Determination of solubility profiles of eflucimibe polymorphs: experimental and modeling.

This work presents the determination of the phase diagram of two polymorphs of Eflucimibe in pure solvents and solvent mixtures at different temperatures. Solid phase changes were analysed by Differential Scanning Calorimetry. Solubility measurements show that the solubility of the two forms are very similar. Experimental data obtained in ethanol, reported in a Van t'Hoff plot, exhibit a transition temperature around 265 K. A single maximum is observed when solubility is plotted against the solubility parameters of solvents or solvent mixture and it is not related to a solid phase change. This phenomenon, known as a positive synergetic effect, has been explained in term of evolution of solute-solvents polar interactions. Several thermodynamics models (UNIFAC, UNIQUAC, Wilson, Scatchard Hildebrand ... ) were tested in order to predict the Liquid-Solid Equilibrium for this system. The semi empirical model UNIQUAC gives the best fit. The results obtained are in good agreement with the experimental data (mean deviation lower than 5%) and the solubility maximum found experimentally for each polymorph is also well described.

[Crystalline polymorphism of eflucimibe]. / Polymorphisme cristallin de l'éflucimibe.

The importance, in therapeutics, of the concept of bioavailability and on-going quality research in the formulation of a drug has prompted us to examine the crystalline polymorphism of eflucimibe as from the research phase. This study has been carried out by re-crystallization of the product in organic solvents having a different polarity in a variety of experimental temperature and pressure conditions, then, subsequently, by re-cooling the previously dissolved substance. The analytical methods applied to identify and then describe the polymorphic forms are thermogravimetry analysis (TGA), differential scanning calorimetry (DSC), X-ray powder diffraction from synchrotron radiation (XRPD), infrared spectrometry (IR), solid-state nuclear magnetic resonance spectrometry (SSNMR) and lastly maximum solubility measurements. By means of XRPD, two polymorphic forms called A and B have been clearly identified at ambient temperature. These two crystalline forms were obtained in a reproducible way, then described by DSC, XRPD, IR and SSNMR. Differential scanning calorimetry analysis has shown for polymorphic form A two endothermic phenomena with low energy at about 35 masculine and 118 degrees C attributed by XRDP to conformational polymorphism. The complex endothermic event that extends between 75 masculine and 105 degrees C appears to correspond to successive alterations of a lamellar structure. The solid-solid transition observed at 110 degrees C is due to a change of crystalline phase, then the melting point occurring at about 130 degrees C. For form B, two changes of crystalline phase are clearly observed at about 80 masculine and 120 degrees C. The reversibility of these changes was observed by thermomicroscopy in polarized light. Form A, which is less soluble in absolute ethanol than form B, is the more stable thermodynamically in the temperature range from 25 masculine to 50 degrees C where the data have been obtained. The Van't Hoff diagram layout for each polymorphic form appears to reveal an A<-->B transition temperature in a temperature range lower than 25 degrees C. This study, undertaken as from the research phase, has enabled us to highlight the polymorphism of this new chemical entity by means of XRDP by explaining the nature of the endothermic phenomena observed by DSC, and lastly identify the thermodynamically more stable polymorphic form, thus contributing to a better knowledge of this future drug.