Solubility of hydrocortisone in organic and aqueous media: evidence for regular solution behavior in apolar solvents

The solubility of hydrocortisone was determined experimentally in a wide variety of solvents. Groups of solvents were selected to emphasize different solute-solvent interactions which can influence the solubility profile of such a large, polyfunctional solute. Regular solution theory for a crystalline solute was shown to be applicable to the solubility behavior of hydrocortisone in solvents that lack strong dipoles and the ability to hydrogen bond. A best-fit solubility parameter of 12.4 (cal/ml)1/2 for hydrocortisone was determined from the latter solubilities and the ideal solubility of hydrocortisone. This solubility parameter estimate was significantly higher than estimates calculated from molar-attraction constants. Even though molar volume ratios between hydrocortisone and the solvents ranged from 2.25 to 3.28, the associated Flory-Huggins entropy term did not seem to be a significant solubility-determining factor. In all cases, the solubility of hydrocortisone in solvents capable of dipole-dipole interactions and hydrogen bonding was shown to be higher by logarithmic orders when compared with regular solution theory predictions. Thus, for this solute, regular solution theory was shown to be appropriate only for solvents where London dispersion forces dominate the interactions between solute and solvent molecules.