Electrochimica Acta 194 (2016) 116–126

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Electrochimica Acta
journal homepage: www.elsevier.com/locate/electacta

Simultaneous determination of paracetamol and 4-aminophenol based

on poly(chromium Schiff base complex) modified electrode at
nanomolar levels
S. Praveen Kumara , K. Giribabua , R. Manigandana , S. Munusamya , S. Muthamizha ,
A. Padmanabana , T. Dhanasekarana , R. Sureshb , V. Narayanana,*
a
Department of Inorganic Chemistry, School of Chemical Sciences, University of Madras, Guindy Campus, Chennai 600 025, India
b
Department of Chemistry, SRM University, Ramapuram Campus, Chennai 600 089, India

A R T I C L E I N F O A B S T R A C T

Article history: Highly selective and sensitive electrochemical method was developed for the simultaneous
Received 25 December 2015 determination of paracetamol (PR) and 4-aminophenol (4-AP) present in the pharmaceutical samples.
Received in revised form 12 February 2016 Poly(chromium Schiff base complex) was fabricated onto the glassy carbon electrode by cyclic
Accepted 14 February 2016
voltammetry technique. The modified glassy carbon electrode (GCE) has exhibited better electrochemical
Available online 17 February 2016
response towards the simultaneous determination of paracetamol and 4-aminophenol than the GCE.
Additionally, the chromium Schiff complex modified GCE exhibits quasireversible process for PR and
Keywords:
reversible process for 4-AP, when compared to that of GCE, this response may be attributed to the
Paracetamol
4-aminophenol
presence of Cr(III) in the modified layer. The effect of pH and scan rate was evaluated for the fabricated
chromium Schiff base complex sensor in order to know the optimum conditions at which better response can be achieved. Moreover the
electrochemical polymerization kinetic parameter of the fabricated sensor was calculated separately for both the analytes. From
electrocatalytic oxidation differential pulse voltammetric (DPV) technique, the peak separation between the PR and 4-AP was
nanomolar detection found to be 300 mV and the electrochemical responses of the both analytes fall in the linear range from
8 nM to 125 nM and 8 nM to 133 nM, with the detection limits of 6.8 nM and 5.6 nM for PR and 4-AP
respectively. From these studies, the proposed method based on electropolymerized chromium Schiff
base complex was simple, rapid, cost effective and convenient for the simultaneous determination of PR
and 4-AP at nanomolar levels in pharmaceutical samples.
ã 2016 Elsevier Ltd. All rights reserved.

1. Introduction literature, there are several methods available to determine 4-AP

Paracetamol, a worldwide known drug which is used to get rid
of mild to moderate pain associated with headache, backache,
arthritis, postoperative pain, and for reducing fevers of bacterial/
viral origin. Simultaneous determination of paracetamol (PR) and
4-aminophenol (4-AP) is more important in the quality control of
synthetic process of paracetamol [1,2], since the co-existing,
4-aminophenol is highly undesirable due to its nephrotoxic and
teratogenic effects on human [3–5]. On exposure to light,
paracetamol may undergo degradation to give 4-aminophenol
as the undesired product. Over usage of paracetamol will lead to
serious side effects such as hepatic toxicity, kidney damage, liver
failure and finally may lead to death. Hence there is a necessity to
determine the 4-AP and PR for industrial and clinical purposes. In
* Corresponding author.
E-mail address: vnnara@yahoo.co.in (V. Narayanan).
and PR separately, to name a few HPLC, titrimetry, capillary
electrophoresis, spectrofluorometry and spectrophotometry [6–9].
However, these methods are more expensive, tedious, time
consuming. Among all the reported techniques, electrochemical
method is conducive because of its ease of handling, real time
monitoring and compact size. 4-AP and PR can be simultaneously
determined by electrochemical methods, since both the com-
pounds have good electrochemical activity and provides distinct
potential difference to detect. The use of bare glassy carbon
electrode (GCE) for the determination of PR shows irreversible
slow electron transfer, poor sensitivity, selectivity and poor
reproducibility. To overcome this, researchers have modified
GCE with appropriate layers to determine PR and 4-AP separately
or simultaneously. Among the modified GCE, few reports were
available for the simultaneous determination of PR and 4-AP based
on poly(3,4-ethylenedioxythiophene) [10], gold nanoparticles and
an organophillic layered double hydroxide [11], phenacetin on
CdSe microspheres [12]. Even though there are reports for the

http://dx.doi.org/10.1016/j.electacta.2016.02.087
0013-4686/ ã 2016 Elsevier Ltd. All rights reserved.
 S.P. Kumar et al. / Electrochimica Acta 194 (2016) 116–126
simultaneous determination of PR and 4-AP, none of them have the
detection limits in nanomolar level. In the present study we
attempt to fabricate chromium Schiff base complex on to the GCE
to detect 4-AP and PR simultaneously. Extensive literature survey
reveal that no work has been reported so far on the simultaneous
determination of PR and 4-AP based on Schiff base complex
electrochemically polymerized-modified electrodes. Chromium
Schiff base complex shows better electrochemical activity which
can influence the electrochemical redox process of PR and 4-AP.
Schiff base ligands and their metal complexes have increasing
interest in the area of research due to their various applications in
different fields, such as antibacterial, antiviral, anticancer and
antifungal agents [13–16]. Some other applications of Schiff base
ligands and their metal complexes are in chemical analysis,
catalysis, pesticides, transport of oxygen and sensors [17–20]. The
salen type Schiff base ligands form more stable complexes with
metal ions, through coordination of phenolic oxygen and imine
nitrogen atoms. Chromium(III) forms stable complex with Schiff
base ligands, due to the d3 electronic configuration [21]. The
chromium metal ion exhibit various oxidation states and good
electrochemical redox properties, therefore chromium is an
important metal for chemical and electrochemical catalytic
reactions [22]. The chromium metal ion is an essential biological
element, it involves in carbohydrate, lipid metabolism and
insufficient quantity of chromium(III) leads to Type II diabetes
and cardiovascular diseases [23–25]. In addition chromium Schiff
base complexes are efficient electrode modifiers for electro-
catalytic reactions and it can be used as better electrocatalytic
sensors [26]. Electropolymerization method is an effective way to
modify the electrode surface, it will be used in variety of
applications in the fields of electrocatalysis and electroanalysis.
Especially, the polynuclear Schiff base complexes show efficient
electron transfer because of their important redox interaction [27].
We have already reported our work for the voltammetric
determination of catechol by the chromium Schiff base complex
modified GCE. In the present study we report the preparation of
chromium Schiff base complex-modified GCE and its application
for the simultaneous determination of PR and 4-AP.
2. Experimental
2.1. Materials
5-methylsalicylaldehyde and chromium Schiff base complex
were synthesized by the previously reported method of our group
[26]. Paracetamol was purchased from the commercially available
drug as injection, 4-aminophenol was purchased from Alfa Aesar,
disodium hydrogen phosphate, potassium chloride, sodium ace-
tate, and sodium hydroxide were purchased from Qualigens and
used without further purification. TBAP (Tetra(n-butyl) ammoni-
um perchlorate) was purchased from Sigma Aldrich. All the
chemicals were used as received. Doubly distilled water was used
as the solvent throughout the experiment.
2.2. Instrumentation
Electrospray ionization mass spectrum of the complex was
performed on a Quan-Tof (Q-Tof) mass spectrometer. Electrochem-
ical Impedance Spectroscopy was carried out with the PGSTAT-
12 electrochemical analyzer (AUTOLAB, The Netherlands BV). The
morphology and EDX of the samples were analyzed by FE-SEM
using HITACHI SU6600 high-resolution analytical field emission-
scanning electron microscopy with variable pressure technology
(AZO NANO, United Kingdom), FT-IR measurements (KBr Pellets)
were carried out on a Bruker-Tensor27 FT-IR. Raman spectrum was
recorded using laser Raman microscope, Raman-11 Nanophoton
117
Corporation, Japan, XRD analysis were performed on Rich Siefert
3000 diffractometer with Cu-Ka1 radiation (l = 1.5406 Å). Photo-
luminescence spectrum was recorded using Perkin-Elmer LS-
45 Fluorescence Spectrometer.
2.3. Electrochemical experiment
Cyclic voltammetry and differential pulse voltammetry (DPV)
methods were utilized to determine the electrochemical sensing
properties of chromium Schiff base complex towards paracetamol
(PR) and 4-aminophenol (4-AP). All electrochemical sensing
experiments were carried out using a CHI 1103A electrochemical
instrument connected to a PC. The electrochemical experiments
were carried out in 0.1 M phosphate buffer solution (PBS), pH 7 in a
conventional three-electrode system using the bare and modified
GCE as the working electrode. Platinum wire was used as an
auxiliary electrode, saturated calomel electrode (SCE) was used as
the reference electrode for sensing experiments and Ag/AgCl
electrode as a reference for examine the electrochemical activity of
chromium(III) Schiff base complex. For cyclic voltammetric
measurements, the sensors were immersed in 30 mL of 0.1 M
PBS containing 1
104 M PR and 4-AP, applying the potential in
the range of 0.5 V to +1.2 V. Differential pulse voltammetry was
carried out in the range of 0.4 to 0.8 V with an increment of
0.004 V, an amplitude of 0.025 V along with a pulse width of 0.05 s
using 0.1 M disodium hydrogen phosphate and 0.1 M sodium
dihydrogen phosphate (pH 7) as the background electrolyte. When
a stable baseline was reached, 0.5 mL of 0.1 mM PR and 4-AP were
added successively, followed by recording the steady-state current.
All solutions used in these sensing experiments were prepared
with double distilled water. All electrochemical experiments were
carried out at room temperature and the potentials were referred
to SCE.
2.4. Preparation of modified glassy carbon electrode
The working glassy carbon electrode was subjected for pre-
treatment before it is applied for the electrochemical polymeriza-
tion for the modification. The GCE was first polished with alumina
slurries of different sizes like 0.03 mm and 0.1 mm to attain mirror
finish. The polished GCE was employed for ultra-sonication in
double distilled water for 20 min. After the mechanical pre-
treatment the GCE was applied for electrochemical pre-treatment,
it was carried out by applying a fixed potential of +0.5 V vs SCE for
300 s. Then a potential cycling was carried out between 1.5 and
1.5 V at a scan rate 50 mV s1 for 20 cycles in 0.1 M sulphuric acid
and acetonitrile solution. Finally the GCE was subjected for the
electrochemical polymerization using the following procedure.
0.1 M chromium Schiff base complex in acetonitrile was taken in
presence of tetrabutylammonium perchlorate (TBAP). TBAP was
used as supporting electrolyte, in the electrochemical polymeri-
zation the potential cycling was carried out between 1.5 to 1.5 V
at the scan rate 50 mVs1 for 20 cycles. After the electrochemical
polymerization chromium(III) Schiff base complex film was
successfully generated on the surface of the clean GCE, then the
film modified GCE was washed with double distilled water and
used for the independent and simultaneous determination of
paracetamol and 4-aminophenol in 0.1 M Phosphate buffer
solution (PBS) at pH 7 as the background electrolyte. The
electrochemically polymerized modified electrode was stored at
4  C when it was not used.
2.5. Solution preparation
0.01 M Paracetamol solution was prepared by the following
procedure, commercially available paracetamol injection was
118 S.P. Kumar et al. / Electrochimica Acta 194 (2016) 116–126
bought and used as it is, to made up in a 100 ml standard flask using
double distilled water. From the 0.01 M solution we prepared
0.1 mM working paracetamol solution using dilution method.
0.01 M 4-aminophenol was prepared using 0.1091 g 4-amino-
phenol dissolved and made up to 100 mL standard flask, from this
stock solution 0.1 mM working 4-aminophenol solution was
prepared using the dilution method. The different pH solutions
were prepared using 0.2 M potassium chloride, 0.1 M acetic acid,
0.1 M sodium acetate, 0.1 M and 0.2 M hydrochloric acid, 0.1 M
sodium hydroxide and 0.1 M disodium hydrogen phosphate
solutions with appropriate mixing/addition.
3. Result and Discussion
3.1. Chromium Schiff base complex
The chromium Schiff base complex contains Cr(III) as central
metal ion, with d3 electronic configuration. The chromium metal
has various oxidation states like +2, +3, +5 and +6. The chromium
Schiff base complex shows an IR band at 1622 cm1 assigned to
n(CH¼N), and a new vibration band appeared at 478 cm1 is due to
metal nitrogen bond n(CrN) and the band appeared at 533 cm1
is due to metal oxygen bond n(Cr O) [28]. The electronic
absorption spectral analysis of metal complex exhibit the
absorption bands at 276 nm, 320 nm, 403 nm and 560 nm. First
peak at 276 nm is due to p ! p electronic transition in the phenyl
ring. The other three bands corresponding to the d-d electronic
transition in chromium (III) metal ion. Three spin allowed d-d
transitions [29] are predicted. The first transition is at 560 nm for
4
T2g (F) 4A2g (F) (n1), the second transition is at 403 nm for 4T1g
(F) 4A2g (F) (n2), the third transition assigned for 4T1g (P) 4A2g
(F) (n3) was not observed, it lies close to the ligand field, hence it
could not be identified. The emission spectrum of the complex is
given in Fig. S1. ESI Mass spectral studies of the chromium Schiff
base complex gave a promising result for our reported molecular
weight. From the mass spectral studies the molecular ion peak
[MH]+ was obtained at 444, it shows that the complex is hydrated.
The coordination of the water molecule with the central metal ion
in the metal complexes has been reported [30], the ESI mass
spectrum of the chromium Schiff base complex was given in
Fig. S2. The powder XRD data of the complex is given in Fig. S3. The
electrochemistry of chromium Schiff base complex shows an
irreversible reduction peak at the potential of 0.88 V which is due
Fig. 1. Cyclic voltammogram for electrochemical polymerization of chromium Schiff base complex in the presence of 0.1 M TBAP using acetonitrile as solvent at the scan rate
of 50 mV s1.
to the one electron redox process, the reduction of Cr(III) to Cr(II) in
the Schiff base complex [26,31].
3.2. Electrochemical polymerization of chromium Schiff base complex
The electrochemical polymerization of chromium (III) Schiff
base complex on the surface of freshly polished glassy carbon
electrode (GCE) was obtained by using 0.1 M chromium Schiff base
complex in acetonitrile solution, between the potential of 1.5 to
1.5 V at the scan rate of 50 mV s1 for 20 cycles as shown in Fig. 1.
The polymer film was formed through the weak conjugation bridge
between the aromatic rings and metal ion in metal complexes [32].
The polymeric films exhibit like the building of the supramolecular
blocks and the salen complexes show a great structural flexibility
for the polymeric film formation by supramolecular building
blocks [33]. The electrochemical polymerization of chromium
Schiff base complex exhibits stacked polymeric films method and it
was given in Scheme 1. The cyclic voltammogram shows the
reduction peak at 0.88 V for Cr(III)/Cr(II) [26]. The surface
coverage concentration of the polymerized chromium Schiff base
complex on the GC electrode surface was calculated using the
following equation [27],
0
G ¼ Q=nFA
0
Where G is the surface coverage concentration of the polymer, Q is
the charge, A is the surface area of GCE, n is the number of electron
transferred in the polymerization process, F is the Faraday constant
(96 485C mol 1) [34]. The surface coverage concentration of the
modified electrode is 3.219
1010 mol cm2 estimated by inte-
grating the charge under the reduction peak of Cr(III)/Cr(II).
3.3. Electrochemical behavior and morphology of the Cr-SBC/GCE
In order to know the electrochemical activity of the chromium
Schiff base complex modified electrode [Cr-SBC/GCE] we carried
out pH effect, scan rate effect and chronocoulometry. The surface
morphology of modified electrode was studied by FE-SEM and EDX
shows the elements which are present on the electrode surface.
Electrochemical redox behaviour of the Cr-SBC/GCE was studied
in different pH (phosphate buffer solution), as supporting
electrolyte. At various pH the Cr-SBC/GCE undergoes a reduction
process in the potential range of 0.75 to 1.25 V as shown in
 S.P. Kumar et al. / Electrochimica Acta 194 (2016) 116–126 119

Scheme 1. The electrochemical redox reaction mechanism of 4-AP and PR.

Fig. 2a. The voltammetric process at different pH is irreversible, at
the higher pH there is not much shift but in the lower pH at acidic
medium there is a considerable shift in the reduction potential. As
the proton concentration decreased reduction potential of modi-
fied electrode becomes higher and the corresponding current
decreased gradually, it clearly explains that proton plays a major
role in the reduction of Cr-SBC/GCE electrode. From this pH effect it
should be noted that the modified electrode shows only a
reduction process and the better electrochemical response was
attained at neutral pH 7. Both the chromium Schiff base complex
and the polymerized complex have same kind of electrochemical
redox nature, it show only a reduction process at the same
potential range. The reduction process occurred at the metal center
Cr(III) ! Cr(II) + e [35].
The effect of scan rate for the redox process of Cr-SBC/GCE
modified electrode was tested at different scan rate from 50–
250 mV s1 and it was shown in Fig. 2b. Fig. 2b, shows an anodic
peak potential at 0.35 V and two cathodic peak potentials at
0.22 V and 1.108 V in higher scan rate. The cathodic peak at
1.108 V is attributed to the reduction of Cr(III)/Cr(II), much
potential shift for the cathodic process of Cr(III) ! Cr(II) + e is due
to stacked polymer films of chromium Schiff base complex.
Another cathodic peak at 0.22 V also appeared for the same
oxidation state of the metal ion. The two electrochemical reduction
peaks appeared for same oxidation state indicates the orbital
overlap for the polymeric film formation. From the scan rate effect
we can conclude that the reduction current was increased with
increase in the scan rate. The double logarithmic plot of scan rate vs
reduction current was shown as inset figure in Fig. 2b, from the
straight line linear regression equation Ipc = 0.4739 logn  0.1035,
the slope value 0.4739 explains that the electron transfer process
is diffusion controlled and there is a linear relation between the
potential and current. The number of electron transferred in the
reduction process at Cr-SBC/GCE can be calculated by using the
following equation [36],
nFQv
ip ¼
4RT
Where, ip is current, n is number of electron transfer in redox
reaction, F is faraday constant, Q is charge, n is scan rate, R is gas
constant and T is temperature, the calculated value of n is 1 for the
reduction process [35].
In the electrochemical polymerization more clustered struc-
tures are formed through overlap of orbitals. The overlap of orbitals

Fig. 2. (a) Cyclic voltammograms of Cr-SBC/GCE in 0.1 M PBS at different pH values. Scan rate: 50 mV s1. (b) Cyclic voltammograms of Cr-SBC/GCE in 0.1 M phosphate buffer
solution (pH 7.0) at different scan rates. a–j: 50, 60, 70, 80, 90, 100, 125, 150, 200 and 250 mV s1. (Inset Figure in 2b): Double logarithmic plot of scan rate vs current.
120 S.P. Kumar et al. / Electrochimica Acta 194 (2016) 116–126
provides possibility to electron transfer between the polymeric
film and electrode surface. The electrochemical redox peaks are
appeared due to overlapping of dp orbitals of the metal ion with p
orbitals of the Schiff base ligand [32]. Due to week electron
conjugation between the aromatic rings and metal ion the
vibrational bands are shifted towards higher region in IR spectral
analysis. The FT-IR and Raman spectra for the polymerized
chromium Schiff base complex were shown in Fig. S4 and S5. In
Fig. S4, the FT-IR spectra were given for both the monomers [26]
and polymers. In the FT-IR spectral analysis C¼N appeared at
1622 cm1 in monomer and it was appeared at 1633 cm1 in
electrochemical polymerized films. The chromium Schiff base
complex polymer film show the metal nitrogen and metal oxygen
vibrational bands at higher region than chromium Schiff base
complex. These bans are appeared at (CrN) 490 cm1 and
n(CrO) appeared at 550 cm1. Without any additional new peaks,
the IR spectrum clearly explains that polymeric films are formed
through week electron conjugation between Schiff base ligand and
chromium metal ion. This result was further confirmed by Raman
analysis.
Chronocoulometry (CC) is an effective tool for the measurement
of electrode surface area, diffusion coefficient, absorption of
electro active species and electron transfer in the electrochemical
redox process. The CC of Cr-SBC/GCE was shown in Fig. 3. The CC
explains the response of charge versus time to an applied potential
step waveform. The electrochemical charge response in CC is due
to redox process of the electro active species with applied potential
[37,38]. The value of charge (Q) is obtained by integrating the
current with respect to time at the given potential step in CC
experiment. CC also has the same assumptions as chronoamper-
ometry (CA), hence the charge at respective time was calculated by
a simply integration of the Cottrell equation with some corrections
due to charge obtained by double layer and an interfacial
interactions, the charge observed at a potential step by the
integrated Cottrell equation known as the Anson equation [39].
2nFACo D1=2 t1=2
Q¼
p1=2
Where, Q = charge, n = number of electrons in the reaction,
F = Faraday’s constant, A = electrode area, Co = concentration of
the system, D = diffusion coefficient.
In the CC analysis we measure charge instead of current since
the charge (Q) is increasing with time for a given potential step it is
the important advantage in CC rather than chronoamprometry.
Based on the above Anson equation we can calculate redox
Fig. 3. Charge intercalated versus time transient for Cr-SBC/GCE in 0.1 M PBS (pH 7.0) electrolyte. The inset figure is Anson plot between charge vs t1/2.
diffusion coefficient (D) using the slope of charge vs t1/2 plot it is
also known as Anson plot. Which is shown in the inset diagram in
Fig. 3, the linear relation between time and charge clears that the
redox process follows diffusion controlled. The redox diffusion
coefficient was calculate by applying the values of n = 1,
A = 0.07 cm2 and Co = 0.1 mM in the above equation we get the
value of D is 2.307
108 cm2 s1.
The surface morphology of the modified electrode was
investigated by SEM technique after the electrochemical polymer-
ization, which is shown in Fig. 4. In Fig. 4a, we observed a sphere-
like morphology, it clearly conforms that the polymerized
chromium complex was deposited on the GCE surface. Fig. 4b, is
vertical view of chromium Schiff base complex modified GCE, it
shows the thickness of modified GCE. The elemental composition
of the modified electrode surface was given in Fig. 4c. From the
SEM and EDX analysis we conclude that the chromium Schiff base
complex was electrochemically polymerized on GCE surface as
spheres and the elemental details of the Cr-SBC/GCE surface.
3.4. Electrochemical behavior of PR and 4-AP on chromium Schiff base
complex modified GCE
The electrochemical behaviors of paracetamol (PR) and 4-
aminophenol (4-AP) at chromium(III) Schiff base complex modi-
fied GCE (Cr-SBC/GCE) was investigated by using cyclic voltam-
metry. The electrochemical response of 0.1 mM PR and 4-AP was
evaluated using bare GCE and Cr-SBC/GCE in PBS buffer solution
(pH 7) at the scan rate of 50 mV s1. The electrochemical behavior
was shown in Fig. 5. Fig. 5a depicts the electrochemical redox
process of PR and 4-AP with irreversible and quasireversible nature
respectively. The DEp value, peak to peak separation for PR and 4-
AP was found to be 120 mV and 100 mV respectively at the bare
GCE [10]. The peak to peak separation for PR and 4-AP at Cr-SBC/
GCE was found to be 130 mV and 40 mV respectively. From the
cyclic voltammograms we could clearly understand that Cr-SBC/
GCE exhibited better DEp. Fig. 5b shows sharp peak when
compared to that of GCE, this clearly indicates the fast electron
transfer process of PR and 4-AP at the modified electrode. This may
be attributed to the presence of several Cr ions in the polymerized
network at the electrode surface. Fig. 5b illustrates the electro-
chemical redox process of PR and 4-AP at Cr-SBC/GCE, PR follows
an irreversible behavior with higher peak currents than at bare
GCE and 4-AP follows reversible process, both the anodic
potentials for PR and 4-AP is lower at Cr-SBC/GCE when compared
with bare GCE. The voltammetric response of PR and 4-AP was
 S.P. Kumar et al. / Electrochimica Acta 194 (2016) 116–126 121

Fig. 4. (a) & (b) are SEM images and c) EDX spectrum of Cr-SBC/GC electrode.

found to greatly improve at the Cr(III) Schiff base complex modified
glassy carbon electrode. The separation between the two anodic
peaks at Cr-SBC/GCE was large enough for the simultaneous
determination of PR and 4-AP. It absolutely reveals that the Cr-SBC/
GCE shows an efficient electrocatalytic activity with sharp peaks,
enhanced peak current, high selectivity and better sensitivity for
PR and 4-AP. The improvement in electrochemical process at Cr-
SBC/GCE was due to the large active surface area on the working
electrode [40–43]. The electrochemical data are listed in Table 1.
3.5. Effect of pH
The electrochemical behavior of 0.1 mM PR and 4-AP at Cr-SBC/
GCE was investigated in the pH range from 3 to 10 by using cyclic
voltammetry was shown in Fig. S6 and S7 respectively. The pH
effect for mixture of 0.1 mM PR and 0.1 mM 4-AP at Cr-SBC/GCE in
the pH range of 5 to 9 was shown in Fig. 6. The oxidation peak
potential was shifted negatively when the pH is increased at the
same time oxidation peak current was increased gradually for PR
and for 4-AP, the increasing peak current from pH 3 to 5, but both
the analytes shows higher peak current at pH 7. Then, the oxidation
peak current was gradually decreased with further increase the pH.
The electrochemical oxidation in phenolic compounds gives
quinone as the end product in the process the transfer of proton
plays an important role [44]. Therefore the pH of the medium
greatly influences the electrochemical response of phenolic
compounds. In the acid medium, the high concentration of H+
can react with PR and 4-AP it will decrease the adsorption amount

Fig. 5. Cyclic voltammogram of the 0.1 mM paracetamol (PR) and 4-aminophenol in phosphate buffer (pH 7) at scan rate of 50 mV s1 (a) bare GCE, (b) poly-CrSBC modified
GCE.
122 S.P. Kumar et al. / Electrochimica Acta 194 (2016) 116–126
Fig. 6. Cyclic voltammograms of 0.1 mM PR and 4-AP at Cr-SBC/GCE in 0.1 M PBS at different pH values. Scan rate: 50 mV s1.
of analyte on the electrode surface likewise the high concentration
of OH also will decrease the adsorption of the amount of analyte
hence the peak current was getting low when compare with
neutral pH (pH 7). The highest response was obtained at pH 7 for
determination of sensitivity, the pH 7 was chosen as the optimal
pH condition, and it will be used for further experiments. In
addition as shown in Fig. 6, both the analytes gets negative shift in
potentials with increased pH, and the regression equations can be
obtained by the plot of potential against pH it was shown in Fig. 7
for PR and 4-AP, the equation can be expressed as Epa (V) = 0.7757–
0.0498 pH, (R2 = 0.9992) and Epc (V) = 0.8080–0.0998 pH,
(R = 0.9977) for PR, Epa (V) = 0.7475–0.0953 pH, (R2 = 0.9970) and
2
Epc (V) = 0.6069–0.0831 pH, (R2 = 0.9968) for 4-AP. The above
expressions clearly demonstrate that the proton is directly
involved in electrochemical redox process. Based on the following
equation, the m/n ratio was calculated,
dEp=dpH ¼ 2:303mRT=nF
Where, m is the number of proton and n is the number of electron
[45]. The calculated m/n ratio of PR is 0.84 and 1.69 for oxidation
and reduction respectively, and for 4-AP the m/n ratio is 1.62 and
1.41. It indicates that the equal number of proton and electron
involved in the electrochemical redox process of PR and 4-AP. The
electrochemical redox mechanism of PR and 4-AP at the Cr-SBC/
Fig. 7. (a) The effect of pH on the redox peak potential of PR, (b) The effect of pH on the redox peak potential of 4-AP.
GCE was given in Scheme 1. The effect of pH on the redox peak
current was shown in Fig. S8 and S9 for PR and for 4-AP it was
represented in Fig. S10 and S11.
3.6. Scan rate effect
The effect of scan rate on the electrochemical redox process of
PR and 4-AP at Cr-SBC/GCE was studied in detail. The scan rate
effect also gives information about the mechanism which involved
in electrochemical redox process of PR and 4-AP. Fig. 8 depicts the
voltammetry response of 0.1 mM PR at Cr-SBC/GCE with the scan
rate range from 10 to 700 mV s1. The redox peak currents at the
modified electrode was linearly increased with increasing in the
scan rate, as well as the potential of the redox peaks was shift with
increasing scan rate the anodic peak was shifted positively and the
cathodic peak was shifted negatively.
However, the electrochemical response of 0.1 mM 4-AP at Cr-
SBC/GCE with different scan rate was shown in Fig. 9, it illustrates
that the electrochemical redox process is like as PR. As shown in
inset figures in Figs. 8 and 9, both the anodic and cathodic peak
currents were linearly proportional to the square root of scan rate
in the range of 10 to 700 mV s1. The regression equations obtained
from the linear relationship as follows, Ipa(mA) = 0.0532 + 0.4474 log
(n) mV s1, (R2 = 0.9975) and Ipc (mA) = 0.4705  0.6067 log(n) mV s1,
 S.P. Kumar et al. / Electrochimica Acta 194 (2016) 116–126 123

Fig. 8. Cyclic voltammograms of Cr-SBC/GCE in 0.1 M phosphate buffer solution (pH 7.0) containing 0.1 mM paracetamol at different scan rates. a–z: 10, 20, 30, 40, 50, 60, 70,
80, 90, 100, 125, 150, 175, 200, 225, 250, 275, 300, 350, 400, 450, 500, 550, 600, 650 and 700 mV s1. The inset figure is double logarithmic plot of scan rate vs current.

(R2 = 0.9956) for PR and Ipa(mA) = 0.0183 + 0.5574 log(n) mV s1, and for 4-AP a is 0.62, based on the following equation were used
(R2 = 0.9967) and Ipc(mA) = 0.1511  0.6040 log(n) mV s1, slopes of the two straight lines in the plot of Ep versus log v:
2
(R = 0.9979) for 4-AP. The results suggest that the electrochemical
Ka a Ka a
reaction on the modified electrode is a diffusion-controlled log ¼ log or ¼
Kc 1a Kc 1  a
process. The linearity explains that the increasing scan rate leads
to a positive shift in anodic potential and a negative shift in Where ka and kc is the slope of the straight lines for Epa versus log
cathodic potential for both the analytes. Epa and Epc linearly v and Epc versus log v, respectively.
depends on the log v, and the regression equations are, Epa The heterogeneous electron transfer rate constant (ks) was
(V) = 0.3519 + 0.0470 log(n) mV s1, (R2 = 0.9954) and Epc calculated based on the following equation [46]:
(V) = 0.1046  0.0591 log(n) mV s , (R = 0.9952) for PR and for 4-
1 2

AP Epa (V) = 0.0365 + 0.0086 log(n) mV s1, (R2 = 0.9932) and Epc
RT að1  aÞnFDEp
log kS ¼ a logð1  aÞ þ ð1  aÞlog a  log 
nFv 2:3RT
(V) = 0.0201  0.0053 log(n) mV s1, (R2 = 0.9943). According to
Laviron theory, a plot between Ep and logn gives two straight Where a is the electron transfer coefficient, n is the number of
lines with their slopes of 2.3RT/anF and 2.3RT/(1a) nF for electron, DEp is the separation of the redox peaks (V), n is the scan
reduction peak and oxidation peak, respectively, the charge rate (V/s). In this work, ks was calculated to be 4.32 s1 and 3.57 s1
transfer coefficient (a) value was calculated to be 0.44 for PR for PR and 4-AP respectively. The results obtained from pH and

Fig. 9. Cyclic voltammograms of Cr-SBC/GCE in 0.1 M phosphate buffer solution (pH 7.0) containing 0.1 mM 4-aminophenol at different scan rates. a–z: 10, 20, 30, 40, 50, 60,
70, 80, 90, 100, 125, 150, 175, 200, 225, 250, 275, 30 0, 350, 400, 450, 500, 550, 600, 650 and 700 mV s1. The inset figure is double logarithmic plot of scan rate vs current.
124 S.P. Kumar et al. / Electrochimica Acta 194 (2016) 116–126
Table 1
Electrochemical redox potential and current for PR and 4-AP.
Electrode Oxidation Reduction
PR 4-AP PR 4-AP
V mA V mA V mA V mA
Bare GCE 0.469 6.29 0.134 4.67 0.349 0.09 0.034
Cr-SBC/GCE 0.342 8.89 0.050 9.69 0.216 1.83 0.010
scan rate studies, the electrochemical redox reaction of PR and 4-
AP at the Cr-SBC/GCE should be a two-electron and two-proton
process with the previous reports [47,48]. The plot of Ep verses logn
has been shown in Fig. S12 and S13 and the effect of scan rate
against peak current was shown in Fig. S14 and S15.
3.7. Analytical determination of PR and 4-AP
Cyclic voltammetry (CV) and differential pulse voltammetry
(DPV) techniques were performed to know the relationship
between peak current and concentration of PR and 4-AP. The
electrochemical response of the PR and 4-AP at Cr-SBC/GCE were
tested by CV and are given in Fig. S16 and S17 respectively. The
electrochemical response in Fig. S16 and S17 indicates that, there is
a linear relationship between the redox peak current and
concentration of the analytes, a gradual increase was obtained
with increase in the concentration. But in this work we chose DPV
for the simultaneous determination of PR and 4-AP, since DPV is a
better sensitive technique than the CV and it suppress the
influence of background current. DPV responses of PR and 4-AP
were shown in Fig. 10 and Fig. 11 respectively. The DPV shows three
peaks, the peak at 0.2 V may be attributed to the central metal ion
redox behaviour. Other two well defined separate peaks for PR at
348 mV and for 4-AP at 48 mV with the potential difference of
300 mV. This anodic peak-to-peak potential separation is sufficient
for the simultaneous determination of PR and 4-AP. The
voltammetric response of Cr-SBC/GCE for PR and 4-AP were
investigated under optimized condition (i.e., phosphate buffer at
pH 7). Fig. 10, illustrates the DPV response of Cr-SBC/GCE by
varying the [PR], keeping the [4-AP] constant. In the same way
Fig. 10. DPV at the Cr-SBC/GCE in the presence of 4-AP (8 nM) for different concentrations of PR (from a to o): 8, 16, 26, 33, 42, 50, 58, 67, 75, 83, 92, 100, 108, 116 and 125 nM at
the pulse period of 0.1 s and amplitude is 0.025 V.
other experiment was carried out by varying [4-AP], keeping [PR]
constant and the DPV response was shown in Fig. 11. The anodic
peak current was linearly increases with increase in the
concentration of both the analytes. The linear relationship was
obtained in the concentration range of 8–125 nM for PR in the
presence of 8 nM 4-AP as shown in the inset of Fig. 10. The linear
5.69 regression equation was obtained from the plot, Ipa (mA) = 0.0411
9.20
[PR] (nM) + 7.267, with the correlation coefficient of 0.9945. The
detection limit was calculated using the following formula based
on signal to noise ratio of 3,
LOD ¼ 3S=s
Where S is the standard deviation and s is the slope of the
calibration curve [49].
The calculated detection limit for PR at Cr-SBC/GCE is
6.8
109 M, which is lower than that of the previous reports
which are listed in Table 2. However, for 4-AP the linear
relationship is observed for the concentration range of 8–
133 nM in the presence of 8 nM PR as shown in the inset Fig. 11
and the regression equation is, Ipa (mA) = 0.0455 [4-AP] (nM) +
8.4156, with the correlation coefficient of 0.9959. Based on the
signal to noise ratio equation the detection limit for 4-AP at Cr-SBC/
GCE is 5.6
109 M, the lowest detection limit observed so far, the
previous reports are given in Table 2 for comparison. The
calibration plots for the determination of PR and 4-AP using the
modified electrode are given in Fig. S18 and S19. It shows that the
two species under investigation do not interfere with each other in
the electrochemical response.
3.8. Interference study
The selectivity of the Cr-SBC/GCE was investigated in the
presence of various species which can interfere in the determina-
tion of PR and 4-AP. Paracetamol was synthesized by the
acetylation of 4-aminphenol in pharmaceutical industries, there-
fore the possible interfering species are acetylsalicylic acid,
ascorbic acid, sodium bicarbonate, saccharine, but these species
do not interfere in the determination PR and 4-AP [58]. In the real
sample analysis, though the redox potentials of uric acid and
dopamine fall in the same potential window, they do not interfere.
In the present study, the aim is to develop a better active sensor for
 S.P. Kumar et al. / Electrochimica Acta 194 (2016) 116–126 125

Fig. 11. DPV at the Cr-SBC/GCE in the presence of PR (8 nM) for different concentrations of 4-AP (from a to q): 8, 16, 26, 33, 42, 50, 58, 67, 75, 83, 92, 100, 108, 116, 125, 133 and
141 nM at the pulse period of 0.1 s and amplitude is 0.025 V.

Table 2
Performance comparison of the fabricated electrode for paracetamol and 4-aminophenol detection with other electrodes.

Electrode Analyte Method Linear Range (mM) LOD (mM) Reference

BDD electrode PR CV 100–8000 10.000 [50]
Graphene/GCE PR DPV 0.1–20 0.032 [51]
Graphite electrode PR DPV 6.10–66.10 2.200 [52]
PANI-MWCNT/GCE PR SWV 250–2000 0.250 [53]
MWCNT/BPPGE PR SWV 0.01–2 0.010 [54]
Graphene–chitosan/GCE 4-AP DPV 0.2–550 0.057 [3]
SWNTs/POAPE/GCE 4-AP LSV 0.2–100 0.060 [55]
Au-r-GO/GCE 4-AP CV 0.4–50 0.093 [56]
Graphene–PANI/GCE 4-AP DPV 1.0–20 0.065 [57]

PEDOT/GCE PR & 4-AP DPV 1–100 (PR) 0.400 (PR) [10]

4–320 (4-AP) 1.200 (4-AP)

Carbon Ionic Liquid Electrode PR & 4-AP DPV 2–220 (PR) 0.500 (PR) [43]
0.3–100 (4-AP) 0.100 (4-AP)

Cr-SBC/GCE PR & 4-AP DPV 0.008–0.125 (PR) 0.0068 (PR) This Work
0.008–0.133(4-AP) 0.0056 (4-AP)

the simultaneous determination of PR and 4-AP for quality control
in pharmaceutical industries. The interference study using the
above mentioned species was given in Fig. S20. It shows that there
is no interference during the determination of PR and 4-AP. The
results indicate that the electrochemical response of the chromium
Schiff base complex modified electrode for the determination of PR
and 4-AP has high selectivity and better sensitivity.
3.10. Samples analysis
The analytical application of the developed electrochemical
sensor for PR and 4-AP in drug was evaluated using DPV at the Cr-
SBC-GCE. DPV was used to measure the concentration of PR
(150 mg per 2 ml injection) and 4-AP in the injection solutions.
Table 3 summarizes the results obtained for the determination of

3.9. Stability, reproducibility and repeatability

Table 3
The stability of Cr-SBC/GCE was tested by CV at the scan rate of
Results of determination of PR and 4-AP in paracetamol and 4-aminophenol
50 mV s1 for 50 cycles. The Cr-SBC/GCE was washed in 60 mL 0.1 M injection solutions.
PBS (pH 7) thoroughly after the end of each experiment and then it
Samples Detected (mM) Added (mM) Found (mM) Recovery (%)
was again used for the studies in the next day. There is a gradual
decrease in the redox peak currents it was found to be around 8.6%. PR 4-AP PR 4-AP PR 4-AP PR 4-AP
The reproducibility and repeatability of the present electrochemi- I 18.2 0.0 30.0 25.0 47.9 24.4 99.4 97.6
cal sensor for the simultaneous determination of PR and 4-AP is II 19.6 0.0 30.0 25.0 49.5 24.9 99.8 99.6
determined; the RSD of DPV response for ten average peak currents III 17.8 0.0 30.0 25.0 47.3 25.1 99.0 100.4
IV 19.3 0.0 30.0 25.0 49.7 25.2 100.8 100.8
of 0.1 mM PR and 4-AP was calculated to be 4.5% and 3.7%, V 20.5 0.0 30.0 25.0 51.2 25.5 101.4 102.0
respectively.
126 S.P. Kumar et al. / Electrochimica Acta 194 (2016) 116–126
PR and 4-AP in Five independent PR and 4-AP injection solutions.
The standard solution of PR and 4-AP were prepared by the
subsequent dilution from the 0.1 M stock solution to get a specified
concentration and then it was employed for recovery tests. The
recovery of PR from the sample solutions was 99.5%, 99.8%, 98.9%,
100.8% and 101.3% respectively, and for 4-AP the recovery is 98.7%,
99.2%, 99.7% 101.5% and 101.9% respectively. The results of recovery
test confirmed that the developed sensors for PR and 4-AP is
reliable for the simultaneous determination. The additives in the
drug formulation do not interfere in the determination of PR and 4-
AP in drug samples.
4. Conclusion
The electroanalytical determination of PR and 4-AP was done
simultaneously, since 4-AP is the starting material, synthetic
intermediate and hydrolytic degradation product of paracetamol,
which cause the teratogenic effect and nephrotoxicity to human.
Due to these impurity and hazardous of 4-AP in PR, there is a
necessity to determine these two analytes at simultaneously,
which can be done through this work. The results of electroana-
lytical determination demonstrate that the electrochemical
oxidation of PR and 4-AP at Cr-SBC/GCE appeared at well peak
to peak potential difference and more negative than the bare GCE.
The peak current also enhanced at the modified GCE. The
electrochemical sensor of chromium (III) Schiff base complex
has better electrochemical redox nature it gives the better sensing
activity towards PR and 4-AP. In the electroanalytical method, the
remarkable potential difference of the two analytes offers that the
method has better selectivity of PR in the presence of 4-AP and
their impurities. This present work shows higher selectivity and
sensitivity with low detection limits at nanomolar level. The
chromium(III) Schiff base complex was synthesis by a simple
microwave method and utilized for a better electrochemical for PR
and 4-AP. The proposed modified electrode (Cr-SBC/GCE) is found
to be an effective sensor for the simultaneous determination of PR
and 4-AP in pharmaceutical industries.
Acknowledgment
One of the authors (S. P. K) wishes to thank Department of
Science and Technology (DST), Government of India for the
financial assistance in the form of INSPIRE fellowship (Inspire
Fellow no: 130032) under the AORC scheme.
Appendix A. Supplementary data
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.
electacta.2016.02.087.
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