Predicting the Solubility of Drugs in Solvent Mixtures: Multiple Solubility Maxima and the Chameleonic Effect

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Abstract
An approach to reproduce the solubility profile of a drug in several solvent mixtures showing two solubility maxima is proposed in this work. The solubility of sulphamethoxypyridazine was determined at 25°C in several mixtures of varying polarity (hexane: ethyl acetate, ethyl acetate:ethanol and ethanol: water). Sulphamethoxypyridazine was chosen as a model drug because of its proton-donor and proton-acceptor properties. A plot of the mole fraction of the drug vs the solubility parameter of the solvent mixtures shows two solubility peaks. The two peaks found for sulphamethoxypyridazine demonstrate the chameleonic effect as described by Hoy and suggest that the solute-solvent interaction does not vary uniformly from one mixture to another. The different behaviour of the drug in mixtures of two proton-donor and proton-acceptor solvents (alcohol and water), and in mixtures of one proton acceptor (ethyl acetate) and one proton donor-proton acceptor (ethanol) is rationalized in terms of differences in the proton donor-acceptor ability of the solvent mixtures. An approach based on the acidic and basic partial solubility parameters together with the Hildebrand solubility parameter of the solvent mixtures is developed to reproduce the experimental results quantitatively. The equation predicts the two solubility maxima as found experimentally, and the calculated values closely correspond to the experimental values through the range composition of the solvent mixtures. These results show that the chameleonic effect can be described in a quantitative way in terms of Lewis acid-base interactions; this approach can assist the product formulator to choose the proper solvent mixture for a new drug. A good solvent blend should result in a solubility parameter close to that of the drug; the acidic and basic partial solubility parameter values should provide maximum acid-base interaction of the mixed solvent with the drug. The failure in one of these conditions results in decreased solubility. Solubility parameters as well as the acidic and basic parameters are tabulated or they can be obtained from group contribution methods, making easier the evaluation of the best solvent mixture for a drug.