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

Srinivasulu Aitipamula; Pui Shan Chow; Reginald BH Tan

doi:10.1107/S1600536810012407

. 2010 Apr 10;66(Pt 5):o1045–o1046. doi: 10.1107/S1600536810012407

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

Srinivasulu Aitipamula ^a,^*, Pui Shan Chow ^a, Reginald BH Tan ^a,^b,^*

PMCID: PMC2979229 PMID: 21579106

Abstract

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].

Related literature

For information on three polymorphs of a 1:1 co-crystal involving ethenzamide and gentisic acid, see: Aitipamula et al. (2009a ▶). For other co-crystals of ethenzamide, see: Aitipamula et al. (2009b ▶); Moribe et al. (2004 ▶). For related information on the drug activity of ethenzamide, see: Hirasawa et al. (1999 ▶). For the crystal structure of ethenzamide, see: Pagola & Stephens (2009 ▶). For related information on the drug activity of gentisic acid, see: Lorico et al. (1986 ▶). For more information on the supramolecular heterosynthons, see: Fleischman et al. (2003 ▶). For reviews on pharmaceutical co-crystals, see: Schultheiss & Newman (2009 ▶); Almarsson & Zaworotko (2004 ▶). For more information on the hydrogen bonding, see: Desiraju & Steiner (1999 ▶).

Experimental

Crystal data

2C₉H₁₁NO₂·C₇H₆O₄·C₂H₄O₂
M _r = 544.55
Triclinic,
a = 8.8083 (18) Å
b = 8.8802 (18) Å
c = 19.880 (4) Å
α = 93.65 (3)°
β = 93.55 (3)°
γ = 119.45 (3)°
V = 1343.5 (6) Å³
Z = 2
Mo Kα radiation
μ = 0.10 mm⁻¹
T = 110 K
0.33 × 0.29 × 0.22 mm

Data collection

Rigaku Saturn CCD area-detector diffractometer
Absorption correction: multi-scan (Blessing, 1995 ▶) T _min = 0.967, T _max = 0.978
19296 measured reflections
6594 independent reflections
6074 reflections with I > 2σ(I)
R _int = 0.025

Refinement

R[F ² > 2σ(F ²)] = 0.050
wR(F ²) = 0.135
S = 1.11
6594 reflections
380 parameters
H atoms treated by a mixture of independent and constrained refinement
Δρ_max = 0.25 e Å⁻³
Δρ_min = −0.23 e Å⁻³

Data collection: CrystalClear (Rigaku, 2008 ▶); cell refinement: CrystalClear; data reduction: CrystalClear; program(s) used to solve structure: SHELXS97 (Sheldrick, 2008 ▶); program(s) used to refine structure: SHELXL97 (Sheldrick, 2008 ▶); molecular graphics: X-SEED (Barbour, 2001 ▶); software used to prepare material for publication: SHELXTL (Sheldrick, 2008 ▶) and PLATON (Spek, 2009 ▶).

Supplementary Material

Crystal structure: contains datablocks global, I. DOI: 10.1107/S1600536810012407/fb2192sup1.cif

e-66-o1045-sup1.cif^{(23.6KB, cif)}

Structure factors: contains datablocks I. DOI: 10.1107/S1600536810012407/fb2192Isup2.hkl

e-66-o1045-Isup2.hkl^{(322.7KB, hkl)}

Additional supplementary materials: crystallographic information; 3D view; checkCIF report

Table 1. Hydrogen-bond geometry (Å, °).

D—H⋯A	D—H	H⋯A	D⋯A	D—H⋯A
N1—H1⋯O2	0.926 (19)	1.941 (18)	2.6472 (19)	131.6 (14)
N1—H2⋯O5ⁱ	0.90 (2)	2.085 (18)	2.9550 (17)	163.0 (15)
N2—H7⋯O4	0.879 (18)	1.959 (17)	2.6536 (16)	135.0 (17)
N2—H10⋯O9ⁱⁱ	0.912 (18)	2.057 (17)	2.9542 (17)	167.4 (17)
O6—H11⋯O1ⁱⁱⁱ	1.02 (2)	1.53 (2)	2.5327 (15)	167.0 (18)
O7—H16⋯O5	0.90 (2)	1.80 (2)	2.6183 (15)	149 (3)
O8—H19⋯O9^iv	0.96 (2)	1.77 (2)	2.7231 (16)	173 (2)
O10—H20⋯O3^v	0.99 (2)	1.56 (2)	2.5446 (15)	171 (2)
C8—H8A⋯O1^vi	0.99	2.46	3.3768 (19)	154
C13—H13⋯O8^vii	0.95	2.55	3.452 (2)	159
C14—H14⋯O10^viii	0.95	2.53	3.348 (2)	145

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Symmetry codes: (i) Inline graphic ; (ii) ; (iii) ; (iv) ; (v) ; (vi) ; (vii) ; (viii) .

Acknowledgments

This work was supported by the Institute of Chemical and Engineering Sciences of A*STAR (Agency for Science, Technology and Research), Singapore.

supplementary crystallographic information

Comment

Ethenzamide (2-ethoxybenzamide) belongs to a non-steroidal anti-inflammatory drug (NSAID) used mainly in combination with other ingredients for the treatment of mild to moderate pains (Hirasawa et al., 1999). The crystal structure of ethenzamide has been recently solved using the high-resolution powder X-ray diffraction (Pagola & Stephens, 2009). Gentisic acid (2,5-dihydroxybenzoic acid) is also a NSAID (Lorico et al., 1986).

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.

The crystal structure contains two molecules of ethenzamide, one molecule of gentisic acid and one molecule of acetic acid in the asymmetric unit (Fig. 1). In the structure, gentisic acid and acetic acid molecules are engaged in the formation of acid-amide heterosynthons with symmetry independent molecules of ethenzamide involving 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 (Table 1) (Desiraju & Steiner, 1999). The anti-N—H of the primary amide of ethenzamide and the 2-hydroxy group of gentisic acid form an intramolecular N—H···O [N···O = 2.6472 (19) and 2.6536 (16) Å] and O—H···O [O···O = 2.6183 (15)] hydrogen bonds, respectively (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 physico-chemical 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.

Experimental

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.