Particle Engineeringin a Continuous CrystallizerCascade

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).