Cosolvency and cosolvent polarity.

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.