Thermodynamic Correlation between Liquid–Liquid Phase Separation and Crystalline Solubility of Drug-Like Molecules

Abstract

The purpose of the present study was to experimentally confirm the thermodynamic correlation between the intrinsic liquid–liquid phase separation (LLPS) concentration (S0LLPS) and crystalline solubility (S0c) of drug-like molecules. Based on the thermodynamic principles, the crystalline solubility LLPS concentration melting point (Tm) equation (CLME) was derived (log10S0C=log10S0LLPS−0.0095Tm−310 for 310 K). The S0LLPS values of 31 drugs were newly measured by simple bulk phase pH-shift or solvent-shift precipitation tests coupled with laser-assisted visual turbidity detection. To ensure the precipitant was not made crystalline at <10 s, the precipitation tests were also performed under the polarized light microscope. The calculated and observed log10S0C values showed a good correlation (root mean squared error: 0.40 log unit, absolute average error: 0.32 log unit).