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The purpose of this study was to identify a degradation product formed in the clinical parenteral formulation of BMS-204352, investigate the role of excipients in its formation, and develop a strategy to minimize/control its formation. The degradant was identified as the hydroxy methyl derivative (formaldehyde adduct, BMS-215842) of the drug substance based upon liquid chromatography/mass spectroscopy (LC/MS), liquid chromatography/mass spectroscopy/mass spectroscopy (LC/MS/MS), nuclear magnetic resonance (NMR), and chromatographic comparison to an authentic sample of hydroxymethyl degradation product, BMS-215842. An assay method for the detection of formaldehyde based on HPLC quantitation of formaldehyde dinitrophenylhydrazone was developed to quantitate its levels in various Polysorbate 80 and PEG 300 excipient lots. A direct relationship between the levels of formaldehyde in the excipients and the formation of the hydroxymethyl degradant was found. To confirm the hypothesis that the formaldehyde impurity in these two excipients contributed to the formation of the hydroxymethyl degradant, several clinical formulation lots were spiked with formaldehyde equivalent to 1, 10, and 100 mg/g of BMS-204352. A correlation was found between the formaldehyde level and the quantity of the hydroxymethyl degradant formed upon storage at 5 and 25 degrees C. From these experiments, a limit test on the formaldehyde content in polysorbate 80 and PEG 300 can be set as part of a strategy to limit the formation of the degradation product.

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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.

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This is a summary report of the "AAPS Workshop on the Role of Dissolution in QbD and Drug Product Life Cycle" organized by the AAPS In Vitro Release and Dissolution Testing (IVDRT) Focus Group. Representatives from the pharmaceutical industry, regulatory authorities, and academia in the U.S. and Europe attended this workshop to discuss the role of dissolution in a Quality by Design (QbD) setting and its relevance in drug product development. Other areas of discussion included IVIVC/R and hot topics like alcohol dose-dumping. Numerous case studies were presented, and issues relevant to the dissolution scientist and areas needing further research were highlighted at this workshop. Views expressed in this paper are those of the participants from the industry and the agency and do not necessarily represent those of the FDA and USP.