Structural Correction and Process Improvement for Control of a Critical Process Impurity of Ezetimibe

Autor:	Pradeep Kumar, Venugopal Reddy Gaddam, Rajasekhara Prasad Kottapalli, Madhava Rao Mannam, S. P. Natarajan, Srimurugan Sankareswaran
Rok vydání:	2019
Předmět:	Materials science 010405 organic chemistry Organic Chemistry Process improvement 010402 general chemistry 01 natural sciences 0104 chemical sciences Ezetimibe Impurity Innovator Computational chemistry Scientific method medicine Process control Physical and Theoretical Chemistry medicine.drug
Zdroj:	Organic Process Research & Development. 23:919-925
ISSN:	1520-586X 1083-6160
Popis:	A new process-related impurity of ezetimibe was identified and characterized. The impurity is critical and common to most of the manufacturing routes of ezetimibe. Structural characterization using HMBC indicated the presence of a six-membered ring rather than a nine-membered ring as proposed by the innovator of ezetimibe. Prominently, the existing pharmacopoeial methods for ezetimibe are not capable of detecting this impurity. A control strategy was established by appropriate process control that is capable of purging the impurity to levels comfortably below the regulatory requirement. The formation of the diastereomer impurity during the demonstration of a scale-up batch under the optimized conditions is attributed to epimerization of ezetimibe induced by thermal degradation of the silylating agent.
Databáze:	OpenAIRE
Externí odkaz:	https://explore.openaire.eu/search/publication?articleId=doi_________::7d5d12946af9d666dd7359a0ca395f38 https://doi.org/10.1021/acs.oprd.9b00024 Zobrazit plný text záznamu