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

Abstract

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.

Control of Antisolvent Mass Transfer through Porous Membranes for the Crystallization of Organic Compounds

“…In a previous study, we investigated the variation of induction time under different operating conditions. Induction time did not follow a clear trend with the increase or decrease of solution flow rates from either side of the membranes but correlated directly with the transmembrane mass transfer rate such that a faster mass transfer resulted in a shorter induction time …”

“…Induction time did not follow a clear trend with the increase or decrease of solution flow rates from either side of the membranes but correlated directly with the transmembrane mass transfer rate such that a faster mass transfer resulted in a shorter induction time. 14 3.3. Crystal Shape, CSD, and the Crystalline System.…”

“…12 Membrane material can differ to match environments of different pH and temperature, with a wide pore range and thicknesses; and (iv) it is a promising solution to process intensification integrating other process functions besides crystallization such as reaction purification. 13 MAAC nonetheless, is yet to overcome some limitations to its efficient application: (i) membrane pore clogging can occur depending on the interactions between the solute and membrane surface; 14 (ii) different membrane modules exist on the market, but only flat-sheet and hollow-fiber ones have been explored so far, so spiral-wound or tubular membrane modules are yet to be explored to facilitate their application; and (iii) the transmembrane mass transfer is not yet understood nor its correlation with resulting crystal properties.…”

Recent Progress in Antisolvent Crystallization of Pharmaceuticals with a Focus on the Membrane‐Based Technologies

“…The excellent stability of the drugs was proved as the obtained drug nanoparticles remained unchanged for the 28 days during repeated production. In another study, Chergaoui et al [78] examined the effect of solution velocity, the effect of antisolvent composition, and temperature and gravity in a glycine-water-ethanol crystallization system supported by polypropylene membranes. Based on the obtained results, all of the studied parameters played a crucial role on the final morphology and size of the glycine crystals, for instance, by changing the temperature in the range of 25-35°C, the final crystal size changed significantly (Fig.…”

“…(f ) The SEM images of glycine crystals obtained from the bulk solution after MAAC operation at different temperatures. Reproduced with permission from reference [78].…”