Application of gas chromatography analysis to quality control of residual organic solvents in clopidogrel bisulfate [Supplementary Material]

• Published in: Journal of the Serbian Chemical Society 2014-01, Vol.79 (10), p.1279
• Main Authors: Pavlović, Aleksandar D, Ignjatović, Ljubiša M, Popov, Saša Z, Mladenović, Aleksandar R, Stanković, Igor N
• Format: Article
• Language: English
• Subjects: Acetic acid; Acetone; Butanol; Chromatography; Cluster analysis; Cyclohexane; Dehydration; Dichloromethane; Flame ionization; Gas chromatography; Ionization; Isomers; Multivariate analysis; Principal components analysis; Quality control; Reliability analysis; Solvents; Statistical analysis; Statistical methods; Toluene
• ISSN: 0352-5139; 1820-7421
• DOI: 10.2298/JSC131120013P

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 gas-chromatographic 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.