reduced graphene oxide modified pencil graphite sensor for the electrochemical trace determination of paroxetine in biological and pharmaceutical media

Journal Pre-proof Polyoxometalate/reduced graphene oxide modified pencil graphite sensor for the electrochemical trace determination of paroxetine in biological and pharmaceutical media

Abbas Hassan Oghli, Ahmad Soleymanpour PII:

S0928-4931(19)33021-8

DOI:

https://doi.org/10.1016/j.msec.2019.110407

Reference:

MSC 110407

To appear in:

Materials Science & Engineering C

Received date:

15 August 2019

Revised date:

14 October 2019

Accepted date:

7 November 2019

Please cite this article as: A.H. Oghli and A. Soleymanpour, Polyoxometalate/reduced graphene oxide modified pencil graphite sensor for the electrochemical trace determination of paroxetine in biological and pharmaceutical media, Materials Science & Engineering C (2019), https://doi.org/10.1016/j.msec.2019.110407

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© 2019 Published by Elsevier.

Journal Pre-proof

Polyoxometalate/reduced graphene oxide modified pencil graphite sensor for the electrochemical trace determination of paroxetine in biological and pharmaceutical media Abbas Hassan Oghli, Ahmad Soleymanpour*

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School of Chemistry, Damghan University, Damghan 3671641167, Iran

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Corresponding author, Tel.: +98-23-35220095, Fax: +98-23-35220095

Abstract

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E-mail address: [email protected] (A. Soleymanpour)

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Paroxetine is an effective drug for the treatment of depression and stress which has been

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commonly used in recent years. Because of the widespread use and therapeutic effects of paroxetine, a rapid and sensitive method is needed to determine the trace concentration of paroxetine. Herein, an electrochemical sensor was constructed for the measurement of paroxetine using a modified pencil graphite electrode (PGE). Modification of the PGE was carried out by the reduced graphene oxide/phosphotungstic acid (rGO/PWA) by potentiostatic procedure at -1.2 V for 5 min in phosphate buffer solution with pH=7.0. Surface morphology analyzing of the modified PGE was performed by scanning electron microscopy (SEM), Raman, XRD, FTIR and electrochemical impedance spectroscopy (EIS) techniques. The kinetic parameter of electron transfer coefficient (α) was calculated for the oxidation process of paroxetine at the modified PGE. Differential pulse voltammetry (DPV) was performed for the determination of PRX. The 1

Journal Pre-proof calibration graph exhibited linear characteristics in the range of 8.0 ×10−9 ‒ 1.0 ×10-6 M of PRX concentration (R2=0.998). The relevant limit of detection was found to be 9.0 ×10−10 M. The modified PGE was successfully performed for the determination of PRX in paroxetine tablets and real samples such as human serum and urine.

Keywords: Sensor; differential pulse voltammetry; reduced graphene oxide; drug determination;

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paroxetine

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1. Introduction

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A vast variety of antidepressants which are called selective serotonin-reuptake inhibitors (SSRTs) have been globally applied for the therapy of major depressive, obsessive compulsive,

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social anxiety and panic disorders [1]. The usages of this class of drugs have been continuously

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increased because of the propagation of undesirable psychiatric conditions [2]. Paroxetine (PRX, Fig. 1), (3S,4R)-3-[(1,3-Benzodioxol-5-yloxy)methyl]-4-(4-fluorophenyl)piperidine, is one of

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these drugs which is most commonly used as an effective antidepressant agent with greatest

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inhibitory activity in recent years [3]. It has also been used for the night sweats after menopause [4]. Paroxetine can be used lonely or combined with other drugs [5,6] and is considerably safe in overdose [7], since most of antidepressants need to be used in a sufficiently high dose to have optimal therapy effectiveness [8]. The efficiency of paroxetine in depressive and stress disorders therapy is presumably related to its potency for serotonergic effect in the central nervous which leads to the inhibition of neuronal reuptake of serotonin [9]. A few side effects of paroxetine consumption has been known such as vision changes, weakness, drowsiness, dizziness, sweating, anxiety, sleep problems (insomnia), loss of appetite, constipation and suicide risk in people underage. However, it is still one of the most prescribed antidepressant drugs [10]. Due to the high consumption and therapeutic effects of paroxetine, it is necessary to develop selective, fast 2

Journal Pre-proof and sensitive analytical techniques for trace level determination of this drug in various biological and clinical media without considerable interferences from other species in the sample solution. F

HN

O

O O

Fig. 1. Structural formula of paroxetine.

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Several analytical techniques have been found for the measurement of paroxetine such as

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chromatography [11-14], spectroscopy [15-17] and electrochemistry [18-20]. Compared to other

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determination techniques, electroanalysis has the advantages of simplicity, high sensitivity and,

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in most cases, selectivity for the determination of analytes in different samples [21,22]. Pencil graphite electrodes (PGE) have been frequently used to prepare modified electrodes for the

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measurement of different biological and pharmaceutical species [23-25]. In contrast to other

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carbon and usual metallic electrodes, PGEs have important characteristics such as high availability, low cost, high mechanical stability, low background current, vast potential window,

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high conductivity, ease of modification, less time consuming pretreatment process and ability to

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miniaturization. Moreover, it is easy to remove the effects of memory and pollution caused by previous tests by removing several millimeters of graphite surface which is easier than the polishing method which is usually applied to the other solid surface electrodes like Pt and glassy carbon electrodes. Various nanoparticles have been used to enhance the sensitivity of electrochemical sensors due to their unique structural properties [26]. In recent years, the unique features of graphene oxide (GO) such as high mechanical strength and heat conductance, high conductivity, low density, high effective surface, usability in different solutions, easily `deposition on electrode surface, fast and easy synthesis and low cost have led to its wide applications in electrochemical devices such as supercapacitors [27], batteries [28] and electrochemical sensors 3

[29-35].

Journal Pre-proof Specially, high conductivity, chemical functionalization [36], acceleration of electron transfer at the electrode surface [37] and excellent electrocatalytic properties of GO [38] have always been considered in the modification of electrodes [39]. During the reduction of GO the resulted reduced graphene oxide (rGO) is resemble to graphene but include residual oxygen and other heteroatoms plus structural defects. Reduced form of graphene oxide has a higher electrical capacity due to the recovering of graphene honeycomb hexagonal mesh and so restoring the electrical conductivity [40]. Generally, due to the presence of functional groups of oxygen and

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negative charge and also network defects, the electrochemical activity of rGO is greater than of

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graphene and graphene oxide [41]. Generally functionalizing carbon nanomaterials and combination of them with modifiers such as nanoparticles [42-49], polyoxometalate [50] and

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cyclodextrins [51] Cause the electrochemical properties of the composite become stronger than

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their separate and initial form [42]. So, they have been used for developing the modified

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electrodes with excellent electrochemical characteristics for the determination of different pharmaceutical and biological species and also electrochemical devices such as fuel cells and

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capacitors [42-48]. Phosphotungstic acid (PWA) with catalytic properties is a super acid which

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has high ability in proton transfer [52,53]. PWA can participate in electrocatalytic process on the

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modified electrodes which contain this species as one of the modifier components [54,55]. In this work, a novel sensor was developed by the modification of pencil graphite electrode for the trace determination of paroxetine. To improve the performance of the PGE, phosphotungstic acid and graphene oxide were used as modifiers which were deposited electrochemically on the electrode surface in one step with a constant potential. As a result, a composite of reduced graphene oxide and phosphotungstate was formed on the electrode, which increased the sensitivity and catalysis of paroxetine oxidation. The modified PGE exhibits excellent response characteristics such as high selectivity and low limit of detection to paroxetine which enable it to determine PRX in different media. Generally, in this work rGO-PWA composite is made in a very short time and electrochemically in one step. Although, a few 4

Journal Pre-proof electrode modifications with rGO and PWA composite have been reported, however, in all of them more time and steps were required for the reduction of GO or formation the rGO-PWA composite. For example, Chengen He et al., reported the chemically synthesis of this composite after 12 h at 180 °C [56]. Moreover, there are some reports which describe the synthesis of this composite during more than 24 h [57-59].

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2. Experimental

experiments

were

accomplished

on

an

Autolab

PGSTAT

30

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Electrochemical

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2.1. Apparatus

electrochemical system (Netherlands) equipped with NOVA software. A three-electrode system

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containing a PGE (Rotring Co. Ltd, Germany, R505210N of Type H) with a diameter of 2 mm

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as the working electrode, a platinum rode auxiliary electrode and an Ag/AgCl/KCl (sat,d)

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reference electrode was utilized. SEM was recorded with Leo 1450VP microscope. A Metrohm 827 pH meter was applied for the pH determination of solutions. X-ray diffraction (XRD)

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spectra were carried out with a D8 Advance Bruker diffractometer using CuKα radiation

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(λ=0.15406 nm Å) in the 2θ range from 10 to 70°. FT-IR spectra were recorded as KBr pellets on a Perkin–Elmer spectrum RXI FT-IR spectrophotometer. Raman spectra were obtained by a Takram P50C0R10 spectrometer.

2.2. Chemicals All chemicals (Analytical Reagent Grade) were applied as received and doubly distilled water was used for the providing of all solutions. Pencil leads commonly consisted of natural graphite and were used as obtained. Paroxetine was bought from Sigma-Aldrich and utilized without further purification. Serum samples and human urine were obtained from a healthy 5

Journal Pre-proof volunteer and all samples were kept in the dark at 5 centigrade degree. An appropriate value of PRX was dissolved in double distilled water in order to prepare a paroxetine stock standard solution (1×10-4 M) and then was kept at 5 oC in a refrigerator before use. Deoxygenation of the test solution was carried out before each electrochemical determination with highly pure nitrogen for 350 s.

2.3. Preparation of graphene oxide

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Hummers method was used for the preparation of graphene oxide through the graphite

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oxidation [60]. Graphite flakes (1 g) and sodium nitrate (1 g) were mixed in 30 mL of sulfuric acid (98%) under continuous stirring for two hours in a 500 mL volumetric flask maintained at

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an ice dish. To the resulted suspension, KMnO4 (4 g) was added gently and the temperature of

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mixture was kept below 15 °C. Then, the mixture was continuously stirred for two days at 34 °C

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until a brownish paste was resulted and then was slowly diluted with water. The color was changed to brown and the temperature of reaction was increased rapidly to 97 °C with poppling.

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A 200 mL of water was additionally added to the paste under continuous stirring. Finally, 5 mL

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H2O2 was added to the solution to finalize the synthesis by the observation of yellow color. The product was purified by rinsing with 10% HCl and then washing with deionized water several

temperature [61].

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times. The graphene oxide (GO) was resulted as powder after drying under vacuum at ambient

2.4. Electrochemically modification of PGE The surface of PGE was carefully polished on a smooth white paper and its body was firmly coated with a Teflon strip. Electrical connection to the PGE was done with a stainless steel wire. The PGE was vertically immersed into the test solution in which the contact was only attained by its cross section. To a 5 mL of solution containing PWA (2 mM) and phosphate buffer (0.05 M), 5 mg graphene oxide (GO) was added. The mixture was located in an ultrasonic bath for 5 min 6

Journal Pre-proof until a suspension uniformly was formed. The suspension was transferred to the electrochemical cell and a constant voltage (-1.2 V) was applied for 300 seconds to the above PGE until a layer of modifier was deposited on its surface.

2.5. Analytical procedure For differential pulse voltammetry technique, 5 mL of sample solution having appropriate quantities of PRX in 0.1 M Briton-Robinson (BR) buffer (pH=7.0) was delivered into the

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electrochemical cell where the experiment was performed. The voltammograms were recorded

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by changing the potential towards the positive side from +0.5 to +1.2 V with scan rate of 30 mV s-1. The peak current was measured at +0.96 V for PRX. A blank solution without PRX was used

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to estimate the blank peak current.

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2.6. Paroxetine determination in pharmaceutical tablet

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For determination of PRX in pharmaceutical formulation, four tablets (20 mg) were exactly weighed and grinded in a mortar. Appropriate amount of obtained powder, equivalent with a

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stock solution (300.0 nM), was exactly weighed and delivered to a 100 mL volumetric flask and

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diluted with BR buffer solution (pH=7.0). More diluted solutions were obtained by further dilution of this solution with BR buffer. Finally, the content of PRX in the prepared sample

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solution was measured by DPV by the standard addition method.

2.7. Determination of paroxetine in real samples Biological samples containing human blood serum or urine (obtained from healthy volunteers) were diluted 10 times with 0.1 M BR buffer solution (pH=7.0). Prior to voltammetric analysis, samples were filtered through a filter paper. 5 mL of the filtered solution was delivered to the cell where the electrochemical test was done. Various values of PRX in the therapeutic range were separately spiked into the cell and then using standard addition method the PRX amount of solution was measured by the modified PGE. 7

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3. Results and discussion 3.1. Characterization of the surface modified electrode Specification of the electrode modifier layer on the PGE surface was performed by X-ray diffraction (XRD) analysis and the obtained spectra are shown in Fig. 2a. In the XRD spectrum of GO, a strong peak at 11° is observed, whereas, in the XRD spectrum of rGO and rGO/PWA this peak is disappeared and instead a broad peak is observed in the region of 20-30 centering at

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25° indicating the electrochemical reduction of GO to rGO on the electrode surface [62,27].

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Moreover, the XRD pattern of rGO/PWA in Fig. 2a (specified peaks) is totally corresponds with

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PANalytical X'Pert HighScore (XRD database) for PWA which confirms the presence of PWA

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in the modifier layer [63].

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The IR spectrum is used as a powerful tool for detection of functional groups in modifier layers. Fig. 2b shows the IR spectra of the GO, PWA, rGO and rGO/PWA. As can be seen, the

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GO spectrum contains stretching vibration peaks at 1064 cm-1 (C-O epoxy group), 1560 cm-1

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(C=C), 1750 cm-1 (C=O) and 3500 cm-1 (O-H). However, in the rGO and rGO/PWA spectra, peaks at 1750 and 1064 cm-1 are disappeared indicating the properly reduction of GO. Also,

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PWA spectrum contains vibrational peaks at 1088 cm-1 (P-Oa), 1002 cm-1 (W=Ot), 900 cm-1 (WOb-W) and 810 cm-1 (W-Oc-W), (Oa denotes the central tetrahedral PO4 oxygen, Ob and Oc are the oxygen of W–Ob–W bridges located between two different and same W3O13 groups, respectively and Ot is the terminal oxygens bonded to a singular tungsten). These peaks can also be seen in the rGO/PWA spectrum which confirms the existence of the PW12O403- anion in the composite structure [59]. Raman technique is an appropriate method to investigate the nature of graphene-based modifiers. Fig. 2c shows the Raman spectra of GO, rGO and rGO/PWA. The observed peaks at 1351 cm-1 and 1588 cm-1 are known as D and G bands, which are related to sp3 and sp2 in-plane 8

Journal Pre-proof vibrations of bonded carbons of graphene [29,47]. Using the ratio of the intensity of D and G bands, it can be concluded the degree of defect and graphitization in the generated modifier structure [45,46]. With respect to the Raman spectrum in Fig. 2c, the ratio of ID/IG increased from 0.86 in GO to 1.1 and 0.98 in rGO and rGO/PWA, respectively. This decrease in the number of sp2 bonds is surely because of the decreasing of C=O bonds during the reduction process in rGO and rGO/PWA. The morphology of modified electrode surface was also studied with scanning electron

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microscopy (SEM). Fig. 3 shows SEM scans of bare PGE, rGO and rGO/PWA modified

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electrodes. Fig. 3a reveals the smooth surface of the PGE. Modification of the PGE with rGO

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creates porous sheets of the rGO on the electrode surface (Fig. 3b). The SEM image of

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rGO/PWA

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Intensity (a.u.)

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a

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rGO/PWA

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rGO

0

10

20

GO 30

40 2θ (Degree)

50

60

70

80

c

b

Intensity (a.u.)

rGO/PWA

%T

rGO

PWA

rGO/PWA

rGO GO GO

9 3400

2400 1400 -1 Wavenumber (cm )

400

0

500

1000 1500 Wavenumber (cm-1)

2000

2500

Journal Pre-proof Fig. 2. (a) The XRD analysis of GO, rGO and rGO/PWA modifier layers (the marked peaks are PWA peaks according to its standard pattern), (b) FT-IR spectrum of GO, PWA, rGO, and rGO/PWA and (c) Raman spectrum of GO, rGO and rGO/PWA.

modified electrode surface (Fig. 3c) shows that PWA anchored on the surface of reduced graphene oxide sheets through the electrostatic interaction which can prevent restacking of graphene oxide sheets [56]. Comparison of the morphology of the PGE (Fig. 3a) and modified

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PGE surface (Fig. 3c) shows that the PGE has a relatively flat surface versus modified electrode

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surface containing rGO/PWA (Fig. 3c), which is in the form of porous rGO and PWA filaments in the form of crystals on the surface of PGE electrode. These develop the roughness of the

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electrode and enhance the surface area of modified electrode which in turn increased the rate of

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electron transfer between bulk analytical solution and the electrode surface [64].

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a

2µm c

2µm

10

Journal Pre-proof Fig. 3. SEM images of (a) bare PGE, (b) rGO/PGE and (c) rGO/PWA/PGE modified electrodes.

3.2. Electrochemical oxidation of PRX at modified and bare electrode The cyclic voltammogram of blank solution and a solution containing PRX (0.68 µM) in BR buffer (pH=7.0) are shown in Fig. 4A. The voltammogram represents an irreversible process for PRX which oxidizes at potential of 1.0 V on the modified PGE. Fig. 4B shows the differential voltammogram of PRX oxidation (0.4 µM) on the bare PGE, rGO/PGE and rGo/PWA/PGE. As

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can be seen in Fig. 4B, the unmodified PGE exhibited a weak oxidation peak for PRX (peak a)

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and its current increases at the presence of rGO (peak b). Finally, in the presence of rGO/PWA the oxidation peak (c) more increased with a shift to the negative potential indicating the

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oxidation process is occurred easier on the modified PGE with rGO and PWA due to the

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electrocatalytic role of PWA. Thus, PGE can more sensitively respond to the concentration

2

c

B

I (µA)

1.6

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changes of PRX if it is modified with both of rGO and PWA modifiers.

b

1.2

0.8 a 0.4

0

0.5

0.7

0.9

1.1

1.3

1.5

E (V)

Fig. 4. (A) Cyclic voltammograms at rGO/PWA/PGE in the (a) absence and (b) presence of PRX (0.68 µM) in BR buffer (pH=7.0). (B) Differential pulse voltammogram of PRX oxidation (0.4 µM) in BR buffer (pH=7.0) for (a) PGE, (b) rGO/PGE and (c) rGo/PWA/PGE.

3.3. Impedance and effective surface area investigation 11

Journal Pre-proof Electrochemical impedance spectroscopy (EIS) technique was performed to investigate the electrical behavior of electrodes in 2.0 mM K3[Fe(CN)6]/K4[Fe(CN)6] and 0.1 M KCl solutions. The resulted Nyquist curves are displayed in Fig. 5. As seen in Fig. 5, the Rct (charge transfer resistance) of rGo/PWA/PGE (491 Ω) is lower than rGO/PGE (711 Ω) and the bare PGE (985 Ω) representing the higher conductivity of rGO/PWA which should be according to the increasing of charge transfer rate due to the both enhanced effective electrode surface and electrocatalytic characteristics of PWA [65,66]. Furthermore, the values of CPEdl (constant factor indicating the

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double layer capacitance) were calculated 770, 969 and 984 pF for PGE, rGO/PGE and

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rGO/PWA/PGE, respectively, indicated that the rGO/PWA effective surface was enhanced [67]. These results indicate that more effective interfacial electron transfer take places at the

1200 c

b

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a

800

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Z′′ ((Ω)

1000

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rGO/PWA/PGE compared to the bare PGE and also rGO/PGE.

600

200 0 0

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400

400

800

1200

1600

2000

Z′ (Ω)

Fig. 5. Nyquist curves for (a) PGE, (b) rGO/PGE and (c) rGO/PWA/PGE in 2 mM [Fe(CN)6]3/[Fe(CN)6]4- and 0.1 M KCl solutions. The effective surfaces of modified and bare electrodes can clearly represent the modification of the PGE electrode. Therefore, effective surface area of the PGE, rGO/PGE and rGO/PWA/PGE were calculated by obtaining the cyclic voltammograms of K3Fe(CN)6 at different scan rates and application of Randles-Sevcik equation [68] as following: 12

Journal Pre-proof Ip = (2.69 × 105) n3/2 A D1/2 ν1/2 C D is diffusion coefficient of K3Fe(CN)6 (5×10−6 cm2/s), Ip is the anodic peak current (A), n is the number of transferred electrons (n=1), ν is the scan rate (v/s), C is the K3Fe(CN)6 concentration (mol/cm3) and A is the effective surface area of the electrode in cm2. Then, A can be calculated using the slope of Ip against ν1/2 graph. The values of effective surface area were obtained 0.031 cm2, 0.052 cm2 and 0.072 cm2 for the bare PGE, rGO/PGE and rGO/PWA/PGE, respectively. It can be concluded that the effective surface of the rGO/PWA/PGE considerably enhanced by a

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coefficient of 2.3 with respect to the bare PGE which demonstrated the superiority of

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electrochemical activity of rGO/PWA/PGE.

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3.4. Optimum conditions for the PGE modification and PRX determination

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3.4.1. pH effect

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The influence of pH on the current value of PRX oxidation peak (0.2 µM) was studied in the

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Briton-Robinson buffer within the range of 3 to 12 and the obtained results are shown in Fig. 6. As seen, with increasing of pH from 3 the peak current started to increase and reaches to a

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maximum value between pH 6-9 and then it decreases. Based on the pKa value of paroxetine

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(pKa=9.8) [69] in the pH of the solution lower than pKa, due to the protonation of PRX, its oxidation process might be more difficult and so the current should be increased with increasing of the pH around its pKa. The pH between 6‒9 was considered as the pH working range of the modified PGE and, subsequently, the pH of solutions were regulated at 7.0 by BR buffer solution in the next studies. The effect of BR buffer concentration on the peak current of PRX was also studied in different concentration of BR solution and the resulted data are represented in Fig. 6. The maximum current value was observed in 0.1 M concentration of BR solution and so this concentration was chosen as optimal.

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Journal Pre-proof 1.5

1.5

b

a 1.2 I (µA)

I (µA)

1.2 0.9

0.9

0.6

0.6

0.3

0.3

0 3

4

5

6

7

8

9

0

10 11 12

0.05

0.075

pH

0.1 [BR]

0.15

0.2

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Fig. 6. The effect of electrolyte pH (a) and concentration of BR buffer solution (b) on the

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oxidation peak current of PRX (0.2 µM).

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3.4.2. Effect of Go and PWA concentrations on the peak current

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The effect of GO and PWA concentration in the modifying solution was tested on the oxidation peak current of PRX. The effect of graphene oxide was studied by dispersing different amounts

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of GO (200, 600, 1000, 1400 and 2000 ppm) in the modifying solution at the presence of

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constant concentration of PWA (6.0×10-4 M). The corresponding peak currents obtained by the resulted modified electrodes are shown in Fig. 7a. According to the obtained data, from 200 to

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1000 ppm, the oxidation peak of PRX was increased and then started to decrease. As a result, 1000 ppm was selected as the optimum GO concentration in the modifying solution. The influence of PWA concentration in the presence of constant value of GO (1000 ppm) was investigated at its various concentrations (0.1, 0.4, 1.0, 2.0 and 3.0 mM). The obtained results are displayed in Fig. 7b. Based on data shown in Fig. 7b 2 mM of PWA concentration was selected as its optimal concentration in the electrode modifying solution.

3.4.3. Effect of modification time on the current

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Journal Pre-proof The effect of modification time (the applied potential time for the modification) was studied on the oxidation peak current of PRX by obtaining the peak currents at different modification times (50, 150, 300, 600, 1500 s). The resulted data are shown in Fig. 7c. As observed in this fig, the peak current was reached to a level off around 300 s and so it was selected as the optimum modification time.

1.2

1.1

a

b

0.6

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0.8

0.4

0.7

700

1400

2100

GO (ppm) 1.2

0

1

2 [PWA]

3

4

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c

2800

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0

1

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I (µA)

0.9

-p

0.8

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1 I (µA)

I (µA)

1

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0.8

0.6 0

250

500

750

1000

t (s)

Fig. 7. The effect of GO (a), PWA (b) concentrations and modification time (c) on the peak current of paroxetine oxidation (0.2 µM) at pH=7.0.

3.5. Electrochemical characteristics of modified rGO/PWA/PGE 3.5.1. Scan rate effect The dependence of the peak potential and peak current to the scan rate at rGO/PWA/PGE was tested using cyclic voltammetry in the presence of PRX (1 µM) at the optimum conditions. 15

Journal Pre-proof Cyclic voltammograms of PRX at various scan rates (20-350 mV s-1) were obtained and the results are displayed in Fig. 8a. As seen, with increasing of scan rate from 20 to 350 mV s-1, the peak currents are also increased and their values are directly proportional to the ʋ1/2 in the limit of tested scan rates (Fig. 8b). The linearity of the peak current with v1/2 confirms diffusioncontrolled nature of the electrooxidation process of PRX. The linear regression equation was obtained as I (μA) = 2.610 ʋ1/2‒8.040 with a correlation coefficient equal to 0.996. The dependency between oxidation peak potential (Ep) and log ν (Fig. 8c) represents a good

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linearity according to the equation of Ep (V) = 0.087log ν (mVs-1) + 0.774 (R2 = 0.998). The

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slope of this equation based on the Laviron equation for irreversible process [70] is 2.303RT/(1-

-p

α)nαF which can be used to acquire the transfer coefficient (α). The resulted (1-α)nα was obtained equal to 0.68 indicating the number of electron participating in the rate determining step of

60 b I (µA)

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electrooxidation process should be one which then the α resulted equal to 0.34.

y = 2.610x - 8.040 R² = 0.996

45 30

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15 0

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0

5

10 ν1/2

1.03

15

20

25

(mVs-1)

c y = 0.0875x + 0.7749 R² = 0.9989

Ep

0.99 0.95 0.91 0.87 1

1.4

1.8 2.2 2.6 log ν (mVs-1)

3

Fig. 8. (a) Cyclic voltammograms of PRX solution (1 µM) in BR buffer (pH=7.0) at different scan rates (20, 40, 70, 150, 200, 250, 300 a nd 350 mV s-1), (b) The graph of peak current (Ip) against (ν1/2) in mV s-1 and (c) the graph of Ep vs. log ν (mV s-1).

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Journal Pre-proof 3.5.2. Chronoamperometric studies Chronoamperometric measurements were applied to obtain diffusion coefficient (D) of PRX in the electrochemical process. A constant potential (950 mV) was applied to the working modified electrode resided in a solution of PRX and the resulted current was followed over the time. Since the mass transfer in these potential is entirely diffusion-controlled, the obtained I-t curve shows changes of concentration gradient near the electrode surface. This is the case refers gradual expansion of diffusion layer while it depletes from the electroactive species. Therefore,

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the intensity of the current can be expressed according to the Cottrel Equation as following:

𝐼=

1 2

−1

= 𝐾𝑡 2

-p

𝜋 𝑡

1 2

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1

𝑛𝐹𝐴𝐶𝐷2

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Where I is the current (A), C is the bulk concentration (mol cm-3), A is the surface of electrode

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(cm2), t is the time (s) and D is the diffusion coefficient (cm2 s-1). Chronoamperometric graphs of rGO/PWA/PGE at potential step 950 mV for three concentrations of PRX (0.1, 0.46 and 0.82

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mM) are displayed in Fig. 9 and the corresponding I vs. t-1/2 plots are shown in the inset a. The diffusion coefficient can be extracted using the slopes of these plots. For this purpose, the slopes

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of the resulted lines were depicted versus the PRX concentration (inset b). Based on the resulted

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slope, D for PRX was calculated equal to 5.3×10-5 cm2 s-1.

17

Journal Pre-proof 30 y = 28.5x + 2.5157 R² = 0.997

24 18 12

39

6 0 0.2 0.6 C (mM)

31

y = 16.17x + 22.48 R² = 0.985

23

y = 5.0921x + 17.613 R² = 0.9655

15 0.25

1

0.35

0.45

0.55

t-1/2 (s-1/2)

ro

of

-0.2

y = 25.612x + 35.046 R² = 0.9795

47 I/µA

Slope

55

b

-p

Fig. 9. Chronoamperometric graphs for rGO/PWA/PGE in 0.1 M BR buffer (pH= 7.0) at

re

potential step of 950 mV at various concentration of PRX (0.1, 0.46 and 0.82 mM). Insets: (a)

lP

Plot of I vs. t-1/2 for the different concentrations of PRX (0.1, 0.46 and 0.82 mM) and (b) plot of the slopes of resulted straight lines in inset a versus the PRX concentrations.

na

3.6. Calibration curve and analytical performances

ur

The calibration curve for the modified sensor were obtained by the measurement of PRX under

Jo

optimum experimental condition using rGO/PWA/PGE in BR buffer (pH=7.0) with pulse voltammetry (DPV) method. The obtained voltammograms for different concentrations are displayed in Fig. 10. Based on the calibration curve (inset Fig. 10) the current is linear from 8.0 ×10−9 to 1.0 ×10-6 M (R2=0.998) with linear equation of Ip (μA) = 6.442C (µM) + 0.03. The detection limit (signal/noise = 3) for 8 repeated measurements of the blank solution was obtained 9.0×10−10 M. This low value of detection limit reveals that very low determination of PRX concentration can be done by the modified PGE in various samples. Relative standard deviations (RSD) for successive determinations of 40 and 100 nM PRX were obtained 2.4% and 2.7% (n=5), respectively. To investigate the reproducibility, 6 electrodes were prepared in a same day and used to measure PRX at a concentration of 0.1 μM. The calculated RSD was 2.7%. To 18

Journal Pre-proof investigate the stability of the modified electrode during 15 days, a modified electrode was used to determine 0.1 μM PRX after 1, 7 and 15 day. The RSD was 3.1%. The results showed that the modified electrode has an appropriate reproducibility and stability for PRX determination. 7

10

I (µA)

5 I (µA)

y = 6.4422x + 0.03 R² = 0.9986

8

6

6 4 2 0

4

0

0.3

0.6

0.9

1.2

C (µM)

of

3

ro

2

0 0.6

0.7

0.8

0.9 E (V)

1

1.1

1.2

re

0.5

-p

1

lP

Fig. 10. DPVs of different concentrations of PRX (0.008 -1.0 µM) at the rGO/PWA/PGE in 0.1

3.7. Interference effects

na

M BR buffer (pH=7.0). Inset: The relevant calibration curve for the given concentration range.

ur

The influence of diverse species with possible interference ability in measurement process

Jo

of PRX was examined for the ions and some molecules which are typically the components of tablets or biological media. Interference effect was examined by carrying out the determination of 0.1 μM PRX solution containing various concentrations of foreign species at the optimum conditions. The tolerance limit is considered as the maximum concentration of the interference species which cause less than nearly 5% error [71]. The obtained data showed that ions (500 fold concentration) such as Na+, Ca2+, Mg2+, K+, Fe3+, Al3+, NH4+, Cl¯, F¯, NO3¯, PO43−, CO32−, biological molecules (400 fold concentration) such as glucose, lactose, uric acid, ascorbic acid, glycine, urea, proline and some pharmaceutical species (300 fold concentration) such as caffeine, theophylline, dopamine, acetaminophen, metformin, tryptophan, olanzapine and phenylephrine 19

Journal Pre-proof didn’t make any significant interference at the studied concentration ranges in the determination of PRX. This indicated that the determination of PRX can be selectively occurred in the presence of probable diverse species or excipients in pharmaceutical media without any significant pretreatment steps.

3.8. Analytical applications

of

The practical applicability of the modified PGE was investigated by the measurement of

ro

PRX in real samples such as pharmaceutical tablets, urine and human blood serum by standard addition method. Two typical DPVs and standard addition plots in serum and urine samples are

1 0.8 0.5 0.2 0

a

na

0.6

y = 5.265x + 0.402 R² = 0.9946

1.1 0.8 0.5 0

0.03

CPRX (µM)

0.2

0 0.35

0.06

0.09

CPRX (µM

Jo

0.4

b

y = 5.637x + 0.413 R² = 0.999

0.2

0.03 0.06 0.09

ur

I (µA)

0.8

Ip (µA)

1.1

Ip (µA)

lP

re

-p

displayed in Fig. 11 and the determination results are given in Table 1.

0.55

0.75

0.35 1.15

0.95

0.55

0.75

0.95

1.15

E (v)

E (v)

Fig. 11. DPVs of PRX with various concentrations in (a) blood serum and (b) urine samples. Insets: corresponding standard addition plots.

Table 1 Assay PRX in tablet, urine and serum samples. 20

Sample

Added (nM)

Found (nM)a

Recovery (%)

Precision Accuracy (%)b (%)c

t-value (4.30)d

Tablet

0.0e

70.0

‒

‒

‒

‒

80.0

148.1 ± 1.3

97.6

1.66

2.37

2.53

72.0

73.2±1.1

101.6

1.53

1.67

1.89

162.3±1.8

98.4

1.09

1.64

165.0 78.0

76.4±1.2

97.9

1.54

2.05

2.31

250

253.2±2.5

101.3

of

Journal Pre-proof

1.01

2.21

Serum

2.60

0.72

ro

Urine

Average of three repeated measurements.

b

Precision %: relative standard deviation (RSD).

c

Bias %: [(found-added)/added] ×100%.

d

Reference t-value at two degrees of freedom and 95% confidence limit.

e

The real concentration was 72.0 nM.

lP

re

-p

a

The obtained determination values demonstrated that the recoveries are quantitative at

na

various real samples and various PRX concentrations. The corresponding t-values were calculated and inserted in Table 1. As seen, the t-values were spread in the limit of 1.89‒2.60

ur

which were less than the reference value (4.30) at 2 degrees of freedom and 95% confidence

Jo

limit indicating there are not any meaningful difference between the mean values measured by the sensor and real values. It can be concluded that the modified GCE can be an appropriate alternative tool for precise and accurate determination of low concentration of PRX in different real samples.

3.9. Comparison of the proposed sensor with those reported sensors for PRX The linear range, detection limit and sensitivity of the developed electrochemical sensor, as three important analytical factors, and those reported previously for the measurement of PRX are represented in Table 2 for comparison. The given data indicates that the constructed sensor is 21

Journal Pre-proof superior with respect to these important analytical features for sensitive low level determination of PRX in different media. The better features of the sensor can be attributed to the combination of excellent electrocatalytic characteristics of polyoxometalate and unique electrochemical modification properties of reduced graphene oxide which have been represents more sensitivities than the other modifiers in modified electrodes [58]. In addition to better analytical performances, it should also be noted that the electrode of the sensor is pencil graphite which itself has

of

important advantages such as high availability, low cost, high mechanical stability, low

ro

background current and, especially, ease of modification in comparison with the other electrodes

na

lP

re

-p

such as diamond, GCE and mercury electrodes.

Table 2

ur

The comparison of analytical performances of the PGE/rGO/PWA sensor with those previously

Jo

reported for PRX determination.

Electrode/Modifier c

SMDE

LRa (μM)

DLb (μM)

Sensitivity (μA/μM)

Ref.

0.1-0.9

0.060

3.01

18

EPGEd

0.01-5.0

0.001

0.23

19

BDDEe

0.7-3.5

0.007

0.38

19

GCE/Nafion/MWCNTf

0.1-2.5

0.060

1.13

20

GCEg

20-800

2.000

‒

72

rGO/PWA/PGE

0.008-1.0

0.0009

6.44

This work

a.

Linear range

b

Detection limit 22

Journal Pre-proof c

Static mercury-drop electrode

d

Edge plane graphite electrode

e

Boron-doped diamond electrode

f

Multiwalled carbon nanotube

g

Glassy carbon electrode

4. Conclusions For the selective, fast and nanomolar measurement of PRX, an electrochemical sensor was fabricated by the modification of a pencil graphite electrode with the reduced graphene oxide

of

and phosphotungstate. The rGO/PWA/PGE sensor showed more conductivity and effective

ro

surface versus the bare pencil graphite electrode and so displayed better electrochemical features

-p

than the rGO/PGE and bare PGE. The sensor revealed good selectivity, excellent sensitivity and

re

low detection limit to paroxetine. PRX can be precisely measured up to 1.0×10-9 M by the developed sensor. The high selectivity of the sensor permitted the determination of PRX in

lP

various real samples like tablet, human serum and urine samples without any former

na

pretreatment steps. Comparison of the proposed sensor with those previously reported electrochemical sensor for PRX showed that the sensor is superior according to sensitivity, linear

Jo

ur

range and limit of detection.

Acknowledgement

The authors gratefully acknowledge the support of this research by Damghan University Research Council.

23

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Conflict interest

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The Authors declare that there is not any conflict with anyone or any institution. Ahmad Soleymanpour

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Graphical abstract

Research Highlights

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An electrochemical sensor for paroxetine fabricated based on rGo/PWA/PGE.

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The sensor has very low detection limit (0.9 nM).

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The sensor is highly selective towards paroxetine.

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Journal Pre-proof

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The sensor can measure paroxetine in pharmaceutical and biological media.

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