Solubility determination and correlation, solvent effect and thermodynamics of itraconazole in sixteen mono solvents and ternary mixtures of N-methyl-2-pyrrolidone, diethylene glycol monoethyl ether, and ethanol

Abstract

In this study, the experimental mole fraction solubility of itraconazole in 16 mono solvents (acetone, acetonitrile, 1-butanol, chloroform, DEGME, dichloromethane, DMA, DMF, DMSO, ethanol, methanol, NMP. 1-propanol, 2-propanol, tetrahydrofuran, and water) and ternary solvent system (NMP + DEGME + ethanol) was determined using the well-known shake-flask technique. The rank order of solubility of itraconazole in sixteen mono solvents at 298.15 K is as follows: chloroform (5.04 × 10⁻²) > dichloromethane (3.27 × 10⁻²) > NMP (2.20 × 10⁻²) > DMA (1.18 × 10⁻²) > DMF (1.07 × 10⁻²) > tetrahydrofuran (2.12 × 10⁻³) > DMSO (1.75 × 10⁻³) > DEGME (7.30 × 10⁻⁴) > acetone (6.37 × 10⁻⁴) > acetonitrile (7.95 × 10⁻⁵) > methanol (3.79 × 10⁻⁵) > 1-butanol (2.30 × 10⁻⁵) > 2- propanol (2.14 × 10⁻⁵) > 1-propanol (2.05 × 10⁻⁵) > ethanol (1.91 × 10⁻⁵) > water (2.43 × 10⁻⁷). According to the regression results of the KAT-LSER model, the solubility of itraconazole was principally affected by dipolarity/polarizability and solvent–solvent interaction. The mole fraction solubility of itraconazole increased with the increasing temperature and mass fraction of NMP in the ternary mixtures (NMP + DEGME + ethanol). In addition, the solubility parameters were applied to comprehensively understand and describe the solubility of itraconazole in a ternary solvent system. Four thermodynamic models, including van’t Hoff model, modified Apelblat model, Jouyban–Acree model, and Jouyban–Acree–van’t Hoff model, were used to fit the solubility data of itraconazole. The thermodynamic properties of itraconazole during the dissolution processes were estimated using the Gibbs equation and modified van’t Hoff analysis. The solid–liquid equilibrium solubility in sixteen different mono solvents and ternary solvent systems, solvent effect on the solubility, four correlation models, and thermodynamic properties could be helpful for pre-formulation study, extraction, purification, crystallization, and development of liquid formulation, including topical solution.