Utilizing the phase-field method to investigate liquid-liquid phase separation in the ternary system of water/ethanol/butylparaben

Abstract

Small-molecule compounds targeted for drug development have frequently exhibited poor solubility in water, leading to instances of liquid-liquid phase separation (LLPS) during cooling crystallization and anti-solvent crystallization processes. Addressing strategies for managing crystallization processes involving LLPS has become a significant concern. Predicting changes in the structure and concentration of each separated phase over time would contribute to setting conditions and guiding process design to prevent oiling-out and achieve particles with desired morphology. In this study, we assessed the potential of the phase-field method to predict LLPS through simulations in a typical LLPS system, especially a ternary water/ethanol/butylparaben system. Consequently, the phase states in each zone (stable, metastable, and unstable) were determined to be thermodynamically valid. Additionally, the size of the spherical dispersed phase was confirmed to change in proportion to one-third of the time according to the Ostwald ripening rule. Furthermore, the qualitative analysis of factors influencing phase structure, local composition, delay time for phase separation in spinodal decomposition, and the localized LLPS during anti-solvent addition is also feasible. These findings suggest that the phase-field method holds potential as a tool to aid in the design of crystallization processes.