Molecular mechanism of liquid–liquid phase separation in preparation process of crystalline materials

Molecular mechanism of liquid–liquid phase separation (LLPS) before nucleation in the preparation of crystalline materials is not well understood. In this work, the evolutions of solute–solvent intermolecular interactions and molecular self-assembly before and after LLPS were investigated by using citicoline sodium as model compound. Raman spectroscopy and molecular dynamics simulation (MD) were applied to reveal different interactions. It was found that the solute–solvent intermolecular interactions were firstly enhanced and then weakened before and after LLPS, indicating that LLPS was caused by the enhanced solute–solvent intermolecular interactions. Solute molecules will self-assemble to form clusters in binary mixed solvents, according to the 2D 1H–1H NOESY measurements and small angle X-ray scattering (SAXS). The clusters will further self-assemble to form a dense liquid phase with the process proceeding. Based on these results, the molecular mechanism of LLPS was proposed and discussed.