Equilibrium solubility of edaravone in some binary aqueous and non-aqueous solutions reconsidered: Extended Hildebrand solubility approach, transfer property and preferential solvation

The accessible equilibrium solubility data of edaravone in methanol/ethanol/isopropanol (1) + water (2) and ethyl acetate/acetonitrile (1) + methanol/ethanol/n-propanol (2) mixtures was investigated in terms of solvent-solute molecule interactions based on extended Hildebrand solubility method. For methanol (1) + water (2) with x(1) (mole fraction) from 0 to 0.8, ethanol (1) + water (2) with x(1) from 0 to 0.5 and isopropanol (1) + water (2) with x(1) from 0 to 0.3, the interaction energies of solute-solvent molecules were greater than the geometric average values of regular solution, specifying some association between edaravone and mixed solvents. While in the other regions for the three aqueous solutions and ethyl acetate/acetonitrile + methanol/ethanol/n-propanol mixtures, edaravone solutions acted as regular ones at several points. A quartic expression of energy term W in terms of solvent solubility parameter of these mixtures could be successfully used to predict the equilibrium solubility of edaravone in the studied blended mixtures. The preferential solvation of edaravone by means of inverse Kirkwood-Buff integrals tool for the isopropanol/ethanol/methanol + water and ethyl acetate + n-propanol/methanol/ethanol mixtures was analyzed. For the isopropanol/ethanol/methanol + water blended solvents, the drug edaravone was surrounded preferentially by water in water-rich ranges, and by alcohols in other composition regions of binary blended solvents except for isopropanol solutions with isopropanolrich compositions, where edaravone was preferentially solvated by water. As well, edaravone was preferentially solvated by ethanol for ethyl acetate + ethanol mixture with rich ethyl acetate compositions. The highest degree of preferential solvation was observed in aqueous isopropanol solutions. Selective solvation of the edaravone by water (isopropanol/ethanol/methanol + water mixtures) or ethanol (ethyl acetate + ethanol mixture) was attributable to greater acidity of water or ethanol that enabled interactions with Lewis basic groups of edaravone. In addition, the apparent dissolution enthalpy and transfer Gibbs free energy (Delta(tr)G(o)), transfer enthalpy (Delta H-tr(o)) and transfer entropy (Delta S-tr(o)) were derived and deeply discussed. (C) 2021 Elsevier B.V. All rights reserved.

Automated summary

The study investigated the equilibrium solubility of edaravone in various mixed solvents, revealing some association between edaravone and certain solvents while acting as regular solutions in others. A quartic expression using solvent solubility parameters successfully predicted edaravone solubility. Preferential solvation analysis showed water or ethanol selectively solvated edaravone in certain mixtures due to their acidity and interactions with Lewis basic groups. This study also derived and discussed various thermodynamic parameters related to dissolution.