Polystyrene: Î²-Cyclodextrin Inclusion Complex Supported Y2O3

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C: Surfaces, Interfaces, Porous Materials, and Catalysis

Polystyrene: #-Cyclodextrin Inclusion Complex Supported Y2O3 Based Electrochemical Sensor: Effective and Simultaneous Determination of 4-aminoantipyrine and Acyclovir Drugs Palraj Ranganathan, Bhuvanenthiran Mutharani, Shen-Ming Chen, and Pedaballi Sireesha J. Phys. Chem. C, Just Accepted Manuscript • DOI: 10.1021/acs.jpcc.9b00465 • Publication Date (Web): 18 Apr 2019 Downloaded from http://pubs.acs.org on April 18, 2019

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The Journal of Physical Chemistry

Polystyrene: β-Cyclodextrin Inclusion Complex Supported Y2O3 Based Electrochemical Sensor: Effective and Simultaneous Determination of 4-aminoantipyrine and Acyclovir Drugs Palraj Ranganathan1, Bhuvanenthiran Mutharani2, Shen-Ming Chen2∗, Pedaballi Sireesha3

1Institute

of Organic and Polymeric Materials and Research and Development Center for Smart

Textile Technology, National Taipei University of Technology, Taipei, Taiwan, R.O.C 2Department

of Chemical Engineering and Biotechnology, National Taipei University of

Technology, No. 1, Section 3, Chung-Hsiao East Road, Taipei 106, Taiwan, Republic of China. 3Department

of Materials and Mineral Resources Engineering, National Taipei University of

Technology, Taipei, Taiwan, R.O.C

Corresponding Author: *S.M. Chen, Fax: +886227025238, Tel: +886227017147, E mail: [email protected]

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ABSTRACT: In this study, novel polystyrene: β-Cyclodextrin inclusion complex supported yttrium oxide (Y2O3) modified glassy carbon electrode (PS: β-CD IC/Y2O3/GCE) was developed for the simultaneous determination of selected drugs, 4-aminoantipyrine (4-AAP) and acyclovir (ACV) for the first time. The results showed that PS: β-CD IC/Y2O3/GCE exhibit well-defined oxidation peak currents with a lower positive shift in peak potential in the simultaneous determination of 4-AAP and ACV compared to bare GCE, demonstrating the superior catalytic activity. The fabricated sensor showed the linear ranges of 0.01-655 µM and 0.01-918 µM with a low detection limit of 0.01 µM and 0.02 µM for the determination of 4-AAP and ACV, respectively. Further, the as-prepared PS: β-CD IC/Y2O3/GCE has been applied to the simultaneous and individual determination of 4-AAP and ACV in human urine and commercial ACV tablet samples with satisfactory recovery (98-99.3% and 88-96.6%), thereby showing a notable potential for extensive applications in the electrochemical field.


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INTRODUCTION 4-Aminoantipyrine (4-AAP) is a metabolite of aminophenazone and barely administered as an analgesic, antipyretic, and non-steroid anti-inflammatory drug because of its possible side effects. 4-AAP residues in the environment possess a potential threat to human health, such as the risk of agranulocytosis its use as a drug is discouraged.1,2 Moreover, 4-AAP is utilized as a reagent for biochemical reactions constructing peroxides or phenols.3,4 It is also used in the calorimetric detection of phenolic compounds and pesticides in the aquatic environment.5,6 Since, schiff bases of 4-AAP and its metal complexes are extensively used in the pharmaceutical industry, biochemical research, catalysis, clinical applications, and environmental monitoring.7 The toxic effect of 4-AAP on experimental animals was reported by the Occupational Safety and Health Administration.8 4-AAP stimulates liver microsomes and is also used to measure extracellular water. S.G. Sunderji and co-workers proved that 4-AAP can reduce blood flow and 13, 14-dihydro-15-keto prostaglandin F2 alpha concentration after it is infusing into the animal body.9 Therefore, it was very vital to monitor the 4-AAP concentration over time to prevent its side effects. Acyclovir, (ACV, 9-2-hydroxyethoxymethyl guanine), is a synthetic deoxyguanosine analog, play a key role in the therapy of virus diseases.10 ACV is an emerging prototype antiviral agent that acts as a specific inhibitor of herpes virus family, such as herpes simplex viruses (HSV), hepatitis B viruses (HBV), and varicella zoster viruses (VZV).11,12 Typically, it can be used as an intravenously or orally for the treatment of chickenpox and shingles, though its oral absorption is only 20%. The toxicity of ACV in human is notable. Several contrary reactions would occur if ACV was abused, such as nephrotoxicity (crystallization of ACV within real tubule, enhancement of serum creatinine, and transient), urticaria, diarrhea, neurotoxicity (coma,



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hallucinations, lethargy, seizures, and tremors), phlebophlogosis, cephalalgia, emesis, and swoon.13,14 Based on the aforementioned description, quantitative determination of 4-AAP and ACV seems to be very imperative. Literature survey reveals several analytical techniques including spectrophotometry, fluorescence,

high-performance

liquid

chromatography,

capillary

electrophoresis,

and

electrochemical sensor have been reported for the detection of 4-AAP and ACV in biological and clinical samples.15-18 Despite, electrochemical methods are used extensively over other analytical methods due to the merits of sensitivity, accuracy, simplicity, uncomplicated apparatus and ease of on-site detection. There are several electroanalytical methods have reported for the individual detection of 4-AAP and ACV.

19,20

Despite, there is no official electroanalytical method report

for simultaneous detection of 4-AAP and ACV. Hence, it is essential to develop simply as well as a significant selective and sensitive method for the simultaneous determination of 4-AAP and ACV. In recent years, the chemical modification of electrode surfaces is one of the broad interest and developing an approach. This modified electrode process has many advantages such as drug determination and increases in the electron transfer kinetic rate at the electrode surface. In recent years, β-Cyclodextrin (β-CD) have shown their potential in chemical and biochemical drug sensing applications. β-CD is a well-known non-reducing oligosaccharide consist of seven α-D glucose unit in a condensed cone structure with a hydrophobic interior cavity and a hydrophilic exterior.21 Significantly, β-CD can form a stable inclusion complex (IC) with various organic/inorganic and biological molecules through host-guest interaction with its cone-shaped cavity or nanostructure supramolecular assemblies into their hydrophobic interior.22 In particular, the combination of the advanced chemical properties of β-CD incorporated polymer based IC supported inorganic metal oxide is a subject of great scientific interest with


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promising applications in numerous fields such as nanotechnology, catalysis, environmental science, drug delivery, chemical sensing, and so forth.23-25 The β-CD IC modified electrodes have been revealed to display varying catalytic behavior that would play a vital role in electrocatalysis and electrochemical sensors.26 In particular, the design and preparation of β-CD functionalized colloidal composite microspheres that consist of polymeric (organic) core and inorganic particle shell are of great attention owing to the developed properties (e.g. physical, chemical, mechanical, rheological, optical, electrical, catalytic, and so on) in comparison with their relevant component counterparts.27 In this colloidal and core-shell line polymers, polystyrene (PS) has been widely used. PS is one of the most extensively used commodity polymers in the world owing to its ready availability, reasonable cost, low density, chemical inertness, and capability to be functionalized easily. PS-based products have been manufactured on a large-scale range for both engineering and consume usages. The addition of metal nanoparticles or carbon materials in a PS matrix produced highly dispersed colloidal composites nanocomposite or thin films that are reusable semiconducting and display an ambipolar effect, where the PS plays as the nanocatalyst stabilizer or support.28 On the other hand, PS based colloidal organic-inorganic nanocomposites are valued for being robust, long-lasting, and multifunctional species with applications as high-performance materials. Numerous types of inorganic metal nanoparticles have been incorporated on the surface of the PS matrix. Recently, intensive research interest has been focused on the fabrication of colloidal composites with rare earth metal oxides as shell materials. Among them, yttrium oxide (Y2O3) have been intensively considered because of their excellent chemical durability, thermal stability (up to 2200 ℃), and low photon energy properties arising from their 4f electrons. Y2O3 is an n-type semiconductor material, is vital for numerous applications, such as host matrices of phosphors, dielectric



insulators of electroluminescent devices, cataluminescences gas sensing, laser gain media, luminescent security inks, catalyst support or even catalyst, and in medicinal applications.29 Therefore, we have taken Y2O3 for core shell inorganic material in this study. To our knowledge, the fabrication of PS: β-CD core/shell structure like IC supported Y2O3 modified glassy carbon electrode (PS: β-CD IC/Y2O3/GCE) for the simultaneous and individual detection of 4-AAP and ACV have not yet been reported. For the first time in this present work, we report a new and direct electrooxidation strategy for selective simultaneous sensing application of 4–AAP and ACV using a PS: β-CD IC/Y2O3/GCE. Herein, we have chosen PS and Y2O3 as a candidate to enhance the stability with increased electron transfer efficiency. PS: β-CD IC was synthesized in situ following the route proposed by Xu et al.30

The formation of Y2O3 supported PS: β-CD IC occur on the interaction of PS

aromatic groups and β-CD hydroxyl groups with the metal surface. The electroanalytical assay showed high sensitivity, low detection limit, and a wide linear range for 4-AAP and ACV, moreover, good recoveries in human urine and commercial ACV tablet samples. EXPERIMENTAL SECTION Materials and Methods. Styrene (C8H8), β-Cyclodextrin (β-CD, C42H70O35), yttrium nitrate hexahydrate (Y(NO3)3.6H2O), 4-aminoantipyrine (4-AAP), acyclovir (ACV), potassium persulfate (KPS), and urea were obtained from Sigma Aldrich. Sodium dihydrogen phosphate (NaH2PO4) and disodium hydrogen phosphate (Na2HPO4) was used to prepare the phosphate buffer solution (PBS) were also obtained from Sigma Aldrich. All the reagents used were of analytical grades and the solutions were obtained using double distilled (DD) water.


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Apparatus. The Fourier transform infrared spectra (FTIR) of the PS: β-CD IC/Y2O3 samples were carried out by using a CHI 1000C (FT/IR-6600) instrument. The X-ray diffraction (XRD) was implemented by X-ray diffractometer (XPERT-PRO instrument). The morphology and size of the PS: β-CD IC/Y2O3 was employed by using transmission electron microscopy (TEM; HRTEM H-7600) and Field emission scanning electron microscopy (FE-SEM; ZEISS sigma 300). The surface composition and the oxidation states of the PS: β-CD IC/Y2O3 samples were recorded by using a Thermo ESCALAB 250 X-ray photoelectron spectroscopy (XPS) analyzer instrument. Electrochemical impedance spectroscopy (EIS) was carried out on ZAHNER instrument. All the electrochemical experiments were executed with a CHI 1205B (USA) containing 10 mL of solution in a typical three-electrode system comprise of PS: β-CD IC/Y2O3/GCE as working electrode, Ag/AgCl and Pt wire as a reference electrode and counter or auxiliary electrode. Synthesis of Yttrium Oxide (Y2O3). In brief, 8g of Y(NO3)3.6H2O and 1g of urea dissolved in 90 mL of DD water with constant vigorous stirring to get a clear solution, which was transferred to a 100 mL containing autoclave and subjected to hydrothermal treatment at 160 oC for 24 h. The obtained white precipitate was collected and centrifuged by DD water several times. Subsequently, it was dried in a vacuum oven at 70 oC. Finally, the product was dehydrated and decomposed by heated at 600 oC for 4 h to obtain Y2O3 microstructures. Synthesis of PS: β-CD IC. The PS: β-CD IC was prepared by adding 10 mL of styrene, 90 mL of DD water, and 1.25 g of β-CD into a three-necked round bottom flask equipped with a condenser and a stirrer, followed by stirring to get a homogeneous solution and passing nitrogen (N2) for 30 min. Afterward, 0.3 g of KPS was added to allow the polymerization reaction for 6 h



under N2 atmosphere at 70 oC. After complete the reaction, the PS: β-CD IC was centrifuged with water and ethanol several times. Finally, vacuum drying was allowed. Fabrication of the PS: β-CD IC/Y2O3/GCE. The bare GCE was polished with 0.05 µm alumina powder and cleaned consecutively with DD water for 10 min. To get a homogeneous suspension, 5 mg of as prepared PS: β-CD IC and 10 mg of Y2O3 was dispersed in 1 mL of DD water and kept under ultra-sonication for 3 h. The as-proposed PS: β-CD IC/Y2O3 dispersion (6µL) was drop cast on the surface of GCE and it was dried at room temperature. Finally, the PS: β-CD IC/Y2O3/GCE was obtained for further electrochemical measurements. Scheme 1 shows the overall schematic illustration of PS: β-CD IC/Y2O3 and its electro-oxidation of 4-AAP and ACV.


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Scheme 1. The schematic illustration of PS: β-CD IC/Y2O3 and its electrochemical detection of 4-AAP and ACV.

RESULTS AND DISCUSSION Characterizations of PS-β-CD IC/Y2O3. FTIR spectroscopy involves the study of different functional groups of PS: β-CD IC and PS: β-CD IC/Y2O3, β-CD, and Y2O3 by analyzing the significant changes in the shape and position of the absorbance bands (Figure 1A). In the FTIR



spectra of neat β-CD, the absorption band at 3410 cm-1, 1454 cm-1, 1219 cm-1, 946 cm-1, and 860 cm-1 are assigned to the ѴO-H stretching vibration, ѴO-H deformation, ѴC-C-O stretching vibration, skeletal vibration involving α-1,4 linkages, and a breath of glucose ring. However, for the spectrum of PS: β-CD IC shows the absorption bands shifting values from neat β-CD to IC were noted as 3410 to 3448 cm-1(ѴO-H stretching), 2927 to 3010 cm-1 (ѴC-H stretching), 1454 to 1612 cm-1 (ѴO-H deformation), and 1219 to 1227 cm-1 (ѴC-C-O stretching). These changes in the absorption peak values may indicate the successful encapsulation of hydrophobic PS into the hydrophobic interior cavity of β-CD via hydrophobic interaction.30 In the Y2O3 spectrum, a three specific absorption band in the region at 566 cm-1 and 642 cm-1 is due to the stretching vibrations of Y-O. In addition, in the PS: β-CD IC/Y2O3 spectrum, all of the characteristic absorbance peaks of β-CD, PS: β-CD IC and Y2O3 obviously appear, but their peak intensities are reduced in the PS: β-CD IC/Y2O3, which reveals that the strong electrostatic interaction between PS aromatic backbone and β-CD hydroxyl groups with Y2O3 metal surface via hydrophobic, covalent or noncovalent, and hydrogen bonding interactions, during the formation of PS: β-CD IC/Y2O3 composite.


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Figure 1. (A) FT-IR spectra and (B) XRD pattern of neat β-CD, PS: β-CD IC, neat Y2O3, and PS: β-CD IC/Y2O3. XRD pattern of the as-prepared Y2O3, β-CD, PS: β-CD IC, and PS: β-CD IC/Y2O3 were collected (Figure 1B) and further demonstrated the packing structure of β-CD and formation of pure Y2O3 on the surface of PS: β-CD IC. From Figure 1B, XRD pattern of Y2O3 shows the series of diffraction peaks at 2θ ≈ 20.7o, 29.1o, 33.8o, 39.9o, 43.4o, 48.5o, 57.6o, and 78.6o corresponding to the lattice planes of (211), (222), (400), (332), (134), (440), (622), and (662) are clearly discerned and can be indexed to the cubic phase structure of Y2O3 (which is in good agreement with the standard JCPDS: 89-5591).30 As shown in Figure 1B, the XRD pattern of the neat β-CD has the reflections at 2θ ≈ 11.1o, 12.4o, and 19.4o, which is agreed with the distinctive diffraction of the cage-type stacking. But the PS: β-CD IC showed a diffraction peak at 11.6o, characteristic for the channel-type structure.31 It is interesting, nonetheless, after the incorporation of β-CD into PS matrix, the peak intensity of the β-CD was completely disappeared. These results indicated that the hydrophobic and amorphous structure of the PS matrix suppresses the crystallinity of β-CD. The reduction of lamellar crystal thickness and the formation of imperfect heterogeneous crystals structure of PS: β-CD IC could be one of the reasons for this phenomenon. In the pattern of the PS: β-CD IC/Y2O3, the peak corresponds to Y2O3 also seemed, signifying that the PS: β-CD IC does not affect the phase structure of Y2O3. These results confirmed the existence of PS: β-CD IC and Y2O3 in the PS: β-CD IC/Y2O3 matrix prepared by the proposed method. Although, notable changes have been observed in the crystalline phase of Y2O3 by the presence of PS: β-CD IC, thus implies the addition of Y2O3 with PS: β-CD IC suppresses the crystallinity of Y2O3. Moreover, the addition of amorphous PS: βCD IC dilutes the crystallizable Y2O3 particles and reduces the crystallinity. It is worthy to note



that the amorphous structure of the materials can improve the electrocatalytic activity. A similar deed was reported by Zhong et al. in PS-CoFe2O4.32

Figure 2. (A, B) TEM images of PS: β-CD IC, (C) PS: β-CD IC/Y2O3, (D) EDX spectra of PS: β-CD IC/Y2O3, and (E, F, G, and H) elemental mapping images of PS: β-CD IC/Y2O3. Figure 2A-C illustrate the TEM microstructures of PS: β-CD IC and PS: β-CD IC/Y2O3. As shown in Figure S1A, the as-prepared neat PS microspheres display well-defined sphere-shaped outline and smooth surface. In contrast, PS: β-CD IC revealed that β-CD discretely coated on the surface of PS microspheres, showing a core/shell-like structure (Figure 2A and B). The characteristic surface morphology as compared with PS microsphere showed clear evidence of the successful formation of PS: β-CD IC. As can be seen in Figure S1B, the representative FESEM image of Y2O3 remains as a flake-like structure. FE-SEM and TEM image of neat β-CD exhibited a flake-like structure and is depicted in Figure S2A and B. On the other hand, the addition of PS: β-CD IC with Y2O3 in the synthesis process resulted in the good distribution of Y2O3 on the surface of PS: β-CD IC (Figure 2C). For further characterizations of PS: β-CD


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IC/Y2O3, the energy-dispersive X-ray spectroscopy (EDX) analysis was performed and is shown in Figure 2D. The EDX analysis showed the presence of carbon (C), oxygen (O), and yttrium (Y) elements, which quantitatively indicate the distribution of Y2O3 on the PS: β-CD IC surface. Figure 2E-H illustrates the elemental mapping analysis of PS: β-CD IC/Y2O3, which is clearly revealed that Y2O3 present in the PS: β-CD IC along with carbon (C), oxygen (O), and yttrium (Y).

Figure 3. (A) The overall XPS spectra and high-resolution XPS spectra of (B) C 1s, (C) O 1s, and (D) Y 3d of PS: β-CD IC/Y2O3.



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For further confirming the surface composition and oxidation states of the as-prepared PS: βCD IC/Y2O3, the XPS technique is investigated. The overall XPS survey spectrum can be found in Figure 3A, which reveals the existence of C, O, and Y elements in PS: β-CD IC/Y2O3. The core level XPS survey of C 1s is depicted in Figure 3B, where three peaks with binding energy (BE) located at 284.6 eV, 286.3 eV, and 288.5 eV could be ascribed to C-H and C-C in PS: βCD IC.33,30 In the high-resolution spectra of O 1s (Figure 3C), there are three predominant peaks with BE located at 528.3 eV, 532.4 eV, and 536.3 eV corresponding to the lattice oxygen in Y2O3, C-O in β-CD molecules, and surface –OH groups in Y2O3.

34,30

Further, the Y 3d XPS

spectra are shown in Figure 3D, the two main fitted peaks at 156.4 eV and 159.2 eV can be attributed to Y 3d5/2 and Y 3d3/2, respectively.35,36 The XPS analyses clearly illustrate the Y2O3 has been successfully incorporating into the surface of PS: β-CD IC. Electrochemical Properties of PS: β-CD IC/Y2O3/GCE. The different modified electrodes were scrutinized by EIS in 5 mM [Fe(CN)6]3-/4- containing 0.5 M KCl at 1 x 10-1 Hz to 1 x 102 kHz. The semicircle part at high frequencies corresponding to the charge transfer resistance (Rct), which estimates the electron transfer process of different modified electrodes. Figure 4A shows the Nyquist plot of bare GCE (a), PS: β-CD IC/GCE (b), Y2O3/GCE (c) and PS: β-CD IC/Y2O3/GCE (d). Figure S3A exhibits the EIS plot of PS/Y2O3/GCE (a), β-CD/GCE (b), and βCD/Y2O3/GCE (c). The large semicircle exhibits higher Rct value at 593 Ω, which relates to the poor conductivity of bare GCE. By contrast, the Rct value was about 133 Ω, 80 Ω,73 Ω, 70 Ω, and 66 Ω for PS: β-CD IC/GCE, PS/Y2O3/GCE, Y2O3/GCE, β-CD/GCE, and β-CD/Y2O3/GCE. For the PS: β-CD IC/Y2O3/GCE, the Rct value was about at 65 Ω, which revealed that the Rct of [Fe(CN)6]3-/4- on PS: β-CD IC/Y2O3/GCE was considerably reduced as compared with that on


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PS: β-CD IC/GCE, PS/Y2O3/GCE, Y2O3/GCE, β-CD/GCE, β-CD/Y2O3/GCE, and also surface of bare GCE. Figure 4B displays the calibration plot of different modified electrodes vs. Rct values.

Figure 4. (A) EIS curve of (a) bare GCE, (b) PS: β-CD IC/GCE, (c) Y2O3/GCE, and (d) PS: βCD IC/Y2O3/GCE in 5 mM [Fe(CN)6]3-/4- containing 0.5 M KCl in the frequency ranges of 0.1



Hz to 100 kHz. (Insert: Right: the enlarged image of EIS plot, Left: Randles circuit model), (B) the corresponding calibration plot between the modified electrodes vs. Rct, (C) CVs curve of (a) bare GCE, (b) PS: β-CD IC/GCE, (c) Y2O3/GCE, and (d) PS: β-CD IC/Y2O3/GCE in 5 mM [Fe(CN)6]3-/4- containing 0.5 M KCl at a scan rate of 50 mV/s, (D) CVs response of PS: β-CD IC/Y2O3/GCE in 5 mM [Fe(CN)6]3-/4- containing 0.5 M KCl at different scan rate from 10-100 mV/s, (E) the linear plot for square root of scan rate vs. current response, and (F) the calibration plot relationship between the modified electrodes vs. active surface area. The electron transfer property of PS: β-CD IC/Y2O3/GCE was also investigated by using the electrochemical process. Figure 4C displays the cyclic voltammograms (CVs) obtained at bare GCE (a), PS: β-CD IC/GCE (b), Y2O3/GCE (c), and PS: β-CD IC/Y2O3/GCE (d) in 5 mM [Fe(CN)6]3-/4- containing 0.5 M KCl at 50 mV/s. As can be seen from Figure 4C, a pair of redox peaks (Ipa = 38.82 µA and Ipc = -36.70 µA) with the potential difference (ΔEp) of 160 mV was obtained at bare GCE. Whereas at PS: β-CD IC/GCE (Ipa = 67.80 µA and Ipc = -62.58 µA) and Y2O3/GCE (Ipa = 69.14 µA and Ipc = -63.48 µA), the ΔEp was reduced to 130 mV and 120 mV. At PS: β-CD IC/Y2O3/GCE, the ΔEp value was remarkably reduced to 100 mV with redox current response (Ipa = 76.34 µA and Ipc = -68.26 µA) 2.1 times higher than bare GCE, which demonstrating that the PS: β-CD IC/Y2O3/GCE shows fast electron transfer kinetics and large surface area than other modified electrodes. CVs for PS/Y2O3/GCE (a), β-CD/GCE (b), and βCD/Y2O3/GCE (c) in 5 mM [Fe(CN)6]3-/4- containing 0.5 M KCl at 50 mV/s are shown in Figure S3B. As can be seen in Figure S3B, a maximum redox peak currents are obtained at βCD/Y2O3/GCE than β-CD/GCE and PS/Y2O3/GCE, these obtained results are lower than PS: βCD IC/Y2O3/GCE. In addition, the CVs response of the PS: β-CD IC/Y2O3/GCE at different scan rate ranges of 10-100 mV/s and depicted in Figure 4D. The corresponding linear plot of the


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anodic and cathodic peak currents as a function of the square root of scan rates (Figure 4E) implies a diffusion-controlled electrochemical process. The electroactive surface area of bare GCE, PS: β-CD IC/GCE, Y2O3/GCE, and PS: β-CD IC/Y2O3/GCE was estimated based on using Randles Sevcik equation [Eq. 1] and can be expressed as follows,37 𝑖𝑝𝑎 = 2.69 Χ 105 𝑛3/2𝛼1/2𝐷1/2 𝐴 𝐶 ʋ1/2

(1)

By using the above equation [1], the electroactive surface area was found to be 0.033, 0.056, 0.060, 0.064, 0.070, 0.078, and 0.088 cm2 for bare GCE, PS: β-CD IC/GCE, PS/Y2O3/GCE, Y2O3/GCE, β-CD/GCE, β-CD/Y2O3/GCE, and PS: β-CD IC/Y2O3/GCE, indicating that composite material has higher electroactive surface area than other modified electrodes. Figure 4F illustrates the corresponding calibration plot of modified electrodes vs. active surface area. Electrocatalytic Oxidation of 4-AAP and ACV at Different Modified Electrodes. The electrochemical oxidation responses for a mixture of 500 µM 4-AAP and ACV in pH 7.0 PBS at bare GCE (a), PS: β-CD IC/GCE (b), Y2O3/GCE(c), and PS: β-CD IC/Y2O3/GCE (d) are recorded CVs at a scan rate of 50 mV/s and are given in Figure 5A. The CVs of the binary mixture of 4-AAP and ACV shows broad peaks and poor current responses and with higher oxidation potential occur (Epa = 0.48 V and Epa = 1.19 V) at bare GCE, illustrating sluggish electron transfer kinetics. While at the surface of PS: β-CD IC/GCE, the two well-resolved peaks were observed at about Epa = 0.44 V and Epa = 1.15 V for 4-AAP and ACV. Moreover, the current response of 4-AAP and ACV was slightly increased through the surface of Y2O3/GCE at the potential of Epa = 0.43 V and Epa = 1.14 V, respectively.



Figure 5. (A) CVs curve of (a) bare GCE, (b) PS: β-CD IC/GCE, (c) Y2O3/GCE, and (d) PS: βCD IC/Y2O3/GCE with existence of 500 µM 4-AAP and ACV in 0.1 M PBS (pH 7.0) at 50


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mV/s, (B) CVs performance of PS: β-CD IC/Y2O3/GCE for varying the concentration of 4-AAP and ACV (100-500 µM) simultaneously in 0.1 M PBS at a scan rate of 50 mV/s, (C and D) the corresponding linear plot of log (4-AAP) and log (ACV) vs. log (I / µA), and (E and F) CVs curve of PS: β-CD IC/Y2O3/GCE in different concentrations of 4-AAP and ACV (150-500 µM) at 50 mV/s. As shown in Figure S3C, the CVs obtained for PS/Y2O3/GCE, β-CD/GCE, and β-CD/Y2O3/GCE in 0.1 M PBS at 50 mV/s. At PS/Y2O3/GCE, β-CD/GCE, and β-CD/Y2O3/GCE, the 4-AAP and ACV peak currents are lower than PS: β-CD IC/Y2O3/GCE. In great contrast, at the PS: β-CD IC/Y2O3/GCE, the 4-AAP and ACV mixture exhibited two well-defined peaks at Epa = 0.39 V and Epa = 1.09 V attributing to the oxidation of 4-AAP and ACV, respectively. Further, the oxidation current response at PS: β-CD IC/Y2O3/GCE has prodigiously increased with lower oxidation potential for the detection of 4-AAP and ACV. At PS: β-CD IC/Y2O3/GCE, the oxidation peaks of 4-AAP at 0.39 V and 0.59 V owing to direct oxidation of –NH2 group and antipyrine ring in the 4-AAP molecule.19 The oxidation peak at 1.09 V due to the oxidation of ACV to 8-oxoacyclovir.36 On the basis of the EIS and CV results, we concluded that PS: β-CD IC/Y2O3 can interact with 4-AAP and ACV through the following interactions: (1) 4-AAP and ACV interacts with exterior hydrophilic regions of β-CD via hydrogen-bonding like interactions between the amide and amine hydrogen of 4-AAP and ACV with the available oxygen atom in the β-CD. (2) Strong π-π stacking between phenyl groups of the PS and phenyl group of the 4AAP and ACV. (3) The combination of PS: β-CD IC and Y2O3 offer the faster electron transfer activity, owing to the interaction between PS: β-CD IC with Y2O3 via hydrophobic, covalent or noncovalent, and hydrogen bonding interactions. This statement agrees with the EIS results. (4) Besides, the amorphous structure of the PS: β-CD IC/Y2O3 can improve the electrocatalytic



activity and it can provide a conduction pathway for the electron transfer. This kind of interconnection network between PS: β-CD IC/Y2O3 matrix with 4-AAP and ACV will be favorable for the direct electrooxidation of 4-AAP and ACV. It may conclude that the PS: β-CD IC/Y2O3 matrix play an important role in the simultaneous determination of target analytes. The plausible electrooxidation mechanism of 4-AAP and ACV is illustrated in Scheme 2.

Scheme 2. The plausible electrooxidation mechanism of 4-AAP and ACV.


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Figure 6. (A) CVs of PS: β-CD IC/Y2O3/GCE in the presence of 300 µM 4-AAP and ACV in 0.1 M PBS (pH 7.0) at different scan rates from 10-100 mV/s, (B) the linear plot between the square root of scan rates and oxidation peak current for 4-AAP and ACV, (C and D) the linear plot between the log of scan rate vs. oxidation potential for 4-AAP and ACV. Effect of 4-AAP and ACV Concentration on PS: β-CD IC/Y2O3/GCE. Figure 5B displays the CVs response of PS: β-CD IC/Y2O3/GCE for varying the concentration of 4-AAP and ACV simultaneously from 100-500 µM in 0.1 M PBS at 50 mV/s. According to the results, the increased peak current of 4-AAP and ACV by raising the concentration of 4-AAP and ACV. The



corresponding linear plot between the concentration of 4-AAP and ACV are shown in Figure S4A and B. Figure 5C and D illustrate the liner plot of log (4-AAP (µM)) and log (ACV (µM)) vs. log (I / (µA) with linear regression equation can be assessed as Ipa (µA) = 0.8283x – 1.6637; R2 = 0.994 and Ipa (µA) = 0.7567x – 1.0149; R2 = 0.994 for 4-AAP and ACV, respectively. In addition, the individual CVs curve of PS: β-CD IC/Y2O3/GCE with different concentration (150500 µM) of 4-AAP and ACV in 0.1 M PBS at 50 mV/s and are depicted in Figure 5E and F. As a result, the peak current of 4-AAP and ACV increases with increasing the concentration, which confirms that the as-prepared PS: β-CD IC/Y2O3/GCE can be applied for individual and simultaneous detection of 4-AAP and ACV. The Influence of Scan Rate and pH.

The kinetics of the electrode reactions were

demonstrated by exploring the influence of scan rate on the anodic peak currents (Ipa) of 4-AAP and ACV. Figure 6A displays the CVs of 300 µM of 4-AAP and ACV on the PS: β-CD IC/Y2O3/GCE in 0.1 M PBS at different scan rates were ranges of 10-100 mV/s. While the increase of scan rate, the anodic peak currents of 4-AAP and ACV increased. The oxidation peak currents of 4-AAP and ACV are linearly dependent on the square root of scan rate (v1/2) (Figure 6B) with the linear regression equation would be expressed as Ipa (µA) = 0.2342x + 0.5755; R2 = 0.995 and Ipa (µA) = 0.5736x + 2.6602; R2 = 0.993 for 4-AAP and ACV, illustrating that the reaction process corresponding to a diffusion-controlled electrochemical process. In addition, there is a good linear relationship between the anodic peak potential (Epa) vs. log of scan rate with linear regression coefficient can be expressed as Epa (V) = 0.0635x + 0.3072; R2 = 0.995 and Epa (V) = 0.0784x + 0.9752; R2 = 0.980 for 4-AAP and ACV are shown in Figure 6C and D, Using the slope of Epa vs. log of scan rate, the charge transfer coefficient (𝛼) [Eq. 2] was estimated as follows;


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𝑅𝑇

𝐸𝑝𝑎 = 𝐸𝑜 - ( 𝛼𝑛𝐹) 𝑙𝑛ʋ

(2)

Where ‘Epa’ is the anodic peak potential, ‘R’ is the gas constant, ‘T’ is the temperature, ‘Eo’ is the formal potential, ‘ʋ’ is the scan rate, ‘n’ is the number of electrons, ‘F’ is the Faraday constant, and ‘𝛼’ is the charge transfer coefficient. The 𝛼 value is calculated to be 0.55 and 0.48 for 4-AAP and ACV, respectively. The influence of pH on the oxidation peak current and potential was scrutinized by monitoring CVs using PS: β-CD IC/Y2O3/GCE in the existence of 500 µM 4-AAP and ACV at different pH values in the range of 3.0-11.0 (50 mV/s). As can be seen in Figure S5A, The Epa of 4-AAP and ACV shifted along with increasing the different pH value, illustrating that the proton transfer process were occurred on the surface of PS: β-CD IC/Y2O3/GCE toward 4-AAP and ACV. The Ipa of 4-AAP and ACV increased gradually and then decreased (Figure S5B and C), the higher peak current was obtained at pH 7.0. Thus, the pH 7.0 was chosen for the supporting electrolyte in the electrochemical oxidation of 4-AAP and ACV. Electrochemical Determination of 4-AAP and ACV at PS: β-CD IC/Y2O3/GCE. Under optimum conditions, the individual and the simultaneous determination of 4-AAP and ACV using the PS: β-CD IC/Y2O3/GCE was employed in 0.1 M PBS at a scan rate of 50 mV/s by differential pulse voltammetry (DPV). When the concentration of one analyte changed, the concentration of another analyte remained constant. Figure 7A displays the different concentration of 4-AAP in the existence of 50 µM ACV. The Ipa for 4-AAP raised linearly with an increase in the addition of 4-AAP concentration with two linear ranges were found to be 0.01105 µM (lower concentration) and 115-655 µM (higher concentration). Moreover. DPV graph appears to have two linear ranges, at lower concentration and at higher concentration. This can



be due to 4-AAP and ACV absorbed electrode surface. There are two linear relationships between the peak current and concentration (Figure 7B) of 4-AAP with linear regression equation of Ipa (µA) = 0.0148x + 1.0249; R2 = 0.985 and Ipa (µA) = 0.0036x + 2.2853; R2 = 0.991, respectively.


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Figure 7. DPV of 4-AAP and ACV at PS: β-CD IC/Y2O3/GCE in 0.1 M PBS (pH 7.0) at 50 mV/s. (A) 4-AAP concentrations: 0.01-105 µM and 115-655 µM in the existence of 50 µM



ACV, (B) the linear relationship between the higher concentration of 4-AAP vs. peak currents; (inset: linear plot for the lower concentration of 4-AAP vs. peak current), (C) ACV concentrations: 0.01-118 µM and 148-918 µM in the presence of 50 µM 4-AAP, (D) the corresponding linear plot of higher concentration of ACV vs. peak currents; (inset: linear plot for the lower concentration of ACV vs. peak current), (E) DPV of different concentrations of 4-AAP and ACV (15-155 µM) at 50 mV/s, and (F) the corresponding linear plot of concentration of 4AAP and ACV vs. current. The detection limit (LOD) and sensitivity were estimated to be 0.01 µM and 2.44 µA µM-1 cm-2 for 4-AAP, respectively. Similarly, Figure 7C exhibits that the Ipa of ACV escalated linearly with increasing the concentration of ACV from 0.01-118 µM (lower concentration) and 148-918 µM (higher concentration), while the concentration of 4-AAP fixing constant at 50 µM. Figure 7D portrays that the corresponding linear plot of peak currents of ACV and concentration of ACV. The two linear regression equation can be calculated as Ipa (µA) = 0.0195x + 1.533; R2 = 0.991 and Ipa (µA) = 0.0042x + 3.3913; R2 = 0.989 for lower and higher concentration, moreover, the LOD and Sensitivity was calculated to be 0.02 µM and 1.18 µA µM-1 cm-2 for ACV. The obtained results demonstrate that the electrochemical peaks of 4-AAP and ACV were independent of each other at PS: β-CD IC/Y2O3/GCE. It was clearly evident that the selective determination of 4-AAP in the existence of ACV and, similarly, the determination of ACV in the existence of 4-AAP are possible. Also, applicability of PS: β-CD IC/Y2O3/GCE for simultaneous determination of 4-AAP and ACV is investigated in Figure 7E and the corresponding linear regression equation can be calculated as Ipa (µA) = 0.0132x + 1.555; R2 = 0.997 and Ipa (µA) = 0.0083x + 1.322; R2 = 0.991 for 4-AAP and ACV (Figure 7F). The DPV curves were observed by simultaneously changing the concentrations of both 4-AAP and ACV. The obtained results


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exhibit that the two well-distinguished oxidation peaks corresponding to 4-AAP and ACV at PS: β-CD IC/Y2O3/GCE. The analytical parameters of 4-AAP and ACV at PS: β-CD IC/Y2O3/GCE is compared with previously reported modified GCE and the corresponding results are given in Table 1 and Table 2. Table 1. Comparison of Analytical Parameters with Previously Reported Different Modified Electrodes for the Electrochemical Detection of 4-AAP. Linearity range

Modified Electrodes

LOD (µM)

Reference

(µM) Nano Riboflavin/GCE

-

0.05

[39]

MWCNTs-CTAB/GCE

0.005-0.04

0.00016

[40]

-

3.6

[41]

-

375

[42]

-

278

[43]

0.01-105

0.01

This work

Diffusion layer titration at dual-band electrochemical cell Titanium phosphate/nickel hexacyanoferrate/GPE Dipyrone (DP)(1-phenyl-2,3-dimethyl-5pyrazolone-4-methylaminomethanesulfonate sodium PS: β-CD IC/Y2O3/GCE

and 115- 655

Table 2. Comparison of Analytical Parameters with Previously Reported Different Modified Electrodes for the Electrochemical Detection of ACV.



LOD (µM)

Reference

27.0-521.0

2.64

[44]

GCE

2-100

0.35

[45]

Self-assembled monolayer/GE

0.2-2

0.07

[46]

0.08-10

0.03

[47]

P-OAP/MWCNTs-ZnO NPs-CPE

0.399-35.36

0.3

[48]

PS: β-CIC/Y2O3/GCE

0.01-118 and

0.02

This work

Modified Electrodes

Linearity range

Page 28 of 38

(µM) Copper NPs/CPE

MWCNTs-DHP/GCE

148-918


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Figure 8. (A) DPV curves of selectivity studies with existence of 4-AAP and ACV (100 µM) and 50-fold excess concentration of interfering compounds (DA, UA, AA, GLU, CPZ, Mg2+, SO4-, Cl-, Ca2+, and Br-, (B) corresponding error bar diagram, (C) DPV curve of stability (1st and 25th run) at PS: β-CD IC/Y2O3/GCE in 0.1 M PBS with the existence of 4-AAP and ACV (200 µM), and (D) corresponding calibration plot between number of run and peak currents. Interference, Stability, and Reproducibility.

To estimate the selectivity of the proposed

sensor, the inference effect of several metal ions and some common co-interfering compounds (dopamine (DA), uric acid (UA), ascorbic acid (AA), glucose (GLU), chlorpromazine (CPZ), Mg2+, SO4-, Cl-, Ca2+, and Br-) was investigated by DPV (Figure 8A). The anodic current responses of PS: β-CD IC/Y2O3/GCE in the existence of a 50-fold excess concentration of Mg2+, SO4-, Cl-, Ca2+, Br-, DA, UA, AA, GLU, and CPZ were compared with current responses observed for 4-AAP and ACV. As can be seen in Figure 8B, no significant signals were obtained with the addition of all interfering compounds including DA, UA, and AA (

Polystyrene: Î²-Cyclodextrin Inclusion Complex Supported Y2O3

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