Solubility measurements and molecular dynamics simulations of perphenazine (form I) in three binary solvent systems

This study aimed to investigate the perphenazine (form I)’s solubility in three binary solvent systems: acetone + water, n-propanol + water, and N,N-dimethylformamide (DMF) + water, within the temperature range of 278.15 K to 318.15 K. The solubility data were obtained using a dynamic method and fitted using four models: the NRTL model, modified Apelblat equation, CNIBS/R-K model, and Jouyban-Acree model. All four models provided satisfactory fitting results, with the CNIBS/R-K model exhibiting the best performance. In all cases, it was observed that the solubility of perphenazine (form I) exhibited a positive correlation with temperature while keeping the solvent composition constant. Specifically, in the DMF + water binary solvent system, the solubility of perphenazine (form I) increased with higher mass fractions of the positive solvent. Additionally, the phenomenon of co-solvency was observed when perphenazine (form I) was dissolved in the acetone + water and n-propanol + water binary solvent systems. To gain insights into the intermolecular interactions within the perphenazine (form I) crystal, Hirshfeld surface (HS) analysis was employed. The Dmol3 module was used to calculate the electrostatic potential of perphenazine molecules, followed by molecular dynamics simulation, analysis of the solute–solvent and solvent–solvent radial distribution functions (RDF), and calculation of solvation free energy. Overall, this study enhances the understanding of the dissolution behavior of perphenazine (form I) and provides valuable data to support further investigations into its crystallization process.