Electrochemical mechanism and kinetics studies of haloperidol and its assay in commercial formulations

Article abstract of DOI:10.1016/j.electacta.2010.11.049

The kinetics and mechanism for electrochemical reduction of haloperidol, a psychotherapeutic drug used in the treatment of schizophrenia, were studied using square wave and cyclic voltammetries allied to a hanging mercury drop electrode. The experimental and voltammetric parameters were optimized at 0.04 mol L^-1 Brinton-Robinson buffer (pH 10), with a pulse potential frequency of 100 s^-1, a pulse amplitude of 30 mV and scan increment of 2 mV. Two well-defined peaks were observed, which exhibited properties of fast electron transfer with a strong adsorption process of reactants and products on the electrode surface. The first peak was related to a fast and reversible anion-radical formation originating from the reduction of the carbonyl group, and the second was related to the irreversible reduction of the anion-radical previously formed. Analytical parameters such as: linearity range, equation of the analytical curves, correlation coefficients, detection and quantification limits, recovery efficiency, and relative standard deviation for intraday and interday were compared to similar results obtained by use of the UV-vis spectrophotometry technique, and the analytical results obtained in commercial formulations show that the voltammetric procedure using a hanging mercury drop electrode is suitable for analyzing haloperidol in complex commercial formulation samples.

Full text of DOI:10.1016/j.electacta.2010.11.049

Electrochimica Acta 56 (2011) 2036–2044
Contents lists available at ScienceDirect
Electrochimica Acta
journal homepage: www.elsevier.com/locate/electacta
Electrochemical mechanism and kinetics studies of haloperidol and its assay in
commercial formulations
a
b
a
a
Francisco W.P. Ribeiro , Janete E.S. Soares , Helena Becker , Djenaine De Souza ,
a
a,∗
Pedro de Lima-Neto , Adriana N. Correia
Departamento de Química Analítica e Físico-Química, Centro de Ciências, Universidade Federal do Ceará, Bloco 940 Campus do Pici 60455-970, Fortaleza, CE, Brazil
Departamento de Farmácia, Faculdade de Farmácia, Odontologia e Enfermagem, Universidade Federal do Ceará, Rua Capitão Francisco Pedro, 1210 Rodolfo Teófilo 60430-370,
a
b
Fortaleza, CE, Brazil
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 6 September 2010
Received in revised form
The kinetics and mechanism for electrochemical reduction of haloperidol, a psychotherapeutic drug used
in the treatment of schizophrenia, were studied using square wave and cyclic voltammetries allied to
a hanging mercury drop electrode. The experimental and voltammetric parameters were optimized at
1
1 November 2010
−
1
−
1
0
.04 mol L Brinton–Robinson buffer (pH 10), with a pulse potential frequency of 100 s , a pulse ampli-
Accepted 13 November 2010
tude of 30 mV and scan increment of 2 mV. Two well-defined peaks were observed, which exhibited
properties of fast electron transfer with a strong adsorption process of reactants and products on the
electrode surface. The first peak was related to a fast and reversible anion-radical formation originating
from the reduction of the carbonyl group, and the second was related to the irreversible reduction of the
anion-radical previously formed. Analytical parameters such as: linearity range, equation of the analyt-
ical curves, correlation coefficients, detection and quantification limits, recovery efficiency, and relative
standard deviation for intraday and interday were compared to similar results obtained by use of the
UV–vis spectrophotometry technique, and the analytical results obtained in commercial formulations
show that the voltammetric procedure using a hanging mercury drop electrode is suitable for analyzing
haloperidol in complex commercial formulation samples.
Available online 21 November 2010
Keywords:
Haloperidol
Mechanism redox
Cyclic voltammetry
Square wave voltammetry
Electrochemical behaviour
©
2010 Elsevier Ltd. All rights reserved.
1
. Introduction
at electrified interfaces (electrode/solution) when electroanalytical
techniques are employed [5].
Over the last decade, a great number of the research studies
According to previous reports, many procedures involving the
use of square wave voltammetry (SWV) have been employed to
study the electrochemical behaviour of different organic and inor-
ganic compounds [6–8]. Currently, detailed information on the
electrochemical behaviour of pharmaceutical compounds can be
found in the available literature, with more attention to research
studies in analytical determination, due to certain convenient fea-
tures including high sensitivity, accuracy, precision and simplicity
in experimental procedure, as well as a large linear dynamic range,
with relatively low costs in the instrumentation and short duration
of analysis [9].
Regarding pharmaceutical compounds, haloperidol {4-[4-(4-
chlorophenyl)-4-hydroxyphenyl)-1-butanone} (HP), a psychother-
apeutic drug used in the treatment of schizophrenia, mania and
neurological disorders [10], has been considered as a suitable elec-
tron receptor. For this reason, it can be reduced, producing currents
that are proportional to the analytical concentration. Its analytical
determination has been evaluated using a static mercury drop elec-
trode [11], a hanging drop mercury electrode (HMDE) [12], a glassy
carbon electrode [13], a platinum and gold rotating disc electrode
[14], glassy carbon electrode [15] and a glassy carbon electrode
modified with multi-walled carbon [16].
worldwide have developed various electroanalytical procedures,
which can be used in drug control laboratories for pharmaceu-
tical compounds, in quantification of its commercial formulation
products, determining its degradation products, and the quantifi-
cation of residues in biological fluids, such as blood and urine
[
1–4].
However, few attempts have been made in these studies to
obtain information concerning the kinetics and the charge transfer
mechanisms involved in the reduction or oxidation process of phar-
maceutical compounds and other molecular reactions of biological
interest. This information is of great importance in the evaluation
of the redox properties of pharmaceutical compounds, identify-
ing the intermediate reactive species, elucidating the drug action
mechanism, evaluating metabolic events of drugs, and supplying
information about redox properties in humans. In addition, this
reaction in humans is very similar to redox processes that occur
∗ Corresponding author. Tel.: +55 85 3366 9050; fax: +55 85 3366 9982.
E-mail address: adriana@ufc.br (A.N. Correia).
0
013-4686/$ – see front matter © 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.electacta.2010.11.049

F.W.P. Ribeiro et al. / Electrochimica Acta 56 (2011) 2036–2044
2037
In these studies, the metallic and glassy carbon electrodes
presented excellent mechanical and electrical properties [17].
However, their use was at times limited, due to the adsorption
process of the HP or the resultant products of the HP electrochem-
ical reduction, producing low sensitivity and reproducibility of the
electrochemical responses. The data obtained on the modified elec-
trodes confirm the difficulties involving the use of these electrodes
in analytical applications [16].
By the use of mercury electrodes, in the static or hanging
mode, the controlled formation of the electrode surface offers
highly reproducible, readily renewable, and stable and smooth sur-
faces, which are the more important properties of this material.
Moreover, the electroanalytical procedures developed using these
electrodes permitted its direct trace assay in commercial formula-
tions and human biological fluids. However, the voltammetric data
have not been well explored regarding kinetics and mechanistic
aspects.
900 nm. A quartz cell with an optical path of 1 cm was employed in
these measurements.
A Micronal B474 pH meter equipped with a 3.0 mol L 1
Ag/AgCl/KCl–glass combined electrode was used to adjust the pH
values. All the solutions were prepared with water purified by a
Milli-Q system (Millipore Corp.).
−
−
3
−1
−4
−1
Stock solutions of 1.0 × 10 mol L and 1.0 × 10 mol L of
USP-grade HP were prepared daily by dissolving a suitable quantity
of it in pure ethanol, which was then stored in a dark flask and kept
in a refrigerator to prevent degradation.
−
1
0.04 mol L
of Britton–Robinson (BR) buffer, prepared as
described in a previous paper [18], was used as the supporting elec-
trolyte and the pH was adjusted to the desired value by adding
−
1
suitable amounts of 0.2 mol L NaOH stock solution.
2.2. Working procedure
The use of the modern voltammetric techniques promotes
a substitution of traditional polarographic techniques, reducing
the mercury residues and decreasing the time for each analysis.
Besides, the use of modern electroanalytical instruments permits a
considerable decrease in mercury residues.
All measurements were carried out under ambient conditions.
The appropriate solutions were transferred into the electrochem-
ical cell and the optimization of the analytical procedure for SWV
was carried out following a systematic study of the experimental
parameters that affect the responses, such as the pH of the medium,
the pulse potential frequency (f) related to total pulse duration,
the amplitude of the pulse (a), and the height of the potential step
In relation to environmental problem in the pharmaceutical
industry, similar to research laboratories, the adequate manage-
ment, following a set of required and recommended operating
procedures and guidelines designed to reduce the amount of mer-
cury discharged, permit that the mercury could be used as working
electrode. As the dental offices, the mercury waste can be ade-
quately stored, and leaded to treatment by specialized company.
A detailed search in previously published works had shown the
employ of the HMDE in the analytical determination of organic
compounds, such as pesticides and pharmaceutical compounds. In
someworks, this electrode is used due tothe productsofredox reac-
tion are strongly adsorbed in electrode surface, and for this the use
of solid electrode no possibility the acquisition of the reproducibil-
ity in the responses. Besides, when the HMDE is used, the samples
are used without pre-treatment or extraction steps, reducing the
time and costs in the analysis.
The greater part of this study comprises a detailed investi-
gation of the mechanism of electrochemical reduction of HP on
the HMDE using a combination of cyclic (CV) and square wave
voltammetries, by appropriate use of a well-developed theoret-
ical model for current and potential responses, which can give
information about the kinetics and mechanism of electron trans-
fer. Moreover, the SWV data are explored in order to establish an
appropriate and efficient methodology for the analytical determi-
nation of HP in commercial formulations, with comparison to the
ultraviolet–visible spectrophotometry (UV–vis) technique, as rec-
ommended by British Pharmacopeia [10].
(ꢀE ) or scan increment. All parameters were properly optimized
s
since their values exert high influence on the sensitivity of voltam-
metric analysis [6,7]. The mentioned parameters were optimized in
relation to the maximum value of peak current and the maximum
selectivity (half-peak width).
To accomplish this experimental sequence, the working elec-
trode was placed in the measuring cell filled with 20 mL of BR buffer
solution containing a known concentration of HP. After this, the
experimental and voltammetric parameters were evaluated. Before
each experiment, a stream of N2 was passed through the solution
for 10 min. Following oxygen removal, negative scans were made
in the interval of 0.0 V to −1.2 V, using CV and SWV techniques.
After the optimization of voltammetric parameters, analytical
curves were obtained in pure electrolyte by the standard addition
method. The standard deviation of the mean current measured at
the reduction potential of the HP compound for ten voltammo-
grams of the blank solutions in pure electrolytes was used (Sb)
[19,20] in the determination of the detection and quantification
limits (DL and QL, respectively) together with the slope of the
straight line of the analytical curves (s) as follows:
DL = 3
QL = 1
Sb
(1)
(2)
b
03S
b
b
The recovery experiments were carried out using voltammet-
ric and spectrophotometric procedures. For this, a known amount
of pharmaceutical formulations was added to the supporting elec-
trolytes, followed by standard additions of the HP stock solutions
and plotting the resulting analytical curves. All measurements were
taken in triplicate. The recovery efficiencies (%R) were calculated
using Eq. (3), where the value [HP]found refers to the concentration
obtained by extrapolating the analytical curves of the correspond-
ing artificially spiked samples:
2
. Experimental
2.1. Reagents and equipment
All the voltammetric measurements were taken with a poten-
tiostat (Autolab PGSTAT 30, Metrohm-Eco Chemie) controlled
by a personal computer, using GPES version 4.9 software (Gen-
eral Purpose Electrochemical System, Metrohm-Eco Chemie). A
conventional cell with a three-electrode system, consisting of
[
HP]found
%R = [
× 100
(3)
HP]added
−
an Ag/AgCl/Cl saturated electrode as the reference electrode, a
graphite rod as the auxiliary electrode, and a hanging mercury drop
electrode (663 VA Stand from Metrohm, surface area 0.52 mm ) as
a working electrode.
For UV–vis measurements, a Varian spectrophotometer model
Cary 1E was employed, with the wavelength operating from 190 to
The precision of the proposed procedure was evaluated based
on reproducibility experiments realized with different standard
solutions of HP on different days (intraday). The accuracy was eval-
uated from experiments regarding repeatability obtained in ten
replicated determinations in the same solution of HP (interday).
2

2
038
F.W.P. Ribeiro et al. / Electrochimica Acta 56 (2011) 2036–2044
The relative standard deviations (RSD) were calculated for
-1.6
reproducibility and repeatability measures, using the relationships
between the standard deviation and the mean of the peak current
values obtained.
The proposed procedure was compared to the UV–vis spec-
trophotometry measurements in the same optimized experimental
conditions, according to the procedure recommended by British
Pharmacopeia [10], where the spectrum and the characteristic
absorbance of the HP were evaluated at 245 nm.
0
.30
.25
-
-
-
-
-
1.5
1.4
1.3
1.2
1.1
0
0.20
0.15
2.3. Application of methodology
0.10
2
4
6
8
10
12
After calculating the DL and QL for the determination of HP in the
pH
BR buffer, the accuracy, reproducibility and precision of the proce-
dure, and the interference from excipients used in the commercial
formulations were studied. This was done by means of recovery
experiments with distinct commercial products purchased locally.
Two commercial formulations were assayed, the first being
Fig. 1. Relationships between the pH values and the peak potentials (right y-axis)
and currents (left y-axis) for HP determination using the HMDE and cyclic voltam-
metry technique, considering the more negative peak. Electrolyte composed of
−
1
−1
0
.04 mol L of BR buffer with scan rate of 20 mV s .
®
Haldol tablets from Janssen-Cilag, Brazil, each tablet containing
different inclination values, using the following equations:
Ep = 1.040 + 0.051 pH (First inclination)
1
mg of HP (1 mg/tablet) and lactose, starch, sucrose, talcum pow-
der and magnesium stearate. The tablets were crushed into a power
and a carefully weighed portion of the powder, sufficient to produce
(4)
(5)
−4
−1
a final concentration of 1.06 × 10 mol L of HP, was transferred
Ep = 1.227 + 0.030 pH (Second inclination)
where values of potential are given in Volt.
Eq. (4), for the first inclination, represents a straight line with
a slope very close to the theoretical value predicted by the Nernst
equation as shown below:
into 25 mL volumetric flasks and diluted to volume with ethanol.
®
The second commercial formulation was also Haldol in the com-
mercial oral solution formulation from Janssen-Cilag, Brazil, which
contains 2 mg of HP in each 1 mL (2 mg/mL). The solution was pre-
pared taking up a suitable amount of the oral solution, placing it in
a 10 mL volumetric flask and completing the volume with ethanol
to a final HP concentration of 1.0 × 10 mol L . All samples were
used immediately after their preparation to prevent decomposition
by light or heat. The samples were used to evaluate the recovery
percentages using SWV and UV–vis experiments.
ꢀ
ꢁ
2.303RTm
nF
o
−4
−1
Ep = E −
pH
(6)
˛
where ˛ is the transfer electron coefficient, m is the number of
protons involved in the reaction, and the other terms remain with
their usual meanings [21], for an electrochemical reduction process
involving the same number of protons and electrons. Eq. (5), for
the second inclination, represents a reduction process related to
one proton for two electrons. Furthermore, a close analysis of the
values of the interception of the two straight lines, which occurs
at pH 8.8, shows that this pH is close to the value of pKa (i.e. 8.3),
reported in the literature [22]. Moreover, the maximum current
value was obtained for pH 10.0, as shown in Fig. 1, which is above
the pKa value; it is the value where the highest current signal can
be observed. In this condition (pH > pKa) the reduction peak can be
related to the formation of very reactive species, such as a radical-
anion, or dimmers that can occur between the anion-radical and
neutral molecules present in low concentration near the electrode
surface [23].
3
. Results and discussion
All experimental results of the CV and SWV were used to eval-
uate the mechanism and kinetics of the HP reduction process by
use of the adequate diagnostic criteria developed for each tech-
nique and compared with similar data in the literature. Moreover,
all SWV results were employed to evaluate the experimental con-
ditions in which it was possible to obtain the best analytical signal,
considering the higher intensity of signal with a suitable half-peak
width for analytical purposes.
3.1. Preliminary experiments
Using CV the pH dependence in the HP reduction process was
3.2. Cyclic voltammetry
−5
−1
−1
investigated to 2.91 × 10 mol L
of HP in 0.04 mol L of BR
buffer with pH values from 2.0 to 12.0. The potential was scanned
from 0 to −1.8 V, and the voltammetric responses showed the pres-
ence of two peaks: a smaller peak current at less negative potential
values, and the other with a well-defined profile and high signal
intensity at more negative potential values. For the smaller, less
negative peak, the increase in pH produced practically no modifi-
cation in the peak currents and peak potential values up to pH 8.0.
However, pH above this value promoted shifts in peak potential to
more negative values and small increases in peak currents.
Some cyclic experiments were developed in order to under-
stand the electrochemical behaviour of HP at HMDE using
−
5
−1
−1
2.91 × 10 mol L
of HP in 0.04 mol L of BR buffer (pH 10.0).
When the potential was scanned from 0 to −1.8 V, the HP responses
revealed a small peak, followed by second very well-defined peak,
which the authors called peak 1 and peak 2, respectively, as shown
in Fig. 2. When the scan direction was changed, no oxidation pro-
cess was observed, indicating the irreversibility for the two redox
processes. Successive scans were performed, and a complete dis-
appearance of peak 1 and a considerable decrease in peak 2 was
observed, due to the irreversible adsorption process of the HP
reduction products on the HMDE.
For the more negative peak, the voltammetric responses show
that the peak potential (Ep) shifts towards more negative values as
the pH increases, as shown in Fig. 1. It can also be observed that
peak potential variation with pH implies that in pH values above
.0 the electron transfer step is followed by protonation, which is
probably rate-determining in the redox process [21]. This shift in
potential with pH can be represented by two straight lines, with
When the potential was scanned from 0 to −1.2 V, a well-defined
peak was observed in the reverse scan, as shown in the insert of
Fig. 2, suggesting that the redox process in peak 2 is related to the
reduction products formed at lower potential. When the potential
8

F.W.P. Ribeiro et al. / Electrochimica Acta 56 (2011) 2036–2044
2039
with another HP molecule in the neighbourhood of the electrode
producing a dimmer that can be quickly oxidized in the reverse
scan [24].
In peak 2, a shift of Ep to more negative values with the increase
of v confirmed the irreversible nature of this redox process. More-
over, the linear dependence of peak potential on the logarithm of
scan rate and Ep vs log v relationship showed a slope of 0.049 V,
which can be related to:
peak 2
-
-
-
-
0.8
0.6
0.4
0.2
-
-
-
0.09
0.06
0.03
0
0
.00
.03
∂
Ep
29.6
˛na
-
0.9
-1.0
-1.1
-1.2
=
(7)
-
E vs (Ag/AgCl/Cl saturated) / V
∂ log ꢁ
peak 1
where na is the electron number in the determining step, and poten-
tial is considered in V. Therefore, considering ˛ = 0.5, a typical value
for electron transfer involving organic compounds, the transfer of
one electron occurs, according to the theoretical model proposed
by the electrochemical–chemical mechanism, with fast electrode
kinetics and fast chemical kinetics [23].
0
.0
-
1.0
-1.2
-1.4
-1.6
-1.8
-
E vs (Ag/AgCl/Cl saturated) / V
−
5
−1
Fig. 2. Cyclic voltammograms for 2.91 × 10 mol L HP solution in BR buffer (pH
−1
1
0.0) on the HMDE at 20 mV s , showing scan potential from 0 to −1.8 V vs
3.3. Square-wave voltammetry components
−
Ag/AgCl/Cl saturated. Insert: similar responses obtained for potentials scanned
from 0 to −1.2 V vs Ag/AgCl/Cl− saturated.
−
5
−1
−1
SWV experiments in 2.91 × 10 mol L of HP in 0.04 mol L of
BR buffer (pH 10) were performed for preliminary evaluation of the
electrochemical behaviour of HP by analysis of backward (Fig. 3A),
forward (Fig. 3B), and net components (Fig. 3C). Therefore, realiz-
is completely scanned the species formed in lower potentials was
completely and irreversible reduced and the reverse peak vanishes.
−
1
−1
The scan rates (v) were evaluated between 0.02 and 0.5 V s
ing a scan potential from 0 to −1.7 V, with f = 100 s , a = 50 mV and
for potential intervals scanned from 0 to −1.2 V. The voltammet-
ric responses showed that the ratio between anodic and cathodic
peaks (Ipa/Ipc) in the function of scan rates presented values lower
than the unit, and this value was reduced while the scan rate was
increased. According to the criteria of redox process evaluated by
CV, this result suggests a reversible charge transfer followed by a
reversible chemical reaction [24].
ꢀEs = 2 mV, we can observe that the resultant square wave voltam-
mograms presented two voltammetric peaks towards the forward
component of current, the first around −1.0 V and the second at
approximately −1.5 V.
The backward component was characterized by a backward
peak smaller than the forward peak, but with an intense and narrow
maximum. This peak only appears at amplitudes higher than 40 mV,
and, according to SWV theory [28], this can indicate the case of a
fast and chemically reversible surface redox process, similar to ear-
lier responses observed in the CV experiments. Furthermore, due to
the peak separation in the forward and backward components, for
peak 1 the net component is characterized by the presence of two
peaks; one resulting from the reductive responses present in for-
ward component contribution at lower potential values, and the
other peak resulting from the backward component contribution
present in oxidative responses at higher potential values. These
types of responses are frequently called split in net responses.
According to Mir cˆ eski and Lovri c´ [6,28,31], the split in net
responses can appear when the redox reaction is fast and reversible,
and it is a consequence of the current sampling procedure. When
a pulse potential is applied a disturbance occurs in the redox
equilibrium, which occurs between the electrode surface and the
solution, promoting the appearance of peak currents to obtain a
new equilibrium. When this equilibrium is reached, often quickly,
the backward component can be reduced or may entirely vanish.
This quick and reversible redox process was experimentally con-
firmed by variation in f values. The voltammograms obtained show
that while f was increased, the separation between forward and
backward components was diminished. Consequently, the split in
For potential intervals from 0 to −1.8 V, the scan rates in the CV
experiments, considering the same experimental procedure used
−1
earlier, ranged from 0.02 to 0.5 V s . In this potential interval, it
was observed that the increase in scan rates promoted no change
in peak potential values for peak 1, indicating a possible nature of
irreversibility in the redox process. However, in the reverse scan, no
peak was observed, indicating that the irreversibility in the redox
process can be induced by the following chemical reaction, which
removes the reduced species more quickly than reverse electron
transfer [25].
The peak current values were also studied considering different
scan rates for a potential scanned from 0 to −1.8 V. For peak 1, the
peak current presented a linear dependence on the scan rate and
log Ip vs log ꢁ relationship showed a slope of 0.91, very close to 1.0,
an expected value for an adsorption-controlled process. For peak
2
, the peak current presented a linear dependence on the square
root of the scan rate, and the log Ip vs log ꢁ relationship showed
a slope of 0.74, an intermediate value, which suggests a “mixed”
diffusion–adsorption peak.
Some articles report that peak 1 corresponds to an adsorptive
pre-peak typical of the strong adsorption process due to the differ-
ence of free energy between the chemical species strongly adsorbed
and chemical species without adsorption on the electrode surface
−
1
net responses vanishes to f values above 300 s . This behaviour
[
11,12,26]. However, we believe that voltammetric peak 1 is related
promotes a considerable increase in peak current values up to
500 s . Above this value, the peak current decreased, and the peak
potential presented more negative values.
−
1
to the charge transfer, and the HP results confirm that this process
is due to an electron transfer following chemical reaction, typical of
the mechanism related to the reduction process of ketone groups
Plotting the ratio between peak current and the square root of
f values (ꢀIp/f1 ) vs 1/f one obtains a parabola-like curve depen-
dence [29], which corresponds to the theoretical dependence on
the peak current in the critical kinetic parameter (Ämax). The maxi-
mum can be use to estimate the kinetic constants (ks). According to
Komorsky-Lovri c´ and Lovri c´ [30], the maximum in the parabola is
called the “quasi-reversible maximum” and depends on the coeffi-
cient of electron transfer and of the amplitude pulse, and occurs
/2
[
11,21,27].
For peak 1, then, the obtained results indicated that an elec-
tron transfer occurred following chemical reaction, where the HP
molecule can be reduced to a radical anion, which can immedi-
ately abstract a proton from the solvent, similar to reactions that
occur with the reduction processes of ketones and aldehydes in
weakly alkaline media, or the radical anion that formed reacted

2
040
F.W.P. Ribeiro et al. / Electrochimica Acta 56 (2011) 2036–2044
calculated by:
(
A)
Peak 2
Forward component
-
-
-
-
-
2.5
2.0
1.5
1.0
0.5
ks = Ämax × fmax
(8)
where Ämax is the theoretically calculated critical kinetic param-
eter. When ˛ is not known exactly, the Ämax value used is
Ämax = 1.18 ± 0.05, which applies in the range of 0.25 ≤ ˛ ≤ 0.85.
Therefore, the ks value for HP, with the optimized experimental
parameters used, was determined to be 590 s confirming the fast
kinetics in the redox process.
As the forward peak, which appears at more positive potentials,
is higher than the backward peak, we can affirm that the ˛ is higher
than 0.5 [28], thus indicating a fast electron transfer, similar to
the behaviour observed by CV. Therefore, the ˛ values could be
calculated using the ratio between forward and backward current
components [29]:
Peak 1
−
1
0
.0
-1.0
-1.2
-1.4
-1.6
ꢂ ꢃ
I
f
log
= 1.3205˛ − 0.723
(9)
-
-
-
-
-
2.5
2.0
1.5
1.0
0.5
(B)
I
b
Backward component
where I and I are the peak currents in forward and backward com-
f
b
ponents, respectively, since the potential separation between split
peaks is insensitive to the electron transfer coefficient. Considering
−
1
f = 100 s and the ration of the I /I as 1.606, the ˛ value was cal-
f
b
culated as 0.7. These results confirm a fast electron transfer with
the formed product able to be quickly consumed by a subsequent
chemical reaction [25].
The related electrochemical process presents a very well-
defined peak in the forward component and a small backward peak
in the same direction of the forward component, typical of an irre-
versible reaction. Consequently, the net current is smaller than the
absolute value of the forward component, as shown in Fig. 3C. These
responses are typical of the process that occurs – strong adsorption
of the reactant and/or product on the working electrode surface,
preventing the electron transfer and reducing a backward com-
ponent, similar to the reduction process in a totally irreversible
process following by chemical reaction [31].
Peak 2
Peak 1
0
.0
-
1.0
-1.2
-1.4
-1.6
(
C)
Net component
-
-
-
-
-
2.5
2.0
1.5
1.0
0.5
Peak 2
3.4. Square-wave voltammetry parameters
Peak 1
As is well known, changes in f, a and ꢀEs exert obvious effects on
the voltammetric responses. Based on this, these effects on the Ip in
−
5
−1
the HP reduction process were investigated for 2.9 × 10 mol L
−1
−1
HP solution in BR buffer (pH 10.0) for f values from 10 s to 700 s
,
a values from 5 to 80 mV, and ꢀEs from 2 to 10 mV. Therefore,
the variation in each voltammetric parameter promoted different
responses in peak 1 and peak 2.
In peak 1, the net component is characterized by a split in the
responses, as discussed in the analysis of the current components
0
.0
-
1.0
-1.2
-1.4
-1.6
(Fig. 3C). The increase in f values led to a decrease in difference
-
E vs (Ag/AgCl/Cl saturated) / V
between the peak separations (ꢀEp), due to the fact that the poten-
tials corresponding to the maxima of the two components are less
separated and, as such, the splitting of the net components van-
ishes. This is followed by the significant increase of all currents,
similar to the expected reversible redox reaction followed by a fast
surface chemical reaction [28].
−
5
−1
Fig. 3. Square wave voltammograms for 2.91 × 10 mol L HP solution in BR buffer
−1
(
pH 10.0) on the HMDE, recorded with f = 100 s , a = 50 mV and ꢀEs = 2 mV, and
showing forward, backward and net component of currents for the reduction of HP.
particularly in quasi-reversible redox process and in reversible
redox process with strong adsorption between reactants and prod-
ucts.
Considering peak 1 and peak 2, a linear relationship between
the peak current and the f values was observed for f values until
−
1
100 s , as shown in Fig. 4A and B, considering peak 1 and peak 2,
−
1
The Ämax is independent of the number of electrons transferred
and the amplitude pulse employed; nor does it depend on the inter-
actions between adsorbed molecules. As such, the “quasi-reversible
maximum” is a consequence of the current sampling procedure and
appears when the frequency of the sampling is synchronized with
the rate of the charge transfer [30,32]. Thus, using the maximum
of the curve and the corresponding frequency values, called critical
frequency (fmax), the kinetic constant of the redox process may be
respectively. For f values above 100 s no linear relationships were
observed (not shown). According to the theoretical model proposed
by Lovri c´ and Komorsky-Lovri c´ [32] for SWV, this type of current
response may indicate an adsorption-controlled process character-
istic of the surface redox reaction. Additionally, an increase in the
f values was accompanied by a shift towards more negative values
in peak potentials, a behaviour indicating that both peaks involve
reactant and/or product adsorption as the rate-determining step in

F.W.P. Ribeiro et al. / Electrochimica Acta 56 (2011) 2036–2044
2041
2.0
1.5
1.0
0.5
0.0
2
1
1
.0
.5
.0
(A)
(B)
0.5
0.0
0
20
40
60
1
80
100
0
20
40
60
80
100
-
1
-
f / s
f / s
2
1
1
0
0
.0
.5
.0
.5
.0
2
1
1
.0
.5
.0
(C)
(D)
0.5
0.0
0
20
40
60
80
0
20
40
60
80
a / mV
a / mV
−
5
−1
Fig. 4. Relationship between the peak current and frequency of pulse potential and pulse amplitude obtained from square wave voltammograms for 2.91 × 10 mol L HP
solution in BR buffer (pH 10.0) on the HMDE, with variation of each parameter.
electron transfer. Therefore, for analytical purposes, an f value of
Several electroanalytical procedures to determine pharma-
ceutical compounds in commercial formulations are carried out
employing the application of specific potential values for accumu-
lation times. However, as the goal of this study was the application
of the procedure in the analytical determination of commercial
formulations, the steps for pre-concentration were not used, pre-
cluding interference from the excipients.
−1
1
00 s was employed due to this value presenting a maximum,
considering the linear interval between peak currents and f values
employed.
The influence of amplitude on the intensity of peak current was
also considered for the HP reduction process for values from 5 to
8
0 mV, and the voltammetric responses indicated that an increase
in peak current occurred as long as a values were increased. The
behaviour of peak current values with a can be represented by two
straight lines, with different inclination values, as shown in Fig. 4B
and C, considering peak 1 and peak 2, respectively. Furthermore,
close analysis of the values of the interception of the two straight
lines, which occurs at 40 mV for peak 1 and at 30 mV for peak 2, are
indicative that, above these values, a change in redox mechanism
occurs. In addition, an increase in the a values promoted practically
no change in the peak current.
Moreover, the variation in a values shows that a split in net com-
ponent only occurred for amplitude pulses above 40 mV, where the
appearance of the backward component occurs, indicating that the
critical amplitude for split net response appearance was 40 mV.
Additionally, all peak potential values shift to more positive val-
ues as long as a values were increased, typical to redox processes
involving strong adsorption from products and reactants at the
electrode surface [33]. Thus, for analytical applications, a value of
3.5. Redox mechanism
Based on the abovementioned observed results in conjunction
with information in literature reports [21–25], it can be ascertained
that the most feasible mechanism for reduction of HP on HMDE
involves two steps, which could be analyzed in the peak around
−1.0 V and in the peak around −1.5 V.
In the first step, around −1.0 V, the formation of a radical-anion
from a carbonyl group probably occurred. This radical-anion is a
very instable species, which, with a pH higher than the pKa value
(pH > 8.3), immediately abstracted a proton from the solvent in a
subsequent chemical reaction. When the potential was scanned up
to −1.2 V, the radical-anion was reversible, formed from a fast and
reversible redox process.
For scan potentials up to −1.8 V, the anion-radical formed in the
first step was reduced by breaking the double carbon–oxygen bond
in the carboxyl group and the subsequent reduction to a hydroxyl
group, as shown in Fig. 5.
3
0 mV was chosen for a.
For scan increments, the increase in this value will also increase
the signal and the sensitivity of the technique. However, for larger
values of ꢀEs, a widening of the peaks may occur, thus diminishing
the resolution of the analysis. For this reason, ꢀEs was evaluated
for the reduction of HP on HMDE. The voltammograms obtained,
therefore, show that the ꢀEs has promoted an increase in peak
current values, without linear dependence between peak currents
and ꢀEs, which is typical of the voltammetric responses in reactions
involving reactants and products adsorbed on the electrode surface.
Consequently, the value for this parameter was 2 mV in subsequent
experiments.
3.6. Analytical curves
All the aforementioned parameters were employed not only to
draw the analytical curves for the HP reduction process on HMDE
in a supporting electrolyte medium, but also to determine the
sensitivity of the proposed procedure, and for applications in com-
mercial HP formulations.
The analytical curves were drawn as described in Section 2,
considering only the voltammetric responses for peak 2, which

2
042
F.W.P. Ribeiro et al. / Electrochimica Acta 56 (2011) 2036–2044
(A)
-
-
-
-
-
1.0
0.8
0.6
0.4
0.2
0.0
-1.45
-1.50
-1.55
-
-1.60
-1.65
E vs (Ag/AgCl/Cl saturated) / V
(B)
1.0
0
0
0
0
0
.8
.6
.4
.2
.0
0
.0
0.5
1.0
1.5
2.0
2.5
3.0
3.5
4.0
-
6
-1
(
[HP] / 10 ) / mol L
−
1
Fig. 6. (A) Square wave voltammograms for HP in 0.04 mol L BR at pH 10.0 on
−
1
the HMDE with f = 100 s , a = 30 mV, ꢀEs = 2 mV, and concentrations in the interval
−
7
−6
−1
from 2.49 × 10 to 3.38 × 10 mol L of HP. (B) Analytical curves obtained from
voltammograms presented in part (A).
significance test in order to determine if the difference between
the interception obtained in these analytical curves and the stan-
dard values originated from random error [34]. The t-test was used
according the equation:
√
n
t = ( x¯ − ꢂ)
(11)
s
where x¯ is the average from interception values obtained, ꢂ is the
standard value expected in the case of the interception being zero,
n is the number of determinations and s is the standard deviation
of the current responses.
Fig. 5. Proposed mechanism for reduction process of HP on the HMDE.
The t value calculated was 2.21, which was lower than the criti-
cal value (tcritical = 4.30) at an assurance level of 95%, indicating that
no considerable differences occurred from the medium value calcu-
lated to the standard expected value, and the negative interception
was free from random errors.
The DL and QL values obtained by the proposed procedure were
determined using the standard deviation of the mean current mea-
sured at the HP reduction potential and the slope of the straight
line of the analytical curves, as recommended by IUPAC [19] and
described in Section 2. Table 1 lists the analytical parameters eval-
uated where the linearity range (LR), correlation coefficient (r),
which determines the degree of linearity of the correlation between
the concentration of HP and peak currents, as well as the stan-
presented higher signal intensities. The curves were performed
−7
−6
−1
for concentrations ranging from 2.49 × 10 to 3.38 × 10 mol L
,
with aliquots from HP stock solution added consecutively to the
electrochemical cell. The voltammetric responses were recorded
−1
with f = 100 s , a = 30 mV and ꢀEs = 2 mV.
The analytical curves indicated a linear increase in the responses
as a function of the increase in the analytical concentration of HP,
without displacement in peak potential values. Fig. 6 shows the
voltammograms and the linear correlation between peak currents
and added concentrations.
As can be observed in the insert of Fig. 6, the analytical curves
for HP on HMDE presented a negative interception, as shown in Eq.
dard deviation of the arithmetic mean of ten blank solutions (S ),
b
(
10):
the DL, the QL and RSD for intraday and interday experiments are
shown to medium voltammetric data, which were calculated from
the medium values from triplicate experiments.
Ip(␮A) = −1.918 × 10−8 + 0.307[HP](mol L−1
)
(10)
which presented a correlation coefficient of 0.9996. Therefore, an
evaluation of the presence of random errors was realized by a
Analytical curves were also performed by UV–vis in order to
compare the results obtained with SWV on the HMDE. The UV–vis

F.W.P. Ribeiro et al. / Electrochimica Acta 56 (2011) 2036–2044
2043
Table 1
Parameters of the analytical curves obtained in the determination of HP using SWV and UV–vis (LR: linearity range, r: correlation coefficient; Sb: standard deviation from the
arithmetic mean of ten blank solutions; DL: detection limits, QL: quantification limits and RSD: relative standard deviation for interday and intraday experiments).
Parameter
LR (mol L 1
Equation curve
r
SWV
UV–vis
−
−7
−6
−7
−6
)
2.49 × 10 to 3.38 × 10
1.00 × 10 to 1.50 × 10
−
8
−3
4
−Ip = −1.06 × 10 + 0.30[HP]
Abs = 1.19 × 10 + 2.02 × 10 [HP]
0.9996
0.9955
−10
−4
−8
−7
Sb
4.78 × 10
(A)
4.94 × 10 (u.a.)
−
1
−9
−8
−1
−1
−1
−1
DL (mol L
)
4.75 × 10 (1.78 ␮g L
)
)
7.34 × 10 (27.59 ␮g L
)
)
QL (mol L−1)
1.58 × 10 (5.94 ␮g L
2.44 × 10 (91.71 ␮g L
RSD (interday)
RSD (intraday)
1.89% (n = 12)
2.33% (n = 7)
1.85% (n = 12)
1.56% (n = 7)
determinations of HP were performed using the experimental
parameters presented in Section 2, which are similar to the spec-
trophotometry conditions already reported by Lea et al. [35] and
recommended by British Pharmacopeia as the standard proce-
dure to determine HP in commercial formulations [10], where the
detection was realized in 245 nm. The obedience of Beer–Lambert
recovery efficiencies from 70% to 130% are accepted as an indication
of the suitable analytical procedures [20].
The precision and accuracy of the procedure were also cal-
culated. The precision was evaluated based on reproducibility
experiments involving seven different measurements of a stan-
−
7
−1
dard solution containing 9.90 × 10 mol L PH in different days
(interday), and the RSD values were determined, with the results
showing values below 1.90%. The accuracy of the measurements
was also evaluated from ten replicated determinations realized
in the same day (interday) of a standard solution containing
−
7
law was observed in the concentration range from 1.0 × 10 to
−
6
−1
1
.5 × 10 mol L , the analytical curves were obtained in triplicate
and the results reported here represent the average of the values
obtained.
−
7
−1
The DL and QL values calculated by the proposed procedure were
very close to values published previously using mercury electrodes,
in the hanging or static mode [11,12], or glassy-carbon electrodes
9.90 × 10 mol L of PH. The resulting RSD also showed values
lower than 2.50%. The calculated values for RSD, for intraday and
interday experiments, indicated that the procedure showed good
repeatability and reproducibility, and could be employed with suc-
cess for practical applications, such as analytical determinations of
HP in commercial formulations.
[
13], but lower than values obtained for other butyrophenone phar-
maceutical compounds on platinum and gold rotating electrodes
14]. Moreover, the DL and QL values calculated by the proposed
[
procedure presented values lower than similar data calculated from
the use of the analytical procedure indicated by British Pharma-
copeia. As such, the present procedure proved to be a good choice
for determining HP, since its use in simplifying the analytical proce-
dure, lowering costs and providing reliable sensitivity for analytical
purposes.
Recovery experiments were also performed using the SWV on
the HMDE and UV–vis experiments in order to evaluate and com-
pare the efficiency of the proposed methodology. The recovery
curves were constructed in triplicate according to the description
in Section 2. The results obtained are shown in Table 1 for SWV on
the HMDE and for UV–vis experiments.
3
.7. Application of the procedure in commercial formulations
Stability, recovery, specificity and precision data of commercial
formulations were determined to evaluate the applicability of the
proposed procedure for complex samples. To this end, we used
samples of two different forms of HP commercially available in
Brazil (tablets and oral solution), which were prepared following
the procedure described in Section 2.
The recovery curves were built by the standard addition method
and the recovery percentage was identified graphically, with the
abscissa axis referring to the concentration of HP in the electro-
chemical cell. Extrapolating the curve along this axis yields the
sample concentration, allowing for the calculation of the recovery
values. All curves were built in triplicate. Additionally, a statisti-
cal analysis of the results considering the concentrations recovered
by SWV and UV–vis experiments and the concentrations initially
present in the samples were evaluated by BIAS.
Table 2 shows the recovery efficiencies, the RSD values cal-
culated between triplicate recovery curves, and the BIAS values
calculated for the two samples employed and the SWV and UV–vis
experiments. Despite the presence of complex mixtures in the
tablets and oral solution, the percentages of recovery, obtained by
SWV can be considered specific for HP, with little interference from
other compound experiments and the recovery efficiencies were
satisfactory for analytical procedures [20], and the SWV procedure
offers good precision and accuracy, and is especially suitable for
routine studies of HP in different commercial formulations, or even
better similar data observed by use of UV–vis. Moreover, the SWV
responses were practically insensitive to variations in the compo-
sition of the standard solution, indicating a suitable robustness and
specificity of the proposed procedure.
For the voltammetric experiments, the pure electrolyte, com-
−
1
posed of 0.04 mol L BR buffer (pH 10) solution, was spiked with
9
−7
−1
.9 × 10 mol L of HP, followed by the addition of the standard
solutions and voltammetric experiments to observe the peak cur-
rents and quantify the amounts of HP added, as described in Section
2. For the UV–vis experiments, the recovery efficiencies were cal-
culated using the relationship between the observed experimental
concentration value and the expected concentration value. The
recovery data calculated are shown in Table 1, in which can be
observed a recovery of 106.18% and 95.70% for SWV and UV–vis
experiments, respectively.
The recovery data were used to calculate the accuracy of the
procedure using SWV on the HMDE and UV–vis experiments. The
accuracy represents, statistically, the concordance between the
added concentration and the recovered concentration. Therefore,
the accuracy was calculated from the BIAS parameter:
ꢀ
ꢁ
x¯ − x
0
%
BIAS =
× 100
(12)
x
0
where x¯ is the average from recovered concentrations and x0 is
the added concentration [36]. The calculated BIAS values were,
therefore, 6.16% and −4.96% for SWV and UV–vis experiments,
respectively. Based on the International Conference on Harmoniza-
tion (ICH), the recovery, the BIAS and the RSD values from recovery
curves are very satisfactory for analytical procedures, for which
The [HP]found results from SWV and UV–vis were statistically
compared, by analysis of calculated F-values and t-test, considering
95% confidence limit. So, the theoretical F-value was considered as
19.0 and the calculated values were 4.59 and 1.60 for tablet and oral
solution, respectively. Since the calculated F-values did not exceed

2
044
F.W.P. Ribeiro et al. / Electrochimica Acta 56 (2011) 2036–2044
Table 2
HP concentrations recovered using SWV on HMDE and UV–vis procedures, in two commercial formulations. The [HP]added is related to the sample solution prepared from
commercial dosage.
SWV
UV–vis
Tablets
Oral solution
2 mg/mL
Tablets
Oral solution
2 mg/mL
Nominal dosage
1 mg/tablet
1 mg/tablet
−
−7
−1
−7
−1
)
[
[
[
HP]added (mg L 1)
0.372 (9.90 × 10 mol L
)
0.469 (12.50 × 10 mol L
−1
HP]found (mg L
HP]found (mol L
)
0.332
0.374
0.513
0.337
−
1
−7
−
−7
−7
−7
−7
−7
−7
)
8.84 × 10
9.96 × 10
13.66 × 10
9.49 × 10
7
Confidence interval
Recovery (%)
RSD (%)
± 0.98 × 10
± 0.97 × 10
± 0.48 × 10
± 1.72 × 10
89.24
100.54
3.96
109.38
1.43
76.12
6.34
4.48
BIAS (%)
−10.68
0.61
9.28
−28.36
the theoretical value, there were no significant differences between
proposed and standard procedure, considering the reproducibility
data. For t-test, considering t critical as 4.30, the t calculated values
were 2.04 and 3.56 for tablet and oral solutions, respectively. In
these samples, the calculated t values were lower than the critical
value.
Acknowledgements
The authors wish to thank the Brazilian research funding insti-
tutions CNPq, CAPES, FINEP for their financial support. Djenaine De
Souza also wishes to thank the CNPq (process 35.0014/2010.8) and
FUNCAP (process DCR-0039-1.06/09) for the PhD grant.
As can be observed there is a good agreement between the two
methods (statistically proved according to the paired t-test), indi-
cating that the proposed voltammetric method was found to be
more sensitive than the spectrophotometric method.
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