Thermodynamic Properties of R-3-Hydroxybutyric Acid in Three Binary Mixed Solvent Systems and Its Molecular Mechanism

Abstract

Crystallization is critical for drug purification, and thermodynamic data is essential for its development and optimization. To address the existing gap in data on the solubility and thermodynamic properties of R-3-hydroxybutyric acid (R-3HB), its solubility in three binary mixtures of solvents (methyl tert-butyl ether + n-pentane, methyl tert-butyl ether + n-heptane, and methyl isobutyl ketone + n-heptane) was measured using a dynamic method over a temperature range of 273.15-303.15 K. The solubility of R-3HB in binary mixed solvents increases with rising temperature and the fraction of methyl tert-butyl ether (MTBE) or methyl isobutyl ketone (MIBK), with solvent composition playing a dominant role. In the MTBE + n-pentane system, solubility increases approximately 5-fold upon 30 K temperature increase, while raising the MTBE mole fraction from 0.2 to 0.9 leads to a ∼33-fold solubility gain. Among four thermodynamic models, the CNIBS/R-K model provides the best correlation (ARD = 2.34 × 10⁻², RMSD = 1.079 × 10⁻³). Molecular simulation results indicate that solubility differences stem from the combined effects of solute–solute, solute–solvent, and solvent–solvent interactions, rather than solvent polarity alone. This work provides fundamental thermodynamic data and mechanistic understanding to support the crystallization of R-3HB.