Thermodynamic analysis and molecular dynamic simulation of the solubility of risperidone (form I) in the pure and binary solvents

Risperidone is one of the second-generation anti-schizophrenia representative drugs, which is widely used in the treatment of acute and chronic schizophrenia. In this work, the solubility of risperidone (form I) in thirteen pure solvents and three binary solvent mixtures (ethanol + water, acetone + water and 2propanol + water) was determined. The measured temperature range was 278.15-313.15 K and the measurement was accomplished by utilizing a gravimetric method under the barometric pressure. The experimental solubility data were correlated by the Apelblat equation, kh equation, NRTL model, UNIQUAC model, Jouyban-Acree model and CNIBS/R-K model with all the calculated solubility data dovetailing well with the experimental solubility data. The solubility of risperidone (form I) in selected solvent systems was positively correlated with the temperature and the co-solvency phenomenon was observed in all the three binary solvent systems, which was different from the results obtained from the literature. The Hirshfeld surface (HS) analysis was applied to understand the intermolecular interaction of the crystal packing of risperidone (form I). The molecular dynamic simulation was then carried out and the Radial distribution function (RDF) analysis was employed to illustrate the intermolecular interaction between the solute and solvent molecules, and it turns out that the results of the RDF analysis can well explain the co-solvency phenomenon. In addition, based on the van't Hoff equation, the apparent thermodynamic properties of risperidone (form I) in selected solvent systems were calculated and the results show that the dissolution of risperidone (form I) is a process of endothermic and entropy-driven. (c) 2022 Elsevier B.V. All rights reserved.

Automated summary

In this study, the solubility of risperidone in various solvents was determined, and the dissolution process was investigated. The results showed a positive correlation between solubility and temperature, and the phenomenon of co-solvency was observed. The intermolecular interactions between the solute and solvent were analyzed using Hirshfeld surface analysis and molecular dynamic simulation.