Solubility parameter of drugs for predicting the solubility profile type within a wide polarity range in solvent mixtures

The solubility enhancement produced by two binary mixtures with a common cosolvent (ethanol–water and ethyl acetate–ethanol) was studied against the solubility parameter of the mixtures (δ1) to characterize different types of solubility profiles. Benzocaine, salicylic acid and acetanilide show a single peak in the least polar mixture (ethanol–ethyl acetate) at δ1 = 22.59, 21.70 and 20.91 MPa1/2, respectively. Phenacetin displays two solubility maxima, at δ1 = 25.71 (ethanol–water) and at δ1 = 23.30 (ethyl acetate–ethanol). Acetanilide shows an inflexion point in ethanol–water instead of a peak, and the sign of the slope does not vary when changing the cosolvent. The solubility profiles were compared to those obtained in dioxane–water, having a solubility parameter range similar to that covered with the common cosolvent system. All the drugs reach a maximum at about 90% dioxane (δ1 = 23 MPa1/2). A modification of the extended Hildebrand method is applicable for curves with a single maximum whereas a model including the Hildebrand solubility parameter δ1 and the acidic partial solubility parameter δ1a is required to calculate more complex solubility profiles (with inflexion point or two maxima). A single equation was able to fit the solubility curves of all drugs in the common cosolvent system. The polarity of the drug is related to the shape of the solubility profile against the solubility parameter δ1 of the solvent mixtures. The drugs with solubility parameters below 24 MPa1/2 display a single peak in ethanol–ethyl acetate. The drugs with δ2 values above 25 MPa1/2 show two maxima, one in each solvent mixture (ethanol–water and ethanol–ethyl acetate). The position of the maximum in ethanol–ethyl acetate shifts to larger polarity values (higher δ1 values) as the solubility parameter of the drug δ2 increases.