Synthesis Of Clopidogrel Impurities Working Standard

Objective: Clopidogrel impurity A and impurity B are the specified impurities listed in the Clopidogrel hydrogen sulfate monograph from European Pharmacopoeia, and their standards should be used extensively during the quality research. The homemade clopidogrel impurity standards can be used in daily test and quality research instead of the expensive legal standards.Method: According to the structures of clopidogrel impurity A and B provided in European pharmacopoeia, we infer the possible sources for the two impurities. On this basis, we design the synthetic route and optimize the reaction conditions to obtain the target products. The clopidogrel impurity A is obtained by the hydrolysis of final clopidogrel hydrogen sulfate at the presence of acid catalyst, impurity B is obtained by grignard reaction, esterification, condensation and cyclization from the starting material of 3-bromine thiophene. Then characterize and standardized the homemade impurities.Results: The test data of infrared spectrum, nuclear magnetic resonance spectrum and mass spectrum demonstrate the structures of the two homemade impurities are consistent with clopidogrel impurity A and impurity B. The results of system suitability, detection limit, quantitation limit, linear and accuracy tests show that the clopidogrel related substances method provided in European Pharmacopoeia is suitable for testing the contents of clopidogrel impurity A and impurity B. The standardized results show the assay for clopidogrel impurity A and B are 99.2% and 99.0% respectively, they meet the requirements of working standard.Conclusion: The homemade working standards can replace the legal standards and save the research and development costs. If necessary, the impurities can be synthesized again according to the established synthetic route, that is benefit to daily test and stability test of post-marketing in the future.