Solubility behavior of Rosiglitazone in ten pure solvents: Model correlation, thermodynamic calculations, and molecular simulation

Rosiglitazone is an oral antidiabetic medication primarily used to treat type 2 diabetes. Herein, the single crystal structure of Rosiglitazone (a = 14.0613(7) Å, b = 8.4675(4) Å, c = 29.8841(16) Å, space group Pbca, Z = 8, V = 3558.1(3) Å3) was analyzed for the first time. Through solubility measurements, model correlation, thermodynamic calculations, and molecular simulations, the dissolution of Rosiglitazone in ten pure solvents was comprehensively investigated. The solubility order at 298.15 K is acetone > methyl acetate > ethyl acetate > butyl acetate > acetonitrile > alcoholic solvents (methanol, ethanol, n-propanol, iso-propanol, n-butanol). Rosiglitazone exhibits higher solubility in non-alcoholic solvents, whereas its solubility in alcoholic solvents is similar and relatively low. Subsequently, the correlation between the experimentally measured solubility of Rosiglitazone and the Modified Apelblat model, λh model, NRTL model, and Van't Hoff model was examined. The Van't Hoff equation calculations proved that the dissolution of Rosiglitazone was an endothermic process driven by entropy and characterized by non-spontaneity. The calculation of solvent polarity and Hansen solubility parameters (HSP) reveals that the primary factor influencing the solubility of Rosiglitazone is polarity in highly polar solvents, while the dominant factor is molecular volume in low-polarity solvents. Furthermore, the molecular interactions of solute and solvents were investigated by molecular simulation, including the calculation of electrostatic potential, 2D fingerprint plots and solvation free energy, which provided insights into the mechanism of Rosiglitazone dissolution behavior in different solvents. © 2024 Elsevier B.V.