Abstract 17290: Prevalence of Free Methyl Chloride as an Impurity in Generic Clopidogrel Preparations. Safety Implications in Cardiovascular Patients
Various salts of clopidogrel are known to degrade by two main pathways including racemization and methyl ester hydrolysis. Methyl ester hydrolysis of hydrochloride salts of clopidogrel leads to the formation of methyl chloride. Alkyl halogenides such as methyl chloride are known to exhibit genotoxic properties. Several generic versions of clopidogrel hydrochloride have recently become available throughout the world. Some of these products have been reported to contain methyl chloride. The purpose of this investigation was to compare the methyl chloride impurity levels in eight Indian and three European clopidogrel hydrochloride preparations. A modified gas chromatographic method was employed using the flame ionization detection to quantitate methyl chloride. The TTC (threshold of toxicologic concern) is considered to be 20 ppm, considering a daily dose of 75 mg, expressed as clopidogrel base. In the European generic preparations, the amount of methyl chloride was found to be between 40–50 ppm, whereas in the preparations marketed in India, the level of methyl chloride ranged from 10–110 ppm. Although the shelf life of the preparations from India is not known, these levels of methyl chloride are likely to increase at higher storage temperatures. These studies clearly underscore the need for additional analytical studies to check the purity of generic versions of clopidogrel hydrochloride and investigations of potential variations in their pharmacodynamic activity.
- © 2010 by American Heart Association, Inc.