Annals of West University of Timisoara

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1 Annals of West University of Timisoara Series of Chemistry 19 (1) (2010) DETERMINATION OF VALPROATE IN PHARMACEUTICAL PREPARATIONS USING A VALPROATE-SELECTIVE SENSOR Monica Sava, V.A. Chiriac, Dana Vlascici West University of Timisoara, Faculty of Chemistry, Biology, Geography, Inorganic Chemistry Department, Pestalozzi, 16, Timisoara, , ROMANIA Received: 10 May 2010 Modified 28 May 2010 Accepted 3 June 2010 SUMMARY The performance characteristics of a new valproate-selective sensor are presented. The membrane carrier consists of the ion-pair complex of sodium valproate with Aliquat 336S. The obtained sensor exhibits a near-nernstian slope of mv/decade valproate in a concentration range from 5x10-5 1x10-2 M with a detection limit of 30 µm. The sensor has a good selectivity towards a lot of anions and it was successfully applied to the determination of valproate from pharmaceutical preparations by direct potentiometry. Keywords: Anion-selective electrode, Valproate, Pharmaceuticals, Drug monitoring; Potentiometry INTRODUCTION Valproate, 2-propylpentanoic acid sodium salt (Figure 1) has a clinical use as an anticonvulsant and mood-stabilizing drug in the treatment of epilepsy, bipolar disorder, migraine headaches and schizophrenia. Its principal mechanism of action is believed to be the inhibition of GABA transaminase [1]. 91

2 S AVA M., C HIRIAC V.A., V LASCICI D. Figure 1. Sodium valproate the chemical structure A lot of methods have been used for the determination of valproate in pharmaceutical preparations such as: high-performance liquid chromatography (HPLC) [2], capillary electroseparation techniques [3] and potentiometry with ion-selective electrodes [4, 5]. Both, HPLC and capillary electroseparation techniques requires expensive equipment while potentiometry is a simple, low cost and sensitive method which is often used in the detection of pharmaceuticals. In the present paper, a new valproate-selective sensor based on ion-pair complex of valproate and Aliquat 336S (tricaprylmethylammoniuym chloride) is described. The sensor, which has a linear range between 5x10-5 1x10-2 M with a detection limit of 30 µm was successfully used for the determination of valproate levels in drugs (Depakine chrono). MATERIALS AND METHODS Reagents For polymer membrane preparation, Aliquat 336S, n-dodecanol, poly (vinyl chloride) (PVC, high mol.wt.), tetrahydrofuran (THF, distilled prior to use) were purchased from Fluka and Merck. All aqueous solutions were prepared with salts of the highest purity available. The sample solutions for all potentiometric measurements consisted of sodium salts of the given anions in buffer of ph = 5.5 (4-morpholino-ethanesulfonic acid (MES) adjusted to ph = 5.5 with NaOH). 92

3 DETERMINATION OF VALPROATE IN PHARMACEUTICAL PREPARATIONS USING A VALPROATE-SELECTIVE SENSOR For the preparation of the sodium valproate (Sigma) stock solution (1x10-2 M) a rigorous amount of solid was diluted in the previously mentioned buffer. The standard solutions for all potentiometric measurements consisted of dilutions of the former stock solution with the ph adjusting buffer (ph = 5.5). Electroactive material 5.0 g of Aliquot 336S were mixed with 5.0 g of n-dodecanol and then equilibrated with ten separate aliquots of 0.01 M valproate solution. The organic phase was washed with distilled water until the reaction of chloride ion was negative and then centrifuged until a clear solution was obtained. Membrane material The ion-pair complex of the quaternary ammonium cation, tricapryl methyl ammonium, with valproate was used in a PVC matrix using dioctylphtalate (DOP) as plasticizer. The membrane composition was: 5.0% electroactive material, 30% PVC and 65% DOP. Construction of the electrodes The electroactive material, the solvent mediator and PVC were mixed with 5 ml of THF to obtain a transparent solution. The mixture was transferred on a glass plate of 20 cm 2 and left over night to allow THF to evaporate at the room temperature. A flexible membrane having the electroactive material trapped in the PVC matrix was in this way obtained. The following galvanic cell was used for the potentiometric measurements: Ag/AgCl/KCl(sat)/sample/ion-selective membrane/ag(hg)/internal cable Before the EFM measurements, the electrodes were conditioned for 2 h in a 0.01 M valproate solution. All the experiments were performed at room temperature (24±2 o C). The potentiometric measurements were measured using a Hanna Instruments HI223 ph/mv-meter. Potentiometric selectivity coefficients were determined according to the separate solution method [6] by using the experimental EMF values obtained for 10-3 M solutions of the tested anions (in ph = 5.5 buffer MES-NaOH) and a theoretical slope of 59.2 mv/decade valproate. Sample preparation The amount of valproate was assayed in Depakine chrono tablets. Five tablets of each formulation were weighed, disintegrated, powdered and the amount of the homogenized mixture was weighed, suspended in buffer solution, set aside for 30 min., filtered and then diluted to the exact volume in a flask using the ph = 5.5 buffer. The samples prepared to have a final concentration in the linear range of the obtained sensor. 93

4 S AVA M., C HIRIAC V.A., V LASCICI D. RESULTS AND DISCUSSION The potentiometric response of the obtained sensor to valproate at ph = 5.5 is presented in Figure 2. Figure 2. The potentiometric answer to valproate at ph = 5.5 As it could be seen from figure 2, the sensor has a linear working range from 5x x10-2 M valproate with a near Nernstian slope of 57.7 mv/decade valproate at ph = 5.5 in MES-NaOH buffer. The potentiometric selectivity coefficients were calculated by the separate solution method [6] with the primary and interfering anions at 1x10-3 M all of them prepared in the same experimental conditions (in buffer solution of ph = 5.5). The obtained values are presented in Table I. 94

5 DETERMINATION OF VALPROATE IN PHARMACEUTICAL PREPARATIONS USING A VALPROATE-SELECTIVE SENSOR pot Tabel I. Potentiometric selectivity coefficients, log K. valproate, X Ion (X) pot. log K valproate, X Acetate Nitrite Benzoate Tartrate Iodide Metabisulphite Chloride Citrate Nitrate Salicylate The valproate-selective sensor obtained by us has a good selectivity over all tested anions. The most important fact is that the selectivity against chloride is which is sufficient for the clinical application of the sensor. Analytical application To evaluate the utility of the developed sensor solid sample (tablets) were used. The drug assay was carried out by direct potentiometry, following the preparation procedure described previously and using the standard curve constructed with pure valproate solutions. Table II indicates the average of 3 measurements obtained by direct potentiometry for the valproate-selective sensor. Table II. Valproate determination in pharmaceutical preparations Sample Label amount (mg) Found by proposed electrode (mg) Depakine chrono ± 4.2 Depakine chrono ± 6.4 Average of three measurements The obtained results show the analytical usefulness of the sensor. CONCLUSIONS 1. A new valproate-selective sensor was developed. The sensor has as the electroactive material the ion-pair complex of valproate and Aliquat 336 S trapped in a PVC matrix. 95

6 S AVA M., C HIRIAC V.A., V LASCICI D. 2. The linear range of the sensor is between 5x10-5 to 1x10-2 M with a detection limit of 30 µm with good values of the selectivity coefficients. 3. The sensor was successfully used for the analytical detection of valproate in pharmaceutical preparations. REFERENCES 1. Perucca E., Pharmacological and therapeutic properties of valproate: a summary after 35 years of clinical experience, CNS Drugs, 16 (2002) British Pharmacopoeia, vol II (1998), Pharmaceutical Press, London, p Ölvecká E., Koníková M., Grobuschek N., Kaniansky D., Stanislawski B., Direct determination of valproate in serum by zone electrophoresis-isotachophoresis on a column-coupling chip, J. Sep. Sci., 26 (2003) Katsu T., Ido K., Moriya A., Nakae Y., Sakata I., Valproate-selective membrane electrode based on gallium(iii) tetraphenylporphyrin, Electroanal., 12(16) (2000) Santos E.M.G., Araujo A.N., Couto C.M.C.M., Conceicao M., Montenegro B.S.M., Construction and evaluation of PVC and sol-gel sensor membranes based on Mn(III)TPP-Cl. Application to valproate determination in pharmaceutical preparations, Anal. Bioanal. Chem., 384 (2006) Umezawa Y., Buhlmann P., Umezawa K., Tohda K., Potentiometric selectivity coefficients of ionselective electrodes. Part I. Inorganic cations, Pure Appl. Chem., 72(10) (2000)