Synchronous Wet Milling-Crystallization Operation for Particle Size Distribution Modulation

We show that the particle size distribution (PSD) output by a continuously wet milled antisolvent crystallization can be predicted during scale up based on laboratory experiments. Desupersaturation and turbidity measurements indicate the crystallization kinetics are impacted by the mill speed, seed load and specific seed surface area (i.e., a joint measure of total seed surface area), and antisolvent feed rate (AR). These parameters determine the product PSD and can steer the crystallization towards growth or nucleation-dominated mechanisms. The resulting PSDs, as determined by laser diffraction, are described by a newly proposed dimensionless parameter that accounts for the mill energy input to the crystals, the total seed surface area, mill residence time and AR. The milling curve model effectively represents the crystallization behavior of a model compound over 10−250 g scales. Applying this methodology to acetaminophen recrystallization demonstrates the proposed framework’s applicability to other molecules.