Continuous antisolvent crystallization of paracetamol with an in-line hydrodynamic cavitation device

Continuous crystallization offers significant advantages over batch processes in the pharmaceutical industry, including improved product consistency, smaller process equipment, and greater productivity. In this work, we investigated the continuous antisolvent crystallization of paracetamol in a methanol-water system, incorporating an in-line vortex-based hydrodynamic cavitation (HC) device for the first time to modify crystal size distribution (CSD). A loop configuration was employed to augment a continuous stirred tank reactor (CSTR) and improve mixing performance. Experimental results demonstrated that the recirculation loop enhanced yield and productivity while reducing mean particle size. The introduction of HC further reduced and narrowed the CSD by promoting secondary nucleation and breakage through cavitation and shear. A population balance model (PBM) was developed to describe crystallization kinetics and estimate parameters for primary nucleation, secondary nucleation, growth, and breakage. The model successfully simulated steady state supersaturation profiles and CSD, confirming the efficacy of HC in tailoring CSD. The model was then used to predict yield and productivity across different residence times, illustrating a quantitative framework for optimizing operating parameters. The prediction was verified with an additional experiment conducted at a new operating condition not covered earlier for validating the computational model. This work represents the first integration of hydrodynamic cavitation into a continuous crystallization (continuous cavi-crystallization) process, offering a scalable approach for process intensification in pharmaceutical manufacturing.