A new solvate of epalerstat, a drug for diabetic neuropathy

The title compound, epalerstat acetone monosolvate, is isotypic with the previously reported tetrahydrofuran solvate.


Chemical context
Investigation of solid forms of pharmaceuticals has attracted a great deal of attention as different crystal forms may imply different physicochemical properties (Putra et al., 2016a,b). Moreover, pharmaceutical processing stages during manufacturing, such as crystallization, can lead to the unexpected occurrence of new crystalline phases (Putra et al., 2016c). One of the important classes of pharmaceutical solids that can occur during crystallization is solvates. Solvates are defined as multi-component crystalline systems in which solvent molecules are included within the crystal structure in either a stoichiometric or non-stoichiometric manner (Griesser, 2006). It has been estimated statistically that around 33% of organic compounds have the ability to form solvates with organic solvents (Clarke et al., 2010).

Supramolecular features
In the crystal, the epalerstat molecule is connected to two adjacent epalerstat molecules and one solvent molecule via both conventional and non-conventional hydrogen bonds. The details of the hydrogen bonds and hydrogen bonding architecture are listed and presented in Table 1 and Fig. 2, respectively. A pair of O3-H3AÁ Á ÁO2 ii hydrogen bonds is observed between two carboxylic acid moieties forming an inversion dimer with an R 2 2 (8) loop. This dimer is linked to adjacent dimers by a pair of C6-H6Á Á ÁO1 ii hydrogen bonds, which enclose R 2 2 (20) loops, and form chains along direction [101]. In addition, acetone molecules are linked to the chain by a C1-H1Á Á ÁO4 iii hydrogen bond (Table 1 and Fig. 2).

Discussion
Interestingly, the new solvate reported here is isotypic with epalerstat tetrahydrofuran monosolvate . Both solvates crystallize in the triclinic system with the same space group, P1. As illustrated in Fig. 3, they have a similar molecular arrangement and the solvent molecules are located in similar pockets in the unit cell. The unit cell similarity index (Å) and the mean elongation (") values were calculated (Fá biá n & Ká lmá n, 1999) and found to be Å = 0.0016 and " = 0.0005. As the Å and " values are nearly zero, epalerstat acetone monosolvate and tetrahydrofuran monosolvate have isostructural crystals. The solvent-occupied spaces, in which the solvent molecules were deleted from the crystal structure, and the voids were calculated using the contact surface  Table 1 Hydrogen-bond geometry (Å , ).

Figure 2
A view along the b axis of the crystal packing of the title compound. Blue and orange dashed lines represent O-HÁ Á ÁO and C-HÁ Á ÁO hydrogen bonds, respectively. Only H atoms involved in these interactions have been included.

Figure 1
The molecular structure of epalerstat acetone monosolvate, with the atom labelling and displacement ellipsoids drawn at the 50% probability level.
method with probe radius and approximate grid spacing set equal to 1.2 and 0.7 Å , respectively (Putra et al., 2016d;Macrae et al., 2008). The solvent occupied spaces for the acetone and tetrahydrofuran solvates are 199.86 and 221.89 Å 3 , respectively. As expected, the larger occupied space in epalerstat tetrahydrofuran solvate corresponds to the larger solvent molecule. Interestingly, both solvents occupy nearly the same percentage of the total volume of the unit cell; the acetone and tetrahydrofuran molecules occupy 22.2 and 23.8%, respectively.

Database survey
A search of the Cambridge Structural Database (CSD, V5.38, last update July 2017; Groom et al., 2016) for epalerstat yielded 16 hits. They include the ethanol monosolvate (Ishida et al., 1989(Ishida et al., , 1990, the methanol monosolvate (Igarashi et al., 2015), the methanol disolvate (Nagase et al., 2016), the dimethylformamide monosolvate , the dimethylsulfoxide disolvate , the tetrahydrofuran monosolvate (  The packing view along the b axis of (a) epalerstat acetone monosolvate and (b) epalerstat tetrahydrofuran monosolvate shows the isostructurality between the two solvates. H atoms have been omitted for clarity, and the epalerstat molecules and the solvent molecules are drawn as capped sticks and spacefill models, respectively.

Refinement details
Crystal data, data collection and structure refinement details are summarized in Table 2. The hydrogen atom attached to an oxygen atom was located in a difference-Fourier map and freely refined. The C-bound H atoms were included in calculated positions and treated using riding model: C-H = 0.9-1.0 Å with U iso (H) = 1.5U iso (C-methyl) and 1.2U iso (C) for other H atoms. Initially the site occupancy factor of the acetone molecule was refined and determined to be 1.005 (4).