Indirect Ultrasonication in Continuous Slug-Flow Crystallization

Continuous-flow solution crystallization is an approach to manufacture pharmaceutical crystals with improved control of product characteristics, simplified postcrystallization operations, higher production rate flexibility, and reduced capital costs and footprint. An indirect ultrasonication-assisted nucleation process is designed to vary the seed generation rate during operation independent of mass flow rate, by varying the ultrasonication power. The ultrasonication probe is pressed against a tube to generate a spatially localized zone within the tube inside of a temperature bath for the generation of crystal nuclei without heating or contaminating the supersaturated solution. This nucleation design is integrated into a continuous slug-flow crystallization process to generate uniform-sized product crystals within each slug at a high supersaturation level and a short residence time of ∼8.5 min, without inducing significant secondary nucleation. By increasing size uniformity, the indirect ultrasonication-assisted slug-flow crystallizer has potential as a final crystallization step to produce crystals for direct compression tableting without having any possibility of metal contamination.