First-principles and direct design approaches for the control of pharmaceutical crystallization

Crystallization is the main separation and purification process for the manufacturing of drug substances. Not only does crystallization affect the efficiency of downstream operations such as filtering, drying, and formulating, the efficacy of the drug can be dependent on the final crystal form. Advances in simulation and control algorithms and process sensor technologies have enabled the development of systematic first-principles and direct design approaches for the batch control of crystallization processes. These approaches address different challenges associated with pharmaceutical crystallization control. This paper provides an overview of recent technological advances in the in situ control of pharmaceutical crystallization processes. Implementation of the first-principles and direct design approaches are compared, and their relative merits are explained. Areas of future opportunities for application of advanced control strategies in pharmaceutical crystallization are presented.