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

Abstract

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.

Drug-Rich Phases Induced by Amorphous Solid Dispersion: Arbitrary or Intentional Goal in Oral Drug Delivery?

“…These drug-rich phases were suggested to form through the liquid-liquid phase separation (LLPS) of the drug-water binary system only if the concentration of free drug molecules in solution exceeds the critical value at the binodal line. Indeed, similar solute-rich liquid phases generated by the LLPS process have been extensively reported in the protein, inorganic ion and organic molecule solutions [67]. As the free energy barrier to form metastable liquid phases is smaller than that to form crystalline solid nuclei, a two-step nucleation pathway, via the formation of metastable drug-rich liquid phases (pathway (ii) in Figure 1C), is thermodynamically favored over the classical one.…”

Liquid-Liquid Phase Separation in Nucleation Process of Biomineralization

“…Gibbs (Gibbs, 1878) firstly proposed this theory in the 19th century to describe the condensation process of supersaturated vapor into a liquid phase. After many efforts by other founders, CNT has been widely applied now to explain nucleation kinetics from solutions (Guo and Severtson, 2003;Qiao et al, 2019;Xu et al, 2021). It contained explanations to two situations including homogeneous nucleation and heterogeneous nucleation.…”

“…Non-classical nucleation theory demonstrates a process that before the formation of the crystal nuclei from the liquid phase, a metastable precursor phase firstly appears, and the crystal nuclei could next appear in this metastable precursor phase (Ma et al, 2017;Schreiber et al, 2017;Liu et al, 2019;Xu et al, 2021). Precursor phases could be shown in several forms including amorphous nanoparticles, droplets, complexes and so on.…”

The intertwined physics of active chemical reactions and phase separation

“…Phase separation plays a crucial role for providing robust microstructures in technology [1][2][3][4], biology [5][6][7], and even cooking [8]. In many cases, these structures provide a basis for controlling chemical reactions or are themselves affect by reactions.…”

“…To illustrate the connection between phase separation and chemical reactions, let us consider a fluid comprising two molecular species, A and B, which can phase separate and interconvert, A B. In the simplest case, phase separation leads to two homogeneous phases whose compositions are respectively characterized by the concentration pairs {c (1) A , c (1) B } and {c (2) A , c (2) B }. The concentration ratios between the two compartments define partition coefficients…”