Thermodynamics of fenofibrate and solubility in pure organic solvents

Abstract

Highlights! ! Solubility data of fenofibrate FI was collected between 5-45°C in seven pure solvents.! ! Melting data and heat capacity of the solid and the melt were measured with DSC.! ! Fusion thermodynamics and ideal solubility were calculated using experimental data.! ! The heat capacity component of the enthalpy of fusion is shown to be important.! ! In some solvents the activity coefficient term controls the shape of van't Hoff plots. AbstractCalorimetric 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 Raoult's law framework. Except for ethyl acetate solutions which are almost ideal, solutions in all evaluated solvents exhibit positive deviation from Raoult's 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).

Towards controlling the crystallisation behaviour of fenofibrate melt: triggers of crystallisation and polymorphic transformation

“…Form I can be obtained by a slow solvent evaporation method. 13 The metastable form called form II was reported by Di Martino et al and Heinz et al [14][15][16] It was produced by the recrystallization of amorphous FEN from the melt. The melting point of the product was 74 C. It converts to the stable form I during heating via melt recrystallization and melts again at 80 C. [14][15][16] Balendiran and co-workers reported the single crystal structure of a FEN form they called form II.…”

Thermodynamic Stability Analysis of Tolbutamide Polymorphs and Solubility in Organic Solvents

“…the equations for the Gibbs energy of fusion and its enthalpic and entropic component terms become: [9] ) ( ) ( ) ( fus fus fus…”

(Solid+liquid) solubility of organic compounds in organic solvents – Correlation and extrapolation

“…It is important to note, however, that this does not imply a linear van't Hoff plot. The temperature dependence of the slope of a van't Hoff curve is given by equation (5). Both the enthalpy of fusion and the activity coefficient term depend on temperature, and it follows from this fact that all van't Hoff curves, including solid phase activity curves, will be inherently non-linear.…”