PREDICTING THE SOLUBILITY OF DRUGS IN SOLVENT MIXTURES - MULTIPLE SOLUBILITY MAXIMA AND THE CHAMELEONIC EFFECT

An approach to reproduce the solubility profile of a drug in several s olvent mixtures showing two solubility maxima is proposed in this work . The solubility of sulphamethoxypyridazine was determined at 25 degre es C in several mixtures of varying polarity (hexane:ethyl acetate, et hyl acetate:ethanol and ethanol:water). Sulphamethoxypyridazine was ch osen as a model drug because of its proton-donor and proton-acceptor p roperties. A plot of the mole fraction of the drug vs the solubility p arameter of the solvent mixtures shows two solubility peaks. The two p eaks found for sulphamethoxypyridazine demonstrate the chameleonic eff ect as described by Hoy and suggest that the solute-solvent interactio n does not vary uniformly from one mixture to another. The different b ehaviour of the drug in mixtures of two proton-donor and proton-accept or solvents (alcohol and water), and in mixtures of one proton accepto r (ethyl acetate) and one proton donor-proton acceptor (ethanol) is ra tionalized in terms of differences in the proton donor-acceptor abilit y of the solvent mixtures. An approach based on the acidic and basic p artial solubility parameters together with the Hildebrand solubility p arameter of the solvent mixtures is developed to reproduce the experim ental results quantitatively. The equation predicts the two solubility maxima as found experimentally, and the calculated values closely cor respond to the experimental values through the range composition of th e solvent mixtures. These results show that the chameleonic effect can be described in a quantitative way in terms of Lewis acid-base intera ctions; this approach can assist the product formulator to choose the proper solvent mixture for a new drug. A good solvent blend should res ult in a solubility parameter close to that of the drug; the acidic an d basic partial solubility parameter values should provide maximum aci d-base interaction of the mixed solvent with the drug. The failure in one of these conditions results in decreased solubility. Solubility pa rameters as well as the acidic and basic parameters are tabulated or t hey can be obtained from group contribution methods, making easier the evaluation of the best solvent mixture for a drug.