV was spiked into pharmaceutical tablet solutions in three different concentrations (0.10, 0.15, and 0.20 mM) and recovery values were calculated based on recorded DP voltammograms of both reduction and oxidation of FAV. The calculated recovery values (Table 3) were found to be between 98.9 and 106.0 % for the reduction and oxidation of FAV. Recovery studies were also carried out for spiked real human urine and artificial blood serum samples. Known volumes of stock FAV solution were individually added to these samples to be 10.0, 25.0 and 50.0 μM FAV in the final spiked samples. It can be seen from Table 3, that acceptable recovery results for both oxidation and reduction of FAV were also obtained from both real human urine and artificial blood serum samples. As an example, standard addition DP voltammograms and standard addition curves of urine and artificial blood serum samples (spiked with 25.0 μM FAV) were given in Figures S8 and S9 for both reduction and oxidation. As can be seen from Figure S8B that a high oxidation peak apart from that of FAV at 1.2 V was seen at around +400 mV which is attributed to the oxidation of uric acid in the real urine sample. In the voltammograms of the artificial blood serum sample (Figure S9B), in addition to the peak at +400 mV, which is attributed to the sum of uric acid and dopamine, another oxidation peak was also observed at +250 mV attributed to ascorbic acid. However, the peaks attributed to these electroactive species appeared in more negative regions than the analyte peak and it was mentioned in the section on interference studies that these peaks did not affect the analyte at the determined ratios of analyte:interference. All these results indicate that the proposed method provides high applicability toward sensitive and accurate determination of FAV in real or artificial samples with different matrices.

Table 3.

Obtained results from applications of proposed methods for determination of FAV in pharmaceutical tablets and samples spiked with different concentrations of FAV.

Sample	Added (μM)	REDUCTION		OXIDATION
Sample	Added (μM)	Found (μM)	Recovery (%)	Found (μM)	Recovery (%)
Pharmaceutical tablet	0	119±3	–	118±5	–
	100	217±7	98.9±3.4	223±9	102.0±4.1
	150	283±4	106.0±1.1	275±3	102.1±1.1
	200	323±8	101.3±2.4	332±6	104.0±1.9
Urine	0	–	–	–	–
	10.0	10.2±0.4	102.0±3.9	9.96±0.2	99.6±2.0
	25	25.6±0.8	102.4±3.2	25.8±0.9	103.2±3.5
	50	51.3±1.5	102.6±3.0	50.9±1.3	101.8±2.6
Artificial Blood Serum	0	–	–	–	–
	10.0	10.3±0.5	103.0±4.9	9.98±0.4	99.8±4.0
	25	26.1±1.1	104.4±4.2	26.2±1.3	104.8±4.9
	50	51.7±1.8	103.4±3.5	52.2±2.4	104.4±4.6

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4. Conclusion

In the present study, electrochemical reduction of FAV was proposed for the first time and its determination based on reduction was successfully performed at unmodified disposable PGE. In addition, electrochemical determination of FAV based on its oxidation was also performed at PGE as reported in previously published studies using various modified electrodes. Results showed that the sensitivity of FAV based on its reduction is higher than that based on its oxidation. On the other hand, sensitive results were obtained from the voltammetric determination of FAV based on its oxidation in previously published modified electrodes. However, unmodified PGE has some advantages over these electrodes, such as disposability, low cost, commercial availability, and no hard and time‐consuming polishing or preparation procedures. In addition, the sensitivity of FAV based on reduction is competitive with these previously reported electrodes as well as having a wide linear range. The electrochemical methods proposed based on both reduction and oxidation were successfully used for the determination of FAV in the pharmaceutical tablet. Moreover, satisfactory recovery results were obtained from spiked pharmaceutical preparations, human urine, and artificial blood serum samples by a simple, rapid, selective, and sensitive DP voltammetric technique. As a result, an accurate, sensitive, and reproducible electrochemical method has been developed using PGE for the determination of FAV in samples with different matrices.

5. Supporting information

As a service to our authors and readers, this journal provides supporting information supplied by the authors. Such materials are peer reviewed and may be re‐organized for online delivery, but are not copy‐edited or typeset. Technical support issues arising from supporting information (other than missing files) should be addressed to the authors.

Supporting Information

Click here for additional data file.^{(2.3MB, pdf)}

Data Availability Statement

Data openly available in a public repository that issues datasets with DOIs.

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2.Covid 19 2022. https://covid19.who.int/. Accessed 23 August 2022.
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52.GUIDELINE IHT Validation of analytical procedures: text and methodology, Q2 (R1) 1. 2005.

Associated Data

This section collects any data citations, data availability statements, or supplementary materials included in this article.

Supplementary Materials

Supporting Information

Click here for additional data file.^{(2.3MB, pdf)}

Data Availability Statement

Data openly available in a public repository that issues datasets with DOIs.

[elan202200295-bib-0001] 1.Covid 19–2020. https://www.who.int/director-general/speeches/detail/who-director-general-s-opening-remarks-at-the-media-briefing-on-covid-19-11-march-2020.

[elan202200295-bib-0002] 2.Covid 19 2022. https://covid19.who.int/. Accessed 23 August 2022.

[elan202200295-bib-0003] 3. Cucinotta D., Vanelli M., Acta Biol. Med. 2020, 91, 157–160. [DOI] [PMC free article] [PubMed] [Google Scholar]

[elan202200295-bib-0004] 4. Huang C., Wang Y., Li X., Ren L., Zhao J., Hu Y., Zhang L., Fan G., Xu J., Gu X., Cheng Z., Yu T., Xia J., Wei Y., Wu W., Xie X., Yin W., Li H., Liu M., Xiao Y., Gao H., Guo L., Xie J., Wang G., Jiang R., Gao Z., Jin Q., Wang J., Cao B., Lancet 2020, 395 (10223), 497–506. [DOI] [PMC free article] [PubMed] [Google Scholar]

[elan202200295-bib-0005] 5. Woelfel R., Corman V. M., Guggemos W., Seilmaier M., Zange S., Mueller M. A., Niemeyer D., Vollmar P., Rothe C., Hoelscher M., Bleicker T., Bruenink S., Schneider J., Ehmann R., Zwirglmaier K., Drosten C., Wendtner C., Nature 2020, 581, 465–469. [DOI] [PubMed] [Google Scholar]

[elan202200295-bib-0006] 6.https://www.health.gov.au/ministers/the-hon-greg-hunt-mp/media/two-anti-viral-covid-19-treatments-approved. 20 January 2022.

[elan202200295-bib-0007] 7.W. Fischer, J. J. Eron, W. Holman, M. S. Cohen, L. Fang, L. J. Szewczyk, T. P. Sheahan, R. Baric, K. R. Mollan, C. R. Wolfe, E. R. Duke, M. M. Azizad, K., Borroto-Esoda, D. A. Wohl, A. J. Loftis, P. Alabanza, F. Lipansky, W. P. Painter, medRxiv 2021.

[elan202200295-bib-0008] 8. Joshi S., Parkar J., Ansari A., Vora A., Talwar D., Tiwaskar M., Patil S., Barkate H., Int. J. Infect. Dis. 2021, 102, 501–508. [DOI] [PMC free article] [PubMed] [Google Scholar]

[elan202200295-bib-0009] 9. Pilkington V., Pepperrell T., Hill A., J. Virus Erad. 2020, 6, 45–51. [DOI] [PMC free article] [PubMed] [Google Scholar]

[elan202200295-bib-0010] 10. Aktaş A., Tüzün B., Aslan R., Sayin K., Ataseven H., J. Biomol. Struct. Dyn. 2021, 39 (18), 7263–7273. [DOI] [PMC free article] [PubMed] [Google Scholar]

[elan202200295-bib-0011] 11. Shiraki K., Daikoku T., Pharmacol. Ther. 2020, 209, 107512. [DOI] [PMC free article] [PubMed] [Google Scholar]

[elan202200295-bib-0012] 12. Guo Q., Xu M., Guo S., Zhu F., Xie Y., Shen J., Chem. Pap. 2019, 73 (5), 1043–1051. [Google Scholar]

[elan202200295-bib-0013] 13. Nazifa Sabır Ali S., Mobina L., Mehfuza M., Seema P., Ahmed A., Khan G. J., J. Pharm. Res. Int. 2021, 33(48B), 254–271. [Google Scholar]

[elan202200295-bib-0014] 14. Megahed S. M., Habib A. A., Hammad S. F., Kamal A. H., Spectrochim. Acta Part A 2021, 249, 119241. [DOI] [PMC free article] [PubMed] [Google Scholar]

[elan202200295-bib-0015] 15. Hazarika I., Kalita T., Deka P., Gogoi S. K., Althubeiti K., Thakuria R., Gogoi B., ACS Appl. Nano Mater. 2021, 4 (12), 13927–13937. [Google Scholar]

[elan202200295-bib-0016] 16. Mikhail I. E., Elmansi H., Belal F., Ehab Ibrahim A., Microchem. J. 2021,165, 106189. [DOI] [PMC free article] [PubMed] [Google Scholar]

[elan202200295-bib-0017] 17. Bulduk İ., Iran. J. Pharm. Res. 2021, 20, 57–65. [DOI] [PMC free article] [PubMed] [Google Scholar]

[elan202200295-bib-0018] 18. Morsy M. I., Nouman E. G., Abdallah Y. M., Zainelabdeen M. A., Darwish M. M., Hassan A. Y., Gouda A. S., Rezk M. R., Abdel-Megied A. M., Marzouk H. M. J., Pharm. Biomed. Anal. 2021, 199, 114057. [DOI] [PMC free article] [PubMed] [Google Scholar]

[elan202200295-bib-0019] 19. Marzouk H. M., Rezk M. R., Gouda A. S., Abdel-Megied A. M., Microchem. J. 2022, 172, 106917. [DOI] [PMC free article] [PubMed] [Google Scholar]

[elan202200295-bib-0020] 20. Duse V. P., Baheti G. K., J. Pharm. Res. Int. 2021, 33, 275–281. [Google Scholar]

[elan202200295-bib-0021] 21. Ahmad R., Khan M., Mishra P., Jahan N., Ahsan M. A., Ahmad I., Khan M. R., Watanabe Y., Syed M. A., Furukawa H., Khosla A., J. Electrochem. Soc. 2021, 168 (1), 017501. [Google Scholar]

[elan202200295-bib-0022] 22. Noureldeen D. A. M., Boushra J. M., Lashien A. S., Hakiem A. F. A., Attia T. Z., Microchem. J. 2022, 174, 107101. [DOI] [PMC free article] [PubMed] [Google Scholar]

[elan202200295-bib-0023] 23. Rezk M. R., Badr K. A., Abdel-Naby N. S., Ayyad M. M., Biomed. Chromatogr. 2021, 35 (7), e5098. [DOI] [PubMed] [Google Scholar]

[elan202200295-bib-0024] 24. Allahverdiyeva S., Yunusoğlu O., Yardım Y., Şentürk Z., Anal. Chim. Acta 2021, 1159, 338418. [DOI] [PMC free article] [PubMed] [Google Scholar]

[elan202200295-bib-0025] 25. Mehmandoust M., Khoshnavaz Y., Tuzen M., Erk N., Microchim. Acta 2021, 188 (12), 434. [DOI] [PMC free article] [PubMed] [Google Scholar]

[elan202200295-bib-0026] 26. Galal A., Ahmed Y. M., Ahmed M. H. M., Atta N. F., J. Electrochem. Soc. 2021, 168, 116512. [Google Scholar]

[elan202200295-bib-0027] 27. Kanbeş Dindar Ç., Bozal-Palabiyik B., Uslu B., Electroanalysis 2022, 34, 1174–1186. [Google Scholar]

[elan202200295-bib-0028] 28. Wang S., Wang C., Xin Y., Li Q., Liu W., Microchim. Acta 2022, 189 (3), 125. [DOI] [PMC free article] [PubMed] [Google Scholar]

[elan202200295-bib-0029] 29. Mohamed M. A., Eldin G. M. G., Ismail S. M., Zine N., Elaissari A., Jaffrezic-Renault N., Errachid A., J. Electroanal. Chem. 2021, 895, 115422. [DOI] [PMC free article] [PubMed] [Google Scholar]

[elan202200295-bib-0030] 30. Akca Z., Özok H. İ., Yardım Y., Şentürk Z., Turk. J. Chem. 2022, 46, 869–880. [DOI] [PMC free article] [PubMed] [Google Scholar]

[elan202200295-bib-0031] 31. Asran A. M., Mohamed M. A., Eldin G. M. G., Mishra R. K., Errachid A., Microchem. J. 2021, 164, 106061. [Google Scholar]

[elan202200295-bib-0032] 32. Mohamed M. A., Saad A. S., Koshek S. H., El-Ghobashy M. R., New J. Chem. 2018, 42 (12), 9911–9919. [Google Scholar]

[elan202200295-bib-0033] 33. Mehmandoust M., Khoshnavaz Y., Tuzen M., Erk N., Microchim. Acta 2021, 188, 434. [DOI] [PMC free article] [PubMed] [Google Scholar]

[elan202200295-bib-0034] 34. Wang J., Kawde A. N., Sahlin E., Analyst 2000, 125, 5–7. [DOI] [PubMed] [Google Scholar]

[elan202200295-bib-0035] 35. Akanda M. R., Sohail M., Aziz M. A., Kawde A. N., Electroanalysis 2016, 28, 408–424. [Google Scholar]

[elan202200295-bib-0036] 36. David I. G., Popa D.-E., Buleandra M., J. Anal. Methods Chem. 2017, 2017, 1–22. [DOI] [PMC free article] [PubMed] [Google Scholar]

[elan202200295-bib-0037] 37. Emir G., Dilgin Y., Apak R., ChemElectroChem. 2020, 7, 649–658. [Google Scholar]

[elan202200295-bib-0038] 38. Saglam Ö., Kızılkaya B., Uysal H., Dilgin Y., Talanta 2016, 147, 315–321. [DOI] [PubMed] [Google Scholar]

[elan202200295-bib-0039] 39. Senel M., Alachkar A., Lab Chip. 2021, 21, 405–411. [DOI] [PubMed] [Google Scholar]

[elan202200295-bib-0040] 40. David I. G., Buleandra M., Popa D. E., Cheregi M. C., David V., Iorgulescu E. E., Tartareanu G. O., Processes 2022, 10 (3), 472. [Google Scholar]

[elan202200295-bib-0041] 41. Alves G. F., Lisboa T. P., Faria L. V., Farias D. M., Matos M. A. C., Matos R. C., Electroanalysis 2021, 33 (2), 543–549. [Google Scholar]

[elan202200295-bib-0042] 42. Karakaya S., Kartal B., Dilgin Y., Monatsh. Chem. 2020, 151, 1019–1026. [Google Scholar]

[elan202200295-bib-0043] 43. Güneş M., Karakaya S., Kocaağa T., Yıldırım F., Dilgin Y., Monatsh. Chem. 2021, 152 (12), 1505–1513. [Google Scholar]

[elan202200295-bib-0044] 44. Özcan H. M., Sezgintürk M. K., Biotechnol. Prog. 2015, 31, 815–822. [DOI] [PubMed] [Google Scholar]

[elan202200295-bib-0045] 45. Moshikur R. M., Ali M. K., Wakabayashi R., Moniruzzaman M., Goto M., Mol. Pharm. 2021, 18 (8), 3108–3115. [DOI] [PubMed] [Google Scholar]

[elan202200295-bib-0046] 46.Favipiravir, https://go.drugbank.com/drugs/DB12466.

[elan202200295-bib-0047] 47. Aydınoglu S., Bozyel M., Iran. J. Chem. Chem. Eng. 2022. (Article in press). [Google Scholar]

[elan202200295-bib-0048] 48. Zolotarev E. E., Kashevskii A. V., Bazhenov B. N., Finkelshtein B. L., Safronov A. Y., Electrochem. Commun. 2014, 45, 23–26. [Google Scholar]

[elan202200295-bib-0049] 49. Nuñez-Vergara L. J., Squella J. A., Dominguez M., Blazquez M., J. Electroanal. Chem. 1988, 243, 133–142. [Google Scholar]

[elan202200295-bib-0050] 50. Brolo A. G., Irish D. E., J. Chem. Soc. Faraday Trans. 1997, 93, 419–423. [Google Scholar]

[elan202200295-bib-0051] 51. Pasadakis-Kavounis A., Baj V., Hjelm J., Molecules 2021, 26, 1–13. [DOI] [PMC free article] [PubMed] [Google Scholar]

[elan202200295-bib-0052] 52.GUIDELINE IHT Validation of analytical procedures: text and methodology, Q2 (R1) 1. 2005.

PERMALINK

Voltammetric Determination of Favipiravir Used as an Antiviral Drug for the Treatment of Covid‐19 at Pencil Graphite Electrode

Teslime Erşan

Didem Giray Dilgin

Elif Kumrulu

Umur Kumrulu

Yusuf Dilgin

Abstract

1. Introduction

2. Materials and Method

2.1. Chemicals and Apparatus

2.2. Electrochemical Studies

2.3. Preparation of Samples

3. Results and Discussion

3.1. Voltammetric Behavior of FAV

3.1.1. The Effect of pH

Figure 1.

3.1.2. The Effect of Scan Rate

Figure 2.

Figure 3.

3.1.3. Reduction and Oxidation Mechanism of FAV

Figure 4.

3.2. Optimization Studies for Differential Pulse Voltammetric Determination of FAV

Figure 5.

Figure 6.

3.3. Analytical Performance Studies

Table 1.

Table 2.

3.4. Interference Studies

3.5. Real Sample Analysis

Table 3.

4. Conclusion

5.

Supporting information

Data Availability Statement

References

Associated Data

Supplementary Materials

Data Availability Statement

ACTIONS

PERMALINK

RESOURCES

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