Ethenzamide–gentisic acid–acetic acid (2/1/1)

In the title co-crystal solvate, 2-ethoxybenzamide–2,5-dihydroxybenzoic acid–ethanoic acid (2/1/1), 2C9H11NO2·C7H6O4·C2H4O2, two nonsteroidal anti-inflammatory drugs, ethenzamide (systematic name: 2-ethoxybenzamide) and gentisic acid (systematic name: 2,5-dihydroxybenzoic acid), together with acetic acid (systematic name: ethanoic acid) form a four-component molecular assembly held together by N—H⋯O and O—H⋯O hydrogen bonds. This assembly features two symmetry-independent molecules of ethenzamide, forming supramolecular acid–amide heterosynthons with gentisic acid and acetic acid. These heterosynthons involve quite strong O—H⋯O [O⋯O = 2.5446 (15) and 2.5327 (15) Å] and less strong N—H⋯O [N⋯O = 2.9550 (17) and 2.9542 (17) Å] hydrogen bonds. The overall crystal packing features several C—H⋯O and π–π stacking interactions [centroid–centroid distance = 3.7792 (11) Å].

Pharmaceutical cocrystals can be defined as molecular complexes formed between a neutral or ionic active pharmaceutical ingredient (API) and a pharmaceutically acceptable compound that is a solid under ambient conditions (Almarsson & Zaworotko, 2004). With our interest in pharmaceutical cocrystals and polymorphism, we recently reported three polymorphs of a 1:1 cocrystal involving ethenzamide and gentisic acid, and showed that the dissolution rates of the cocrystal polymorphs were improved twice when compared to that of the parent ethenzamide (Aitipamula et al., 2009a).
In attempt to prepare pure polymorphs of a cocrystal involving ethenzamide and gentisic acid, they were cocrystallized in 1:1 molar ratio from several organic solvents. Whereas all the crystallization batches resulted in reported 1:1 cocrystal polymorphs (Aitipamula et al., 2009a), crystallization from acetic acid yielded a solvate in which the ethenzamide, gentisic acid, and acetic acid were present in 2:1:1 molar ratio. We present here its crystal structure and analyze the hydrogen bonding.  (Table   1) (Desiraju & Steiner, 1999) (Table 1). Hydroxy atom of O8 of the gentisic acid acts as a hydrogen bond donor to atom O9 of the acetic acid at (2-x,1-y,1-z), and generates a four-component molecular assembly which involves two molecules of ethenzamide, one molecule each of gentisic acid and acetic acid (Fig. 2). It is worth mentioning that the solvent (acetic acid) molecule is an integral part of the four-component molecular assembly, which is bonded in the same way as the remaining constituents that participate in the heterosynthon formation. The four-component molecular assemblies are further stabilized in the crystal structure by various C-H···O interactions (Table 1) (Desiraju & Steiner, 1999), and by the π-π stacking interaction involving the phenyl rings of the molecules of ethenzamide and gentisic acid: Cg1···Cg2 (1-x, 1-y, 1-z) = 3.7792 (11) Å, where Cg1 and Cg2 denote the centroids of the rings C1-C6 and C19-C24 of ethenzamide and gentisic acid, respectively (Fig. 3).
In the light of the overwhelming interest in the development of pharmaceutical cocrystals for improving the physicochemical properties of the APIs (Schultheiss & Newman, 2009), the title cocrystal solvate reported here presents some special features. First, it contains two APIs and thus can be considered as a multi-API cocrystal. Second, it contains the pharmaceutically acceptable acetic acid in the crystal structure. These two aspects make the title cocrystal solvate a potential solid form for development of a combination drug involving ethenzamide and gentisic acid.
The title cocrystal solvate was obtained by slow evaporation of a glacial acetic acid (5 ml) solution of a 1:1 molar ratio of ethenzamide (100 mg, 0.605 mmol) and gentisic acid (93.3 mg, 0.605 mmol) at ambinent conditions. The block-shaped crystals, the dimensions of which were typically as those of the used sample for data collection, were obtained within 7 days.

Refinement
Though all the H-atoms could be dinstinguished in the difference electron density map, the H-atoms bonded to C-atoms were included at the geometrically idealized positions and refined in riding-model approximation with C-H = 0.95 Å (aryl), 0.99 Å (methylene), and 0.98 Å (methyl). Uiso(H) aryl/methylene =1.2 Ueq(C) and Uiso(H) methyl =1.5 Ueq(C). The positional parameters of the H-atoms bonded to N and O were allowed to be refined freely while Uiso(H) amine =1.2 Ueq (N) and Uiso(H) hydroxyl =1.5 Ueq(O). Fig. 1. The title molecules of ethenzamide, gentisic acid and aceitic acid with the atom labels and 50% probability displacement ellipsoids for non-H atoms.

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.
Refinement. Refinement of F 2 against ALL reflections. The weighted R-factor wR and goodness of fit S are based on F 2 , conventional R-factors R are based on F, with F set to zero for negative F 2 . The threshold expression of F 2 > σ(F 2 ) is used only for calculating Rfactors(gt) etc. and is not relevant to the choice of reflections for refinement. R-factors based on F 2 are statistically about twice as large as those based on F, and R-factors based on ALL data will be even larger.