Effects of intermolecular interactions and solvent properties on the solid-liquid phase equilibrium of isosorbide 5-mononitrate

The solute-solvent interaction was studied by the radial distribution function and solvation free energy. It was closely related to the dissolution behavior of isosorbide 5-mononitrate. Meanwhile, the solubility of isosorbide 5-mononitrate was determined by the physicochemical properties of the solvents. • Solubility of isosorbide 5-mononitrate was measured by the laser dynamic method. • Four thermodynamic models were used to correlate the solubility of 5-ISMN. • The effects of solvent properties and solute-solvent interactions on the solid-liquid phase equilibrium were investigated. • The mixing thermodynamic properties were derived and discussed. Isosorbide 5-mononitrate (5-SIMN) is an organic nitrate pharmaceutical for the treatment of angina pectoris. In this work, first, the solubility of 5-ISMN in ten organic solvents was determined by the laser dynamic method at temperatures ranging from 278.15 K to 318.15 K. The results showed that the equilibrium solubility of 5-ISMN was temperature-dependent and increased monotonically with temperature. In addition, the effect of solvent properties on the dissolution behavior of 5-ISMN was also investigated, in which the “like dissolves like” principle played a critical role in the equilibrium solubility of 5-ISMN in different solvents. Next, four models (Apelblat equation, Van't Hoff equation, λh equation, and NRTL equation) were used to verify and correlate the experimental solubility data. The Apelblat equation fits the data well, and the maximum ARD% was less than 3%. Furthermore, molecular dynamics simulations were explored to reveal the effect of solute-solvent interactions on the dissolution behavior. Finally, the mixing thermodynamic properties of 5-ISMN were derived, and the results demonstrated that the mixing process was entropy-driven and spontaneous.