The solubilities of three poorly water soluble drugs, phenytoin, diazepam and benzocaine, were measured in various cosolvent-water mixtures. The data were generally described by the relationship: log (S(m)/S(w)) = Σf₁σ₁ where S(m) is the solubility of the drug in the cosolvent-water mixture, S(w) is the solubility of the drug in water, f₁ is the volume fraction of cosolventi and σ₁ is the slope of the log(S(m)/S(w)) vs. f₁ plot. In most cases, some positive or negative deviation from the log-linear solubility equation is observed. The deviation is similar for all three drugs in many of the cosolvent-water mixtures. This suggests that the deviation is primarily due to interactions between the solvent components. However, it could not be predicted from any of the physical properties of the solvent mixtures. Changes in the solute crystal structure could not be identified as a source of nonideality. The deviations from the log-linear solubility equation may involve such factors as changes in solvent structure, hydrophobic hydration, density changes and hydrogen bonding differences between solute and cosolvent. The slopes, σ₁, of the solubilization plots were related to various indexes of solvent polarity including dielectric constant, solubility parameter, partition coefficient, surface tension and interfacial tension. The best correlations were obtained with measures of solvent cohesive forces such as interfacial tension and solubility parameter. In general, the solubilities in mixtures of aprotic cosolvents and water are higher than predicted by any of the polarity indexes. The slopes are thus related to the hydrogen bonding ability of the cosolvent as expressed by the density of proton donor and acceptor groups of the neat cosolvent. The slopes of the solubilization plots can be predicted from linear relationships with polarity indexes of the cosolvent. Therefore it is possible to estimate the slope, σ, in any cosolvent-water mixture from the solubilities in two solvents for a given drug. Furthermore, the solubility in any cosolvent water mixture can be estimated by combining the log-linear solubility equation with the estimated slopes.

The effect of triacetin in combination with common cosolvents on the solubility of phenytoin and diazepam was studied. The cosolvents were PEG 400 and propylene glycol. In addition, the data were used to test the following model: UNFORMATTED EQUATION FOLLOWS: log Sᵈ(c,p,w) = log Sᵈ(w) + f(c)σᵈ(c) + [Sᵖ(w)10(f(c)σᵖ(c))/D(p)] σᵈ(p). UNFORMATTED EQUATION ENDS. The term on the left side of the equation is the solubility of a drug in the ternary system. This is related to the aqueous solubility of the drug, the solubility of the drug in a completely miscible organic solvent (CMOS), and the solubility of the partially miscible organic solvent (PMOS). This model was proposed by Gupta et al. (1989) and predicts the solubility of a ternary system composed of a CMOS and PMOS. The results indicate the triacetin does increase the solubility of the two poorly water-soluble drugs. There is good correlation between the observed and predicted increase in the solubility of the drugs.