Reducing the Induction Time Using Ultrasound and High-Shear Mixing in a Continuous Crystallization Process

Continuous crystallization in tubular crystallizers is of particular interest to the pharmaceutical industry to accurately control average particle size, particle size distribution, and (polymorphic) shape. However, these types of crystallizers require fast nucleation, and thus, short induction times at the beginning of the flow process, which is challenging for larger and complex organic molecules. High shear and/or the presence of bubbles were identified to influence the nucleation behavior. This work investigates the effects of both high-shear mixing and ultrasound on the anti-solvent crystallization of paracetamol in acetone-water. Both devices generate intense amounts of shear and gas bubbles. Generally, the results show that increasing input power decreases the induction time significantly for both the rotor-stator mixer and ultrasound probe. However, the induction time is almost independent of the supersaturation for the ultrasound probe, while the induction time significantly increases with decreasing supersaturation for the rotor-stator mixer. In contrast, the particle size distribution for the rotor-stator mixer is independent of the supersaturation, while increasing supersaturation decreases the particle size for the ultrasound probe.