(672d) Using Eutectic Mixtures to Predict Enthalpy of Fusion for Small Organic Molecules

The solubility of drugs is still one of the largest challenges in pharmaceutical formulation development. The compound must be dissolved into solution and then absorbed across the gastrointestinal track into the bloodstream to elicit a physiological effect at its biological target. The solubility of a compound is a function of the crystal structure and the liquid mixing between the compound and solvent. By knowing the magnitude of the crystal structure and liquid mixing contributions to solubility, a formulation scientist can choose the most effective solubilization technique for the compound. The crystal structure contribution to solubility is a function of the enthalpy of fusion and melting temperature of the compound. Quantifying the enthalpy of fusion becomes a problem when the compound degrades upon melting. It is hypothesized that through the formation of a eutectic mixture, the melting point of a thermally labile compound can be lowered to a significant extent to prevent thermal degradation and the true heat of fusion for the compound can be determined from the thermal properties of the eutectic mixture.

This work will outline efforts to develop thermodynamic models to predict the enthalpy of fusion for the components in a eutectic mixture. A thermally stable system of acetaminophen and anhydrous caffeine was chosen to test the thermodynamic models. Two entropic models were derived based on a Hess Law diagram for the formation of a eutectic mixture and a third model was derived starting from chemical potentials of the minor component, solute, in its pure and eutectic forms. The third model required a correction factor to give accurate predictions. The correction factor was challenged by another eutectic system to ensure that its inclusion in the third model was necessary. The phase diagram for the thermally stable system identified the eutectic mole fraction composition as 58% acetaminophen and 42% anhydrous caffeine. Comparisons between the model predictions and the experimentally measured enthalpy of fusion for both components showed that the entropy of mixing of the two components in the liquid phase was unnecessary for accurate predictions. The model derived from chemical potentials gave very accurate predictions when the correction factor was included. This work will describe the theoretical considerations for choosing a eutectic system, the results from the thermodynamic model predictions, reasons for errors in the various models, and some general conclusions on how the results can be implemented in formulation design of small molecule pharmaceuticals.