Materials Science & Engineering C 91 (2018) 64–77

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Materials Science & Engineering C

journal homepage: www.elsevier.com/locate/msec

Simultaneous determination of acetaminophen, pramipexole and T

carbamazepine by ZSM-5 nanozeolite and TiO2 nanoparticles modified
carbon paste electrode
⁎
Seyed Karim Hassaninejad-Darzi , Farshad Shajie
Department of Chemistry, Faculty of Basic Science, Babol Noshirvani University of Technology, Shariati Ave., Babol 47148-71167, Iran

A R T I C LE I N FO A B S T R A C T

Keywords: In this present paper, a simple voltammetric method has been reported for the simultaneous determination of
ZSM-5 nanozeolite acetaminophen (AC), pramipexole (PRX) and carbamazepine (CBZ) using ZSM-5 nanozeolite-TiO2 nanoparticles
TiO2 nanoparticles composite modified carbon paste electrode (ZSM-5/TiO2/CPE). X-ray diffraction (XRD), Fourier transform in-
Modified CPE frared spectroscopy (FTIR), field emission scanning electron microscopy (FESEM) and N2 adsorption-desorption
Acetaminophen
isotherm were used to characterize the structure of synthesized ZSM-5 nanozeolite. Also, cyclic voltammetry
Pramipexole
(CV), choronoamperometry and differential pulse voltammetry (DPV) were used to investigate the performance
Carbamazepine
Simultaneous determination of the modified electrode. The oxidation peak currents of AC, PRX and CBZ at the surface of ZSM-5/TiO2/CPE
were increased dramatically against CPE and their overpotentials decreased. Also, DPV method was used for the
simultaneous determination of three drugs in ternary mixture. The effects of modifier amount, pH and scan rate
were investigated on the electrochemical response of AC, PRX and CBZ oxidation. The diffusion coefficient, D,
and the catalytic rate constant, kcat, were estimated for the oxidation of AC, PRX and CBZ at the surface of
modified electrode. Under the optimized experimental conditions, AC, PRX and CBZ give linear response over
the range of 2.5–110, 0.6–105 and 6.0–97 μM, respectively. The detection limits were found to be 0.58, 0.38 and
1.04 μM (S/N = 3) for AC, PRX and CBZ, respectively. The fabricated electrode showed good stability, re-
producibility and repeatability as well as high recovery. The practical application of the modified electrode was
demonstrated by measuring the concentration of spiked AC, PRX and CBZ in human plasma as real sample. The
proposed method is simple, rapid and inexpensive and can be utilized as a valuable analytical tool in quality
control of the pharmaceutical industry.

1. Introduction chromatographic methods [3], mass spectrometry [4] and multivariate

Acetaminophen (N-acetyl-p-aminophenol, paracetamol) (scheme 1
in supplementary data), is a valuable drug in widespread use for pain
management and as antipyresis in a variety of patients, including
children, pregnant women, the elderly, those with fever, cold, os-
teoarthritis, simple headaches, non-inflammatory musculoskeletal
conditions [1]. AC acts as painkiller by inhibiting prostaglandin's
synthesis in the central nervous system and relieves fever by sedating
the hypothalamic heat-regulating center. Generally, the limited use of
AC is safe and has no harmful side effect. However, overdose or long-
term use of AC may cause adverse effects on health because of the
accumulation of toxic metabolites, which can lead to severe and
sometimes fatal hepatotoxicity and nephrotoxicity. Consequently, in
recent years different techniques have been used for the determination
of AC in a variety of matrices including UV–vis spectrophotometry [2],
calibration methods [5].
Pramipexole (PRX), (S)-4, 5, 6, 7-tetrahydro-N6-propyl-2, 6- ben-
zothiazolediamine (scheme 1 in supplementary data), is a new dopa-
minergic agonist used for the treatment of Parkinson's disease. It is an
effective drug used in the treatment of signs and symptoms of idiopathic
Parkinson's disease [6]. PRX used as an adjunct to antidepressants or
mood stabilizers, appeared to be effective and safe in the treatment of
unipolar and bipolar depression. The ability of PRX to alleviate the
signs and symptoms of Parkinson's disease is believed to be related to its
ability to stimulate dopamine receptors in the striatum. With the in-
creased use of the drug, its demand for analytical assay is growing [6].
Few analytical methods have been reported for the determination of
PRX that most methods are based on complex, expensive and time
consuming steps which include analysis of biological fluids using
spectrophotometric methods [7], GC-MS [8], UHPLC–MS/MS [9] and

⁎
Corresponding author.
E-mail address: hassaninejad@nit.ac.ir (S.K. Hassaninejad-Darzi).

https://doi.org/10.1016/j.msec.2018.05.022
Received 29 October 2017; Received in revised form 26 April 2018; Accepted 5 May 2018
Available online 07 May 2018
0928-4931/ © 2018 Elsevier B.V. All rights reserved.
S.K. Hassaninejad-Darzi, F. Shajie
electrophoresis [10] in pharmaceutical formulations.
Carbamazepine (CBZ), chemically known as 5H-dibenzo [b,f] aze-
pine-5-carboxamide, is a highly lipophilic neutral tricyclic compound
(see scheme 1). It is an anticonvulsant, antiepileptic and mood stabi-
lizing drug used primarily in the treatment of epilepsy and bipolar
disorder [11]. CBZ is usually administered daily as an oral dose ranging
from 200 to 1200 mg, which give rise to drug plasma levels of
4–12 mg L−1 [11]. However, CBZ can produce some adverse effects
such as neurotoxicity which leads to blurred vision, dizziness, impaired
task performance, hypersensitivity and leukopenia. The neurotoxicity
of CBZ is highly dependent on the dosage and notably, about 28% of the
orally administered CBZ is discharged to the environment through
feces. Therefore, it became important to develop and establish new,
fast, and accurate methodologies for the determination of this drug in
pharmaceutical preparations and biological samples. Some analytical
techniques such as HPLC [12], GC/MS [13], capillary electrokinetic
chromatography [14], chemiluminescence [15] and fluorescence po-
larization immunoassay [16] have been developed for the determina-
tion of CBZ in commercial formulations and human body fluids.
Most of the methods reported are highly sophisticated, costly, time
consuming and require special sample preparation and needs expensive
materials and apparatus. For these reasons, the rapid, simple and ac-
curate method is expected to be established. Among of different ana-
lytical methods, electroanalytical techniques have important ad-
vantages such as, high sensitivity, reasonable accuracy and precision,
and rapidity low detection limits, relative simplicity, low costs and
portable field based equipment for determination of biological mate-
rials [17,18]. These techniques are based on the direct oxidation or
reduction of substrate onto an electrode surface. Surely, the uses of
traditional electrodes for simultaneous determination of these com-
pounds still have a number of limitations. Hence, a wide variety of
modified electrodes have been developed to overcome this limitations
[19]. Because AC, PRX and CBZ are electroactive compounds, their
electrochemical quantifications have been reported and some modified
electrodes have been used to determine them. Hence, modified elec-
trodes have been widely used for electrochemical determination of
different compounds because modification of the electrode surfaces
significantly increases the sensitivity along with considerable decrease
in detection limit and interfering effects. Various modifiers have been
used for electrochemical detection of AC [20–25], PRX [26–30] and
CBZ [31–36] individually or simultaneously with other chemical drugs.
The development of techniques for the production of suitable ma-
terials will make it ready to implement and commercialize biosensors
based on different biological materials in many practical applications
[37]. On the other hands, nanostructure materials can decrease the
overpotential of the redox process of electroactive species due to their
large surface to volume ratio [19]. The arrival of materials in the
nanometer range has made it possible to use them as modifier in carbon
paste electrodes. Nano-TiO2 has a wide range of technological appli-
cations as gas sensors, photo and thermal catalysts, and photoelec-
trocatalysts due to its excellent chemical and photochemical stability,
non-toxicity, and capability for the photooxidative destruction of most
organic pollutants. Nano-TiO2 also has excellent physical and chemical
properties and has been used in coating, sensor, solar cell, and photo-
catalyst applications [38]. Zeolites are microporous crystalline alumi-
nosilicates with the ability to sort molecules according to size and shape
due to the molecular dimensions of its pore structure. Recently, there
has been a great deal of interest in the synthesis of nanocrystalline
zeolites, that is zeolites with discrete uniform crystals with dimensions
of < 100 nm. The zeolite nanoparticles are more efficient catalysts and
adsorbent materials because of their higher surface areas compared to
the conventional micron size zeolites. By reducing the particle size, the
diffusion path lengths will decrease and active sites will be accessible
readily [39]. ZSM-5 is a medium pore zeolite composed of ten tetra-
hedral rings with a pore dimension of 0.54–0.56 nm. Due to its unique
pore structure, ZSM-5 exhibits extremely high thermal and acid
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Materials Science & Engineering C 91 (2018) 64–77
stability, high selectivity and high activity in certain catalytic conver-
sions especially in the isomerization, alkylation and aromatization
processes [39].
Based on our knowledge, no attempt has been developed so far to
investigate the simultaneous determination of acetaminophen, prami-
pexole and carbamazepine by any analytical method. Compared with
conventional methods, simple enzyme-free electrochemical methods
have received vast interest in recent years due to their simplicity, rapid
response, low cost, more sensitivity and high selectivity. Hence, the
goal of this work was to develop a new, simple and sensitive electro-
chemical methodology for the simultaneous determination of these
drugs in pharmaceutical formulations and biological samples. The
electrochemical sensor was a carbon paste electrode modified with
ZSM-5/TiO2 nanocomposite.
2. Experimental
2.1. Reagents and materials
All utilized materials were of analytical reagent grade and used as
purchased without further purification. In order to synthesis the ZSM-5
nanozeolite, tetraethyl orthosilicate (TEOS, 98 wt%), aluminium iso-
propoxide (AIP) and tetrapropylammonium hydroxide (TPAOH, 40%
aqueous solution) were purchased from Merck company (Darmstadt,
Germany) and used as silicon source, aluminium source and template,
respectively. TiO2 nanoparticles (nanoparticles size ~ 21 nm, > 99.5%)
was purchased from Sigma-Aldrich company (USA) and used for pre-
paration of the modified electrode. High viscosity paraffin oil
(d = 0.88 g cm−3) and graphite powder from Daejung company (South
Korea) and diethyl ether from Merck company (Darmstadt, Germany)
were used to fabricate the carbon paste electrode. Carbamazepine
(> 99% purity), pramipexole dihydrochloride monohydrate (> 99%
purity), acetaminophen (> 99% purity) and acetonitrile (99.8%) in
analytical grades were obtained from Sigma-Aldrich company (USA).
Acetonitrile was used to dissolve CBZ powder and twice distillated
water was used to dissolve AC and PRX standards. Phosphoric acid
(H3PO4), potassium dihydrogen phosphate (KH2PO4), potassium hy-
drogen phosphate (K2HPO4) and potassium phosphate (K3PO4) were
purchased from Merck company (Darmstadt, Germany) and used to
prepare phosphate buffer solutions (0.1 M) in different pH values. The
biological samples were obtained from Blood Transfusion Organization
(Babol, Iran). Potassium chloride (KCl) and potassium ferricyanide
(K4Fe(CN)6) were prepared from Merck company (Darmstadt,
Germany). Tablets of AC (500 mg), CBZ (400 mg) and PRX (0.7 mg)
were purchased from local drug store. Stock solutions of 0.01 M AC,
PRX and CBZ were used for further preparation of the final solutions.
For this purpose, 0.1182 g CBZ was dissolved in 50 mL acetonitrile and
also 0.0755 g AC and 0.1056 g PRX were dissolved in 50 mL twice dis-
tillated water, separately.
2.2. Apparatus
The electrochemical measurements were carried out using po-
tentiostat/galvanostat electrochemical analyzer (SAMA500, Iran) with
a conventional three electrode cell using carbon paste electrode (CPE)
and modified CPE as working electrode, Ag|AgCl|KCl (3 M) as reference
electrode (Azar electrode, Iran) and Pt wire as counter electrode (Azar
electrode, Iran). All experiments were carried out in phosphate buffer
solution (0.1 M) at room temperature. A pyrex-glass reactor with a re-
flux system, a magnetic stirrer with hot plate (Ghatran shimi tajhiz,
Iran), a rotary evaporator (Heidolph, Germany), and an electric furnace
(Fater electronic, Iran) were used to the synthesis of ZSM-5 nanozeolite.
FT-IR spectrum were recorded on a Varian 640 FTIR instrument
(Mintek Co., South Africa) with a resolution of 4 cm−1 using the KBr
wafer technique. The X-ray diffraction (XRD) patterns were obtained
using a Maxima-XRD-7000 powder diffractometer (Shimadzu, Japan)
S.K. Hassaninejad-Darzi, F. Shajie Materials Science & Engineering C 91 (2018) 64–77

using Cu Kα radiation (40 kV, 30 mA). The micropore volumes pore

diameter and external surface areas of the samples were calculated
using the BET method based on N2 adsorption isotherms
(Micromeritics-Tristar-3000,USA). Morphology and crystals size of the
synthesized zeolite were examined by field emission scanning electron
microscopy (FESEM) using a scanning electron microscope (MIRA3 XM
TESCAN, Czech Republic). A digital Huna pH-meter (Padova, Italy) was
used to read the pH of the buffered solutions.

2.3. Synthesis of ZSM-5 nanozeolite

Nanosized zeolite was prepared according to a modified procedure

that reported previously by J. Aguado et al. [40]. The AIP was added to
an aqueous solution of TPAOH and the mixture was stirred at 0 °C to
obtain a clear solution. Then, TEOS was added to the above mixture and
the final mixture was stirred at room temperature for several hours to
hydrolyze TEOS completely. Afterward, the alcohols formed were re-
moved by vacuum heating at 40 °C. The molar composition of the ob-
tained clear supersaturated solution was as follows: Al2O3: 60 SiO2: 11
TPAOH: 900 H2O. The mixture were crystallized in a polyteflon vessel
with a reflux system under stirring (100 rpm). Crystallization time was
190 h and the synthesis took place at a temperature of 90 °C. The ob-
tained solid product was separated by centrifugation, washed several
time with distilled water, dried overnight at 110 °C and calcined in air
at 550 °C for 5 h.

2.4. Preparation of the modified electrode

For fabrication of the modified electrode, the percentage of the

ZSM-5 nanozeolite and TiO2 nanoparticles in the modified electrode
were optimized. For this purpose, several modified electrodes were
prepared with different percent of the ZSM-5 and TiO2 in the presence
of graphite powder and paraffin oil (35% wt) by hand mixing in an
agate mortar to get homogeneous carbon paste. The paste was then
packed into one end of a glass tube (ca. 0.35 cm i.d. and 10 cm long)
and pressed tightly. A copper wire was inserted through the opposite
end to establish an electrical contact. Prior to experiment, the surface of
the prepared electrode was polished with fine paper. The unmodified
electrode were prepared in the same way without adding any modifier
and using only graphite powder and paraffin oil (bare CPE).
2.5. Preparation of the real samples
Then tablets of each drug (500 mg AC per each tablet, labeled
400 mg CBZ per each tablet and labeled 0.7 mg PRX per each tablet)
were weighed for obtaining the average mass of each tablet. Then ta-
blets were completely ground and homogenized, and an amount of one
tablet of each drug was transferred to a 50 mL beaker and dissolved in
its solvent and shaken well for 10 min. Then, the solution was cen-
trifuged and quantitatively diluted with the selected supporting elec-
trolyte (phosphate buffer solution, pH = 5.0) in a 50 mL volumetric
flask. Serum samples were obtained and stored frozen until the analysis.
For preparation of serum samples, 5 mL of each sample was diluted to
50 mL by phosphate buffer solution (pH = 5.0). Then, 20 mL of this
solution was transferred to the voltammetric cell without any further
pretreatment and different amounts of AC, PRX and CBZ from standard
solution and tablet solutions were added. The content of the drug in the
tablet and recovery was determined by DPV technique and referring to
the regression equations of each drug. The recovery percentages were
calculated to examine the accuracy of the proposed method.
3. Results and discussion
3.1. Characterization of the synthesized ZSM-5 nanozeolite
The synthesized ZSM-5 zeolite was characterized by means of
Fig. 1. Representation of (A) XRD pattern and (B) FT-IR spectrum of synthe-
sized ZSM-5 nanozeolite.
conventional techniques such as powder X-ray diffraction (XRD),
Fourier transform infrared spectroscopy (FTIR), N2 ad-
sorption–desorption isotherm, field emission scanning electron micro-
scopy (FESEM) and energy dispersive X-ray (EDX) techniques. XRD
pattern of synthesized zeolite is shown in Fig. 1A. The intense peaks can
be observed at 2θ = 8.26°, 9.21°, 23.48° and 23.66°, which confirm the
synthesis of pure phase of ZSM-5 zeolite [39]. It must be emphasized
that when TEOS was used as the silicon source, it can be hydrolyzed and
produce alcohol which was evidenced to have structure directing effect
on the formation of ZSM-5 nanozeolite [39]. The crystallite size (L) of
the synthesized ZSM-5 nanozeolite was also calculated using Debye-
Scherrer equation [41]:
0.9 λ
L=
β cos θ (1)
where λ is the wavelength of the X-ray source used in XRD instrument
(0.15418 nm), β is the breadth of the observed diffraction line at its
half- intensity maximum in radian and θ is the main Bragg peak angle
(2θ = 8.26°). According to the obtained results from XRD pattern, the
crystallite size of ZSM-5 nanozeolite was found to be about 50.6 nm.
Fig. 1B illustrates FT-IR spectrum of synthesized ZSM-5 nanozeolite.
The bands located at 1070–1230 cm−1 are characteristic of SiO4 tet-
rahedron units [39]. The absorption bands at 1230 and 551 cm−1
supply information on the difference between ZSM-5 nanozeolite and
other types of zeolites. The external asymmetric stretching vibration
near 1230 cm−1 is due to the presence of structures containing four
chains of four member rings between SiO4 and AlO4 tetrahedral of ZSM-
5 structure and is a structure sensitive IR band of ZSM-5 zeolite [39].
The bands near 1100 cm−1 and 800 cm−1 are due to the internal

66
S.K. Hassaninejad-Darzi, F. Shajie
Fig. 2. (A) FESEM images and (B) nitrogen adsorption (open symbols) and
desorption (solid symbols) isotherms at 77 K for synthesized ZSM-5 nanozeolite.
asymmetric stretching and external symmetric stretching of external
linkages, respectively [42]. Also, the band at about 551 cm−1 is at-
tributed to a structure-sensitive vibration caused by the double four
member rings of the external linkages and the band near 445 cm−1 is
ascribed to the SieO and AleO bending vibration due to the formation
of only ZSM-5 crystal [42].
Fig. 2A shows FESEM image of the synthesized ZSM-5 nanozeolite.
As can be seen, the sample exhibits a good uniform crystalline mor-
phology with the particle size under 100 nm. This leads to increase
catalyst surface and improve process performance due to better trans-
port phenomena such as diffusion. Also, the obtained data from the EDX
spectrum of the ZSM-5 nanozeolite demonstrates that oxygen (57.85 wt
%), silicon (38.63 wt%) and aluminium (3.52 wt%) are presented on
the structure of the synthesized ZSM-5 sample.
Fig. 2B illustrates the N2 adsorption-desorption isotherms of the
nanocrystalline ZSM-5 sample at 77 K. The hysteresis loop of nitrogen
observes at very high relative pressure (P/P0 = 0.9–1.0) related to the
capillary condensation in inter-crystalline macropores created by
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Materials Science & Engineering C 91 (2018) 64–77
agglomeration of small particles [43]. It can be seen that ZSM-5 na-
nozeolite possess both micro-and mesoporous features. The adsorption
at low relative pressures (P/P0 < 0.05) corresponds with the micro-
spore filling of the ZSM-5 nanozeolite. The textural properties of the
synthesized ZSM-5 nanozeolite are indicated that small ZSM-5 crystal
has high BET surface area (636.1 m2 g−1) and total pore volume
(0.376 cm3 g−1). Also it has micropore volume of 0.146 cm3 g−1 and
average pore diameter of 2.36 nm from BJH method.
3.2. Characterization of the modified electrodes
FESEM images were used to ensure that the combination of ZSM-5
nanozeolite and TiO2 nanoparticles causes to increase electrocatalytic
activity of ZSM-5-TiO2/CPE. Fig. 3A, B, C and D show the FESEM mi-
crographs of bare CPE, 15%TiO2/CPE, 15%ZSM-5/CPE and 15%ZSM-
5/15%TiO2/CPE, respectively. As can be seen in Fig. 3A, the layer of
irregular flakes of graphite powder was present and isolated from each
other on the surface of CPE while as shown in Fig. 3B and C, TiO2
nanoparticles and ZSM-5 nanozeolite were completely distributed on
the surface of 15%TiO2/CPE and 15%ZSM-5/CPE, respectively. Com-
paring of Fig. 3B, C and D demonstrates the simultaneously presence of
TiO2 and ZSM-5 on the surface of 15%ZSM-5/15%TiO2/CPE. Also,
Fig. 3E and F shows the EDX spectrum and elemental analysis of 15%
ZSM-5/15%TiO2/CPE, respectively. Observation of intensive peaks re-
lated to the electron transmissions of carbon, oxygen, aluminium, si-
licon and titanium demonstrates the presence of TiO2 nanoparticles and
ZSM-5 nanozeolite between layers of graphite.
Real surface area of the CPE, 15%TiO2/CPE, 15%ZSM-5/CPE and
15% ZSM-5/15% TiO2/CPE were obtained by cyclic voltammetry (CV)
technique using 1.0 mM potassium ferricyanide (K4Fe(CN)6) as a probe
at different scan rates (Fig. 1S). For a reversible process, the Randles-
Sevcik formula has been used [37]:
3 1 1
Ipa = 2.69 × 105n 2ADR 2 C0 υ 2
(2)
2
where Ipa (A) refers to the anodic peak current, A (cm ) is the active
surface area of the electrode, C0 (mol cm−3) is the concentration of
K4Fe(CN)6, F is Faraday's constant (96,485C mol−1), R is the universal
gas constant (8.314 J mol−1 K−1), T is the absolute temperature
(298 K), n is the number of electron in redox process, DR (cm2 s−1) is
diffusion coefficient and υ (V s−1) is the scan rate. For 1.0 mM K4Fe
(CN)6 in 0.1 M KCl as supporting electrolyte the amount of n and DR is 1
and 7.6 × 10−6 cm2 s−1, respectively [44]. So, the real surface area of
these electrodes were obtained from the slopes of Ipa - υ1/2 relation
according Randles-Sevcik formula. Therefore, the real surface areas
were found to be 0.084, 0.326, 0.390 and 0.473 cm2 for the bare CPE,
15%TiO2/CPE, 15%ZSM-5/CPE and 15%ZSM-5/15%TiO2/CPE, re-
spectively. This means that the surface area for the 15%ZSM-5/
15%TiO2/CPE is 5.6 times as great as that for the bare CPE.
3.3. Optimization of pH and amount of the modifier
Since in majority of the electrochemical studies, amount of modifier
and pH of the buffer solution can have a direct impact on the electro-
chemical reaction of species and voltammetry response of them. Then,
these two important factors must be studied and optimal condition must
be obtained before any real analysis. For this purpose, twelve electrodes
with different percentages of modifiers consisting of bare CPE, 10%
ZSM-5/CPE, 15%ZSM-5/CPE, 20%ZSM-5/CPE, 10%TiO2/CPE,
15%TiO2/CPE, 20%TiO2/CPE, 10%ZSM-5/10%TiO2/CPE, 15%ZSM-5/
15%TiO2/CPE, 20%ZSM-5/20%TiO2/CPE, 15%ZSM-5/7.5%TiO2/CPE
and 20%ZSM-5/15%TiO2/CPE were fabricated and used in different pH
of phosphate buffer solutions (pH = 3–13) in order to simultaneous
determination of constant concentrations of AC, PRX and CBZ using
differential pulse voltammetry method. The results showed that the
peak potential of AC, PRX and CBZ depended on the pH value of the
S.K. Hassaninejad-Darzi, F. Shajie
Fig. 3. FESEM micrographs of (A) bare CPE, (B) 15%TiO2/CPE, (C) 15%ZSM-5/CPE and (D) 15%ZSM-5/15%TiO2/CPE. (E) EDX spectrum and (F) elemental percent
from EDX spectrum of 15%ZSM-5/15%TiO2/CPE.
buffer solution and percent of ZSM-5 and TiO2 nanoparticles on the
structure of modified CPE. Figs. 2S, 3S, 4S, 5S, 6S and 7S demonstrate
CV of all above electrodes for the electro-oxidation of AC, PRX and CBZ
in pH value of 3, 5, 7, 9, 11 and 13, respectively. It should be noted that
the written currents in the all figures are corrected currents that ob-
tained from differences between faradic and non-faradic currents. So
there may be an electrode that has the current peak higher than other
electrodes but it was not selected as the best electrode because of the
higher background.
According to the Fig. 2S at pH = 3, all fabricated electrodes are able
to make the simultaneous responses for three drugs, but there is no
electrode with the ability to create the maximum currents for three
drugs and only 20%ZSM-5/20%TiO2/CPE has the maximum currents in
two peaks corresponding to the AC and PRX. So, this electrode was
selected as the best electrode in pH = 3. Also, at pH = 5 in Fig. 3S, all
fabricated electrodes are able to make three simultaneous peaks and
15%ZSM-5/15%TiO2/CPE has the best response due to highest currents
for all drugs. As can be seen in Fig. 4S at pH = 7, some electrodes were
failed the ability for simultaneous detection of all drugs and anodic
peak currents of them were decrease. In this pH, the 20%ZSM-5/CPE
has the maximum peak currents and best response for all drugs. At
pH = 9 (Fig. 5S), only four electrodes are able to make three simulta-
neous peaks and the 15%TiO2/CPE has the best response because of
maximum oxidation currents in two locations corresponding to the PRX
and CBZ drugs. Also, Fig. 6S shows that at pH = 11 only five electrodes
68
Materials Science & Engineering C 91 (2018) 64–77
are able to make three simultaneous peaks and the 15%ZSM-5/
7.5%TiO2/CPE has the best response because of the maximum oxida-
tion currents in two peaks corresponding to the PRX and CBZ drugs. At
pH = 13 in Fig. 7S, just five electrodes can detect all three drugs and
the 20%TiO2/CPE has the best function due to create highest currents.
Finally, selected electrodes of different pHs were compared with each
other in order to choosing the best electrode and optimal pH for further
experiments (see Fig. 8S). As can be seen in Fig. 8S, there is no electrode
can make highest currents for all three drugs in comparison with other
electrodes. However, 15%ZSM-5/15%TiO2/CPE at pH = 5 has the best
detection ability among electrodes due to highest currents for PRX and
CBZ. Also there is only slight difference between oxidation current for
AC by 15%ZSM-5/15%TiO2/CPE at pH = 5 and maximum current
created by 20%ZSM-5/20%TiO2/CPE at pH = 3. As a result, 15%ZSM-
5/15%TiO2/CPE modified electrode and pH of 5.0 (phosphate buffer
solution, 0.1 M) were selected as the best electrode and optimal pH for
simultaneous determination of AC, PRX and CBZ drugs for further
study. In the next sections, the 15%ZSM-5/15%TiO2/CPE was written
as ZSM-5/TiO2/CPE.
3.4. Cyclic voltammetry behaviors of AC, PRX and CBZ at the surface of
ZSM-5/TiO2/CPE
The electrochemical behavior of AC, PRX and CBZ in phosphate
buffer solution of pH 5.0 was investigated by cyclic voltammetry (CV)
S.K. Hassaninejad-Darzi, F. Shajie
Fig. 4. (A) Cyclic voltammograms of ZSM-5/TiO2/CPE in the blank solution
(phosphate buffer solution solution, 0.1 M, pH = 5.0) and in the presence of
0.1 mM AC, 0.3 mM PRX and 0.1 mM CBZ, separately. (B) Cyclic voltammo-
grams of the above solution at bare CPE. (C) Cyclic voltammograms of (a, b)
CPE and (c, d) ZSM-5/TiO2/CPE; (a, c) in the blank solution and (b, d) in the
presence of 0.1 mM AC, 0.3 mM PRX and 0.1 mM CBZ simultaneously. (Scan
rate in all cases was 40 mV s−1).
method. Fig. 4A shows the cyclic voltammograms of 0.1 mM AC,
0.3 mM PRX and 0.1 mM CBZ at the surface of ZSM-5/TiO2/CPE in
phosphate buffer solution of pH 5.0 and scan rate of 40 mV s−1, sepa-
rately. Also, similar cyclic voltammograms are shown in Fig. 4B at the
surface of bare CPE. As shown in Fig. 4B, a small irreversible oxidation
peak was observed for AC at the surface of bare CPE. Meanwhile, the
anodic and cathodic peaks were appeared at 0.59 and 0.45 V on the
surface of ZSM-5/TiO2/CPE (see Fig. 4A). The appearance of the re-
versible redox peaks indicates that modification of CPE by ZSM-5/TiO2
nanocomposite can significantly accelerate the oxidation reaction pro-
cess. As can be observed in Fig. 4A and B, the anodic peak potential of
AC at the ZSM-5/TiO2/CPE surface in the presence of AC occurs at
0.59 V, which is approximately 0.24 V more negative than the obtained
value at the bare CPE (0.83 V), and this anodic peak current was en-
hanced by approximately 2.7-fold respect to CPE. It can be concluded
69
Materials Science & Engineering C 91 (2018) 64–77
that over potential for the oxidation of AC was decreased at the surface
of modified electrode [25]. Also, the irreversible behavior of electro-
chemical reactions of AC at the bare CPE indicates the sluggish electron
transfer kinetics of this drug at bare CPE, which may be related to
electrode fouling caused by deposition of it and their oxidation products
on the surface of bare CPE [45].
As can be seen in Fig. 4A and B, no reduction peak was observed in
the voltammograms of PRX which reflects the irreversibility of elec-
trode reaction [28]. An anodic signal for PRX oxidation was obtained
with the peak current of 65 μA in bare CPE while, the oxidation peak
current was obtained 197 μA at the surface of ZSM-5/TiO2/CPE. Then,
the anodic peak current of PRX at ZSM-5/TiO2/CPE surface was en-
hanced by approximately 3-fold with respect to the bare CPE. The
anodic voltammetric signals can be ascribed to the oxidation of −NH
group [29]. The higher electrocatalytic behavior of the modified elec-
trode corresponds to the presence of a larger number of electrochemical
active sites and decrease in the charge transfer resistance in the ZSM-5/
TiO2/CPE rather than in the bare CPE. Comparison of CBZ oxidation at
the bare CPE and modified electrode in Fig. 4A and B demonstrates that
anodic peak current of CBZ at ZSM-5/TiO2/CPE was strongly enhanced
respect to that at bare CPE. The CBZ displays an irreversible behavior at
CPE surface with a broad and very weak oxidation peak around 1.32 V;
meanwhile it exhibited a well-defined and very intense irreversible
oxidation peak at about 1.25 V on the surface of ZSM-5/TiO2/CPE, with
no additional post-peak in the forward scan or counterpart peak in the
reverse scan. This indicates the irreversibility nature of electrochemical
oxidation of CBZ at the surface of the two electrodes [34]. Also, the shift
of the peak potential to lower anodic potentials and the peak current
improvement at ZSM-5/TiO2/CPE surface with respect to that at bare
CPE, reflects the decrease of the overpotential for this anodic reaction
and the enhancement of the electron transfer between the CBZ molecule
and the modified electrode. These can be ascribed to the strong ad-
sorptive ability and electrocatalytic surface properties of the ZSM-5/
TiO2 nanocomposite.
Fig. 4C shows cyclic voltammograms of bare CPE and ZSM-5/TiO2/
CPE in the phosphate buffer solution (0.1 M, pH = 5.0) in the absence
and presence of 0.1 mM AC, 0.3 mM PRX and 0.1 mM CBZ, simulta-
neously. As can be seen in Fig. 4C (curves a and c), no faradic current
can be obtained with the electrodes in the absence of drugs but it can be
seen that the background current of the modified electrode is more than
that in bare CPE. This can be attributed to the oxidation–reduction
process of oxygen species in the nanozeolite. Furthermore, the addi-
tional resistance obtained from the presence of ZSM-5 nanozeolite on
the electrode surface cannot be excluded. These two reasons led to the
inclination of the baseline of the voltammogram [46]. As can be ob-
served in Fig. 4C (curves b and d), a rather low redox signal of AC, PRX
and CBZ was obtained on the bare CPE surface while the values of the
anodic peak currents for these three compounds at ZSM-5/TiO2/CPE
were about 3-fold higher than those at the bare CPE. In addition, no
reduction peak was observed at the bare CPE for AC while a reduction
peak was appeared using ZSM-5/TiO2/CPE. These indicate that the
concomitant usage of ZSM-5 nanozeolite and TiO2 nanoparticles in-
creases the catalytic activity and electron transfer ability of the mod-
ified electrode and consequently increase the sensitivity and resolution
of the analytical signal.
3.5. Influence of pH
As the protons took part in the electrode reaction process of AC, PRX
and CBZ, pH of the phosphate buffer solution is very important for
detection of these species. Therefore, the current responses and oxida-
tion potentials of these compounds at ZSM-5/TiO2/CPE were in-
vestigated in the pH range from 3.0 to 13.0 by using DPV method. As
can be seen in Fig. 5A, by increasing pH, the oxidation potentials for
AC, PRX and CBZ became more negative suggesting involvement of
protons in the electrochemical reaction [47]. The relationships between
S.K. Hassaninejad-Darzi, F. Shajie
Fig. 5. Effect of pH on the (A) anodic peak potential and (B) anodic peak
current for the oxidation of 0.1 mM AC, 0.3 mM PRX and 0.1 mM CBZ at the
surface of ZSM-5/TiO2/CPE at scan rate of 40 mV s−1.
the potentials and pH were linear, and the regression equations were
given in Fig. 5A.
The slope values of −0.0564 V pH −1 for AC and − 0.0645 V pH −1
for PRX obtained from the plots of Epa versus pH displayed the parti-
cipation of an equal number of protons and electrons in the electrode
process because these values are very close to the anticipated Nernstian
value of −0.059 V for electrochemical processes [47]. These conclu-
sions are in accordance with the mechanisms of electrochemical reac-
tions of these drugs as reported in the literatures for AC [48] and PRX
[29]. Also, in the pH range of 3.0–13.0, the Epa varies linearly with pH,
with a negative slope of 0.0269 V pH −1. This indicates that the number
of protons released from the CBZ molecule in this anodic process, seems
to be half the number of electrons transferred to the electrode [34,49].
This is in agreement with the suggested mechanism by Kalanur and
Seetharamappa [49], since four electrons and two protons are involved,
when one dicationic radical dimer is produced (see mechanism in
Fig. 6B). On the other hand, the effect of pH on the anodic peak current
of AC, PRX and CBZ within the pH range 3.0–13.0 was investigated and
displayed in Fig. 5B. As can be observed in this fig., the peak currents
were maximum at pH = 5.0 for all three drugs. This is consistent with
results obtained from the previous section and then the pH = 5.0 was
used for further study.
3.6. Differential pulse voltammetry behaviors of AC, PRX and CBZ
Electrochemical behaviors of ZSM-5/TiO2/CPE towards AC, PRX
and CBZ were studied using differential pulse voltammetry (DPV)
70
Materials Science & Engineering C 91 (2018) 64–77
technique. Fig. 6A displays DPVs of CPE and ZSM-5/TiO2/CPE in the
blank solution (phosphate buffer solution, 0.1 M, pH = 5.0) and in the
presence of 80 μM AC, PRX and CBZ simultaneously at scan rate of
50 mV s−1. As can be seen in Fig. 6A (curves a and c), no faradic current
can be obtained with the electrode in the absence of drugs. Also, curves
b and d in Fig. 6A illustrate that a rather low redox signal of AC, PRX
and CBZ was obtained on the bare CPE surface while the values of the
anodic peak currents for these compounds at ZSM-5/TiO2/CPE were
very higher than those at the bare CPE. The separation of the oxidation
peak potentials for AC–PRX and PRX–CBZ are about 310 and 320 mV,
respectively. Then, all three compounds are oxidized with well-defined
and distinguishable sharp peak potentials at ZSM-5/TiO2/CPE. The
catalytic role of ZSM-5 and TiO2 for AC and CBZ are stronger than that
of PRX. Result indicated that the simultaneous application of ZSM-5
nanozeolite and TiO2 nanoparticles increases the catalytic activity of
the modified electrode and therefore increase the sensitivity and re-
solution of the analytical signal.
3.7. Effect of scan rate
The effect of scan rate (υ) on the anodic peak current of AC, PRX and
CBZ was studied at the ZSM-5/TiO2/CPE surface by cyclic voltammetry
at different scan rates in the phosphate buffer solution of pH 5.0. Figs. 7,
8 and Fig. 9S displays this effect for 0.1 mM AC, 0.3 mM PRX and
0.1 mM CBZ, respectively. The results indicated that the peak currents
of all three compounds are linearly with the square root of scan rate
(Figs. 7B, 8B, and 9S(B)), meanwhile there is no linear relationship
between anodic peak currents and scan rate (Figs. 7C, 8C and 9S(C)),
which confirm the diffusion-controlled process for electrooxidation of
three drugs on the surface of ZSM-5/TiO2/CPE in the studied range of
potential scan rates [50].
The effect of scan rate on the peak potentials of AC, PRX and CBZ
electrooxidation was also investigated on the surface of ZSM-5/TiO2/
CPE. Fig. 7D shows that Ep is proportional to the logarithm υ at high
scan rates for AC. As can be seen in Fig. 7A, electrooxidation of AC is
reversible. The total electron transfer coefficient of reaction (α) is es-
timated using averaging αa and αc for anodic and cathodic peaks, re-
spectively. The slopes of the plots in Fig. 7D can be used to extract the
kinetic parameters αc and αa. The slopes of the linear segments are
equal to 2.303RT/(1–α)nF and –2.303RT/αnF for the anodic and
cathodic peaks, respectively [21]. Based on Fig. 6B, the number of
electrons involved in the electrode reaction of AC is two. The mean
value of α is found to be 0.51 indicating rate limiting steps for cathodic
and anodic might be the same step (αa = 0.8336, αc = 0.1841). Also,
Eq. (3) can be used to determine the electron transfer rate constant
between the modifier (ZSM-5/TiO2) and AC [51]:
RT α (1 − α ) nF ΔEp ⎞
log k s = α log(1 − α ) + (1 − α ) log α − log ⎛ ⎞−⎛ ⎜ ⎟
⎝ nFυ ⎠ ⎝ 2.303RT
⎠
(3)
where α = 0.51, and all other symbols have their conventional mean-
ings. The mean value of ks was calculated to be 0.0075 s−1 for AC.
The electrochemical kinetic parameters, the number of electrons
transferred (n), electron transfer coefficient (α) and the rate of the re-
action (ks) were evaluated by subjecting the scan rate results to the
Laviron equation (Eq. (4)) for irreversible reaction [51].
RT RTk s ⎞ RT
E p = E0 − ⎛ ⎞ ln ⎛ +⎛ ⎞ ln v
⎝ αnF ⎠ ⎝ αnF ⎠ ⎝ αnF ⎠ (4)
0
where E is the formal potential, n is the number of electrons trans-
ferred, α is the electron transfer coefficient and ks is the standard rate
constant of the electrode reaction. As shown in Fig. 9S(A) and Fig. 8A,
the electrooxidation of PRX and CBZ at the surface of ZSM-5/TiO2/CPE
are irreversible. For an irreversible oxidation reaction, the values of ks
and αn are deduced from the intercept and the slope of the linear plot of
S.K. Hassaninejad-Darzi, F. Shajie Materials Science & Engineering C 91 (2018) 64–77

Fig. 6. (A) DPVs of (a, b) CPE and (c, d) ZSM-5/TiO2/CPE; (a, c) in the blank solution (phosphate buffer solution, 0.1 M, pH = 5.0) and (b, d) in the presence of
80 μM AC, PRX and CBZ, simultaneously (Scan rate = 50 mV s−1). (B) Mechanism for oxidation of AC, PRX and CBZ at ZSM-5/TiO2/CPE.

Fig. 7. Cyclic voltammograms recorded on the ZSM-5/TiO2/CPE in the presence of 0.1 mM AC in 0.1 M phosphate buffer solution at various scan rates from inner to
outer: 10, 20, 40, 50, 75, 100, 150, 200, 250, 300, 350, 400, 450 and 500 mV s−1. Plots of (B) Ipa vs. υ1/2, (C) Ipa vs. υ and (D) Ep vs. log υ.

71
S.K. Hassaninejad-Darzi, F. Shajie
Fig. 8. Cyclic voltammograms recorded on the ZSM-5/TiO2/CPE in the presence of 0.1 mM CBZ in 0.1 M phosphate buffer solution at various scan rates from inner to
outer: 20, 40, 50, 60, 75, 100, 125, 150, 200, 250 and 300 mV s−1. Plots of (B) Ipa vs. υ1/2, (C) Ipa vs. υ, (D) Epa vs. log υ and (E) Epa vs. υ.
Epa vs. log υ, when the value of E0 was known [26]. The values of E0 for
PRX and CBZ at the surface of ZSM-5/TiO2/CPE were obtained from the
intercept of the plot of Epa vs. υ (see Figs. 9S(E) and 8E, respectively).
Then, the values of E0 was obtained to be 1.17 and 1.3591 for PRX and
CBZ, respectively. From the slope and the intercept of the plot of Epa vs.
log υ (see Fig. 9S(D)), the values of αn and ks for PRX were calculated to
be 0.898 and 2.8757 s−1, respectively. By the same calculation, the
values of αn and ks for CBZ were found to be 1.10 and 2.0976 s−1,
respectively (see Figs. 8D). Since, for a totally irreversible electron
transfer reaction, α is assumed to be 0.5 [52], the value of n for PRX and
CBZ electrooxidation were calculated to be 1.796 and 2.20, respec-
tively. This indicated that two electrons have taken part in the irre-
versible oxidation step of both of them consistent with Fig. 6B.
3.8. Chronoamperometric measurements
Chronoamperometric measurements of AC, PRX and CBZ at ZSM-5/
TiO2/CPE were carried out by setting the working electrode potential at
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Materials Science & Engineering C 91 (2018) 64–77
0.59 V for AC, 1.0 V for PRX and 1.25 V for CBZ vs. Ag|AgCl|KCl (3 M)
for various concentrations of them in phosphate buffer solution
(pH 5.0). Fig. 9, Figs. 10S and 11S exhibit chronoamperograms of redox
process recorded for AC, PRX and CBZ, respectively. For an electro-
active material with a diffusion coefficient, D, the current observed for
the electrochemical reaction under mass transport-limited conditions
can be described by the Cottrell Eq. [53]:
1 −1 −1
I = nFAcD 2 . π 2. t 2 (5)
where n is the number of electron (i.e., 2), F is the Faraday number
(96,485C mol−1), A is the area of the electrode (0.0962 cm2), C is the
known concentration of analyte and D is the diffusion coefficient. Ex-
perimental plots of I vs. t–1/2 for AC were plotted and the best fits for
different concentrations of it were determined (see Fig. 9B). The slope
of the resulting lines was then plotted vs. concentration of AC (Fig. 9C).
From the resulting slope and Cottrell equation, the mean value of D was
found to be 8.9 × 10−5 cm2 s−1 for AC. The same curves were plotted
for PRX and CBZ and the mean values of D was calculated to be
S.K. Hassaninejad-Darzi, F. Shajie
Fig. 9. (A) Chronoamperograms obtained at ZSM-5/TiO2/CPE in the phosphate buffer solution (pH 5.0) for various concentration of AC: (a) 0.0, (b) 0.1, (c) 0.2, (d)
0.3 and (e) 0.4 mM. The potential step was 0.59 V vs. Ag|AgCl|KCl (3 M). (B) Dependence of I on t−1/2, (C) plot of the slope of straight lines vs. AC concentration and
(D) Dependency of Icat/IL on t1/2 for all concentrations.
3.0 × 10−4 and 1.06 × 10−4 cm2 s−1 for PRX and CBZ, respectively
(see Figs. 10S and 11S).
Chronoamperometry can be used to evaluate the catalytic rate
constant, kcat, for the reaction between drugs and ZSM-5/TiO2/CPE
according to the method of Galus according to the following equation
[53]:
Icat 1 1
= (πkcat c0 ) 2 t 2
IL
where, Icat and IL are the currents in the presence and absence of analyte
at ZSM-5/TiO2/CPE, respectively. The c0 is the bulk concentration of
each drugs (mol cm−3) and t is the elapsed time (s). Plots of Icat/IL with
respect to the square root of time (t1/2) presented a linear dependency
for all drugs. From the slopes of the Icat/IL vs. t1/2 for all concentrations,
the average value of kcat was obtained to be 3 × 106 cm3 mol−1 s−1 for
AC (see Fig. 9D). The similar curves were plotted for PRX and CBZ and
the average value of kcat was found to be 1.30 × 105 and
4.25 × 105 cm3 mol−1 s−1 for PRX and CBZ, respectively (see Figs. 10S
and 11S).
3.9. Simultaneous DPV determinations of AC, PRX and CBZ
The next attempt was made to detect AC, PRX and CBZ simulta-
neously by using the ZSM-5/TiO2/CPE and the linear dynamic ranges
and limits of detection were obtained using DPV method. This method
Materials Science & Engineering C 91 (2018) 64–77
was performed by simultaneously changing the concentrations of all
three drugs, and recording the DPVs. If the concentrations of all drugs
increased synchronously, the peak currents increase accordingly as
shown in Fig. 10A. It can be seen that the peak currents for all drugs
increased linearly with their concentrations (see 10B, 10C and 10D for
AC, PRX and CBZ, respectively). Results displays that the slopes of the
Ipa vs. concentrations of these drugs were found to be 0.2453 μA μM−1
in the range of 2.5–110.0 μM for AC; 0.2095 μA μM−1 in the range of
(6)
0.6–105.0 μM for PRX and 0.2838 μA μM−1 in the range of 6.0–97.0 μM
for CBZ. The limit of detection (LOD) and limits of quantification (LOQ)
values were calculated following the methods reported by Shrivastava
and Gupta [54]. The LOD and LOQ of each drugs was calculated using
the typical equations: LOD = 3 s/m and LOQ = 10s/m (where s is the
standard deviation of the peak currents of the blank (five runs) and m is
the slope of the calibration curve for each drugs according Fig. 10B, C
and D. The LODs were found to be 0.58, 0.38 and 1.04 μM, for AC, PRX
and CBZ, respectively. Also, the LOQs were obtained to be 1.93, 1.27
and 3.47 μM, for AC, PRX and CBZ, respectively. For comparison, the
most important reported electrochemical methods for the determina-
tion of AC, PRX and CBZ are summarized in Table 1. The results showed
that ZSM-5/TiO2/CPE is suitable for sensitive, selective and simulta-
neous determination of AC, PRX and CBZ. Also, the lower values of LOD
and broader linear range by ZSM-5/TiO2/CPE are comparable with
values reported by other research groups for electrocatalytic oxidation
of AC, PRX and CBZ at the surface of chemically modified electrode by
73
S.K. Hassaninejad-Darzi, F. Shajie
Fig. 10. (A) DPVs ZSM-5/TiO2/CPE for various concentrations of AC, PRX and CBZ in the mixed solution (from inner to outer): 2.5, 15, 45, 55, 70, 90, 100 and
110 μM of AC; 0.6, 13, 21, 35, 50, 65, 85 and 105 μM of PRX and 6, 30, 35, 45, 60, 80, 85 and 97 μM of CBZ. Plots of the peak currents as a function of the (B) AC, (C)
PRX and (D) CBZ concentration.
other mediators.
3.10. Effect of interferences
The ZSM-5/TiO2/CPE sensor is proposed for determination of AC,
PRX and CBZ in biological samples, so interfering effect of the presence
species in biological compounds must be investigated. This study was
performed by recording the DPVs (n = 5) of 15 μM AC, PRX and CBZ in
the mixed solution and presence of 150 μM of each of the interfering
substance at the ZSM-5/TiO2/CPE surface. For each voltammetric
measurement (in the absence and presence of interference) freshly
modified electrode was used to obtain the reproducible results. The
corresponding results are given in Table 2. The results displayed in-
terfering species did not significantly influence the peak currents of AC,
PRX and CBZ. It confirms that ZSM-5/TiO2/CPE can be considered as a
good electrochemical sensor for recognition of this drugs in biological
samples. Thus, this sensor exhibits good selectivity for detection of AC,
PRX and CBZ without the interference of commonly coexisting sub-
stances.
3.11. Real sample analysis
The applicability of the proposed method was examined by si-
multaneously measuring of three drugs in human serum. After sample
preparation and adequate dilution steps as described earlier, the DPVs
74
Materials Science & Engineering C 91 (2018) 64–77
method was applied to the determination of AC, PRX and CBZ in human
serum samples on the surface of ZSM-5/TiO2/CPE. The summarized
results for the analysis are given in Table 3. Standard solution of three
drugs was spiked to the samples S1 and S2, meanwhile, tablet solution
was spiked to the samples S3 and S4, respectively. The AC, PRX and
CBZ concentrations were determined from a calibration curve by
averaging five repeated measurements (n = 5). The obtained recovery
results in Table 3 indicate that ZSM-5/TiO2/CPE can be successfully
applied to the simultaneous determination of AC, PRX and CBZ in the
human serum samples.
3.12. Repeatability, stability and reproducibility of the ZSM-5/TiO2/CPE
The repeatability of the modified electrode was examined by a
series of ten successive CV measurements of 0.1 mM AC, 0.3 mM PRX
and 0.1 mM CBZ. The RSD in peak currents were found to be 3.8%,
2.5% and 4.3% for AC, PRX and CBZ, respectively. These results in-
dicate that the modified electrode has high repeatability. Long term
stability of the proposed electrode was also investigated by taking the
response of the modified electrode in a period of 30 days. The electrode
was stored in open air when not in use. Then CVs were recorded and
compared with the CVs obtained before storing. The result indicated
that the modified electrode retained 96.4% of its initial response after a
week and 94.6% after 30 days indicating that the ZSM-5/TiO2/CPE has
good stability. The reproducibility of the sensor was evaluated by using
S.K. Hassaninejad-Darzi, F. Shajie Materials Science & Engineering C 91 (2018) 64–77

Table 1
Comparison of the analytical features for the determination of AC, PRX and CBZ using proposed method and different modified electrodes.
Method Electrode Analyte pH LOD (μM) LDR (μM) Ref.

a
DPV 4-ABA/ERGO/GCE AC 7.0 0.01 0.1–65 [21]
DPV D50wx2–GNP/GCPEb AC 6.0 0.0047 0.03–42.2 [20]
DPV nPt-MWCNTPEc AC 7.0 0.17 0.5–100 [22]
DPV ZONM/CPEd AC 7.0 0.91 1–2500 [23]
Amperometry PSi/Pd-NS/CNTPEe AC 5.0 0.1 0.4–353.5 [24]
CV Co(II)–A/ZMCPEf AC 2.0 0.05 0.5–80.6 [25]
SWV Fe(III)-NClino/CPEg AC 6.0 9.9 × 10−4 0.0001–10,000 [45]
DPV GCE AC 4.51 0.36 4–400 [50]
DPV AG-NA/GCEh AC 7.4 0.031 0.05–20 [55]
DPV IMWCNT/GCEi AC 7.0 – 136.4–500 [56]
DPV FeS/RGO/GCEj AC 7.0 0.18 5–300 [57]
DPV ZSM-5/TiO2/CPE AC 5.0 0.58 2.5–110 This work
DPV ERGONR/GCEk PRX 6 0.0028 0.01-15 [26]
SWV PANI–Bi2O3/GCEl PRX 4.5 5.2 15.85–100 [27]
SWV GRP/GCEm PRX 4.5 0.06 0.19–1.42 [28]
CV f-MWCNT/GCEn PRX 7 0.22 12.5–313 [29]
Amperometry 0.20 5–340
DPV TMDS-MWCNT/GCEo PRX 6 0.2 0.8–600 [30]
DPV ZSM-5/TiO2/CPE PRX 5 0.38 0.6–105 This work
DPV GCE CBZ 7.3 46.5 155–2 × 106 [31]
DPV Fulleren-C60/GCE CBZ 7.0 0.91 1–2500 [32]
Amperometry ERGO–SWCNT/GCEp CBZ 5.0 0.029 0.05–3 [33]
LSV MWCNTs/GCE CBZ 6.9 0.04 0.13–1.6 [34]
DPV Au/graphene–AuNPs/GCE CBZ – 3.03 5–100 [35]
SWV Fe-SnO2/SPCEq CBZ 7.0 0.092 0.5–100 [36]
DPV Graphite/GCE CBZ – 3.89 84.6–846 [58]
DPV [BnMIM]PF6/CPEr CBZ 6.8 0.98 7–700 [59]
DPV ZSM-5/TiO2/CPE CBZ 5.0 1.04 6.0–97 This work

a
4-ABA/ERGO/GCE:Poly(4-aminobenzoic acid)-electrochemically reduced graphene oxide modified glassy carbon electrode.
b
D50wx2–GNP–GCE: Dowex50wx2 cation exchanger resin-gold nanoparticles modified glassy carbon electrode.
c
nPt-MWCNTPE: Platinum nanoparticles-multiwalled carbon nanotube paste electrode.
d
ZONM/CPE: ZrO2 nanoparticles-modified carbon paste electrode.
e
PSi/Pd-NS/CNTPE: porous silicon/palladium nanostructure modified carbon nanotube paste electrode.
f
Co(II)–A/ZMCPE: Carbon paste electrode modified with Co(II)-exchanged zeolite A.
g
Fe(III)-NClino/CPE: carbon paste electrode (CPE) modified with Fe(III)-exchanged clinoptilolite nanoparticles.
h
AG-NA/GCE: Activated graphene-Nafion modified glassy carbon electrode.
i
IMWCNT/GCE: Imidazole derivative multi-wall carbon nanotube modified glassy carbon electrode.
j
FeS/RGO/GCE: FeS nanoparticles anchored on reduced graphene oxide modified glassy carbon electrode.
k
ERGONR/GCE: Electrochemically reduced graphene oxide anoribbons modified glassy carbon electrode.
l
PANI–Bi2O3/GCE: Polyaniline–bismuth oxide nanocomposite modified glassy carbon electrode.
m
GRP/GCE: Graphene modified glassy carbon electrode.
n
f-MWCNT/GCE: Functionalized multi-walled carbon nanotubes modified glassy carbon electrode.
o
TMDS-MWCNT/GCE: Tetramethyldisilazane-multi-wall carbon nanotube modified glassy carbon electrode.
p
ERGO–SWCNT/GCE: Electrochemically reduced graphene oxide-single walled carbon nanotube modified glassy carbon electrode.
q
Fe-SnO2/SPCE: Fe doped SnO2 nanoparticles modified screen-printed carbon electrode.
r
[BnMIM]PF6/CPE: Hydrophobic ionic liquid 1-benzyl-3-methylimidazole hexafluorophosphate modified carbon paste electrode.

five equally proposed electrodes for CVs determination of the mixture
of 0.1 mM AC, 0.3 mM PRX and 0.1 mM CBZ. The oxidation potential of
the three species was the same at the prepared five equally electrodes.
The relative standard deviation (RSD) of peak currents was 3.6%, 4.1%
and 2.9% for AC, PRX and CBZ, respectively indicating the good
reproducibility of the developed sensor. In order to investigate the long
term stability of the ZSM-5/TiO2/CPE, this electrode was introduced to
30 cycles between 0.0 and 1.5 V with the scan rate of 50 mV s−1 in
phosphate buffer solution (pH 5.0) containing 0.1 mM AC, 0.3 mM PRX
and 0.1 mM CBZ. The electrode retained 92.6%, 89.5% and 87.2% of its

Table 2
The effects of 150 μM interferences on the DPV response of 15 μM of AC, PRX and CBZ at ZSM-5/TiO2/CPE.
Interferences Current of AC (μA) Signal change (%) Current of PRX (μA) Signal change (%) Current of CBZ (μA) Signal change (%)

No interferent 11.43 – 10.65 – 25.26 –

Dextromethorphan 11.15 2.45 10.86 1.97 24.66 2.37
Diphenylhydramine 11.95 4.55 11.17 4.88 24.45 3.21
Metronidazole 10.94 4.29 11.25 5.63 26.16 3.56
Phenobarbital 11.93 4.37 10.25 3.76 24.11 4.55
Phenylaniline 11.55 1.05 10.11 5.07 25.81 2.18
Phenytoin 12.14 6.21 11.08 4.04 25.62 1.42
Theophylline 12.10 5.86 10.52 1.22 25.95 2.73
Tryptophan 11.23 1.75 10.97 3.00 24.96 1.19
Tyrosine 12.20 6.74 9.98 6.29 24.12 4.51

75
S.K. Hassaninejad-Darzi, F. Shajie
Table 3
Results for simultaneous determination of AC, PRX and CBZ in spiked human serum samples (n = 5) by ZSM-5/TiO2/CPE.
Sample Added (μM) Found (μM)
AC PRX CBZ AC PRX
S1 30.00 5.00 40.00 29.46 5.06
S2 40.00 65.00 90.00 40.22 64.49
S3 65.00 80.00 8.00 66.53 79.00
S4 80.00 20.00 60.00 78.91 20.63
initial current response after 30 cycles for AC, PRX and CBZ, respec-
tively. Also, no significant change was detected in the oxidation peak
potential values. These results indicate mechanical and chemical sta-
bility and also reproducible response of the modified electrode.
4. Conclusions
To the best of our knowledge this is the first report on the si-
multaneous determination of acetaminophen (AC), pramipexole (PRX)
and carbamazepine (CBZ) by a voltammetric technique. This work de-
monstrates that the construction of the ZSM-5/TiO2/CPE sensor and its
application in the simultaneous determination of AC, PRX and CBZ in
pharmaceutical preparations and human serum samples. The result
demonstrates that this modified electrode exhibited high electro-
catalytic activity towards the electrooxidation of AC, PRX and CBZ by
significantly decreasing their oxidation overpotentials and enhancing
the peak currents vs. bare CPE. Large peak separation between AC, PRX
and CBZ could be obtained using CV or DPV methods, indicating that
the ZSM-5/TiO2/CPE facilitated their simultaneous and individual de-
termination. Significant advantages have been achieved by combining
the excellent conductivity, high surface, low resistance and unique
properties of ZSM-5 nanozeolite and TiO2 nanoparticles in the con-
struction of the modified electrode. The ZSM-5/TiO2/CPE displayed a
low detection limit, wide linear concentration range, high stability,
good reproducibility and repeatability and fast response for the detec-
tion of AC, PRX and CBZ in the mixture. Moreover, the proposed
method has been applied to the determination of AC, PRX and CBZ in
the real sample with satisfactory results. Also, fabrication of CPEs has
low cost and they are rich surface chemistry, low back ground current,
ease of surface renewal, and easy to apply modifications.
Appendix A. Supplementary data
Supplementary data to this article can be found online at https://
doi.org/10.1016/j.msec.2018.05.022.
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