Breakage-Facilitated Mixed-Suspension-Mixed-Product-Removal (MSMPR) Crystallization of Pharmaceutical Compounds

Continuous crystallization provides advantages of producing solid products of consistent quality attributes at a small equipment footprint. However, the intrinsic nucleation and growth rates of small-molecule pharmaceuticals constrain the design spaces of their continuous crystallization processes. In this work, a wet milling device, breaking large particles into small fragments, was incorporated into a mixed-suspension-mixed-product-removal (MSMSR) single-stage crystallizer. The MSMPR crystallization was controlled by an ultrasound feedback loop to maintain a constant total slurry volume, while the slurry was constantly being circulated through a wet mill at different milling intensities. The approach was applied to two compounds with distinct crystallization kinetic properties, including paracetamol (fast nucleation and growth) and a proprietary compound (slow nucleation with agglomeration). Experimental data showed that particle attrition provided by wet milling generated a significant number of nuclei that could promote the crystallization rate, which greatly reduced the steady-state supersaturation level. The introduction of the controllable breakage mechanism offered better particle size distribution control, higher yield, and minimized fouling tendency that resulted in a longer operation time than conventional MSMPR.