Application of gas chromatography analysis to quality control of residual organic solvents in clopidogrel bisulfate

Abstract

A direct-injection, split-mode capillary gas chromatographic procedure with flame ionization detection was developed for the analysis of eight solvents used in the synthesis and purification of the anti-thrombotic drug clopidogrel bisulfate. The solvents analyzed were methanol, acetone, dichloromethane (DCM), 2-butanol, cyclohexane, toluene, acetic acid and N, N-dimethylformamide (DMF). In addition, because of dehydration of 2-butanol during the drying process, significant amounts of 2-butanol dehydration products (1-butene, cis- and trans-isomers of 2-butene, 2,2-oxybis[butane] and 1-(1- -methylpropoxy)butane) may be detected in clopidogrel bisulfate samples. The content of each of these volatile products can be evaluated using the same gaschromatographic method, with quantification based on the response factor established for the chromatographic peak of 2-butanol. Based on a large number of result sets, retrospectively, from many different batches analyzed, conclusions were made about process variations and reliability and a lack of consistency was identified in the quality of the active substance from a particular producer source. Multivariate analysis was used as the statistical technique to classify the samples. From the analyzed set of 11 solvents, 6 of them were preselected based upon their occurrence in the samples and both Principal Component Analysis (PCA) and Hierarchical Cluster Analysis (HCA) were performed.