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CCLET-2486; No. of Pages 3

Chinese Chemical Letters xxx (2013) xxx–xxx

Contents lists available at SciVerse ScienceDirect

Chinese Chemical Letters

journal homepage: www.elsevier.com/locate/cclet

Original article

Potentiometric determination of mefenamic acid in pharmaceutical formulation

by membrane sensor based on ion-pair with basic dye
Zholt Kormosh *, Oksana Matviychuk
Eastern European National University, Voli av. 13, Lutsk 43021, Ukraine

A R T I C L E I N F O A B S T R A C T

Article history: The characteristics, performance and application of membrane sensors based on ion-pair Brilliant Green
Received 16 October 2012 mefenamate are described. The sensor’s response to the mefenamate ion has the sensitivity of
Received in revised form 25 December 2012 (86.0  2.0) mV/pC over the range of 9  10 5–1  10 2 mol/L and the detection limit of 4.5  10 5 mol/L at
Accepted 22 January 2013
pH 8.5–12. The sensor is easily assembled at a relatively low cost and has fast response time (5–10 s). The
Available online xxx
proposed sensor displayed good selectivity for mefenamate ion in the presence of different substances. It was
used to determine mefenamic acid in pharmaceuticals.
Keywords:
ß 2013 Zholt Kormosh. Published by Elsevier B.V. on behalf of Chinese Chemical Society. All rights
Mefenamic acid
PVC membrane sensors
reserved.
Potentiometry
Pharmaceutical analysis

1. Introduction 2. Experimental

Mefenamic acid, [N-(2,3-dimethylphenyl)]anthranilic acid
(Fig. 1a) belongs to a class of nonsteroidal anti-inflammatory
drugs (NSAIDs). It is used in the treatment of inflammatory and
degenerative diseases of the articulations such as rheumatoid
arthritis, osteoarthritis, nonarticular rheumatism, and sport
injuries. In pharmacological studies, mefenamic acid has shown
anti-inflammatory, analgesic, and antipyretic activity. With regard
to its analgesic effect, mefenamic acid is not a narcotic.
Drug analysis has an extensive impact on public health. A
number of analytical methods have been developed for the
quantitative determination of mefenamic acid in dosage forms and
in biological samples. Among those are spectrophotometry [1–9],
chromatography [10–15], titration methods [16], chemilumines-
cence [17], and recently, some electrochemical sensors have been
developed [18–20].
The aim of this study is to establish a simple and inexpensive
method for the assaying of mefenamic acid in pharmaceutical
forms. The method is based on an ion-pair of Brilliant Green (BG)
mefenamate (Fig. 1b) and using this ion-pair as an electrode active
substance for a membrane potentiometric sensor.
* Corresponding author.
E-mail addresses: kormosh@univer.lutsk.ua, zholt-1971@yandex.ru
(Z. Kormosh).
All chemicals were of analytical-reagent grade. The modeling of
the membrane composition of the potentiometric sensors used
high molecular weight PVC, dibutylphtalate (DBP), dibutylsebacate
(DBS), dioctylftalate (DOF), dinonylftalate (DNF), tricresylpho-
sphate (TCP) and tetrahydrofuran (THF), which were obtained
from Sigma–Aldrich. Distilled water was used to prepare all
solutions in all experiments. The 0.04 mol/L buffer solutions of pH
6.0–12.0 ranges were freshly prepared. The fresh aqueous standard
solutions (1  10 6–1  10 2 mol/L) of mefenamate ion were
prepared in 0.04 mol/L buffer solution (for the study of effect of
pH) for analytical purposes. Buffer solutions (pH 6.0–12.0) were
prepared by mixing corresponding amounts of 0.04 mol/L H3BO3,
0.04 mol/L CH3COOH, 0.04 mol/L H3PO4 and 0.2 mol/L NaOH.
An ion-pair of Brilliant Green mefenamate (Fig. 1) was prepared
by mixing equal quantities of 1  10 2 mol/L mefenamic acid and
1  10 2 mol/L of basic dye BG. The solution was settled for 2 h and
the ion-pair sediment was filtered (quantitative rapid filter paper).
This residue was treated with 50 mL of cold distilled water. The
precipitate was dried for 24 h at room temperature. This ion-pair
was used as an electrode active substance for preparing the
mefenamate-sensitive sensor.
Plasticized PVC membrane was prepared as follows: Ion-pair of
Brilliant Green mefenamate (0.04 g) was mixed thoroughly with
0.075 g of powdered PVC and with 0.08 mL of TCP as a solvent
mediator in 0.5 mL THF. The resulting mixture was transferred into
a glass dish of 25 mm diameter. The solvent was evaporated slowly
at room temperature. The thickness of the membrane after drying

1001-8417/$ – see front matter ß 2013 Zholt Kormosh. Published by Elsevier B.V. on behalf of Chinese Chemical Society. All rights reserved.
http://dx.doi.org/10.1016/j.cclet.2013.03.001

Please cite this article in press as: Z. Kormosh, O. Matviychuk, Potentiometric determination of mefenamic acid in pharmaceutical
formulation by membrane sensor based on ion-pair with basic dye, Chin. Chem. Lett. (2013), http://dx.doi.org/10.1016/
j.cclet.2013.03.001
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2 Z. Kormosh, O. Matviychuk / Chinese Chemical Letters xxx (2013) xxx–xxx

+ mediators and additives used, we decided to study such effects on

(H5C2)2N
O O
C CH3
H
N CH3
a b
Fig. 1. The chemical structure of mefenamate ion and Brilliant Green.
was 0.5 mm. The mefenamate-sensitive membrane of 5 mm
diameter was cut out and glued to the polyethylene tube by using
10% solution of PVC. Mefenamic acid solution (5.0  10 2 mol/L)
was used as internal reference solution. Then, a copper wire was
immersed into the tube.
All electromotive force (EMF) measurements were carried out
with the following cell assembly. An IA-123 model ionometer with
Ag/AgCl reference electrode were used for the measurements of
potential difference at (25.0  0.1) 8C.
We used a two-phase titration method as a method of
comparison proposed by Kobzar and Isaev [16]. The exact weight
of mefenamic acid was dissolved in 20 mL of N-octanol in the flask
with a ground-in cover. Distilled water (40 mL) and tymolphthalein
(8–10 drops) were added. Solution was titrated by 0.1 mol/L NaOH
solution with intensive stirring until a slight blue tint was observed.
Solid samples: Fifteen tablets were weighed to calculate the
average tablet weight. They were then powdered and homoge-
nized. A portion of the powder equivalent to 241.3 mg of
mefenamic acid was accurately weighed and dissolved in 20 mL
of 0.2 mol/L NaOH, followed by 50 mL distilled water. The resulting
mixture was filtered and adjusted with 0.04 mol/L of buffer
solution acids (H3BO3, CH3COOH, H3PO4) to pH 9. Finally, this
solution was diluted with water in a 100 mL flask and analyzed
under the same procedure described for mefenamic acid in pure
form. This procedure was repeated 5 times.
3. Results and discussion
Because the sensitivity and selectivity of any membrane sensor
are significantly related to the composition of the mefenamate-
sensitive membrane and the nature and amount of the solvent
N(C2H5)2
the behavior of the proposed sensor. The effect of the nature of the
plasticizer and the amount of the ion-pair of Brilliant Green
mefenamate on the potential response of the proposed mefenamic
selective electrode were investigated. The obtained results are
provided in Table 1. Evidently, TCP is a more effective solvent
mediator than all others in the preparation of the mefenamate-
sensitive sensor.
The influence of the membrane thickness on the potential
responses of mefenamic sensor was investigated. The optimum
thickness of the membrane is 0.15–0.35 mm.
The concentration of internal solution does not cause any
significant difference in the potential response of the sensor except
for the change in the intercept of the resulting Nernstian plots.
The effect of the pH of the test solution on the response of the
mefenamate-sensitive membrane sensor was examined for
1  10 3 mol/L and 5  10 2 mol/L concentrations. The potential
remains constant for the range pH of about 8.0–10.5.
The response time of the sensor was measured after successive
immersion in a series of mefenamate solutions with a tenfold
increase of the mefenamate ion concentration each, from
1  10 6 mol/L to 1  10 2 mol/L. The static response time thus
obtained was 5–10 s for 1  10 4–5  10 2 mol/L mefenamate ion
concentration. At lower concentrations (1  10 6–1  10 5 mol/L),
however, the response time approached 15–25 s.
An important characteristic of any potentiometric sensor is its
response to the primary ion in the presence of other ions present
in solution, which is expressed in terms of the potentiometric
selectivity coefficient. The potentiometric selectivity coefficient
pot
for membrane mefenamate sensitive sensor lg KMef ;I
was
determined for a number of anions and cations by the matched
potential method [18]. No interference was noted for most of the
compounds of solutions such as salicylate-(3.1), benzoate-ions
(3.5), S2O32 (4.1), Cl (4.0) and others. A comparison of the
proposed sensor with reported electrodes indicates that the
selectivity coefficients of the proposed sensor are better than
those reported for mefenamate ion-selective electrode. Such
membranes develop phase boundary potentials via a classical ion
exchange mechanism in which the more hydrophilic counter-
anions in the membrane are completely dissociated from the
lipophilic, positively charged cation sites (Brilliant Green).
Consequently, anion interactions with the membrane phase,
and thus membrane transport selectivity, are dictated primarily by

Table 1
Characteristics of different electrode active substances with different solvent mediators of mefenamate ion sensitive sensor.

Amount of the ion-pair (%) Plasticizer (65%) Slope (mV) Linear range (mol/L) Detection limit (mol/L)
4 2 5
2 TCP 85.0  1.0 1  10 –  10 4.5  10
4
4 TCP 88.0  1.0 1  10 –  10 2 6.4  10 5

3
6 DNF 32.0  1.2 1  10 –  10 2 5.8  10 4

3
6 DOF 53.0  1.2 1  10 –1  10 2 2.3  10 4

3
6 DBP 39.0  1.1 1  10 –1  10 2 4.5  10 4

4
6 TCP 89.0  1.0 1  10 –1  10 2 5.2  10 5

3
6 DBS 12.0  1.0 1  10 –1  10 2 1.2  10 3

4
8 TCP 86.0  1.0 2  10 –1  10 2 8.7  10 5

5
10 TCP 78.0  1.0 5  10 –1  10 2 3.4  10 5

Table 2
Recovery data for mefenamic acid amounts in pharmaceutical forms (Ftabl. = 5.05; ttabl. = 1.87).

Sample Label amount (mg) Found by proposed sensore Found by biphase titration [16] F-test t-Test

mg S2 RSD (%) mg S2 RSD (%)

Mefenamic acid, Atanta 500 mg/capsule 500.5  1.1 0.66 0.07 499.3  1.5 1.47 0.11 2.23 1.47
Mefenamic acid, Darnytsa 500 mg/tablet 500.9  1.1 0.82 0.08 499.8  1.8 2.10 0.13 2.56 1.15
Mefenamic acid, Flamingo 250 mg/capsule 250.5  1.0 0.68 0.15 249.2  1.4 1.19 0.20 1.75 1.70
Mefenat, Farmak 25 mg/50 mL gel 25.2  0.8 0.37 1.08 – – –

Please cite this article in press as: Z. Kormosh, O. Matviychuk, Potentiometric determination of mefenamic acid in pharmaceutical
formulation by membrane sensor based on ion-pair with basic dye, Chin. Chem. Lett. (2013), http://dx.doi.org/10.1016/
j.cclet.2013.03.001
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CCLET-2486; No. of Pages 3
Z. Kormosh, O. Matviychuk / Chinese Chemical Letters xxx (2013) xxx–xxx
the partition coefficients of given anions between the aqueous
test solution and the solvent or plasticizer used to prepare the
polymer film. This results in the so-called Hofmeister selectivity
pattern, where the more hydrophobic anions are preferred
(ClO4 > SCN > I > Br > Cl ).
The proposed membrane sensor based on an ion-pair of
Brilliant Green mefenamate was found to work well under
laboratory conditions. It was applied for the determination of
mefenamic acid in pharmaceutical forms (Table 2).
The sensor is easy to assemble at a relatively low cost and can be
used for a period up to 3.5 months without any considerable
divergence in potential.
The proposed membrane sensor is very easy to prepare and
shows high sensitivity and wide pH range. This approach is cost-
effective and has other advantages, such as high accuracy,
selectivity, and fast response for the determination of mefenamic
acide in dosage forms.
4. Conclusions
The results obtained in present work demonstrate that
membrane potentiometric sensors based on the ion-pair of
Brilliant Green and mefenamate with an internal comparison
solution were developed. The proposed sensors exhibit long
lifetime, good stability, sensitivity, precision, accuracy and
selectivity. They are low cost and easy to both prepare and to use.
Techniques with high metrological characteristics for the
quantitative determination of mefenamic acid in pharmaceuticals
were developed. The results of this study show that a potentio-
metric sensor may provide an attractive alternative for mefenamic
acid determination.
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