Incorporating Solvent-Dependent Kinetics to Design a Multistage, Continuous, Combined Cooling/Antisolvent Crystallization Process

Combined cooling and antisolvent crystallization enables crystallization of many pharmaceutical products, but its process design typically neglects solvent composition influences on crystallization kinetics. This paper evaluates the influence of solvent-dependent nucleation and growth kinetics on the design of optimal, multistage mixed-suspension, mixed-product removal (MSMPR) crystallization cascades. The ability to independently select temperature and solvent compositions in each stage of the cascade serves to greatly expand the attainable region for a two-stage cascade, with diminishing returns for additional stages. Failure to include solvent-dependent kinetics can result in simulating incorrect attainable regions, active pharmaceutical ingredient (API) yields, and crystal size distributions. This work also demonstrates that commonly employed crystallization process design heuristics, such as equal antisolvent addition and decreasing temperature in successive stages, can result in suboptimal process design if kinetics are strongly solvent dependent.