valproic acid | Acta Medica Marisiensis

Formulation and Evaluation of Valproic Acid Suppositories for Children

Tăurean Alexandrina¹, Ciurba Adriana², Todoran Nicoleta², Cazacincu R³, Dogaru T. Maria⁴

1 Pharmacy no. 3, County Emergency Clinical Hospital, Tîrgu Mureş, Romania
2 Department of Pharmaceutical Technology, Faculty of Pharmacy, University of Medicine and Pharmacy, Tîrgu Mureş, Romania
3 Department of Pharmaceutical Industry, Faculty of Pharmacy, ”Ovidius” University of Medicine and Pharmacy, Constanța, Romania
4 Department of Pharmacology, Faculty of Pharmacy, University of Medicine and Pharmacy, Tîrgu Mureş, Romania

Introduction: Rectal suppositories of valproic acid were prepared using different lipophilic excipients: Suppocire NAI, Adeps solidus 50, Adeps solidus 3, Lipex 403, Cacao oleum. Each prepared suppository has been evaluated for various physical parameters like weight variation, disintegration and softening time and crushing (breaking) strength.
Methods: Suppositories were prepared by fusion method. The quantity of active drug (valproic acid) added to the suppositories was 200 mg, thus resulting 1.0 g suppositories. Prepared suppositories were visually inspected. Randomly selected suppositories were cut longitudinally and the surfaces were examined with naked eye. For determination of weight variation, 20 suppositories were weighed and the average weight was determined. Disintegration time, softening time and breaking strength of the prepared suppositories were determined according to the 5th European Pharmacopoeia.
Results: All the suppositories were free from pits, fissures and cracks. All formulas studied were disintegrated in less than 30 minutes. Valproic acid decreased the disintegration time of suppositories. The used excipient also influences the disintegration time, with a greater effect on the F1 formula (Suppocire NAI). After one month of preservation, the disintegration time of all formulas increased, but was less than 30 minutes. The softening time of the suppositories was the largest for the F1 formula (Suppocire NAI). The softening time decreases in the presence of valproic acid. The softening time and breaking strength increased for all formulas after one month.
Conclusions: The prepared suppositories were within the permissible range of physical parameters. The results obtained allow the selection of excipients in order to assure the optimum characteristics for prepared suppositories.

Determination of Valproic Acid in Human Plasma by High-Performance Liquid Chromatography with Mass Spectrometry Detection

Vancea Szende¹, Imre Silvia¹, Vari C¹, Dogaru Maria Titica¹, Muntean Daniela-Lucia¹, Căldăraru Carmen², Dogaru G², Donáth-Nagy Gabriella¹

1 Faculty of Pharmacy, University of Medicine and Pharmacy, Tîrgu Mureş, Romania
2 Faculty of Medicine, University of Medicine and Pharmacy, Tîrgu Mureș, Romania

Background: Free valproic acid is shows no characteristic absorption in the ultraviolet region (above 235 nm), therefore its direct quantification and also the quantification of the corresponding metabolites from human plasma has proven to be challenging. Aim: The aim of our study was to develop and validate an effective LC-MS method for the determination of valproic acid in human plasma without using solid phase extraction as sample preparation, with a short analysis time and high sensitivity.
Materials and methods: Valproic acid was analyzed on a reversed – phase column (Zorbax SB – C18, 100 mm x 3 mm I.D., 3.5 μm) under isocratic conditions using a mobile phase of a 40:60 (v/v) mixture of acetonitrile and 0.1% (v/v) acetic acid in water. The flow rate was 1 mL/min and the column temperature 45 ºC. In these chromatographic conditions, the retention time was 2.3 minute for valproic acid. The detection of the analyte was in single ion monitoring mode using a triple quadrupole mass spectrometer with electrospray negative ionization. The monitored ion was 143.1 m/z derived from 144.2 m/z valproic acid. The sample preparation was very simple and consisted in plasma protein precipitation from 0.2 mL plasma using 0.6 mL methanol.
Results: Calibration curves were generated over the range of 2–200 µg/mL with values for coefficient of determination greater than 0.996 and by using a weighted (1/x) quadratic regression. The values of precision and accuracy for valproic acid at quantification limit were less than 3.3% and 7.2%, for within- and between-run assays, respectively. The mean recovery of the analyte was 104%. Valproic acid samples demonstrated good short-term, post-preparative and freeze-thaw stability.
Conclusion: The method is very simple and allows obtaining a very good recovery of the analyte. The validated LC-MS/MS method could be applied to pharmacokinetics and therapeutic drug monitoring study regarding valproic acid in humans.