(466a) Growth and Nucleation Kinetics in Continuous Antisolvent Crystallization Systems

Most crystallizations in the pharmaceutical industry occur as batch processes. However, a shift towards continuous manufacturing is occurring to decrease costs and increase process control. For heat-sensitive compounds or APIs which exhibit weak solubility-temperature dependence, antisolvent crystallization is commonly the purification method of choice. Previous research has not established a clear relationship between nucleation or growth kinetics and antisolvent composition. Current research elucidates the effect of temperature and supersaturation on empirical models of crystal nucleation and growth, either neglecting the effect of antisolvent or by assuming a â??model of best fitâ?? for solvent composition-dependent kinetics, based primarily on batch crystallization studies. In this work, we demonstrate the need to consider antisolvent-dependent growth and nucleation kinetics in continuous crystallization processes. Solvent-dependent growth and nucleation kinetics derived from single-stage, mixed-suspension, mixed-product removal (MSMPR) experiments were applied to model continuous, multi-stage MSMPR systems. The effect of solvent composition on final product specifications, such as yield and mean particle size, was also explored. We successfully showed the implementation of our growth and nucleation kinetic models through the rational design of a multi-stage, continuous, combined cooling/antisolvent crystallization process for an industrially-relevant API. We expect our findings to provide a framework for the design of additional continuous antisolvent crystallization processes in the future.