Epalrestat tetrahydrofuran monosolvate: crystal structure and phase transition

Epalrestat, an important drug for diabetic neuropathy, has been reported to exist in polymphic, solvated and co-crystal forms. Herein, we report on the crystal structure of epalerstat tetrahydrofuran solvate which crystallizes in the triclinic space group P . On desolvation, epalerstat Form II (monoclinic, C2/c) is obtained.

The title compound, epalrestat {systematic name: (5Z)-5-[(2E)-2-methyl-3phenylprop-2-en-1-ylidene]-4-oxo-2-sulfanylidene-1,3-thiazolidine-3-acetic acid}, crystallized as a tetrahydrofuran monosolvate, C 15 H 13 NO 3 S 2 ÁC 4 H 8 O. Epalrestat, an important drug for diabetic neuropathy, has been reported to exist in polymphic, solvated and co-crystal forms. In the molecule reported here, the phenyl ring is inclined to the rhodamine ring by 22.31 (9) , and the acetic acid group is almost normal to the rhodamine ring, making a dihedral angle of 88.66 (11) . In the crystal, pairs of O-HÁ Á ÁO hydrogen bonds are observed between the carboxylic acid groups of epalerstat molecules, forming inversion dimers with an R 2 2 (8) loop. The dimers are linked by pairs of C-HÁ Á ÁO hydrogen bonds, forming chains along [101]. The solvate molecules are linked to the chain by a C-HÁ Á ÁO(tetrahydrofuran) hydrogen bond. A combination of thermal analysis and powder X-ray diffraction revealed that title compound desolvated into epalerstat Form II. One C atom of the tetrahydrofuran solvate molecule is positionally disordered and has a refined occupancy ratio of 0.527 (18):0.473 (18).

Chemical context
Solid-state characterization is an important aspect in the regulation and development as well as intellectual property matter of drugs. Its necessity is based on the requirement to determine the solid-state structure of the drugs because pharmaceutical materials have the ability to exist in various forms, such as polymorphs, salts, co-crystals, and solvates (Putra et al., 2016a,b). An important class of pharmaceutical materials is solvates, which are defined as being a crystalline multi-component system in which a solvent(s) is accommodated within the crystal structure in a stochiometric or nonstochiometric manner (Griesser, 2006). Over the past decades, many different solvates with readily discernible physicochemical properties and marked differences in their performances have been reported (Iwata et al., 2014;Furuta et al., 2015). Different solvate formations play a significant role in drug development because of their physical instability and the potential toxicity from the solvent molecules. In addition, a tendency to form a solvate sometimes limits the number of solvents available for drug development and manufacturing processes (Campeta et al., 2010). Therefore, the study of solvate formation is extremely important for the pharmaceutical industry. ISSN 2056-9890 Epalerstat is an aldose reductase inhibitor and is used for the treatment of diabetic neuropathy, which is one of the most common long-term complications in patients with diabetes mellitus. The mechanism of epalerstat is thought to inhibit the first enzyme in the polyol pathway, which converts glucose to sorbitol. Sorbitol itself has been considered to be the cause for diabetic complications including diabetic neuropathy (Miyamoto, 2002;Ramirez & Borja, 2008). The solid-state forms of epalerstat as well as their properties have been widely investigated.
It is known that this drug exists in five polymorphic forms, of which three polymorphic structures have been determined by single crystal X-ray structure analysis and two forms have been characterized by spectroscopic methods. The three crystal forms are: Form I (triclinic, P1; Igarashi et al., 2013;Swapna et al., 2016), Form II (monoclinic, C2/c), and Form III (monoclinic, P2 1 /c; Swapna et al., 2016). In addition, the Z,Z isomer of epalerstat has been determined crystallographically (Swapna et al., 2016). It has also been reported to exist in multi-component crystal forms, such as solvates with ethanol (Ishida et al., 1990), methanol (Igarashi et al., 2015), methanol disolvate (Nagase et al., 2016), dimethylformamide, dimethylsulfoxide and as a co-crystal with caffeine (Putra et al., 2017). The occurrence of solvated epalerstat crystals themselves is not unexpected owing to the imbalance between the potential donors and acceptors of hydrogen bonds in the epalerstat structure. In the present study, we report on the crystal structure of epalerstat in a new solvated form (tetrahydrofuran monosolvate), and on its thermal behaviour by different physicochemical methods.

Structural commentary
The molecular structure of epalerstat tetrahydrofuran monosolvate is illustrated in Fig. 1. The values of all bond distances and angles, and dihedral angles appear to be within normal limits according to the Mogul geometry check within the CSD software (Bruno et al., 2004;CSD, Version 5.38, update February 2017;Groom et al., 2016). The phenyl ring is inclined to the five-membered ring of the rhodamine unit (N1/S1/C11-C13) by 22.31 (9) . The acetic acid group (C14/C15/O2/O3) is almost normal to five-membered ring of the rhodamine unit with a dihedral angle of 88.66 (11) . In addition, the mean plane of the methylpropenylidene (C7-C10) unit is inclined to the phenyl and rhodamine rings by 29.43 (11) and 9.19 (11) , respectively.

Supramolecular features
In the crystal, each epalerstat molecule is connected to two other epalerstat molecules and one tetrahydrofuran molecule by both conventional and non-conventional hydrogen bonds. Numerical details of the hydrogen bonds are listed in Table 1 and are illustrated in Fig. 2. A pair of O-HÁ Á ÁO hydrogen bonds is observed between the carboxylic moieties of epalerstat molecules, forming an inversion dimer with an R 2 2 (8) loop. The dimers are linked by pairs of C-HÁ Á ÁO hydrogen bonds, forming chains along [101]. The solvate molecules are linked to the chain by a C-HÁ Á ÁO t (t = THF) hydrogen bond.  Table 1 Hydrogen-bond geometry (Å , ).

Figure 2
A view normal to (110) of the crystal structure of epalerstat tetrahydrofuran monosolvate. Hydrogen bonds are shown as dashed lines (see Table 1) and only H atoms involved in these interactions have been included.

Figure 1
The molecular structure of the title compound, with the atom labelling and displacement ellipsoids drawn at the 50% probability level. The minor disorder component of the solvent molecule is not shown for clarity.

Phase transition -thermal behaviour and powder X-ray diffraction
In order to understand the thermal behaviour of this solvate at elevated temperatures, the sample was investigated by thermal gravimetry-differential scanning calorimetry (TG-DSC) and powder X-ray diffraction-differential scanning calorimetry (PXRD-DSC) methods (Figs. 3 and 4). The TG-DSC measurement was performed in the temperature region from room temperature to 448 K at a rate of 3 K min À1 . In addition, the PXRD-DSC measurement was conducted from room temperature to 383 K at a heating rate of 3 K min À1 . The mass loss started from 341.8-357.5 K and the onset peak appeared at 348 K. The total mass loss was observed to be 18.1%, which is almost equivalent to the loss of one molecule of tetrahydrofuran (the theoretical value corresponding to one tetrahydrofuran molecule is 18.4%). Therefore, the occupancy of the solvent molecule was fixed at 1 during crystal-structure refinement. The mass loss corresponds to the desolvation process indicated by the existence of a broad endothermic peak, which occurs in the DSC thermogram at a similar temperature. The enthalpy of desolvation was estimated to be À60.5 J g À1 (8.3 Â 10 À4 kJ mol À1 ).
In order to understand the phase transformation during the heating, a PXRD-DSC measurement was carried out. The desolvation temperature observed by PXRD-DSC was slightly different compared to the TG-DSC measurement. The desolvation started from 303-343 K in this case. The differences in temperature derived from TG-DSC and PXRD-DSC seem to be reasonable due the differences in the experimental conditions of both the methods. A closed pan system was used in the TG-DSC measurement, while an open pan system was applied in the PXRD-DSC measurement. By comparing the powder X-ray diffractogram to those for the reported polymorphic forms of epalerstat, it was seen that epalerstat tetrahydrofuran monosolvate desolvated into epalerstat. The PXRD-DSC scan of epalerstat tetrahydrofuran monosolvate. The blue and red PXRD patterns represent the epalerstat tetrahydrofuran monosolvate and epalerstat form II, respectively.

Synthesis and crystallization
Epalerstat form I (700 mg) was dissolved in tetrahydrofuran (10 ml) and the solution was kept for one week at room temperature, after which yellow plate-like crystals of the title compound were obtained.

Special details
Geometry. All esds (except the esd in the dihedral angle between two l.s. planes) are estimated using the full covariance matrix. The cell esds are taken into account individually in the estimation of esds in distances, angles and torsion angles; correlations between esds in cell parameters are only used when they are defined by crystal symmetry. An approximate (isotropic) treatment of cell esds is used for estimating esds involving l.s. planes.