Integrative Approach for Polymorphic Crystallization Process Synthesis

This article presents an integrative approach for synthesizing a process to crystallize a specific polymorphic form. By considering crystallization compartments, metastable zones, and crystallization kinetics of different polymorphs, strategies for obtaining the desirable form can be developed. The progress of crystallization is followed by visualizing how the process paths move around different regions of a solid−liquid equilibrium phase diagram. Examples involving p-aminobenzoic acid, 2-(3-cyano-4-isobutyl-oxyphenyl)-4-methyl-5-thiazolecarboxylic acid, and two drug candidates are used to illustrate this approach.