Thermodynamic analysis and molecular dynamic simulation of solid-liquid phase equilibrium of griseofulvin in three binary solvent systems

Abstract

In this work, the solid-liquid phase equilibria of griseofulvin (GSF) in three binary solvent systems were investigated by both experimental and molecular dynamic simulation approaches. The equilibrium solubility of griseofulvin (GSF) in three binary solvent mixtures of isopropanol + acetone, isopropanol + 2-butanone, and isopropanol + 4-methyl-2-pentanone was determined by the gravimetric method at temperatures ranging from 283.15 K to 323.15 K under atmospheric pressure. The equilibrium solubility increases monotonously as the temperature increases at a given solvent composition or increases with increasing the solvent composition of good solvent acetone (2-butanone) in binary solvent mixtures, whereas there exists a maximum solubility value in isopropanol + 4-methyl-2-pentanone system. These solubility behaviors were found complying well with the empirical rule “like dissolves likes”. The experimental data were then correlated by the modified Apelblat equation, λh equation, modified Jouyban-Acree equation, and NRTL model, and the modified Apelblat equation receives the best fitting performance. Moreover, the thermodynamic functions including enthalpy, entropy, and Gibb free energy of mixing were derived and expectedly suggested an exothermic and spontaneous process of mixing. Molecular dynamic (MD) simulation was further employed to investigate the solute-solvent interactions behind the dissolution behaviors of griseofulvin. Radial distribution function (RDF) analysis reveals that the rank of solute-solvent interactions can be well correlated with solubility order in binary solvent mixtures and the intermolecular interactions between solute molecules and good solvent molecules are dominant. All the thermodynamic data and models presented here will certainly provide fundamental basis for designing and optimizing the crystallization of griseofulvin, a classic antifungal drug. Our MD simulation results are also helpful to understand the solid-liquid phase equilibrium behaviors in binary solvent systems.