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

• The solubility of risperidone (form Ⅰ) in pure and binary solvent systems were determined. • Experimental solubility data were correlated by different models. • HS analysis was applied to understand the intermolecular interaction of the crystal structure of risperidone (form Ⅰ). • RDF analysis was employed to explain the co-solvency phenomenon. • Thermodynamic properties of the solution were calculated and discussed. 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 2-propanol + 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, λh 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.