Extended Hildebrand Solubility Approach: methylxanthines in mixed solvents.

The solubility profiles of theobromine, theophylline, and caffeine at 25 degrees were examined in binary solvent systems including dioxane-formamide, water-polyethylene glycol 400, and glycerin-propylene glycol. Theobromine solubility was studied in dioxane-water mixtures, a solvent system that was investigated earlier for the solubility of theophylline and caffeine. Solubilities were calculated in these polar systems by a regression method, based on an extension of the Hildebrand-Scatchard equation of regular solution theory. A linear relationship between the mixed solvent solubility parameter, and dielectric constant, epsilon, was introduced earlier and was confirmed in the present study. In addition, it was observed that a regression of log (activity coefficient) on epsilon in a second or higher degree polynomial provides reasonable solubility values for the methylxanthines in mixed solvents. A direct regression of molal or mole fraction (but not molar) solubility against delta 1, epsilon, or against volume percent of one or the other solvent in a binary solvent mixture provided a suitable measure of solubility for these crystalline drugs in mixed polar solvents. The drug's solubility parameter as determined from peak solubility in mixed polar solvents varied somewhat, depending on the specific solvent system employed. It is suggested that a drug may exhibit one (or more) solubility parameters in nonpolar solutions and multiple solubility parameters in polar systems. The extended solubility approach serves for the back-calculation of solubilities in mixed solvent systems, even though the solubility parameter of the solute may vary from one solvent system to the next.