Developing Crystallization Options for Manufacturing

Crystallization is a critical unit operation in the production of active pharmaceutical ingredients.  The importance of controlling particle size, form, and supersaturation have led to extensive development around addition mode for antisolvent or reactive crystallizations.  Three typical addition modes are forward-addition, reverse-addition, and co-addition.  Different addition modes have different inherent risks, equipment requirements, and complexities.  Co-addition crystallizations are typically successful where forward-addition and reverse-addition crystallizations fail; however, co-additions require additional equipment and control than other addition modes.

A case study is presented of a reactive crystallization which had undesirable crystallization behavior in forward and reverse modes, only maintaining supersaturation control with a co-addition strategy.  In the process of understanding this behavior, new process options were developed which allowed a reverse addition to be performed with supersaturation control, providing manufacturing with multiple crystallization options.