Enhancing nucleation using hydrodynamic cavitation for intensifying continuous antisolvent crystallization

In this work, hydrodynamic cavitation (HC) was used to enhance nucleation and intensify continuous antisolvent crystallization processes. The influence of vaporous cavities and nano−/microbubbles generated through HC and aeration on nucleation was first investigated using induction time measurements. Two model systems, carbamazepine-ethanol-water (CBZ-EtOH-H₂O) and paracetamol-methanol-water (PCM-MeOH-H₂O), were considered. HC reduced the characteristic induction time for both systems, with a further reduction observed in the presence of air. Correlations describing the influence of supersaturation on induction time were developed for both systems. Based on these findings, a novel continuous cavi-crystallization configuration was developed in which the active pharmaceutical ingredient (API) containing stream was not directly exposed to cavitation. The developed configuration was evaluated using the PCM-MeOH-H₂O system in a continuous oscillatory baffled crystallizer (COBC). A generalized tanks-in-series population balance model (PBM) was used to simulate the steady-state behavior of the COBC system. The presence of cavitation-generated bubbles reduced fouling/encrustation, and enhanced nucleation, crystal growth, the characteristic crystal size, crystal yield and productivity. The developed approach provides a new pathway for leveraging HC to realize intensified and scalable continuous antisolvent crystallization processes with enhanced productivity and reduced fouling.