(366d) Developing a Selective Crystallization Process for a Complex Reaction System

Authors: Chenchi Wang, Truc Vu, Lucius Rossano.

Research and Development, Bristol-Myers Squibb Company, New Brunswick, New Jersey

A reactive crystallization process often involves multiple complex steps, such as chemical reaction, solid precipitation/crystallization, and particle size control if required.  In this case study, an active pharmaceutical ingredient (API) is prepared in a telescoped process integrating deprotection, free basing and salt formation.  Apart from the chemistry issues encountered that are not the focus of this presentation, the challenges of the crystallization lie in (1) maintaining chemical stability of the free base prior to crystallization, (2) quantitating the free base available for salt formation, (3) maximizing yield of the free base under process conditions, (4) enhancing purity by trace metal removal, and (v) achieving desired particle size for drug product development.  In order to address these important process issues and improve process robustness, a two-step, selective crystallization process was developed.  As a result of this development, a robust API synthesis step, incorporating this well-controlled reactive crystallization, was demonstrated at various scales and consistently generated material with desired purity, yield, and particle size.  The designing and outcomes of this process will be discussed in details.