Abstract
The mole-fraction solubility of itraconazole in four aqueous blends of ethanol/isopropanol/DMSO/methanol within the temperature range of 283.15 to 323.15 K was experimentally obtained using the isothermal shake-flask method. Under the identical temperature and ethanol/isopropanol/DMSO/methanol composition, itraconazole solubility in DMSO+water is much higher than that in ethanol/isopropanol/methanol + water. At the same temperature, the solubility increases monotonically with organic solvent concentration. X-ray power diffraction analysis demonstrated that over the course of the investigations, there was no crystal transition or solvate formation. The modified van’t Hoff-Jouyban-Acree and Jouyban-Acree models adequately related the solubility to solvent composition and temperature, with relative average deviations (RADs) not exceeding 7.65 %. Furthermore, the extended Hildebrand solubility approach was utilized to quantitatively characterize the solubility behavior at 298.15 K for the mixtures of ethanol/isopropanol/DMSO/methanol plus water. In both instances, the RADs were maintained below 4.12 %. The solubility parameter and dipolarity-polarizability of solutions have a major impact on the solubility fluctuation, as indicated by the analysis of the linear solvation energy relationship. The preferential solvation of itraconazole at 298.15 K was examined using the efficient approach of inverse Kirkwood-Buff integrals. The preferred solvation parameters showed positive values in blends within rich and moderate ethanol/isopropanol/DMSO/methanol composition regions. This suggests that the organic solvents preferentially solvated itraconazole. When itraconazole dissolved in the blends, thermodynamic analysis of the entropy-enthalpy compensation and dissolution parameters revealed both an endothermic and an enthalpy-driven mechanism. Furthermore, the microscopic electrostatic characteristics of basicity and acidity were effectively demonstrated by means of the electrostatic potential of molecular surface. The −C=O and −N=groups of the itraconazole molecule, which link the five-membered ring, are the primary targets of the electrophilic attack. An independent gradient model based on Hirshfeld partition analysis was used to demonstrate the weak interactions between itraconazole and solvents.
Published Version
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