Solubilization by cosolvents IV: Benzocaine, diazepam and phenytoin in aprotic cosolvent-water mixtures

The log-linear solubility equation, log (S(m)/S(w)) = fσ, where S(m) and S(w) are the solubilities of drug in the solvent mixture and water respectively, f is the volume fraction of cosolvent, and σ is the slope of the log (S(m)/S(w)) vs. f plot, has been applied to the solubilities of benzocaine, diazepam, and phenytoin in mixtures of polar, aprotic cosolvents, and water. These solvent systems were considered as two groups based on the functional group of the cosolvents; ethers (dioxane, dimethyl isosorbide, triglyme) and double-bonded oxygen compounds (DMSO, DMA, DMF). Solubilities are generally higher in both groups of cosolvent-water mixtures compared to amphiprotic cosolvent-water mixtures. This may be due to the lack of self-association of these cosolvents through hydrogen bonds and their relatively high-base strength. Positive and negative deviation from the predicted linear behavior occurs in these solvents systems as in the case of the amphiprotic cosolvent-water systems. Positive deviation is seen for all three solutes in the case of the ether cosolvent-water mixtures and for benzocaine and phenytoin in the double-bonded oxygen cosolvent-water mixtures. Negative deviations are seen for diazepam in the latter solvent system. The potential reasons for these deviations are discussed.