Particle Engineering in a Continuous Crystallizer Cascade
Giovanni Aprile, Prem K. Reddy, Rajan R. Bhawnani, Cedric Devos, Peter Sagmeister, Aniket Udepurkar, Yuma Miyai, Daanyaal Sajed, Aarna Jindal, Bruno Marco Inzillo, Richard D. Braatz, Allan S. Myerson, Torsten StelzerAbstract
Crystallization is central to the purification and manufacturing of nearly all small-molecule pharmaceuticals. However, continuous crystallization remains sparsely adopted, in part due to the lack of standardized off-the-shelf platforms (≤100 mL) for reproducible development. This study reports the benchmarking of a continuous tower crystallizer (TWC) that constitutes a cascade of 10 mixed-suspension, mixed-product removal (MSMPR) crystallizers to approach plug-flow-like residence time distribution (RTD) in a compact and robust setup (≤80 mL). Using ketoconazole, an agglomeration-prone active pharmaceutical ingredient (API), as a case study, the TWC’s particle engineering capability is compared to a conventional single-tank MSMPR (with similar total volume) utilized as baseline. The advanced supersaturation control achieved in the cascade enables shifting the broad bimodal crystal size distribution (CSD, D90 = 225 μm, span = 4.5) to a unimodal CSD (D90 = 57 μm, span = 3.2) while significantly increasing process yield from 66% (MSMPR) to 90% (TWC). This tunability was further demonstrated through a proof-of-concept for distributed antisolvent addition in the TWC (D90 = 44 μm, span = 2.7).