The Effect of Intermolecular Interactions on the Dissolution Property of Aripiprazole

The measurement and prediction of solubilities of active pharmaceutical ingredients are crucial in the development of polymorphism and the crystallization process. In this work, the solubilities of aripiprazole (APZ) in 11 pure solvents were measured and correlated over the temperature range 293.15–333.15 K. It was found that in all studied solvents, the solubility of APZ increased with the increasing temperature throughout the entire investigated temperature range. In addition, the mixing and dissolution thermodynamic properties of APZ in 11 pure solvents were also calculated. The calculation results indicated that both the mixing and the dissolution processes of APZ are spontaneous. Moreover, the intermolecular interactions in APZ solutions were investigated by molecular surface electrostatic potential analysis, independent gradient model based on Hirshfeld partition analysis, and molecular dynamics simulations. The results showed that the van der Waals interactions had a significantly greater effect on the dissolution process of APZ than did the hydrogen bond interactions. The solubility of APZ was controlled by a combination of the relative magnitude of the newly formed solute–solvent intermolecular interactions and the solvent–solvent intermolecular interactions that were disrupted due to the addition of solute. Finally, a physical quantity, dissolution-driven energy (Edis-driven), was proposed to predict the APZ dissolution tendency in different pure solvents, which was able to characterize the solubility orders of APZ in different pure solvents almost perfectly.