Extended Hildebrand Solubility Approach: Sulfonamides in Binary and Ternary Solvents

Abstract

The extended Hildebrand solubility approach is used to estimate the solubility of sulfonamides in binary and ternary solvent systems. The solubility of sulfisomidine in the binary solvent, dioxane–water, shows a bell-shaped profile with a solubility maximum well above the ideal solubility of the drug. This is attributed to solvation of the drug with the dioxane–water solvent, and indicates that the solute–solvent interaction energy (W) is larger than the geometric mean (δ1δ2) of regular solution theory. The solubilities of sulfadiazine, sulfisomidine, sulfathiazole, and sulfamethoxazole were determined in mixtures of dimethylacetamide, glycerol, and water, and the solubility profiles were well reproduced by use of the extended Hildebrand solubility approach. Since the solubility parameter (δ1 = 11) of the solvent (dimethylacetamide) was approximately equal to the solubility parameters of the sulfonamides, and because of the powerful solvating power of dimethylacetamide, the solubility profiles did not exhibit peaks as observed for sulfisomidine in dioxane–water. When sulfisomidine was dissolved in a ternary mixture, i.e., butyl acetate (δ1 = 8.5), dimethylacetamide (δ1 ≃ 11), and methanol (δ1 = 14.5), a spike was produced in the solubility profile at the solubility parameter of dimethylacetamide. This sharply peaked profile suggests that the two branches be treated as separate solubility curves, which are then independently well reproduced by the extended Hildebrand solubility approach. None of the four sulfonamides yielded log-linear relationships in the ternary mixtures.