The equilibrium solubility of amorphous chloroxine in four co-solvent mixtures of dimethyl sulfoxide (DMSO) (1) + water (2), N,N-dimethylformamide (DMF) (1) + water (2), N-methyl-2-pyrrolidone (NMP) (1) + water (2) and 1,4-dioxane (1) + water (2) is reported. Experiments were performed by using the saturation shake-flask technique over the temperature range from (293.15 to 333.15) K. The maximum solubility was observed in neat DMF (DMSO, NMP or 1,4-dioxane) for the four co-solvent mixtures. By using the Jouyban-Acree model, the chloroxine solubility was well correlated obtaining RAD values lower than 3.64% and RMSD values lower than 8.82 x 10(-6). Quantitative values for the local mole fraction of DMSO (DMF, NMP or 1,4-dioxane) and water around the chloroxine were computed by using the Inverse Kirkwood-Buff integrals method applied to the determined solubility data. Chloroxine was preferentially solvated by water for the studied mixtures in water-rich compositions; while within intermediate and co-solvent-rich compositions, chloroxine is preferentially solvated by DMSO (DMF, NMP or 1,4-dioxane) in DMSO (DMF, NMP or 1,4-dioxane) + water mixtures. Moreover, in the light of Kamlet and Taft linear solvation energy relationships model, the co-solvency effect was rationalized, and the relative importance of solvent-solute and solvent-solvent interactions was recognized. It was shown that the change in solvent-solvent interaction energy accounted by cavity term governed the solubility variation of chloroxine in all aqueous mixtures. (C) 2019 Elsevier Ltd.