Key Parameters Impacting the Crystal Formation in Antisolvent Membrane-Assisted Crystallization

Antisolvent crystallization is commonly used in the formation of heat-sensitive compounds as it is the case for most active pharmaceutical ingredients. Membranes have the ability to control the antisolvent mass transfer to the reaction medium, providing excellent mixing that inhibits the formation of local supersaturations responsible for the undesired properties of the resulting crystals. Still, optimization of the operating conditions is required. This work investigates the impact of solution velocity, the effect of antisolvent composition, the temperature and gravity, using glycine-water-ethanol as a model crystallization system, and polypropylene flat sheet membranes. Results proved that in any condition, membranes were consistent in providing a narrow crystal size distribution (CSD) with coefficient of variation (CV) in the range of 0.5-0.6 as opposed to 0.7 obtained by batch and drop-by-drop crystallization. The prism-like shape of glycine crystals was maintained as well, but slightly altered when operating at a temperature of 35 °C with the appearance of smoother crystal edges. Finally, the mean crystal size was within 23 to 40 µm and did not necessarily follow a clear correlation with the solution velocities or antisolvent composition, but increased with the application of higher temperature or gravity resistance. Besides, the monoclinic form of α-glycine was perfectly maintained in all conditions. The results at each condition correlated directly with the antisolvent transmembrane flux that ranged between 0.0002 and 0.001 kg/m². s. In conclusion, membrane antisolvent crystallization is a robust solution offering consistent crystal properties under optimal operating conditions.