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Strategies to avoid electrode fouling for nimesulide detection using

unmodified electrodes

Article  in  Analytical Methods · June 2013

DOI: 10.1039/C3AY40463C

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Strategies to avoid electrode fouling for nimesulide

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detection using unmodified electrodes

Cite this: Anal. Methods, 2013, 5, 3546

Iranaldo Santos da Silva,ab Bruno Capovilla,a Kellen Heloizy Garcia Freitasc

and Lúcio Angnes*a

Received 19th March 2013
Accepted 13th May 2013
DOI: 10.1039/c3ay40463c
www.rsc.org/methods
Voltammetric quantification of nimesulide presents a serious drawback due to surface fouling on unmodified
electrodes. In the anodic region, the electrode fouling effects are critical and alternative procedures are
required to bypass this effect. In the present study, new strategies for nimesulide quantification in
pharmaceutical agents in the anodic region were developed. We propose a simple procedure to overcome
this problem: just doing an electrochemical conditioning process before measurement. This was achieved
by differential pulse voltammetry (DPV) and multiple pulsed amperometry (MPA), using batch and in flow
injection analyses, respectively. These studies were performed in the presence of 0.1 mol L
1 H2SO4 and
the application of 1.6 V to the electrode surface at short time intervals was effective both for electrode
surface cleaning and for attaining a steady state regime. The new procedures proposed here allow for
quantification of nimesulide in both anodic and cathodic regions, favouring the quantification of this
species in complex samples. The results obtained here were in good agreement with the official
spectrophotometric method recommended in the Brazilian Pharmacopoeia.

Introduction free and conjugated forms. This metabolite appears to contribute

Nimesulide (N-(4-nitro-2-phenoxyphenyl)-methane-sulphona-
mide) is a largely utilized non-steroidal anti-inammatory drug
with analgesic and antipyretic properties, which notably does not
induce gastrointestinal ulceration. However, in the literature,
there are numerous reported cases of nimesulide-induced xed
drug eruptions (FDEs).1,2 FDEs present themselves primarily as
oral lesions with several cases of bullous or multifocal urticarial
lesions. Nimesulide exhibits a pKa value of 6.5, which is very
favourable for gastric tolerability as it avoids the back diffusion of
hydrogen ions responsible for tissue damage.3,4 It is a meth-
anesulphonic acid anilide derivative. In the aromatic ring, the
phenoxylic group (aromatic ether) and amino group are
substituted (Scheme 1).
Nimesulide is currently administered for the treatment of
several different pathologies. It is applied in the treatment of
chronic rheumatoid arthritis or osteoarthritis, inammation of
the genitourinary system, otorhinolaryngological diseases,
odontostomatological practice and postoperative pain. It is
almost completely transformed into 4-hydroxynimesulide in both
to the anti-inammatory activity of the compound.4,5
According to the Biopharmaceutical Classication System
(BCS), drugs can be divided into four classes, depending on their
solubility and permeability. Drugs belonging to class II, such as
nimesulide, are characterised by low solubility and high perme-
ability.5 Thus, nimesulide is virtually insoluble in aqueous
systems (solubility 0.01 mg mL
1).6 The very poor aqueous
solubility of nimesulide gives rise to difficulties in the pharma-
ceutical formulation of oral or injectable solutions and leads to a
variable bioavailability.7
The determination of nimesulide in pharmaceutical formu-
lations and other samples has been carried out mainly by high-
performance liquid chromatography,8–17 followed by spectro-
photometric methods and by electroanalytical methods (mainly
polarographic and voltammetric methods).18–21 According to a

a
Departamento de Quı́mica Fundamental, Instituto de Quı́mica, Universidade de S~
ao
Paulo, Av. Prof. Lineu Prestes 748, 05508-000 S~ ao Paulo, SP, Brazil. E-mail:
luangnes@iq.usp.br
b
ao – Rua Silva Jardim, 307, 65020-
Companhia de Saneamento Ambiental do Maranh~
906, S~
ao Luis, MA, Brazil
c
Faculdade de Quı́mica, Universidade Federal do Pará, Campus Marabá, Quadra 04,
Lote especial, s/n - CEP 068505-080 - Marabá, PA, Brazil Scheme 1 Chemical structure of nimesulide.

3546 | Anal. Methods, 2013, 5, 3546–3551 This journal is ª The Royal Society of Chemistry 2013

Paper
recent review, electroanalytical methods correspond to about
9% of all papers published on the issue.3
El-Sayed et al.22 used adsorptive linear sweep voltammetry for
the determination of nimesulide content in pharmaceutical
agents based on the reduction of the nitro group at a glassy
carbon electrode. The voltammetric behaviour of the drug was
investigated in Britton–Robinson buffer (pH 2.0–12.0), applying
the cyclic voltammetry technique. According to the authors, the
cathodic peak current varied linearly with the concentration of
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nimesulide in the range of 4.0  10
7 to 5.0  10
5 mol L
1.
Kumar et al.23 further described a potentiometric method for
nimesulide determination using a PVC sensor. Herein, quanti-
tation was based on the use of a nimesulide–molybdophos-
phoric acid ion pair complex (NIM–MPA) as the electroactive
material and the response range described was situated
between 1  10
6 to 1  10
2 mol L
1 nimesulide.
The rapid poisoning of the electrode in the anodic region
hampers the direct determination of nimesulide by amperometry
at positive potentials. To overcome this drawback, Catarino et al.24
developed a ow system with the working electrode connected to
the injector valve. With this design, it was possible to change the
position of the electrode between the manifold where the analysis
was done to another line, where a regeneration solution was
owing, to clean the working electrode. This arrangement was
successfully utilised for the analysis of diltiazen and nimesulide.
In this paper, we describe the development and validation of a
procedure for the direct determination of nimesulide in phar-
maceutical products by square wave voltammetry (SWV) without
pre-treatment of the sample. Alternatively the oxidation of
nimesulide was investigated on pyrolytic graphite electrodes, a
substrate on which intense electrode fouling occurs. During this
study, two different strategies to solve this problem were devel-
oped and these aspects are discussed in the following sections.
Experimental
Apparatus
All voltammetric measurements were carried out in a single-
compartment glass cell with a three-electrode system. A glassy
carbon (GC) or a pyrolytic graphite electrode was used as the
working electrode. The Ag/AgCl/KCl(sat) reference electrode was
constructed in the author's laboratory25 and the same unit was
used throughout this study. A platinum wire was utilised as the
auxiliary electrode. All electrochemical measurements were
performed using a potentiostat m-Autolab Type III (Eco Chemie,
the Netherlands), controlled by the Autolab Soware GPES
version 4.8. Absorbance measurements were performed using a
Femto 600 plus spectrophotometer (S~ao Paulo, Brazil) with a
standard quartz cuvette with a 10.0 mm optical path.
For the FIA studies, the same ow cell described elsewhere26
was utilised here. In short, a single channel manifold connected
to a homemade wall-jet ow-cell was employed. A peristaltic
pump (Model 78016-30, Ismatec S/A) was utilised to propel the
solutions and a manually operated rotary valve was used to
introduce the solutions into the ow stream. The working
electrode utilised here was a pyrolytic graphite electrode. The
carrier solution was 0.1 mol L
1 H2SO4. Polyethylene tubes
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Analytical Methods
(0.8 mm i.d.) were used to connect all parts of the system. All
experiments were carried out at room temperature (23  2  C).
Electrodes were treated before their utilisation by the
following methods: the glassy carbon electrode was polished
with alumina slurry (1.0 and 0.05 mm), while the pyrolytic
graphite electrode surface was renewed using emery paper
(2000 mesh). Subsequent to the polishing process, the elec-
trodes were exposed to ultrasound for 2 min, rinsed with
deionised water and dried under nitrogen ow.
Reagents and solutions
All solutions were prepared using pure water, which was double-
ltered, puried by reverse osmosis and then passed through a
Milli-Q (Millipore) system. The resistivity measured aer this
treatment was not lower than 18.2 MU cm. All chemicals used
were of analytical grade. Sodium hydroxide, phosphate buffer,
acetate buffer, potassium chloride and sulphuric acid solutions
of several concentrations were carefully prepared and used in
these preliminary studies to search for the best supporting
electrolyte. Experiments in both cathodic and anodic regions
were performed with all these electrolytes.
Nimesulide was purchased from Sigma-Aldrich and a 1.0 
10
3 mol L
1 stock solution was prepared daily in the adequate
supporting electrolyte. The reference solutions were prepared
by appropriately diluting the stock solution in the supporting
electrolyte.
Procedure
Aer optimisation of the experimental parameters for the
proposed method, the next step was the construction of
analytical curves to evaluate the concentration region where the
responses were linear. The detection limit was calculated as
three times the value of the standard deviation of the blank
solution divided by the slope of the analytical curve.
Two different pharmaceutical formulation samples (con-
taining 100 mg per tablet) were analysed using the proposed
voltammetric method and the method recommended by the
Brazilian Pharmacopoeia (UV spectrophotometry),27 for
comparison. Five tablets were weighed and the average mass
per tablet was determined. In sequence, the tablets were nely
powdered and a portion sufficient to prepare a solution con-
taining 1  10
3 mol L
1 nimesulide was accurately weighed
and dissolved in the supporting electrolyte. An aliquot of 1.00
mL of this solution was transferred to the electrochemical cell
containing 5.00 mL of 1.0 mol L
1 sodium hydroxide; the
square-wave voltammograms were obtained just aer each
aliquot addition. The content of the drug in each tablet was
determined using the standard addition method.
Spectrophotometric measurements were performed in
accordance with the procedure described in the Brazilian
Pharmacopoeia.27 Analytical curves constructed with standard
solutions of nimesulide at 392 nm (in 1.0 mol L
1 NaOH) fol-
lowed the Lambert–Beer law in the concentration interval
explored.
Parameters such as linearity range, accuracy, precision and
selectivity were carefully analysed to consolidate the
Anal. Methods, 2013, 5, 3546–3551 | 3547

Analytical Methods
voltammetric method. The calibration curve was constructed by
plotting the concentration of different standard solutions of
nimesulide versus the corresponding cathodic peak height.
Eleven different concentrations were used and analysed in
triplicate. Linearity was evaluated by linear regression analysis,
which was calculated by the least square regression method.
The accuracy was evaluated by the assay of concentrations of
the sample solution in triplicate. The percent recovery and the
relative error (%) were determined. Precision was checked on
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the same day (n ¼ 5). The results were expressed as the
relative standard deviation (R.S.D.) of the measurements. The
selectivity was evaluated by analysing solutions containing
the excipients employed for the preparation of commercial
nimesulide tablets.
All experiments were carried out in triplicate to obtain more
robust results. All data were presented as means  SD. Student's
t-test at the 95% condence level was used. P < 0.05 was
considered signicant.
Results and discussion
Voltammetric behaviour of nimesulide
Initial studies were performed utilizing cyclic voltammetry. The
rst observation from these experiments was the following:
when the glassy carbon electrode was cycled from 0 V to the
cathodic region, a reproducible redox process was observed for
a series of experiments. Conversely, when the electrode was
cycled (from 0 V) in the anodic direction, a strong decrease in
the voltammetric signal was observed in successive cycles. The
decrease of the signal resulted from a severe electrode fouling
process, an effect which was veried in all electrolytes tested
and notably accentuated within acidic medium.
This observation in addition to the greater solubility of
nimesulide in alkaline medium suggested the utilization of
these conditions in preliminary experiments.
In the cathodic side, cyclic voltammograms of nimesulide at
GCEs showed one cathodic and one anodic peak (results not
shown). The values of Epc–Epa (about 59 mV) and the ratio
between the anodic current peak and the cathodic current peak
(Iap/Icp) was very close to unity, which indicated that the
reduction process of nimesulide at a GCE is reversible accord-
ing to the cyclic voltammetry premise.28 According to the liter-
ature18 the process involves the formation of a nitro radical
anion and can be described by the following reaction:
ARNO2 + e_
! ARNO2

Square wave voltammograms measured on the glassy carbon
electrode conrmed the reversible chemical behaviour of
nimesulide (Fig. 1), veried previously by the cyclic voltammetry
technique. Two well-dened peaks were recorded, one for the
forward direction (cathodic peak) and one when the direction
was reversed (anodic peak). The sum of the contribution of the
two pulses (Ir) was also plotted (versus potential) and this signal
was directly proportional to concentration in the SW
voltammograms.29
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Fig. 1 Square wave voltammograms obtained with a GCE in the presence of 6 
10
5 mol L
1 nimesulide in 1.0 mol L
1 sodium hydroxide; SW parameter: f ¼ 50
Hz; a ¼ 40 mV; DEs ¼ 2 mV; (i1) forward pulse; (i2) reverse pulse; (Ir) resultant
current.
Optimisation of the square wave voltammetry (SWV)
parameters
The cathodic peak current obtained by square wave voltam-
metry depends on various instrumental parameters such as
square wave frequency ( f ), scan increment (DEs) and square
wave amplitude (a). These parameters are interrelated, having a
combined inuence on the peak current response. The inu-
ence of these instrumental parameters on the peak current
response for 6  10
5 mol L
1 nimesulide in 1.0 mol L
1
sodium hydroxide solution was investigated. Table 1 shows the
studied parameters and the optimum values for nimesulide
determination.
Under the optimised conditions (Table 1), the SW voltam-
mograms were obtained for different nimesulide concentrations.
Fig. 2 presents these analytical curves, where the cathodic peak
current at the GCE was proportional to the nimesulide concen-
tration in the range from 4.3  10
5 to 4.2  10
4 mol L
1, with a
detection limit (three times the standard deviation of signal
blank/slope) of 3.2  10
6 mol L
1. The linear regression equa-
tion was: [DIpa (mA) ¼
1.53  10
6  5.04  10
8 + 0.055 
1.52  10
4 Cnimesulide (mol L
1)] (r ¼ 0.9999, n ¼ 3). The cali-
bration curve was made in triplicate.
The precision of this procedure was checked on the same day
by a successive series of voltammetric measurements (n ¼ 5) in
1.0 mol L
1 sodium hydroxide solution containing 6.0  10
5
mol L
1 nimesulide, without renewing the electrode surface.
The results obtained during this series of measurements for
Table 1 Investigated square wave voltammetry (SWV) parameters and their
optimum values for nimesulide determination
Parameter Studied range Optimum value
SW frequency ( f ) 10–100 Hz 50 Hz
SW amplitude (a) 10–100 mV 60 mV
Scan increment (DEs) 1–5 mV 2 mV
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Fig. 2 (A) Square wave voltammograms for various concentrations of nimesu-
lide; (a) supporting electrolyte; (b) 4.35  10
5; (c) 8.37  10
5; (d) 1.21  10
4;
(e) 1.56  10
4; (f) 1.88  10
4; (g) 2.19  10
4; (h) 2.47  10
4; (i) 2.99  10
4;
(j) 3.45  10
4; (k) 3.86  10
4; (l) 4.24  10
4 mol L
1; using GCE in 1.0 mol L
1
sodium hydroxide; SW parameters: f ¼ 50 Hz; a ¼ 40 mV; DEs ¼ 2 mV; and (B)
corresponding analytical curve.
nimesulide were evaluated and the relative standard deviation
(R.S.D.) was calculated as only 1.24%, indicating a very good
response of the electrode under these conditions.
Anodic oxidation of nimesulide
Nimesulide can also be oxidised in the anodic region and as
described elsewhere the anodic signal is probably due to the
oxidation of the methylsulfonamide group present in its struc-
ture.30 This feature is favourable for the utilisation of amper-
ometry coupled with ow injection analysis, once in these
regions the dissolved oxygen is not electroactive and will not
interfere with the analysis. In addition, this second alternative
of analysis is an attractive way to execute a double check for the
analysis of this compound in complex samples. The drawback
observed in the anodic region was the fact that in this region of
potential, nimesulide strongly affects electrode performance,
requiring frequent cleaning of the surface.24
An alternative solution to this problem was the adoption of
ways to regenerate the electrode's surface. In our recent
studies,31 we have demonstrated that ow injection analysis
coupled with multiple pulsed amperometry is an interesting
way for analysis and simultaneous cleaning of the electrode
surface. In the present study, this alternative was applied
successfully to the determination of nimesulide, as will be
detailed in the following sections.
For analysis of nimesulide in the anodic region, aer a
series of pilot studies, it was determined that the best elec-
trolyte was 0.1 mol L
1 H2SO4. To demonstrate the regenera-
tion of the electrode surface, two series of DPV experiments,
one (A) measured without pre-treatment of the electrode and
other (B) applying +1.6 V for 10 s before the start of the next
scan, were carried out. As can be seen in Fig. 3, when the
experiments were repeated without the pre-treatment step, a
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Analytical Methods
Fig. 3 Differential pulse voltammograms using a pyrolytic graphite electrode:
(A) electrode without any pre-conditioning treatment before the experiment; (B)
electrode pre-conditioned at 1.6 V for 10 seconds, before each DPV. a, b and c
represent three consecutive measurements in the same solution. Supporting
electrolyte: 0.1 mol L
1 H2SO4; nimesulide concentration: 1.0  10
5 mol L
1.
decrease of the signal by about 7.2% and 16.6% (in compar-
ison with the rst scan) was observed. A reproducible signal
was obtained when the pre-treatment was applied, avoiding
the fouling of the electrode (standard deviation between the
three peaks: 1.52%).
Flow injection measurements
In conventional systems incorporating both ow injection
analysis and amperometric measurements, the working elec-
trode is maintained at a xed potential. Under these conditions,
the charging/discharging process of the electrical double layer
is virtually zero, allowing the analyst to discriminate small
faradaic currents. FIA allows for the rapid transport of the
analyte to the electrochemical cell and also its wash-out from
the cell region, signicantly reducing the contact between the
sample and the working electrode, preventing (or even elimi-
nating) electrode fouling in many situations. In the case of
nimesulide, even in this short time, the effect on the electrode
response was sufficient to produce a substantial signal
decrease. Different strategies were investigated, with the utili-
zation of multipulse amperometry as the most promising way to
perform these analyses.
To perform the quantication of nimesulide by FIA, the best
results were obtained when a sequence of three pulses (E1 ¼ 1.3
V, for 100 ms; E2 ¼ 1.6 V for 150 ms and E3 ¼ 0.2 V, for 150 ms)
were chosen. These potentials and time intervals were selected
from a range of tested conditions and were found to be the most
favourable in maintaining the working electrode surface
throughout an extensive series of measurements. Similar results
were reported for serotonin using the platinum electrode.32 Fig. 4
illustrates the response of FIA-amperometry for a series of
injections at a xed potential (A) and under a pulsed sequence
(B). As can be seen in this gure, when a xed potential was
applied (1.3 V, without the application of the pulsed program) the
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Analytical Methods
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Fig. 4 Flow injection/amperometric responses for 5.0  10
5 mol L
1 nimesu-
lide, using a pyrolytic graphite electrode utilising (A) amperometry at a constant
potential (1.3 V) and (B) amperometry using multiple pulses (E1 ¼ 1.3 V for 100
ms; E2 ¼ 1.6 V for 150 ms; E3 ¼ 0.2 V for 150 ms). Carrier solution: 0.1 mol L
1
H2SO4; flow rate: 2.0 mL min
1; sample volume: 50 mL.
signal decreased relatively fast (the velocity with which the elec-
trode is blocked depends on a series of factors, between them the
amount of sample injected, the geometry of the cell and the
analyte concentration). In the present case, aer 14 injections,
the signal decreased from 3.45 to 2.93 mA (about 15%) in the
presence of a low concentration of nimesulide (only 5  10
5 mol
L
1). When the sequence of three pulses was applied, no decrease
of the signal was observed, resulting in a larger and very repro-
ducible signal (i ¼ 5.25 mA and relative standard deviation ¼
1.02%).
The comparison between the signals obtained in batch and
utilizing ow injection analysis shows a strong decrease of
current aer three repetitive experiments in batch (Fig. 3A),
similar to the one observed aer 14 injections of nimesulide,
even at 5 times higher concentrations (Fig. 4A). The reason for
this difference is easy to understand. In batch, the electrode
stays all time in contact with the analyte and the products of the
reaction are not mechanically transported out from the elec-
trode surface.
Under owing conditions, the contact between the electrode
and analyte is brief and the owing stream washes the elec-
trode, removing part of the products (or intermediates species)
responsible for the electrode poisoning process.
Table 2 Results of the analyses of two commercial samples containing nimesulide utilizing the (official) spectrophotometric method, cathodic determination using
square wave voltammetry (SWV) and anodic determination utilizing multipulse analysis (MPA). Differences between the official method and both electroanalytical
methods are also presenteda
Nimesulida (mg per tablet)
Sample Label value Official method b
SWV cathodic
A 100.0 103.5  1.7 102.2  1.9
B 100.0 99.7  1.6 96.7  1.8
a
n ¼ 3; mean  SD. b Official method: spectrophotometry, recommended in the Brazilian Pharmacopoeia.27 c DE1 ¼ difference between the official
method and labelled value. d DE2 ¼ difference between cathodic SWV and labelled value. e DE3 ¼ difference between anodic SWV and labelled value.
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Analytical applications
Cathodic and anodic analyses were applied for the determina-
tion of nimesulide in pharmaceutical formulations and the
results obtained were compared to the labelled values and also
with the results obtained using the spectrophotometric method
recommended in the pharmacopoeia27 (Table 2). Statistical
evaluation of the results demonstrated the good accuracy of
both, cathodic analysis, based on SWV and anodic analysis,
based on MPA.
According to the t-test, there were no signicant differences
between the results obtained by either procedure at the 95%
condence level, indicating that both voltammetric methods
can be used for the determination of nimesulide in pharma-
ceutical formulations. The possibility of the use of both condi-
tions (anodic and cathodic analyses) is interesting in cases
involving complex samples as the availability of more than one
form of analysis increases the reliability of the analysis.
Interference studies
The effects of some species such as magnesium stearate, starch
and lactose (sample excipients) on these analyses were investi-
gated. The tests demonstrated that these species were not
electroactive under the conditions utilised here, so their inter-
ference on the quantication of nimesulide was almost
nonexistent.
Addition-recovery experiments were also performed on
pharmaceutical products and the results obtained showed that
the recoveries (average of three analyses) varied from 96.5 to
102% for the proposed method, demonstrating the accuracy of
the procedure adopted here. It is important to note that the
concomitant species present in this sample did not cause
important matrix interference for the samples analysed by the
proposed method.
Conclusions
In this study, we demonstrated the potential of voltammetric
methods for nimesulide quantication in pharmaceutical
products. Different procedures for the determination of this
compound in the anodic and cathodic regions lead to good
results with high accuracy and precision, good linearity range
and achievement of low concentration limits. Square wave vol-
tammetry and multi-pulse amperometry were utilised for the
quantication of nimesulide in pharmaceutical samples and
Relative error%
MPA anodic DE1c (%) DE2d (%) DE3e (%)
104.7  3.1 +3.5 +2.2 +4.7
102.1  4.3
0.3
3.3 +2.1
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the results obtained were in good agreement with those
obtained by spectrophotometry, following the procedure
described in the Pharmacopoeia. The maximum differences
comparing all analyses – spectrophotometric, SWV and MPA –
were situated between +4.7 and
3.3%. The proposed voltam-
metric methods present additional advantages, among them
simplicity and rapid execution, and in many cases they do not
require any time-consuming extraction steps prior to the assay
of the drug. The possibility of performing two different deter-
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minations, one in the anodic and the other one in the cathodic
region, allows the analyst to perform a double check in the case
of complex samples (i.e. biological uids), preventing errors
provoked by the presence of interfering species.
Acknowledgements
The authors gratefully acknowledge the nancial support from
the Brazilian Foundations (Fundaç~ao de Apoio à Pesquisa do
Estado de S~ao Paulo – FAPESP, Coordenaç~ao de Aperfeiçoa-
mento de Pessoal do Ensino Superior – CAPES and Conselho
Nacional de Pesquisa – CNPq). This study was partially sup-
ported by projects CNPq 306504/2011-1, 142008/2009-5 and
480311-2009-9.
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