Cosolvency and Deviations from Log-Linear Solubilization

The solubilities of three nonpolar drugs, phenytoin, diazepam, and benzocaine, have been measured in 14 cosolvent–water binary mixtures. The observed solubilities were examined for deviations from solubilities calculated by the equation log Sm = f log Sc + (1 − f) log Sw, where Sm is the solubility of the drug in the cosolvent–water mixture, Sc is the solubility of the drug in neat cosolvent, f is the volume fraction of cosolvent, and Sw is the solubility of the drug in water. When presented graphically, the patterns of the deviations were similar for all three drugs in mixtures of amphiprotic cosolvents (glycols, polyols, and alcohols) and water as well as nonpolar, aprotic cosolvents (dioxane, triglyme, dimethyl isosorbide) and water. The deviations were positive for phenytoin and benzocaine but negative for diazepam in mixtures of dipolar, aprotic cosolvents (dimethylsulfoxide, dimethylformamide, and dimethylacetarnide) and water. The source of the deviations could not consistently be attributed to physical properties of the cosolvent–water mixtures or to alterations in the solute crystal. Similarities between the results of this study and those of previous investigations suggest that changes in the structure of the solvent play a role in the deviations from the expected solubilities.