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Volume 34, nmero 2, 2009

Potentiometric Determination of Minoxidil in Topical Use

Pharmaceutical Samples
Rogrio Adelino de Sousa1, der Tadeu Gomes Cavalheiro2*
1 Departamento de Qumica, Universidade Federal de So Carlos, Rod. Washington Luiz Km 235, So Carlos, So Paulo, Brasil, CEP
13565-905, Caixa Postal 676.
2 Departamento de Qumica e Fsica Molecular, Instituto de Qumica de So Carlos, Universidade de So Paulo, Av Trabalhador Socarlense, 400, Centro, So Carlos, So Paulo, Brasil, CEP 13560-970, Caixa Postal 780.
*[email protected]

Abstract: A potentiometric titration method for the determination of minoxidil based on its redox reaction with K2Cr2O7 is described. The best results were observed using 1.00 x 10-3 mol
L-1 K2Cr2O7 and 1.00 x 10-2 mol L-1 minoxidil solutions, and the minoxidil as titrant in 2.00
mol L-1 H2SO4 medium. The method was applied to commercial samples and compared with
the results from a chromatographic procedure. Recoveries from 97.4 to 98.7 % were observed
depending on the sample. Comparison with the chromatographic procedure reveled agreement
within 90% confidence level.
Keywords: Minoxidil determination; titration; potenciometry.
Introduction
Minoxidil (2,4-diamino-6-piperidinopyrimidine-3-oxide) is an odorless white crystalline
powder, insoluble in water, acetone or alkaline
solutions, slightly soluble in alcohols, and freely
soluble in acidic solutions [1]. It has been used as
a peripheral vasodilator drug orally administrated,
applied in the treatment of refractory hypertension
patients [2] and liquid retention and hirsutism is
being observed for excessive doses [3].
Minoxidil also shows new applications in
dermatology, especially in the treatment of androgenic alopecia [3,4]. In this case, this drug has
been topically applied in order to stimulate hair
growth by inducing vasodilatation and increasing
the local irrigation and blood flow [4].
Commercially available products typically
contain 2% minoxidil (m/v), in topic use formulations, containing ethanol, and propylene glycol,

Ecl. Qum., So Paulo, 34(2): 23 - 27, 2009

or their mixture with 2-n-nonyl-1,3-dioxolane as

a vehicle [5,6].
Concerning analytical methods, MnO4- has
been proposed for the oxidimetric titration of minoxidil [2,7-8]. In addition, several instrumental
techniques have been described for minoxidil determination in matrixes such as serum and pharmaceutical products. Most of them are based in
chromatographic methods as described in references [3, 9 12].
Potentiometric titration [13,14] using
K2Cr2O7 is proposed in this paper. High purity
K2Cr2O7 is available, it is thermally stable and
standard solutions can be prepared, stable to the
action of light. It is not reduced by hydrochloric
acid (HCl), reacts with organic matter being reduced from Cr(VI), orange, to Cr(III), green, according to the half-reaction (Eq. 1) [15,16].
Cr2O72- + 14 H+ + 6 e- 2Cr3+ + 7 H2O
o
E = 1,33 V
(Eq. 1)

23

Experimental

during 30 minutes and dissolved in 2.00 mol L-1

H2SO4 and then titrated.

Reagents and Solutions

Comparison Method

All the reagents were of analytical grade

and used as received. Solutions were prepared
using water bi-distilled in quartz stiller. Potassium
dichromate (Merck, Germany) solutions were prepared by direct dissolution of the salt in H2SO4
solution (2.00 mol L-1). Minoxidil was from Natural Pharma (Brazil), and H2SO4 from Mallinckrodt
(Mexico).

In order to check the accuracy of the proposed procedure the results were compared with
those from a chromatographic procedure describe
by Zarghi et al. [8], using a HPLC LC-6AD Shimadzu chromatographic system with a SPD10A
VP Shimadzu spectrophotometric detector, Supelco C-18 (150 x 3.9 mm, 4 mm) column, detection
at 254 nm, mobile phase methanol / water (80 /20)
flowing at 1.3 mL min-1.

Potentiometric methods
Potentiometric titrations were performed
within an glass cell containing a platinum electrode (indicator) and a saturated calomel electrode
(reference) and a pH-meter Corning M 425 (Corning, USA)
10.00 mL of a 1.00 x 10-3 mol L-1 K2Cr2O7
in 2.00 mol L-1 H2SO4 were added to cell at (601)
C controlled temperature. Aliquots of 0.500 mL
of minoxidil solutions were added to the K2Cr2O7
solution in acid media from a 10.00 mL full capacity burette. After each addition of titrant the system was let to stabilize during 3 minutes, before
the potential measurement.

Results and Discussion

The redox reaction between the K2Cr2O7
and minoxidil was very slow at 25C. However
significant stabilization of the potential was observed when the system was held for 3 minutes after each addition of the titrant at 60C. The effect
of temperature on the redox titration profile was
investigated for 40, 50, 60 and 70C, as shown
in Figure 2. The profiles of potentiometric curves
and the end points of each titration were compared
Sousa et al. Fig.2

Commercial Samples

24

-450

E / mV vs SCE

The commercial samples used in this work

were Regaine from Pharmacia (USA) and Neoxidil from Galderma (Brazil); both purchased in
the local market. Samples were topic use formulations of minoxidil 2% (20 mg mL-1) in a mixture
of ethanol and propylene glycol as vehicle.
As observed in test titrations both propylene glycol and ethanol present in the commercial samples severely interfered in the minoxidil
determinations. Thus they were removed first by
evaporation of ethanol in a rotary evaporator at
70C under reduced pressure followed by addition
of acetone to the resulting viscous liquid. At this
point minoxidil precipitates as a white solid that
was recovered by filtration in a glass plate funnel. The precipitate was dried at 60C in an oven

400C
500C
600C
700C

-525
-600
-675
-750
-825
-900
-975

12

15

18

Volume of tritant / mL

The best results for the potentiometric curve shape and accuracy of the end point were reached at 60C (Figure 2). Equation 2 gives a sugEcl. Qum., So Paulo, 34(2): 23 - 27, 2009

gestion for the reaction between the minoxidil and

K2Cr2O7.
O

N
5
6

O2N

NH2

1 2N

-2

3
N

+ 2 Cr2O7

+
+ 16 H

- 8H2O

120

NH2
N

(Eq.2)
This suggestion is based on the stoichiometry of the titration in which 2 mols of Cr2O72- are
consumed by 3 mols of minoxidil. The oxidation
of the amine group at position 5 of the aromatic
ring is proposed considering the lower reactivity
of the amine group in position 3.

Sample Determinations
The titrant addition resulted in a potential
change of the platinum electrode. To better identify the end point of potentiometric titrations the
Gram method was used [17] which consists of a
E / V vs volume of titrant added curve, in whi-

A - Regaine

end point = 5.75 mL

B - Neoxidil

60

4 Cr+3 + 3
N

end point = 5.76 mL

90
30

E / V
mV / mL

H2N

ch the intersection between the two linear portions

indicates the end point of the titration, see Figure
3 for an example.

120
90
60
30
0

10

12

14

Titrant volume / mL

Sousa et al. Fig.3

The values of minoxidil concentration
(Table 1) contained in the commercial samples
were consistent with the label values. The proposed method agrees in 90% confidence level, with
the label value of commercial samples and 95%
confidence level, with the values obtained by the
comparative chromatographic method, according
to the Student t-test [18].

Table 1: Results of potentiometric titrations

Samples
Neoxidil
Regaine

Label a
20.0
20.0

Found b*
20.7 0.2
21.0 0.3

Comparison b*
19.4 0.4
20.9 0.5

E1 / % c
+3.72
+4.71

E2 / % d
+6.70
+0.48

n=3
a Concentration in mg mL-1
b Concentration in mg mL-1 SD
c Relative error to the label
d Relative error to the comparison methods
In order to evaluate the accuracy of the
proposed method recovery tests were performed
with recoveries between 98.7% for Neoxidil and
97.4% for Regaine.

Ecl. Qum., So Paulo, 34(2): 23 - 27, 2009

25

[H2SO4] = 2,00 x 10-2 mol L-1; Volume of H2SO4(aq) =

5 mL; Stabilization time = 3 minutes; T = 60C.

FIGURE CAPTIONS
Figure 1: Structural formula of minoxidil.
Sousa et al. Fig.1

Conclusions

NH2

N
N

NH2
Figure 2: Effect of the temperature in the potentiometric titration.

The method proposed in this study was

effective in the determination of minoxidil in
commercial samples for topical applications, considering the apparatus limits and errors inherent to
the classical technique.
Although time consuming, this procedure
can be an alternative for quality control in the magistral pharmacies, presenting low cost and good
precision when compared with other more expensive and waste generating methods as chromatography,.

Acknowledgements

Conditions: [minoxidil] = 1,00 x 10-2 mol L-1;

[K2Cr2O7] = 1,00 x 10-2 mol L-1; Volume of K2Cr2O7(aq)
= 3,00 mL; [H2SO4] = 2,00 x 10-2 mol L-1; Volume of
H2SO4(aq) = 5 mL; Stabilization time = 3 minutes.

The authors are grateful to Brazilian agencies CAPES and CNPq for RAS and ETGC fellowships.

Figure 3: Identication of the end point of the potentiometric titration (Grams method) of the commercial samples; A Regaine; B Neoxidil. Conditions: [minoxidil] = 1,00 x 10-2 mol L-1; [K2Cr2O7] =
1,00 x 10-2 mol L-1; Volume of K2Cr2O7(aq) = 3,00 mL;

Determinao Potenciomtrica De Minoxidil Em Formulaes Farmacuticas De Uso Tpico

Received November 03 2008
Accepted October 14 2009

Resumo: Um mtodo potenciomtrico para a determinao de minoxidil em formulaes farmacuticas baseado na reao redox entre K 2 Cr 2 O 7 e o minoxidil, foi desenvolvido. Os melhores resultados foram obtidos usando concentraes de 1,00 x 10 -2 mol L -1 para o minoxidil e
1,00 x 10 -3 mol L -1 para o K 2 Cr 2 O 7 ambos diludos em uma soluo em de H 2 SO 4 2,00 mol L -1 , a
60C. As recuperaes para mtodo proposto foram da ordem de 98,7 % a 97,4 % dependendo
da amostra comercial. O mtodo proposto foi aplicado amostras comerciais contendo minoxidil e, quando comparado com resultados obtidos a partir de procedimentos cromatogrficos,
apresentou concordncia no nvel de confiana de 95%, de acordo com o teste t-Student.
Palavras chave: Determinao minoxidil; titulao; potenciometria.

26

Ecl. Qum., So Paulo, 34(2): 23 - 27, 2009

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