Elsevier

Fluid Phase Equilibria

Volume 367, 15 April 2014, Pages 143-150
Fluid Phase Equilibria

Thermodynamics of fenofibrate and solubility in pure organic solvents

https://doi.org/10.1016/j.fluid.2014.01.029Get rights and content

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.

Abstract

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 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).

Introduction

Crystallisation is an important unit operation in many branches of the chemical industry where it is widely used for purification. It is of particular importance in the pharmaceutical industry, as most pharmaceutical products contain crystalline material, and it is often necessary that the process can be controlled to yield crystals of required purity and specified size, shape and polymorph. This requires a thorough control of the supersaturation during the process, and thus an understanding of the thermodynamics of solution as well as of the solid state. The ability to predict what solvents are most appropriate for a particular compound and process is highly desirable. This requires an understanding of how the compound interacts with different solvents to explain the solubility and the crystallisation behaviour. 1-methylethyl 2-[4-(4-chlorobenzoyl)-phenoxy]-2-methylpropanoate (fenofibrate) is a medium-sized, flexible, chlorinated and lipophilic molecule. The molecular structure is shown in Fig. 1. The vast majority of literature dealing with this compound concerns its clinical action, bioavailability, and formulation [1], [2], [3], [4], [5]. In addition there is some limited literature concerning its physico-chemical properties [6], [7], [8], [9], [10], [11], including spectroscopic and analytical data [12], [13], [14], [15], and the crystal structures of its two known polymorphs [16], [17], [18]. Some rough solubility data for a number of solvents are reported, with no mention of temperature [7]. However, at the time of writing (to the best of the knowledge of the authors), there is almost no published data of good quality on the solubility in different solvents.

In the present work, the melting properties and the heat capacity of the pure compound in the solid state and as a melt have been experimentally determined and solid phase thermodynamic properties estimated. The solid-liquid solubility has been determined in seven different solvents and is analysed within a thermodynamic framework to estimate solution activity coefficients and to examine the temperature dependence of the solubility. As thermodynamic properties of a solid phase are strongly dependent on the crystal structure, the work includes a careful characterisation by spectroscopic and diffraction methods of the particular solid phase for which the thermodynamic data are presented.

Section snippets

Materials

Table 1 lists the chemicals used, where they were obtained and their listed purity. All chemicals were used as received without further purification.

Solubility

Excess solid fenofibrate was placed in 10–15 ml of solvent in 30 ml sealed vials, equipped with magnetic stirrer bars. The temperature was controlled by a water-bath (Grant GR150, stability ±0.005 K and uniformity ±0.02 K at 310 K). The solutions were stirred for 24 h. Some of the supernatant liquid was extracted into pre-heated syringes and was then

Solid-state characterisation

Fig. 2, Fig. 3 show PXRD patterns and FTIR spectra, respectively, of fenofibrate as received and recrystallised from different solvents.

Essentially no differences between samples of crystals obtained from different solvents were detected by FTIR, NMR or DSC. TGA showed no decomposition or mass loss below 469 K (not shown). It was confirmed by PXRD that the commercially available solid material consists of the stable polymorph (form I), and furthermore only form I was recrystallised from all

Conclusions

The melting point and the melting enthalpy of fenofibrate form I have been determined to be 352.05 ± 0.02 K and 33.53 ± 0.42 kJ/mol, respectively. The heat capacity of the solid has been determined in the range 260–335 K, and that of the melt in the range 305–395 K, i.e. even far below the melting point. These data are used to calculate the Gibbs energy, enthalpy and entropy of fusion up to the melting point. The mole fraction solubility of fenofibrate is far higher in ethyl acetate and acetone than in

Acknowledgements

The financial support of the Science Foundation Ireland (10/IN.1/B3038) and the donation of crystalline fenofibrate by AbbVie are gratefully acknowledged. M.S. gratefully acknowledges the financial support of the Swedish Research Council (621-2010-5391).

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