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Thermodynamic Correlation between Liquid-Liquid Phase Separation and Crystalline Solubility of Drug-Like Molecules
Taiga Uekusa1, Tomohiro Watanabe1, Daiju Watanabe1
1Molecular Pharmaceutics Lab., College of Pharmaceutical Sciences, Ritsumeikan University, 1-1-1, Noji-higasi, Kusatsu 525-8577, Shiga, Japan.
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).
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