Crystallization in the presence of a liquid-liquid phase separation

This paper presents and compares crystallization experiments of an active pharmaceutical ingredient and a biological molecule in the presence of a liquid-liquid phase separation monitored by in situ video. The advantage of this setup is that it requires a small quantity of these products to study the influence of the physicochemical parameters on crystallization. Crystallization mechanisms and kinetics are different depending on the starting position in the phase diagram and on the temperature reduction, when crystallization is temperature-induced. Liquid-liquid phase separation changes the medium and the conditions of crystallization, hinders both primary and secondary nucleation for several hours, and consequently affects the process. For great temperature reduction and, inside the spinodal zone, namely high supersaturation (>15), crystals nucleate inside the droplets. Therefore, we take advantage of the formation of droplets to propose a new approach to spherical crystallization. The final products are quasi-spherical monodisperse agglomerated particles of about 500 mu m made up of small crystals of a few micrometers.