The solubilities of three poorly soluble drugs, phenytoin, benzocaine, and diazepam, in cosolvent-water mixtures have been previously shown to be approximated by the log-linear solubility equation; log (Sm/Sw) = sigma f, where Sm and Sw represent the solubilities of the drug in the solvent mixture and water, respectively, f is the volume fraction of cosolvent, and sigma is the slope of a plot of log (Sm/Sw) vs f. In this study, the slopes, sigma, of the solubility plots were related to indexes of cosolvent polarity including the dielectric constant, solubility parameter, surface tension, interfacial tension, and octanol-water partition coefficient. Those polarity indexes that reflect the cohesive properties of the solvents such as the solubility parameter and interfacial tension resulted in the highest correlations with the slope, sigma. The hydrogen bonding ability of the neat cosolvent, expressed as the density of proton donating groups (HBD) or acceptor groups (HBA), was also found to be highly correlated with sigma. Additional relationships derived from theories involving solubility parameters and interfacial tension provide improved correlations between the cosolvent polarity and sigma. These results and analysis provide the basis for the estimation from physicochemical parameters of the appropriate type and amount of cosolvent needed to solubilize nonpolar drugs.

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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 dimethylacetamide) 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.