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Materials Today: Proceedings 3 (2016) 1854–1863 www.materialstoday.com/proceedings

Recent Advances In Nano Science And Technology 2015 (RAINSAT2015)

Nanocomposite modified electrochemical sensor for sensitive and

selective determination of noradrenaline
Harsha Devnania*, Soami Piara Satsangeea, Rajeev Jainb
a
University Science Instrumentation Centre, Dayalbagh Educational Institute, Dayalbagh, Agra-282005, India.
b
Department of Chemistry, Jiwaji University, Gwalior-474011, India.

Abstract

A glassy carbon electrode was modified with graphene-chitosan nanocomposite for the sensitive and selective determination of
noradrenaline. The morphological characteristics of nanocomposite were studied by scanning electron microscope and atomic
force microscopy. Electrochemical characterization of the modified sensor was done using cyclic voltammetry and
electrochemical impedance spectroscopy. Enhancement in electron transfer process and reduction in charge transfer resistance
was observed. The electrochemical behavior of noradrenaline at nanocomposite modified sensor was investigated in pH 7.4
phosphate buffer solution using cyclic voltammetry and square wave voltammetry. The modified sensor showed high sensitivity
and selectivity for the determination of noradrenaline. The method was also successfully employed for determination of
noradrenaline in a pharmaceutical formulation.
© 2015Elsevier Ltd.All rights reserved.
Selection and Peer-review under responsibility of [Conference Committee Members of Recent Advances In Nano Science and
Technology 2015.].

Keywords:Noradrenaline;Voltammetry;Graphene;Chitosan;Nanocomposite

1. Introduction

Noradrenaline (NA), a catecholamine derivative is secreted and released by adrenal glands. It plays important
physiological roles in the central nervous system [1]. It is also commonly used as the drug of choice as a

* Corresponding author..
E-mail address:harsha.devnani@gmail.com

2214-7853© 2015 Elsevier Ltd.All rights reserved.

Selection and Peer-review under responsibility of [Conference Committee Members of Recent Advances In Nano Science and Technology 2015.
].
 Harsha Devnani, et al./ Materials Today: Proceedings 3 (2016) 1854–1863 1855

vasoconstrictor, cardiac stimulator and bronchodilator [2]. It stimulates arteriole contraction, affects muscle and
tissue control, decreases peripheral circulation and activates lipolysis in adipose tissue. It is critically linked to
mental diseases, heartfailure, DNA breaks in cardiac myoblast cells and diabetes [3]. Thus, it is important to
determine its concentration in the biological fluids selectively.
Various methods have been explored for the determination of NA like spectrophotometry, capillary
electrophoresis and high performance liquid chromatography [4-6]. NA being an electroactive compound, its
electrochemical detection has been explored using various electrodes. Electrochemical detection is advantageous as
offers fast, accurate, cheap and sensitive analysis of analytes undergoing redox reactions. The analysis is hindered at
bare electrodes due to either interference or fouling effect [7]. Ascorbic acid and uric acid share similar redox
potential as NA and thus interfere with its analysis [8]. Chemically modified electrodes using electron transfer
mediators are thus being used to achieve sensitivity and selectivity in detection [3]. In this context, nanomaterials
have gained much attention. Nanocomposites possess unique physical, chemical, optical, mechanical, magnetic and
electrical properties as they combine materials with synergistic or complementary behaviors. Recently, various
nanocomposites consisting of either metal-metal oxide, mixed metal oxides, polymers mixed with metal or metal
oxides, or carbon nanotubes mixed with polymers, metals or metal oxides have attracted attention as active materials
for electrochemical sensing [9].
Graphene, a relatively new carbon-based nanomaterial has attracted interest in fundamental and applied sciences
recently. It’s unusual electrical conductivity, high specific surface area; high mechanical, thermal and chemical
stabilities make it a suitable material for electrochemical catalysis and biosensing [10]. Chitosan, on the other hand
possesses significant film-forming and adhesion properties. It is non-toxic, biocompatible and provides a
hydrophilic environment to biomolecules as it has abundant amino and hydroxyl groups. Thus, it offers to improve
hydrophilicity as well as biocompatibility via covalent grafting techniques [11-12]. In the present work we have
used graphene-chitosan (GRP-CHIT) nanocomposite modified glassy carbon electrode (GCE) for the sensitive and
selective electrochemical determination of NA using cyclic voltammetry (CV) and square wave voltammetry
(SWV). Enhancement in current response was observed at the modified sensor (GRP-CHIT/GCE). Scanning
electron microscopy (SEM) and atomic force microscopy (AFM) was used to study the modifier surface.
Electrochemical impedance spectroscopy (EIS) showed reduction in charge transfer resistance at the modified
sensor. The effect of pH, scan rate and concentration on the electrochemical response was also studied. The
applicability of the modified sensor was tested in human blood serum.

2. Experimental

2.1. Instrumentation

All electrochemical studies were performed on a PC-controlled AUTOLAB PGSTAT 302N (Eco-Chemie B.V.,
Utrecht, The Netherlands) potentiostat-galvanostat with IME663 and software NOVA 1.8. EIS was carried out using
FRA 2 module. A standard three electrode electrochemical assembly was used in the study that contained GCE and
GRP-CHIT/GCE as working electrode, platinum wire as counter and Ag│AgCl (3M KCl) as reference electrode
that were fitted in one compartment cell connected with electrochemical workstation through Metrohm 663VA
stand. The electrochemical cell was fitted with the nitrogen gas bubbler. All pH measurements were made on a
Mettler Toledo pH meter fitted with a glass electrode and Ag│AgCl electrode as a reference which was pre-
standardized with buffers of known pH. All measurements were carried out at room temperature. A DL-180
ultrasonic apparatus was used for sonicating the suspension of GRP-CHIT for modifying GCE. Atomic force
microscopic (AFM) study was carried out at NanosurfEasyscan (Switzerland) with software Nanosurf 1.8. SEM was
performed at Tescan (7718) involving the software, Mira TC.

2.2. Materials and Reagents

Chitosan was purchased from MP Biomedicals (India). GRP (12 nm) was procured from Graphene laboratories.
Noradrenaline standard (≥99%) was obtained from the Sigma Aldrich. Ultra pure water (Milli-Q water with
1856 Harsha Devnani, et al./ Materials Today: Proceedings 3 (2016) 1854–1863

resistivity 18 MΩ.cm) was obtained from ELGA purification system (U.K). Standard solution of NE (1mM) was
prepared by dissolving pure compound in 0.1 M perchloric acid and was further diluted with phosphate buffer to get
the concentration in the working range. Solutions at all the stages of the study were prepared by using analytical
grade reagents and were used without further purification.

2.3. Fabrication of GRP-CHIT modified GCE

Prior to modification, the bare working electrode (GCE) was polished against the alumina slurry (particle size-
0.05−0.3µm) spread over the Buehler cloth, followed by gently blowing under the nitrogen stream to remove the
residual alumina particles and then sequentially rinsed with de-ionized water. For modification, GRP-CHIT was
obtained by dispersing 0.5 mg of GRP in 1mL of 0.5 (wt) % of CHIT solution (in dimethyl formamide; DMF)with
ultrasonication for 5 hours. 1 µL of the modifier was withdrawn and drop-cast over the surface of GCE to get GRP-
CHIT/GCE and left to dry at the room temperature.

2.4. Analytical Procedure

The stock solution of NA (1mM) was prepared in 0.1 M HClO4. Working solutions were prepared by further dilution
with the supporting electrolyte to get the desired concentration range. Initially, a series of phosphate buffer (2.5-12 pH)
was prepared in ultrapure water and used as supporting electrolytes. About 10 mL of electrolyte solution containing
appropriate amount of standard NA or sample were added to the electrolytic cell. Prior to all the electrochemical
measurements, all the solutions were purged with the pure N2 gas to remove the interference due to O2. Then the
electrodes were immersed and the SWV and CV were recorded with potential between -0.2 to 0.8 V. The surface of GCE
was renewed prior to the modification by abrading the surface smoothly against the alumina slurry spread over the
Buehler cloth. Electrochemical impedance measurements were performed in the presence of 5 mMK3Fe(CN)6 by applying
the AC voltage with 5 mV amplitude in a frequency range from 1 Hz to 100 kHz. The results were plotted in the form of
Nyquist plots. All voltammetric measurements were carried out at ambient temperature.

3. Results and Discussions

3.1. Surface characterization of the modifiers

The surface morphology of GRP-CHIT was studied using SEM and AFM techniques. The modifier suspension
was drop-cast over the surface of ITO (Indium Tin Oxide) section for carrying out analysis. Fig. 1 shows the
SEMimage of GRP-CHIT at 10 KX (A). It clearly shows a rough surface owing to the random dispersion of GRP
within the chitosan matrix as well as the solvent (DMF).The surface topology which is an indication of roughness
parameters of the electrode surface was interpreted using AFM. The roughness parameters are tabulated in Table 1,
which reports the peak height, root mean square and surface roughness values. The data imply that the modifier is
well-coated onto the surface of GCE. The nanocomposite coatings were not removed from the surface of GCE by
several flushes with deionized water (Fig. 1B).

Table 1: AFM parameters for GCZ/ITO

Roughness parameters GRP-CHIT
Roughness average (nm) 127.42
Root mean square (nm) 153.85
Peak-valley height (nm) 759.06
Peak height (nm) 311.98
Valley depth (nm) 384.23
Mean value (pm) 46.812
 Harsha Devnani, et al./ Materials Today: Proceedings 3 (2016) 1854–1863 1857

Fig. 1.SEM image at 10 KX (A) and 3D AFM image (B) of GRP-CHIT coated on ITO

3.2. Electrochemical characterization of modified electrodes

The electrochemical response of K3Fe(CN)6 at bare and modified GCE was also checked to examine their
electrocatalytic properties. In comparison to bare GCE, better electrochemical response was observed for K3Fe(CN)6
at GRP-CHIT/GCE as is clear from Fig. 2.
The electro-active area of the bare GCE and GRP-CHIT/GCE was obtained by the CV using 1 mM K3 Fe(CN) 6
as a redox indicator at different scan rates. The peak current Ip can be calculated using RandlesSevcik equation at 25
ºC [13]:
Ip= (2.69x105) n3/2 A C0 D1/2 ν 1/2 (1)
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For K3Fe(CN)6, n=1 and D= 7.6 X 10-6 cm2/s. From slope pe of Ip (µA) vs ν1/2, the area wasdetermined to be 0.028 cm2
2
for bare GCE and 0.085 cm for GRP-CHIT/GCE.Thu Thus, the electro-active surface area of the electrode was
considerably increased on modification.EIS was used to analyze interfacial electrocatalytic properties of surface
modified electrode. Nyquist plots were obtained for modif dified and bare GCE in 5 mMK3Fe(CN)6and are presented in
Fig. 3. By fitting the data using an appropriate equivalent
nt circuit [R(Q[RW])] compatible with the Nyquist plots, the
values of charge transfer resistances (RCT) were obtainned. The electrical equivalent circuit compatible with the
Nyquist plots comprises of ‘RS’ the solution resistance,, ‘Qdl’ the double layer capacitance (constant phase element),
‘RCT’ the charge transfer resistance and ‘W’ the Warbur burg impedance. RCT gives information on electron transfer
kinetics at the electrode interface. The Warburg type im impedance represents the linear line that appeared at lower
frequencies because of the diffusion controlled process,, wwhereas the slightly depressed semi-circles that appeared at
higher frequencies represent the charge transfer resistance
nces. A constant phase element was used instead of the pure
capacitance due to surface inhomogeneity [14]. From Fig Fig. 3, it can be seen that the semi-circle radius is reduced at
the GRP-CHIT/GCE electrode and there by the charge tra transfer resistance is found to decrease at the modified sensor
being 8.7 KΩ for it and 19.8 KΩ for bare GCE.

Fig. 2.Cyclic voltammetric response of the standard redox system K3Fe(

e(CN)6 (1 mM) at bare GCE (a) and GRP-CHIT/GCE (b)

Fig. 3.Nyquist plots of 5 mMK3Fe(CN)6 at bare GCE (a) and GRP-CHIT

IT/GCE (b); inset is the equivalent circuit [R(Q[RW])]
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3.3. Electrochemical behavior of NA at the GRP-CHIT/GC

GCE

The electrochemical determination of NA was analyzed ed at bare GCE and at GRP-CHIT/GCE using CV and SWV
techniques. Fig. 4A and 4B respectively represent the C CV and SWV of NA (1 µM) at bare GCE (a) and GRP-
CHIT/GCE (b).A well-defined oxidation peak is observed ed at bare GCE and also at the modified sensor that can be
ascribed to the oxidation of NA to its respective o-quin uinone [15]. The enhancement in current response at the
modified sensor is attributed to increase in surface area oowing to the porosity of the modified layer. The enhanced
anodic peak current intensity is due to the trapping of the solution containing NA within the multiple layer of the
porous nanocomposite [16-17].Thus, GRP-CHIT/GCE pro roved to be highly sensitive towards oxidation of NA.

Fig. 4.Cyclic voltammograms (A) and square wavevoltammograms (B)) fo

for determination of NA (1 µM) in pH 7.4 phosphate buffer at bare GCE
(a) and GRP-CHIT/GCE (b)

3.4. Effect of supporting electrolyte and pH

The nature of the electrolyte and pH of the med edium affects the peak shape, height and stability of
voltammograms. Phosphate buffer (0.1 M) gave the max aximum current response accompanied with optimum peak
shape and stability. The influence of pH on the NA oxidatiation (1 µM) at GRP-CHIT/GCE was examined over the pH
range 2.5−9 by SWV. The anodic peak current intensityy w was found to be sensitive towards the pH. A small current
was observed at pH 2.5 which increased gradually till pH H 7.4 and decreased beyond it (Fig. 5A). The sensor is thus
suited for physiological applications as it shows the bestst response in pH 7.4. On the basis of these results pH 7.4
phosphate buffer was selected as the optimum supportingg electrolyte. A sequential shift of the anodic peak potential
with the augmentation of solution pH was also observed ed (Fig. 5B), indicating that the protons participate in the
electrode reaction process of NA [18].A linear dependence
nce of peak potential on pH of the supporting electrolyte was
obtained following a linear equation: E/mV = 662.2 – 61.44 pH; R2 = 0.994. The peak potential at 25 ºC is expressed
as [19]:
Ep = Eº - (m/n) 59 pH (2)
where, Eº is the standard potential, m and n are the num
number of protons and electrons respectively. Since the plot
of Epa(mV) vs. pH gave a slope of 61.4 mV/pH, which is cclose to the expected value of 59 mV/pH, we can say m/n
is 1. Thus, in accordance with the Nernst equation (2)) iit can be proposed that the no. of protons and electrons
participating in the electrode process of NA oxidation aree eequal [8].
1860 Harsha Devnani, et al./ Materials To
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6 0.6
A Ep (V) = -0.0614 pH + 0.6622 B
R² = 0.9935
5 0.5

4 0.4
Ip (μA)

Ep (V)
3 0.3

2 0.2

1 0.1

0 0
0 2 4 6 8 10 0 2 4 6 8 10
pH pH

Fig. 5.Dependence of peak current (A) and peak potential (B) of NA (1 µµM) on the pH of phosphate buffer at GRP-CHIT/GCE

3.5. Effect of scan rates

The influence of varying scan rates (20-90 mV/s)) oon the electro-oxidation process of NA (1 µM) at GRP-
CHIT/GCE is shown in Fig. 6. The anodic peak currentt in intensity was found to increase with an increasing scan rate
(Fig. 6). A linear plot of peak current intensity (Ipa) vs.. sc
scan rate (ν) was obtained (Fig. 6: inset plot), following the
linear equation: Ipa (µA) = 0.0651ν(mV/s) + 0.1987; R2 = 0.98, which implies that the redox process of NA at the
GCZ/GCE is diffusion-controlled [20]. Further, it was se seen that no reverse peak was observed at lower scan rates
while relatively small cathodic peaks were observed at higher scan rates, which implies irreversible or quasi-
reversible electrode process for NA.

Fig. 6.Cyclic voltammograms of NA (1 µM) at scan rates 20 - 90 mV/s /s ((a – h: 20, 30, 40, 50, 60, 70, 80 and 90 mV/s respectively) in pH 7.4
phosphate buffer solution at GRP-CHIT/GCE [Inset is the plot of Ipa (μAA) vs. ν1/2 (mV/s)]

3.6. Determination of electrode dynamic parameters (α an

and n) and proposed mechanism of NA
The relationship between Epa and ln ν in the cyclic volt
oltammetry is given by Laviron as follows [21]:
Ep = E0 + [RT/(αnF)] ln [(RTks)/(αnF)] – [RT/(αnF)]] ln ν (3)
whereks is the standard rate constant of the surface ce reaction; n, F, α, Rand T have their usual significance.
Substituting the respective values in Eq. (3), αn=0.97 iss ccalculated from the slope of Epa (V) = 0.0267 ln ν + 0.1986
(r = 0.99). In most cases α is found to lie between 0.3 and
nd 0.7, and it can usually be approximated by 0.5 [22]. So the
lated to be 1.9 ≈ 2. It has been already described that protons
number of electrons (n) involved in the reaction is calcula
arity, Epa (V) = − 0.0614 pH + 0.6622 (R2 = 0.99) and Eq. (4)
participate in the reaction mechanism. So using the lineari
[23], the number of protons part in the electrode reactionn iis calculated to be m =2.08≈2.
Epa = E0 − 2.303(mRT/nF)log H+ (4)
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where E0 is the formal potential, m is the number of the protons involved in the reaction and n is 2 as calculated.
Other symbols have their usual meaning. The NA oxidat dation mechanism thus involves 2 electrons and 2 protons.
This is in accordance with that reported in the literature [8, 15].
3.7. Calibration curve, detection limit and method validati
ation
SWV was recorded with the increasing amounts of NA under the optimized conditions at GRP-CHIT/GCE. A
linear relationship between the peak current and the NA co concentration was observed in the range of 200 to 1400 nM.
The calibration plot of I (µA) vs. concentration (nM) (Fig.
ig. 7) is described by the equation:-
I(µA) = 0.0038 (nM)M) + 4.4443; R2 = 0.97
Limit of detection (LOD) and limit of quantification (LOQ OQ) (estimated as 3 S/m and 10 S/m,respectively, ‘S’being
thestandard deviation and‘m’ being the slope of the ca calibration curve) were obtained as 19.7nM and 65.8nM.
Various statistical parameters for the linear regression equa
quation have been evaluated and reported in Table 2.
Table 2: Square-wave voltammetric method validation parameters for sta
standard linearity
Linearity parameters Results
Slope 0.0038
Intercept 4.4443
Standard deviation 0.025
Correlation coefficient 0.97
Standard error of estimation 0.0876
Limit of detection (nM) 19.7
Limit of quantification (nM) 65.8

Fig. 7.Square wave voltammograms of NA (Phosphate buffer; 7.4 pH) at different concentration levels (a – f: 200 – 1400 nM) at GRP-
CHIT/GCE; Inset is the plot of concentration vs. current

3.8. Reproducibility and stability of fabricated sensor

The reproducibility of the modified electrode was invevestigated by the successive measurement of NA (1 µM) at
GRP-CHIT/GCE by SWV (N = 6). The corresponding rel relative standard deviation of 1.76 % showed that the results
are satisfactorily reproducible (Table 3). The stability of the modified electrode was checked after two weeks of
storage and the results were compared with the respons onse that was obtained at the sensor when it was freshly
fabricated. After two weeks, it was found that the corresp
esponding current response fell less than 2 % and showed a
RSD of 1.92 %.
1862 Harsha Devnani, et al./ Materials Today: Proceedings 3 (2016) 1854–1863

Table 3: Reproducibility results at GRP-CHIT/GCE in the presence of 1 µM NA

Sensor Reproducibility Sensor Repeatability
Sensor Average Current, I (µA) R.S.D (%) Average Current, I (µA) R.S.D (%)
Sensor 1 0.97a 1.8
Sensor 2 0.95a 1.74
0.97a 1.92
Sensor 3 0.96a 1.88
Average 0.96b 1.76
a
Average of 6 replicates, bAverage of three sensors
3.9. Interference Study
The influence of various compounds that are expected to interfere with the determination of NA (1 µM) were
studied under the optimum conditions in pH 7.4phosphate buffer. The interfering species were chosen from
substances commonly found with NA in pharmaceutical formulations and/or in biological fluids. In biological
environments, the main interference is the presence of high concentration of ascorbic acid and uric acid. The
tolerance limit was defined as the maximum concentration of the interfering substance that caused an error of less
than ±5 % for the determination of NA. The interference analysis is presented in Table 4. The results depicted the
high selectivity of the GRP-CHIT/GCE for the determination of NA.
Table 4: Interference of some foreign substances on the determination of 1 µM NA at GRP-CHIT/GCE under the optimized conditions
Species w(Interfering species)/w(NA)
Glucose, sucrose, fructose 350
Urea, uric acid 350
Ascorbic acid 300
Citric acid 200
Ca2+, Mg2+, Na+, K+ 250
F-, Cl-, SO42- 150
CO32- 150

3.10. Assay of NA in human blood serum

The practical applicability of the proposed method using the modified sensor was tested bydetermination of NA
in human blood serum by spiking the diluted samples with known amounts of NA. The human blood serum of a
healthy human body was obtained from a blood bank. To evaluate the accuracy of the method, the standard addition
method was used by spiking different concentration of NA in the sample solution. SWV of unspiked and spiked
samples was recorded under optimized conditions at GRP-CHIT/GCE. Percentage recoveries have been reported in
Table 5. The good recoveries confirm that the detection of NA at the modified sensor, GRP-CHIT/GCE is a reliable
method for the determination of NA in human blood sample.
Table 5: Determination of NA in spiked human blood serum sample using the proposed method at GRP-CHIT/GCE
Standard added (nM) Standard found* (nM) Recovery (%)# R.S.D. (%)
400 392.78 98.2 0.2
600 606.46 101.1 0.22
800 794.92 99.4 0.23
1000 987.73 98.8 0.18
#
[standard found/standard added] x 100
*Amount found represents the average of six observations (n = 6)
4. Conclusions
Graphene-chitosan nanocomposite modified sensor was fabricated to study the voltammetric behavior of NA.
The modified sensor exhibited higher electro-catalytic behavior as compared to the the bare electrode due to the
synergistic effect of graphene and chitosan that enhanced the electrocatalysis towards NA. EIS studies indicated a
considerable decrease in the charge transfer resistance at graphene-chitosan nanocomposite modified sensor. The
surface modifier was successfully characterized by SEM and AFM. The effect of pH of the supporting electrolyte
 Harsha Devnani, et al./ Materials Today: Proceedings 3 (2016) 1854–1863 1863

and varying scan rates on the response characteristics of NA exhibited that its electro-oxidation process at GRP-
CHIT/GCE is a proton coupled and diffusion controlled process. Ascorbic acid and uric acid were found not to pose
interference to quite a good extent. The practicable applicability of the proposed method with enhanced sensitivity,
specificity, reproducibility and accuracy was applied for the estimation of NA in human blood sample.
Acknowledgements
The authors greatly acknowledge their work to the Ministry of Human Resource and Development (MHRD),
India (Grant number: F.16-59/2011-TEL, dated 30-9-2011), for providing funds for carrying out the research work
and DST INSPIRE DST/INSPIRE (Grant number: Fellowship/2012/626, 18th February, 2012). They are also
thankful to Dr. D. K. Avasthi, Dr. S. A. Khan and Mr. Sunil for providing lab facility for carrying out SEM at Inter
University Acceleration Centre, New Delhi, India.

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