Multivariate population balance modeling and simulation of ultrasound-assisted crystallization of a plate-type pharmaceutical: Nucleation, growth, and breakage

Abstract

The application of ultrasound is recently gaining significant interest in crystallization because of its significant impact on nucleation and growth rates, particle breakage, crystal habit, polymorphism, and crystal size distribution. Pyrazinamide, an essential drug for the treatment of mycobacterium tuberculosis, has four different polymorphic forms. The metastable $\delta$-polymorph exhibit plate-type habit which is desirable for downstream operations compared to commercially available needle-type $\alpha$-polymorph. This contribution presents a detail experimental and computational study on the effect of ultrasound and its amplitude on nucleation, growth, and breakage of crystals for unseeded batch cooling sonocrystallization of $\delta$-polymorph of pyrazinamide from its 1,4-dioxane solution. A series of sonocrystallization experiments are conducted with different cooling rates and ultrasonic amplitudes and a bivariate population balance model involving crystal nucleation, growth, and breakage is developed and fully validated. The model simulations give important insights on time evolution of mean crystal size and aspect ratio of plate-type crystals.