The Process Design Scheme About Study And Control Of The Impurity In Production Of Ezetimibe

Ezetimibe,whose chemical name is 1-(4-fluorophenyl)-3(R)-[3-(4-fluorophenyl)-3(S)-hydroxypropyl]-4(S)-(4-hydroxyphenyl)-2-azetidinone,is a single ring β-lactam cholesterol absorption inhibitor,it may be useful in the treatment of hyperlipidemia conjunction with statins.Jilin Broadwell Pharmaceutical Co.conducted researchs and develops production of generic drugs of Ezetimibe which is beneficial to people.The paper focuses on the research and control of impurities in ezetimibe bulk drugs of production process.In this paper,described in detail a variety of Ezetimibe synthetic route reported in the literature,but it’s some shortcomings there,we based on the existing literature,combining its own conditions of experimental and production,avoid some patent restrictions,devised a reasonable route of Ezetimibe synthesis.Bulk drugs of Ezetimibe are not documented in the pharmacopoeia of domestic and abroad,so we according to the drug registration standards of national import and export,as well the relevant literature of Ezetimibe,and developed the related substances detection methods of Ezetimibe within the enterprise.It can be measured the organic impurities of Ezetimibe accurately.Ten consecutive batches samples tested of Ezetimibe,thus a general understanding of impurities situation of Ezetimibe produced by above mentioned company are obtained.By this,we are confirmed that six major impurities present in Ezetimibe with assay more than 0.10%,which all produced by manufacturing.Using flash column,semi-preparative TLC and semi-separation HPLC,to respectively separate and enrich the six kinds of impurities to obtain higher levels of extracted product which Ezetimibe impurities.Initially identified impurities structure through a variety of detection methods.Confirmed the structure of impurities by comparing the melting point,NMR,MS and other test results with extract product.We identified the six kinds of impurities.Then,determine the generated mechanism of these six kinds of impurities by studying mechanism of impurities and verification experiment.Found that the six kinds of impurities were come from the last two steps of the production process:the production processes of silanyl-deprotecting and the benzyl-deprotecting.Therefore,we optimize the last two steps of the production process.Conducted explore adjust the factors conditions of croduction processes by experiments comparing through single factor and multiple factors orthogonal experiment based on the analysis of organic impurities of Ezetimibe.By contrast with the impurity content of products which the original conditions,we found that the bulk drugs of Ezetimibe yield stability,the content of the main impurity reduced significantly,no new impurity production,and improve the quality of the product after production process.