Review of Liquid-Liquid Phase Separation in Crystallization: From Fundamentals to Application

In the field of industrial crystallization, liquid-liquid phase separation (LLPS) easily makes the crystallization process into an uncontrollable state, making it extremely difficult for people to effectively control and optimize the crystallization process, which creates a big bottleneck for the precise control of the desired crystal product (polymorphism, crystal size distribution, crystal shape, etc.). In view of the significant influence of LLPS on nucleation mechanism and kinetics, which is associated with the regulation of crystalline products, we therefore review the research progress of LLPS in the crystallization process in the last 30 years and attempt to summarize the reasons for LLPS from the perspectives of thermodynamics, properties of solvent and solute, short-range attraction, and the nucleation pathway. Furthermore, we highlight the role of the dense liquid intermediate phase in nucleation by revisiting the progress of nucleation theory, especially the classical nucleation and two-step nucleation theory. Finally, we also discuss how to regulate the crystallization outcome with desired properties of crystals in the LLPS process (crystal size distribution, polymorphism, crystal habit, etc.) so as to inspire people about why and how to promote or avoid LLPS during the crystallization process.