Crystallization in the Presence of a Liquid−Liquid Phase Separation

Abstract

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 μm made up of small crystals of a few micrometers.

Phase equilibrium and mechanisms of crystallization in liquid–liquid phase separating system

“…The nucleation is clearly hampered by the LLPS. This is in agreement with previous results [5,16,40,41]. It is reported that in LLPS solution nucleation can take place in both the dispersed phase and the continuous phase [42] or at the interface between them [43].…”

“…Time for nucleation with 95% confidence interval and relative distance to the saturation of droplets solutions (Sols. [1][2][3][4][5][6][7][8][9][10][11][12] with 90-35% ethanol in solvents. Solid dots: average nucleation time of droplet solutions with 95% confidence interval.…”

“…Binary solvent mixtures are commonly used in industrial crystallizations and recently more research on more complex multiphase crystallization processes with liquid-liquid phase separation (LLPS) have been reported. Liquid-liquid equilibrium data have been investigated for some "anti-solvent" crystallization experiments [2,3], spherical crystallizations using a three solvents system [4,5], oiling out phenomena [6][7][8][9][10] and reverse addition processes [11]. The LLPS makes crystallization difficult in protein systems [12,13], prevents drug nucleation [14][15][16], and hinders nucleation in crystallization of droplets [17].…”

Nucleation and polymorphism explored via an easy-to-use microfluidic tool

“…Novel methods such as crystallization robots for high-throughput screening [1] and emulsion-based methods have been developed. Examples of the latter include spherical crystallization by the quasi-emulsion method [2,3], methods using the miscibility gap in the phase diagram [4] or microfluidic methods [5]. Working with small volume systems has already proved valuable and holds great promise for the control and the study of crystallization processes, for instance, producing crystals of controlled size [6].…”

Crystallization-in-emulsion process of a melted organic compound: In situ optical monitoring and simultaneous droplet and particle size measurements

“…This liquid-liquid demixing may hinder primary and secondary nucleation mechanisms. The occurrence of primary nucleation in the droplets at high supersaturation level was visualized [8]. The crystallization of fats and lipid systems in an oilin-water (O/W) emulsion is frequently encountered in the field of food science.…”