Thermodynamics of fenofibrate and solubility in pure organic solvents

Calorimetric data on the melting of 1-methylethyl 2-[4-(4-chlorobenzoyl)-phenoxy]-2-methylpropanoate (fenofibrate) and the heat capacity of the solid and the melt have been determined, from which the Gibbs energy, enthalpy and entropy of fusion are calculated. Solid-liquid solubility data have been collected by a gravimetric method in seven pure solvents (methanol, ethanol, 1-propanol, 2-propanol, ethyl acetate, acetonitrile, and acetone) across a range of temperatures. Fenofibrate is much more soluble in ethyl acetate, acetonitrile and acetone compared to alcohols. In the alcohols the solubility increases with aliphatic chain length. The Gibbs energy of fusion is used to estimate the activity of the solid within a Raoultʹs law framework. Except for ethyl acetate solutions which are almost ideal, solutions in all evaluated solvents exhibit positive deviation from Raoultʹs law, and in the alcohols the activity coefficient ranges up to 25. It is shown that the heat capacity component of the enthalpy of fusion is not negligible at room temperature, in spite of the proximity to the melting point, and furthermore that the temperature dependence of the activity coefficient in the saturated solution has a governing influence on the van’t Hoff enthalpy of solution in acetonitrile and the alcohols. Crystals obtained by two different methods from a range of solvents have been analysed by PXRD, FTIR and NMR spectroscopy, TGA and DSC, and have in all cases been shown to consist of the stable polymorph (form I).