Crystal Shape And Quality Analysis Method Study Of Clopidogrel Hydrogen Sulfate

Clopidogrel bisulfate is an antithrombotic drug that can prevent the formation of atherosclerotic thrombus by effectively inhibiting platelet aggregation.It is known that it has 7 crystal forms,and these 7 crystal forms have obvious differences in solubility and stability.The crystal form has a significant impact on the dissolution,bioavailability,quality and effectiveness of the drug,so exploring the polymorphism of the drug has far-reaching significance for the development of the drug.The research content of this paper is mainly divided into two parts.1.On the basis of the review of the crystal form of clopidogrel hydrogen sulfate,we focus on the types and proportions of crystallization solvents,the order of acid-base addition,The effects of seeding species,stirring rate,crystallization temperature,and the feeding ratio between clopidogrel free base and sulfuric acid on the crystal form of clopidogrel hydrogen sulfate.Through process optimization,an ideal process for preparing the Ⅱ crystal form of clopidogrel hydrogen sulfate is finally obtained.method overcomes the occurrence of mixed crystals.In addition,a systematic study on the determination of the crystal form of clopidogrel hydrogen sulfate is established.the characterizations such as optical microscope analysis,infrared spectrum analysis,Xray powder diffraction analysis,and thermal analysis scanning are carried out,and the differences of crystal form the clopidogrel hydrogen sulfate between form Ⅱ and formⅠ are compared.Based on the differences in solid state characterization between Form I and Form II,a qualitative analysis method for effectively identifying the crystal form of clopidogrel hydrogen sulfate is established,which provided an important research basis for the quality control of the crystal form of clopidogrel hydrogen sulfate API.2.Carry out the impurity profile analysis for the synthetic route of chloropyrrolidone bisulfate,and use Derek and Sarah to evaluate the structure-activity relationship of impurities containing genotoxic warning structures.According to the above research and under the guidance of relevant regulations,the key starting materials(S)-o-chlorophenylglycine methyl ester tartrate(SM1),4-methylbenzenesulfonic acid 2-(thiophen-2-yl)were established Ethyl ester(SM2),key intermediate(S)-2-(2-chlorophenyl)-2-((2-(thiophen-2-yl)ethyl)amino)acetic acid methyl ester hydrochloride,finish sulfuric acid Impurity control strategy for hydroclopidogrel.Finally,with the help of high-performance liquid chromatography and high-performance gas chromatography for drug quality analysis,with reference to the Chinese Pharmacopoeia 2020 Edition Part II,a high-performance liquid-phase main component self-contrast method is established to determine the related substances of clopidogrel bisulfate,and carry out methodological research and verification experiments on the above SM1,SM2,intermediates and finished products.The results of a series of methodological experiments show that the detection methods for related substances of clopidogrel hydrogen sulfate have good specificity,good repeatability,and these methods are reliable and robust,which can be used for the quality analysis and detection of relevant materials ofclopidogrel hydrogen sulfate.