Thermodynamics of fenofibrate and solubility in pure organic solvents
Graphical abstract
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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