(451g) Integrated Approach Toward API Form Selection and Process Development for a Complex Reactive Crystallization Step

Integrated Approach toward API Form Selection and Process Development for a Complex Reactive Crystallization Step

Ernest Carra, Xiang Wang, Brandon Brown, and Fang Wang

Gilead Sciences, Foster City, CA 94404

A suitable salt form of an active pharmaceutical ingredient (API) has been identified and selected for further development. This new salt form was discovered through extensive form screening work.  The screening work produced several crystalline forms: a hemi-succinate salt and individual hemi-solvates of the parent compound with each of the several solvents, including acetone, acetonitrile, ethanol, isopropanol, and MTBE. Among all the newly discovered forms, hemisuccinate proved to be the most suitable form for further development based on its superior stability, manufacturability, and impurity control capability..

A successful manufacturing process was designed and developed using reverse addition of the API sodium salt solution to an aqueous succinic acid solution. This process was designed to overcome challenges presented by the competing crystallization of various solvated forms of the parent compound. Single crystal X-Ray structure data provided key understanding for the competitive crystallization during process development. This integrated approach towards form screen and crystallization process development has proven to be highly efficient as it is based on fundamental understanding of structural information of various API forms.