The Synthesis Of Nimodipine Impurity In EP And The Process Control Of Impurity

Nimodipine is a kind of1,4-dihydropyridines calcium antagonists derivative with a preferential effect on cerebral vessels and brain function.It is suitable for brain function disorder caused by migraine, cerebral vasodilation and improve brain function, cerebral vasospasm, vascular dementia, sudden deafness.Nimodipine was developed successfully by Bayer at1980s firstly, The successful development in our country was by the Chinese Academy of Medical Sciences and Shandong Xinhua Pharmaceutical Co.,LTD. in1986and developed into the market at1989.Because of the definite effect, Decompression effect lasting, Excellent security, the price is relatively cheap, Nimodipine still is one of the best-selling drugs at present.There are three kinds (impurity A, impurity B and impurity C) related substance defined by European Pharmacopoeia about Nimodipine. Because our country at present there is no corresponding impurity reference substance to provide,the method of analysis of related substance is principal component analysis by high performance liquid chromatography(HPLC).We analyze the the three impurities structure compared to existing Nimodipine Production and European Pharmacopoeia defined, formulate a suitable impurities synthetic route.The impurity A is synthetized by Nimodipine dehydrogenation oxidation with manganese dioxide.The impurity B is synthetized by diketene as main raw material, with the structure of dihydropyridine ring symmetrical carboxylic isopropyl side chain. The impurity C is synthetized also by diketene as main raw material, with the structure of dihydropyridine ring symmetrical carboxylic methoxy-ethyl ester side chain.The three impurities achieve a higher purity by the design and optimization of the synthesis process. Spectrum discriminant analysis is corresponding to reference spectrum, analysed by HPLC, IR, MS, UV,1H-NMR and13C-NMR. Three impurities in pure synthesis of the European Pharmacopoeia impurities in Nimodipine can be further used for the pharmacological and toxicological studies of impurities, on the product impurity side effects of Nimodipine research sample support.The Project Clarified the impurity production mechanism, Based on the Nimodipine API production practice, through the synthesis research of impurities.The production process for effective control, the intrinsic quality of the Nimodipine is improved. the safety of drugs are guaranteed ultimately. The preparation of the pure product of the three standard methods, HPLC analysis also can be used as working standard, can save the costs associated with later expensive Pharmacopoeia standards.Through the Nimodipine impurity control, Nimodipine synthesis process more mature reliable, the relevant material effectively control, more suitable for the requirements of production. work for Nimodipine pharmaceutical and relevant material control has accumulated a lot of experience, so as to further enhance Nimodipine API inner quality.