Volume 28 (2003) número 1

www.scielo.br/eq

POTENTIOMETRIC DETERMINATION OF CAPTOPRIL IN

PHARMACEUTICAL FORMULATIONS
P. R. da S. RIBEIRO 1; A. O. SANTINI 2 ; H. R. PEZZA 1 ; L. PEZZA 2

Abstract
A simple, precise, rapid and low-cost potentiometric method for captopril determination in pure
form and in pharmaceutical preparations is proposed. Captopril present in tablets containing known
quantity of drug was potentiometrically titrated in aqueous solution with NaOH using a glass pH elec-
trode, coupled to an autotitrator. No interferences were observed in the presence of common compo-
nents of the tablets as lactose, microcrystalline cellulose, croscarmellose sodium, starch and magnesium
stearate. The analytical results obtained by applying the proposed method compared very favorably with
those obtained by the United States Pharmacopoeia Standard procedure. Recovery of captopril from
various tablet dosage formulations range from 98.0 to 102.0%.

Keywords: potentiometric determination; captopril; pharmaceutical formulations.

Introduction ses procedures are not simple for routine analysis

and required expensive or sophisticated instru-
Captopril, chemically know as 1-[(2S)-3- ments.
mercapto-2-methylpropionyl]-L-proline, (CPT) is Potentiometric methods with ion-selective
used therapeutically as an antihypertensive agent membranes electrodes (ISE’s) can provide valuable
[11, 15], which is also prescribed for the treatment and straightforward means of assaying captopril in
of congestive hart failure [6]. pharmaceutical formulations because of the possi-
Several types of analytical procedures bility to determine directly the active ions in the
have been proposed for the analysis of captopril in solution. ISEs’ low-cost, easy of use and mainte-
pharmaceuticals formulations. These procedures nance, and the simplicity and speed of assay proce-
include capillary electrophoresis [13], high-perfor- dure, and the reliability of the analytical informa-
mance liquid chromatography (HPLC) [3, 4, 5, 9], tion make them very attractive for the assay of phar-
polarography [10], voltammetry [23], coulometry maceutical products.
[20], amperometry [18], conductometry [19], fluo- Potentiometric methods based in the re-
rimetry [12] , colorimetry [1, 2, 7, 14, 22, 24] and activity of thiol group have been used for captopril
flow injection methods.[12, 21, 28]. Some of the- determination in pharmaceutical formulations [8,

1Departamento de Química Analítica – Instituto de Química – UNESP – CEP 14801-970 – Araraquara – SP – Brasil.

2Departamento de Química Orgânica – Instituto de Química – UNESP – CEP 14801-970 – Araraquara – SP – Brasil.

Ecl. Quím., São Paulo, 28(1): 39-44, 2003 39

17, 26]. Apotex (Toronto, Canadian) were used for the
To the best of our knowledge, despite the analysis. Sodium hydroxide and sodium nitrate were
advantages of the glass membrane pH electrode, purchased from Merck (Darmstadt, Germany).
there are no previous reports for the potentiomet-
ric determination of captopril based in the reactiv- Solutions
ity of this carboxyl group using the glass pH elec-
trode. A freshly prepared 1.000 x 10-1 mol L-1
For this reason, the purpose of this work aqueous of solutions of captopril (standard sub-
stance) was used as the stock solution.
was to develop a potentiometric method for direct
determination of captopril in tablet dosage formu- The sodium hydroxide 2.00 x 10-2 mol L -1
lations. The method is based in a potentiometric was prepared, standardized and stored according
titration of captopril (carboxyl group) in aqueous to recommendation of the literature [25].
solutions with sodium hydroxide solution using a The ionic strength (I) of the final solutions
combined glass electrode, coupled to an used for the potentiometric determination was kept
autotitrator. The proposed method is simple, rapid, constant at 0.500 mol L-1 by addition of sodium
precise, accurate and inexpensive. nitrate.
The results agreed fairly well with those
obtained by the United States Pharmacopoeia Recommended procedures
(USP) standard procedure [27] (iodimetric titra-
tion). The influence of interferents normally found For pure form
along with captopril in tablet dosage formulations
in also studied. A standard solution (100 mL) of captopril
1,000 x 10-2 mol L-1 (I adjusted to 0.500 mol L-1 with
Experimental NaNO3) was prepared by suitable dilution of the
stock solution with water.
Apparatus An aliquot of 15.000 mL of this solution
was transferred to a thermostated glass cell
Potentiometric measurements were carried (25.0±0.1)ºC and potentiometrically titrated with a
out using a Metrohm autotitrator, model 716 standard solution of NaOH 2.00 x 10-2 mol L-1 (I =
(Metrohm Ltd., Herisau, Switzerland). The indica- 0.500 mol L-1 in NaNO3).
tor electrode was a Metrohm combined pH elec-
trode model 60234.100. A thermostated titration Tablets analysis
cell (25.0±0.1)OC was employed. Volume measure-
ments (±0.001mL) were performed with a Metrohm
Fifteen tablets were weighed to
automatic burettes model 665.
calculate the average tablet weight. They
were finely powdered and homogenized. A
Reagents
portion of the powder equivalent to about
217.3 mg of captopril was accurately weighed
All chemicals were analytical grade and
and dissolving with 40 mL of water by
solutions were prepared with deionized water (con-
sonicating for 20 min in an ultrasonic bath.
ductivity = 18.2MΩcm). Captopril (standard sub-
The resulting mixture was filtered and its ionic
stance) was purchased from sigma (St Louis, MO,
strength was adjusted to 0.500 mol L-1 with
USA). It was analysed as prescribed in the USP [27]
NaNO 3. Finally, this solution was diluted with
and contains 99.7% of 1-[(2S)-3-mercapto-2-
water in a 100 mL flask and analysed under
methylpropionyl]-L-proline, calculated with refer-
the same procedure described for captopril
ence to the dried substance. It was used as a stan-
in pure form.
dard. The captopril tablets (25 mg) manufactured
respectively by Medley (Campinas, Brazil),
Azupharma Gmbh (Gerlingen, Germany) and Results and discussion

40 Ecl. Quím., São Paulo, 28(1): 33-44, 2003

Potentiometric titration Figure 1(b) shows the first derivative of
the potentiometric titration curve generated by
The development of the titration curves
the internal algorithm of the autotitrator. The
of polyprotic acids depends on the absolute and
evaluation of the potentiometric titration curve
relative values of the respective stepwise ioniza-
by the autotitrator is fully automatic yielding an
tion constants. Theoretically, there will be one in-
flection for each labile hydrogen. However, so that accurate end point. The determination limit of
the proposed method determined as described
an inflection is associated to an adequate variation
by Leite [16] was 180 g mL-1 .
in pH, it is necessary in the first place for the rela-
tionship of the respective ionization constant to
the next one to be greater than 104 (K1/K2 > 104 or
pk2 – pk1 > 4). In the second place, it is necessary Effect of interferents
for the corresponding ionization constant not to
be that of a very weak acid. To assess the usefulness of the pro-
Captopril is dibasic acid having dissocia- posed method, the effect of the common com-
tion constants pk1 = 3.7 (carboxyl group) and pk2 = ponents (additives, adjuvants and excipients),
which often accompany captopril in tablet for-
9.8 (thiol group). Observing the values of pk1 and
mulations (lactose, microcrystalline cellulose,
pk2 of captopril, it can be foreseen that the titration
curve presents a clear inflection for the first point croscarmellose sodium, starch and magnesium
stearate) were investigated in a concentration
of equivalence since k1 = 2 x 10-4 and the relation-
range of least 20 times higher than that of
ship of k1/k2=10 6 (pk 2 – pk1 = 6). However,
captopril. No interferences were observed in
captopril is a very weak acid in relation to its sec-
the presence of the substances tested.
ond hydrogen (k2 10-10) that its titration curve
does not present a perceivable inflection for the
second point of equivalence.
Analytical applications
Figure 1 (a) shows a typical potentiomet-
ric titration curve with only one inflection point. In
the proposed method changes at the titration end
point were enough pronounced to give potentio- The proposed method was success-
metric titration curves of satisfactory shape for an fully applied for captopril determination in tab-
accurate and reproducible end point detection. The let formulations. The results presented in Table
time required for the analyses of captopril (after the 1, agreed fairly well with those obtained by the
samples preparation) in tablet dosage formulations USP standard procedure [27] (iodimetric titra-
by potentiometric method was 8 min. per sample. tion).
For further confirmation, the standard
addition method was applied to test the reli-
ability and recovery of the proposed method.
The recovery studies were carried out after add-
ing known quantities of the standard sub-
stance (pure drug) to the preanalyzed formula-
tions. The results presented in Table 2 show
that the percentage recoveries were found to
be close to 100%; the SDs were within 0.48 –
0.85. These results point out the accuracy and
precision of the method and the absence of sig-
Figure 1. (a) typical potentiometric titration
curve of captopril (sample A) with NaOH solution; (b)
nificant matrix effects on potentiometric mea-
first derivative plot supplied by the autotitrator. surements at least for the samples analysed.
Ecl. Quím., São Paulo, 28(1): 33-44, 2003 41
 exhibited the advantages of simple operation, rea-
sonable selectivity, fast response, low-cost, and
sufficient accuracy for the determination of captopril
in pharmaceutical formulations.

Acknowledgements

We would like to thank FUNDUNESP,

CAPES, CNPq and FAPESP Foundations (Brazil)
for financial support.

RIBEIRO, P. R. S. et al. Determinação

potenciométrica de captopril em formulações
farmacêuticas.

Table 1. Determination of captopril in pure form and in

pharmaceuticals using the proposed method. Resumo
aFor the assay of captopril in pure form, an amount equiva-
Um método potenciométrico simples,
lent to 217.3mg of the standard substance (Sigma) was
taken. preciso, rápido e de baixo custo foi proposto para
bLabel to content for tablets: mg unit–1 .
a determinação de captopril na forma pura e em
cAverage of five determinations ± SD, performed within 2 formulações farmacêuticas. O captopril presente em
– 3 days. comprimidos em uma quantidade conhecida foi
dRelative standard deviation (RSD) potenciometricamente titulado em meio aquoso com
um titulador automático, empregando-se como
titulante uma solução aquosa de NaOH e um
eletrodo combinado de vidro sensível a pH.
Interferências não foram observadas na presença
de componentes comumente encontrados nos
comprimidos, tais como, lactose, celulose
microcristalina, croscarmelose sódica, amido e
estearato de magnésio. Os resultados analíticos
obtidos a partir da aplicação do método proposto
estão em muito boa concordância com aqueles
obtidos pelo método oficial descrito na Farmacopéia
Americana. O recobrimento obtido para o captopril
a partir de um estudo realizado com várias
formulações farmacêuticas variou de 98.0 a
102.0%.

Table 2. Recovery data for captopril spiked to pharmaceu - Palavras-chave: determinação potenciométrica,
ticals. a Average ± SD of three determinations.
captopril, formulações farmacêuticas.

Conclusion
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