Development of a single in vitro dissolution method for a combination trilayer tablet formulation of clopidogrel and pravastatin

Abstract

A fixed-combination dose, trilayer tablet formulation was developed for two drugs already marketed as individual products, Plavix in which clopidogrel, an anti-clotting agent, is the active ingredient and pravastatin, an HMG-CoA reductase inhibitor for the treatment of hypercholesterolemia. To simplify quality control testing, the preference is to use a single dissolution method for the analysis of multiple active components in a combination tablet. However, development of one dissolution method for clopidogrel and pravastatin is particularly challenging because of the divergent pH solubility and pH dependent stability of these two drugs. At low pH (<3), clopidogrel bisulfate is most soluble and stable, whereas pravastatin sodium rapidly degrades due to lactonization and oxidation. Conversely, at a neutral pH and higher, pravastatin sodium is most soluble and stable, but clopidogrel bisulfate undergoes hydrolysis and racemization. This article describes the development of a single dissolution method to accommodate both drugs, including selection of medium pH and surfactant. The method uses USP Apparatus 2 (paddles) at 75 rpm in 1000 mL of citrate buffer (0.05 M, pH 5.5) medium containing 2% CTAB (cetyltrimethyl ammonium bromide, a cationic surfactant) at 37 °C. This dissolution methodology provides good dissolution profiles for both clopidogrel and pravastatin and is able to discriminate the changes in composition, manufacturing process, and stability for the combination tablets. To quantitate both drugs simultaneously, a rapid isocratic reversed-phase liquid chromatographic method was developed and validated.