An enhanced sensing platform for clozapine at 2.0% silver doped TiO2 nanoparticles - A sensitive detection

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ScienceDirect Materials Today: Proceedings 5 (2018) 21271–21278

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ICSEM 2016

An enhanced sensing platform for clozapine at 2.0% silver doped TiO2 nanoparticles - A sensitive detection Nagaraj P. Shettia*, Deepti S. Nayak a, Shweta J. Malodea, Raviraj M. Kulkarnib* a

Department of Chemistry, KLE Society’s K. L. E. Institute of Technology, Hubballi-580030, Affiliated to Visvesvaraya Technological University, Belagavi, Karnataka, India. b

Department of Chemistry, K. L. S. Gogte Institute of Technology (Autonomous), affiliated to Visvesvaraya Technological University Belagavi590008, Karnataka, India

Abstract Metal doped nanoparticles as a modifier have received attention in the development of electrochemical sensors and biosensors. In the current work, we established the electrochemical behaviour and detection of clozapine by utilizing 2.0% silver doped TiO2 nanoparticles modified carbon paste electrode (Ag-TiO2/CPE) at pH 4.2 by employing different voltammetric techniques. Modification enhances the electro-oxidation of clozapine with increased current intensity. The characterization of silver doped titanium dioxide nanoparticles was accomplished by utilizing X-ray diffraction (XRD), scanning electron microscope (SEM), Energy-dispersive X-ray spectroscopy (EDX) and transmission electron microscope (TEM). The influence of parameters like scan rate, pH, accumulation time, amount of the modifier and concentration on the peak current of the drug were studied. The effect of CLZ concentration variation was studied using square wave voltammetric (SWV) technique and got lowest detection limit compared to reported techniques. The fabricated sensor was employed for the determination of clozapine in pharmaceutical and biological samples. © 2018 Elsevier Ltd. All rights reserved. Selection and Peer-review under responsibility of INTERNATIONAL CONFERENCE ON SMART ENGINEERING MATERIALS (ICSEM 2016). Keywords:Carbon paste electrode; Silver doped TiO2 nanoparticles; Electro-oxidation; Clozapine; Pharmaceutical analysis

* Corresponding author. Tel.: +91 9611979743; fax: 0836 – 2330688. E-mail address:[email protected] 2214-7853© 2018 Elsevier Ltd. All rights reserved. Selection and Peer-review under responsibility of INTERNATIONAL CONFERENCE ON SMART ENGINEERING MATERIALS (ICSEM 2016).

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1. Introduction As of late, an ample of research emerged in the field of electrochemistry, by advancing the sensor frameworks for analyte monitoring [1-4]. The study provides more significance in the field of drug discovery, ecology, and in addition biochemistry etc. Recent literature states that, the carbonaceous materials (grapheme, graphite rods, carbon paste electrodes (CPE)) innumerously utilized as sensors because of their rich surface chemistry, lower background current, wider potential window, uncomplicated surface renewal and low detection limit properties [5-7]. In current science and technology one of the crucial uniqueness is to survey and to discover the new efficient materials as electrode surface modifiers. In this aspect, nanoparticles are incredible modifiers to accelerate the sensor performance [8]. Among numerous nanoparticles, TiO2 nanoparticles as electrode surface modifiers captured bountiful attention of researchers and a significant amount of research was instigated in the preceding decades, due to its photocatalytic effect, porosity, steadiness, crystallinity, widespread band gap, high surface area and low toxicity [9]. Under ultraviolet region, the photo-catalytically dynamic TiO2 nanoparticles trigger the formation of surface active radicals, by generating electron-hole pairs which results the oxidization of an adsorbed moiety [10]. Nonetheless, the narrow photocatalytic area, large band hole and poor adsorption limit due to short existence of electron hole pairs are the significant drawback of TiO2 nanoparticles [10]. One of the best technique to boost in the efficiency of TiO2 and to entrap the charge carrier is achieved by doping with transition metals such as silver (Ag), Copper (Cu), ruthenium (Ru) etc. [11]. Actually, on the semiconductor surface, dopants act as an electron sink which diminish the electron-hole pair recombination [11, 12]. In this work silver was utilized as dopants for TiO2 based particles to boost the area of the sensing surface, to reduce the recombination of the photogenerated e- and H+ and in the visible light region to extend the absorption of light [13]. Among different noble metals, silver stood conspicuous dopant for TiO2 nanoparticles, which can provides boosted catalytic activity by easy electron hole separation and in addition this can enhances the surface area by upsurging in anatase to rutile alteration [14]. Clozapine (CLZ) is an atypical antipsychotic drug differs from typical antipsychotics in terms of effectiveness in schizophrenia and their side effects. It may cause a life-threatening depletion of white blood cells which may lead to severe infections. It exhibits a unique pharmacological profile by binding with some kinds of central nervous system receptors [15]. To examine CLZ and its derivatives in biological fluids, number of analytical methods have been employed till now, including various detection techniques such as gas chromatography (GC) with mass spectrometry [16], fluorimetric detection [17], UV [18], mass spectrometry [19], amperometric detection [20] and spectrophotometry [21], Micro extraction packed sorbent-high performance liquid chromatography [22], Liquid-liquid extractioncapillary electrophoreses-UV detection [23], Liquid-liquid extraction- ultra-high performance liquid chromatography–tandem mass spectrometry [24], Solid phase extraction-liquid chromatography-mass spectrometry [25]. In spite of the fact that these techniques are well-demonstrated, generally acknowledged, time-consuming and they require moderately costly equipment and advanced technical expertise.While, on another hand, the electrochemical techniques by utilizing different working electrodes, has been recognized as the best contender for the detection of any drug. Thus, the major stride in the determination of CLZ is the fabrication of a unique sensor. Various electrochemical methods including few techniques like cyclic voltammetry (CV), linear sweep voltammetry (LSV), differential pulse voltammetry (DPV), square wave voltammetry (SWV), and adsorptive differential pulse voltammetry (AdDPV) were reported. Some of fabricated sensors to detect CLZ are glassy carbon electrode [26], sepiolite clay modified carbon paste sensor [26], electrochemically pretreated glassy carbon electrode (EPGCE) [27], carbon nanotubes-sodium dodecyl sulfate modified carbon paste electrode (CNTs-SDS/CPE) [28], ion selective electrode [29], TiO2 nanoparticles modified carbon base (TiO2/CPE) [30], a sensing base made of blended horseradish peroxidase cross-linked with glutaraldehyde and bovine serum in the matrix of a CPE [31]; in situ surfactant modified carbon ionic liquid electrode [32], multiwall carbon nanotubes (MWCNTs)/new coccine (NC) doped polypyrrole [33], gold electrode modified with 16-mercaptohexadecanoic acid self-assembled monolayer (MHA/Au) [34], pencil graphite electrode [35], catechol-modified chitosan system [36] have been proposed for the determination of CLZ. From the literature survey, we found that there is a gap in CLZ determination in trace quantity. Therefore in the present study, an incredible modifier i.e. 2% silver doped TiO2 nanoparticles (2% Ag-TiO2) was synthesized by liquid impregnation (LI) method. This electrochemical study accentuates the enhanced sensing ability of 2% silver doped TiO2 nanoparticles modified carbon paste electrode (2% Ag-TiO2/CPE) compared to CPE and (TiO2/CPE) towards clozapine detection. The performance of 2% Ag-TiO2/CPE is demonstrated by the determination of CLZ in pharmaceutical formulation and human urine samples as well. We received excellent recoveries from urine;

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pharmaceutical samples and good percentage of relative standard deviation (RSD) values indicate the supremacy with regard to reproducibility and repeatability of the 2% Ag-TiO2 modified sensor. Nomenclature A Surface area of the electrode (cm2) * C0 Concentration (mol dm-3) D0Diffusion coefficient (cm2s-1) Ep Peak potential (V) F Faraday constant (C mol-1) Ip Peak Current (μA) k0 Standard Heterogeneous Rate Constant (s-1) LOD Limit of Detection (mol dm-3) LOQ Limit of Quantification (mol dm-3) n Number of electrons transferred R Gas constant (J K-1mol-1) RSD Relative Standard Deviation S Standard deviation of the peak currents T Temperature (K) υ Scan rate (mV s-1) α Transfer coefficient 2. Experimental 2.1. Instrumentation and chemicals The pH measurements were accomplished by using Elico pH meter (Elico Ltd., India). The crystal structure and particle size of utilized Ag-TiO2 nanoparticles were determined by SEM (Jeol JSM-6360), TEM Philips (CM200), powder XRD analysis (Phillips PW1729, Cu kα). An electrochemical analyser (CHI Company, D630, USA) with three electrode system was used to study the electrochemical behaviour of CLZ at room temperature (25±10C) using 2% Ag-TiO2/CPE. A2% Ag-TiO2/CPE serves as the working electrode, a platinum wire as the counter electrode, and an Ag/AgCl (3.0 M KCl) as the reference electrode, respectively. CLZ were purchased from Sigma Aldrich and were used as received without any further purification. A stock solution of CLZ (0.1 mM) was prepared by dissolving an appropriate amount of pure powdered sample in methanol and stored at low temperature. Phosphate buffer saline (PBS) solution (I = 0.2 M) of different pH ranging from 3.011.2 was used as supporting electrolyte [37]. N

N Cl

N

N H

Scheme 1.Chemical structure of Clozapine (CLZ).

2.2. Ag-TiO2 nanoparticles preparation In a pyrex beaker (500 ml), 500 mg of TiO2 was added to 100 ml deionized water and to this suspension 1 and 2% (molar ratio) of AgNO3 was added, for silver doping. The resultant slurry was mixed rigorously by strong stirring and at room temperature it was allowed to settle to overnight. Accordingly obtained liquid was dried at 100°C in an oven for 12 hours to remove access moisture remained. Thus, gained solid material was calcined for 3 hours at 500°C in a muffle furnace. These finally attained fine powdery particles are Ag-TiO2 nanoparticles [38]. 2.3. Preparation of modified electrode By using a mortar and pestle, the preparation of unmodified CPE was done via mixing graphite powder and mineral oil (7:3). For self-homogenization the paste was allowed to stand for 24 hours. The CPE modified with 2.0 % Ag-TiO2 was prepared by homogeneous mixing of graphite powder: Ag-TiO2: mineral oil in an appropriate ratio. In a polytetrafluoro ethylene tube (PTFE), the resulting paste was packed firmly and the surface was smoothened by polishing against filter.

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The dynamic surface area of the sensing platform was calculated by using Randles - Sevcik equation; area was investigated utilizing cyclic voltammetric technique, 1.0 mM K3Fe (CN)6 as a test solution and 0.1 M KCl as supporting electrolyte, at different sweep rates in [39]. Ip = (2.69 x 105) n3/2 A D01/2 ν1/2 C0* (1) From the slope of the plot of Ip vs. ν1/2, the surface area of the bare electrode was found to be 0.042 cm2 and for the modified electrode, the calculated surface area was 0.34 cm2. 2.4. Analysis of pharmaceutical dosage forms By utilizing a mortar and pastel, the CLZ tablets i.e. clozapex (25 mg CLZ per tablet) were finelyground, and related weight with the stock solution was dissolved and diluted up to 100 ml with 4.2 pH in volumetric flask. Proper dissolution was attained by sonication for ten minutes. The precision of the proposed technique was tested by recovery examines. 2.5. Analysis of human urine samples Urine samples were obtained from two healthy volunteers and at room temperature (25 ± 0.1 0C) was centrifuged for 5 minutes at 7000 rpm. The obtained samples undergotwo-fold dilution, using phosphate buffer of pH 4.2 and the test solution was prepared by spiking the filtrate with the known amount of CLZ (0.1mM). 3. Results and discussion 3.1. Characterization of 2% Ag-TiO2 nano particles From the XRD study, the synthesized nanoparticles affirmed that the major phase was anatase Figure 1. A. By broadening the main intense peak of anatase phase and using Scherrer equation, an average crystalline size of nanoparticles was calculated. The crystalline size of undoped TiO2, 1% Ag-TiO2, 2% Ag-TiO2 nanoparticles was found to be 17.00 nm, 14.17 nm, 13.07 nm respectively, which shows good accordance with former report [40]. Figure 1. B. represents the SEM image of the Ag-TiO2nanoparticles, which describes the heterogeneous aggregates of the Ag-TiO2 nanoparticles with high surface area. The non-uniformly discrete tubular crystalline structures were strikingly observed in the TEM image of the Ag-TiO2nanoparticles Figure 1. C. The disseminated black minute spots detected were presumed to be Ag particles on TiO2 nanoparticles with a particular size of 10-15 nm breadth and length of 40-45 nm approximately. The chemical composition of the modifier was studied by the EDX examination Figure 1. D. It shows the prepared nanoparticles have Ti and O with small amount of silver, as its major composition.

Fig. 1: Characterisation of synthesized nanoparticles: (A) XRD patterns of (a) undoped TiO2 (b) 2% Ag-TiO2; (B) SEM image of 2% Ag-TiO2; (C) TEM image of 2% Ag-TiO2; (D) EDX study

3.2. Augmentation of quality of CPE with the modification Figure.2. Unveils the results of cyclic voltammetric (CV) studies, which accentuates the enhanced catalytic activity of 2% Ag-TiO2/CPE sensor compared to TiO2/CPE and CPE, towards CLZ detection in 4.2 PBS at scan rate of 0.05 Vs-1.The peak potential of CLZ oxidation at the 2% Ag-TiO2/CPE was shifted to be less, in comparison with that at the unmodified CPE. Similarly, the anodic peak current for the oxidation of CLZ at the 2% Ag-TiO2/CPE was pointedly increased in comparison with that at the bare CPE and TiO2/CPE. The present system is reversible one, showing anodic peak (Ep= 451 mV) as well as a cathodic peak (Ep= 411 mV). The tailoring of CPE sensing

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base with 2% Ag-TiO2 results fast electron transfer and consequently enrichment of the electrochemical reaction. Exploiting the high surface range provided by 2% Ag-TiO2 nanoparticles and additionally CLZ adsorption at fabricated sensor.

Fig. 2: Voltammetric behaviour of 0.1 mM CLZ in pH 4.2, phosphate buffer (I = 0.2 M) at scan rate = 0.05 Vs-1; Acc. Time= 10s: (a) blank CPE; (a*) CV of 0.1 mM CLZ at CPE; (b) blank TiO2-CPE; (b*) CV of 0.1 mM CLZ at TiO2-CPE; (c) blank 2% AgTiO2-CPE; (c*) CV of 0.1 mM CLZ at 2% AgTiO2-CPE. Inset: Variation in peak current and peak potential at different electrodes.

3.4. Effect of accumulation time Effect of accumulation time was studied which significantly affect sensitivity of the determination method by recording the voltammograms of CLZ at different accumulation time ranging between 0-100s. There was a gradual increase in the peak current from 0-10s and beyond 10s peak currents were almost constant. The maximum peak current was observed at 10s; hence it was opted for further studies. 3.5. Influence of pH on the voltammetric response of CLZ To know electrochemical response of CLZ, the impact of pH was studied at modified sensor in 0.2 M PBS. The cyclic voltammograms of 0.1 mM CLZ at different pH buffer ranging from 3.0-11.2 at a scan rate of 50 mVs-1were recorded in Figure 3. The peak potential budged more negatively as the pH of the supporting electrolyte increases, which recommends the H+ ions involvement in the present system [41]. The maximum peak current was obtained at pH 4.2 (Figure. 3. B) and thus, for further studies the working pH chosen was 4.2 which yielded higher current intensity. The linear relationship between Ep and pH is expressed in Figure. 3. A.; with a regression equation Ep= 0.040 pH + 0.632; R2 = 0.973. The slope of -0.040 V/pH indicates the involvement of same number of protons and electrons in the electro-oxidation of CLZ.

Fig. 3. Cyclic voltammograms obtained for 0.1 mM CLZ in buffer solution of different pH at 2% AgTiO2-CPE at scan rate = 0.05 Vs-1; Acc. Time= 10s. (A) Variation of peak currents Ip/ µA of CLZ with pH. (B) Influence of pH on the peak potential Ep/ V of CLZ.

3. 6. Effect of scan rate To identify the clear electrochemical mechanism of this reversible system, voltammograms were recorded on the new sensor surface, using CV technique by varying scan rates (Figure. 4.). It was observed that the peak current Ip of process varies linearly with the scan rate, indicating that the electrode process is adsorption controlled (Figure. 4. A). Further, a value close to the theoretical value of 1.0 from the slope of log Ip versus log ν, confirms the electrode process to be adsorption-controlled process (Figure. 4. B) [42]. The corresponding equation is as follows: log Ipa= 0.670 log ν + 1.437; R2= 0.987; log Ipc = 0.740 log ν + 0.915; R2 = 0.994.

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The relationship between peak potential (Ep) and logarithm of scan rate (log ν) shows good linearity (Figure. 4. C). Under these conditions, the k0 can be obtained according to the following equations [43] Epa = E0 +

Epc = E0 

2.303 RT

log 

(1- nF)

2.303 RT nF)

2.303 RT

log

(1- nF)

log 

2.303 RT

RTk0

log

RT nF

nF

(2)

(3)

RTk0

(nF)

log k0 =  log (1- ) + (1- ) log log

nF (1- )

-

nFp 2.303RT

(4)

Where k0 is heterogeneous electron transfer rate constant, and α is diffusion coefficient respectively. From the slopes of two curves of the plot Ep vs. log ν, α was calculated to be 0.55 and number of electrons (n) was two. Using Eq. (4), the heterogeneous rate constant (k0) was calculated, and it was found to be 4.7 × 10-3 s−1.

Fig. 4. Cyclic voltammograms of 0.1 mM CLZ at 2% AgTiO2-CPE in pH 4.2 (I = 0.2 M ) with acc. time = 10s at scan rate of : (1) blank; (2) 0.01; (3) 0.02; (4) 0.03; (5) 0.05; (6) 0.07; (7) 0.09; (8) 0.1; (9) 0.15; (10) 0.17; (11) 0.2; (12) 0.25 V s-1. Acc. Time= 10s. (A) Dependence of peak current Ip/ µA on the scan rate υ / Vs-1. (B) Plot of logarithm of peak current log Ip/ µA versus logarithm of scan rate log υ / Vs-1. (C) Plot of variation of peak potential Ep/ V with logarithm of scan rate log υ / Vs-1.

4. Analytical Applications 4.1. Influence of concentration variation Figure 5 shows square wave voltammetry (SWV) curves of CLZ at various concentrations from 3.0×10−8 M to 4.0×10−6M in PBS at pH 4.2. Under optimized conditions, the linear regression equation is Ip (µA) = 10.567 C (µM) + 0.6197 with correlation coefficient of R2 = 0.973. The LOD and LOQ for the determination based on three and ten times of the blank standard deviation (3Sb, 10Sb) were 0.31 nM and 1.04 nM, respectively [44]. Referring to the analytical performances of some recently published reports (Table 1), the present work results very sensitive.

Fig. 5. Square wave voltammograms with increasing concentrations of CLZ in pH 4.2 phosphate buffer solution at 2% AgTiO2-CPE with acc. time = 10s: (a) blank; (b) 3.0 x 10-8; (c) 5.0 x 10-8; (d) 8.0 x 10-8; (e) 1.0 x 10-7; (f) 2.0 x 10-7; (g) 3.0 x 10-7; (h) 4.0 x 10-7; (i) 5.0 x 10-7; (j) 6.0 x 10-7; (k) 7.0 x 10-7; (l) 8.0 x 10-7; (m) 9.0 x 10-7; (n) 1.0 x 10-6;. Inset: Plot of concentration versus peak current Ip/ µA.

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Table 1. Comparison of detection limits of clozapine by voltammetric methods using various working electrodes.

a

Electrodes GCEa CPMEb EPGCEc ISEd TiO2/CPEe HRP/CPEf PPY/CNT/GCEg MHA/Auh GPEi 2% AgTiO2-CPE

Technique DPVj DPV DPV Potentiometry Ad(DPV)k Cyclic Voltamperometry LSVl DPV DPV SWVm

Linearity Range (µM) 0.19-1.07 0.1-0.84 0.1-1.0 10-10000 0.5-45 1.0-10.0 0.01-5.0 1.0-10.0 0.0095-1.5 0.9-40

LOD (nM) 22.57 108.12 8.0 3400 61.0 170 3.0 7.0 2.86 0.43

Reference [26] [26] [27] [30] [31] [32] [33] [34] [35] Present work

Glassy carbon electrode; b Carbon paste modified electrode; c Electrochemically pretreated glassy carbon electrode; d Ion selective electrode; eTiO2 nanoparticles modified carbon paste electrode; f Horseradish peroxidase modified carbon paste electrode; g Polypyrrole coated carbon nanotube modified glassy carbon electrode; h 16-mercaptohexadecanoic acid modified gold electrode; i Graphite pencil electrode; j Differential pulse voltammetry; k Adsorptive differential pulse voltammetry; l Linear sweep voltammetry; m Square wave voltammetry.

4.2. Tablet analysis and recovery test The proposed sensor was tested for the determination of CLZ in pharmaceutical samples by employing SWV method. The solution of CLZ was prepared as described in section 2.4. The analytical results obtained are presented in Table 2. Table 2. Analysis of CLZ in tablets by SWV and recovery studies at 2% Ag-TiO2/CPE. Sample Tablet sample 1 Tablet sample 2 Tablet sample 3

Declared (mol/L) 0.5 x 10-5 0.3 x 10-5 0.1 x 10-5

Detected (mol/L)* 0.489 x 10-5 0.283 x 10-5 0.095 x 10-5

Recovery (%) 97.8 94.3 95.6

RSD

% RSD

0.0179 0.0185 0.0183

1.79 1.85 1.83

*Average five readings

4. 4. Detection of CLZ in urine samples No pre-extraction process was involved in urine sample analysis. The recovery studies were performed by spiking drug-free urine sample with known amount of CLZ. The results showed that satisfactory recovery for CLZ could be obtained (Table 3). Table 3.Application of square wave voltammetry for the determination of clozapine in spiked human urine samples. Urine samples Sample 1 Sample 2 Sample 3

Spiked (10-4 M) 1.0 0.5 0.1

Detected (10-4 M)* 0.989 0.493 0.098

Recovery (%) 98.9 98.6 98.0

% RSD 0.518 0.519 0.522

*Average five readings

5. Conclusions The noble metal silver is used as dopant for TiO2 nanoparticles to enhance its catalytic activity. 2% Ag-TiO2 nanoparticles were synthesized and characterized by XRD, SEM, TEM and EDX analysis. The prepared 2% AgTiO2 nanoparticles were utilized for tailoring of modulated CPE. Thus formed sensor displays an augmentation of selectivity and resolution in the voltammetric response for the determination of CLZ at pH 4.2. From the obtained data, an adsorption-controlled process involving two electrons and two protons was witnessed. The present study is expedient due to the low detection limit, sensitivity and selectivity, compared to earlier reports. This method has been successfully employed to analyse CLZ in pharmaceutical dosage forms and biological fluids. Furthermore, the analytical response was unaffected by the presence of common interfering agents in biological fluids. Acknowledgements One of the author (Deepti S. Nayak) thanks,Department of Science and Technology, Government of India, New Delhi for the award of Inspire Fellowship in Science and Technology.

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