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Chiang Mai J. Sci. 2011; 38(3) 405 Chiang Mai J. Sci. 2011; 38(3) : 405-411 http://it.science.cmu.ac.th/ejournal/ Contributed Paper Supramolecular Structure of Cocrystallized J-Amino Butyric Acid and Oxalic Acid Nongnaphat Khosavithitkul*[a] and Kenneth J. Haller**[b] [a] The Center for Scientific and Technological Equipment, Suranaree University of Technology, Nakhon Ratchasima 30000, Thailand. [b] School of Chemistry, Institute of Science, Suranaree University of Technology, Nakhon Ratchasima 30000, Thailand. Authors for correspondence; *e-mail: [email protected], **e-mail: [email protected] Received: 27 October 2010 Accepted: 29 November 2010 ABSTRACT Pharmaceutical cocrystals are crystalline molecular complexes that contain therapeutically active molecules. In many cases properties important to the bioavailability or processing of pharmaceutical solids have been demonstrated to be improved upon via cocrystallization. The structural elements (strong hydrogen bond donor, strong hydrogen bond acceptor, and nonpolar region) of J-amino butyric acid, GABA, are typical of small drug molecules, and GABA is a major neurotransmitter inhibitor of the central nervous system. GABA and oxalic acid, OX, were cocrystallized as part of a study on formation of cocrystals of pharmaceutically interesting molecules via hydrogen bonding. The crystal structure of the resulting transparent colorless 2GABA:OX cocrystal was studied by single crystal X-ray R analysis (monoclinic; P21/c; a = 7.4153(9), b = 10.2052(13), c = 9.7584(12) A, E = 108.396(3) , V = 700.72(15) A3, Z = 2, T = 298 K). The supramolecular structure contains extensive OHO, NHO and CHO interactions leading to an elaborate three-dimensional hydrogen bonded network. The ammonium cation participates in three separate OHîNîHO motifs (half of the R42(8) synthon), but the R42(8) synthon itself is not found. Notable features in the structure include an S33(10) string containing a serpentine carboxylic acid-carboxylate motif alternating with the ammonium motif. Additional strings and other concerted hydrogen bond motifs are also present. Keywords: supramolecular structure, cocrystal, GABA. 1. INTRODUCTION Cocrystals are crystalline molecular complexes containing two or more species with essentially molecular properties. The species can, at least in principle, be separated into pure components with similar chemical nature to those they possess in the cocrystal. Phar- maceutical cocrystals are, therefore, crystalline molecular complexes containing therapeutically active molecules, usually in conjunction with molecules that do not have therapeutic value. In many cases properties, including solubility and physical stability, important 406 to the bioavailability or processing of pharmaceutical solids have been demonstrated to be improved upon via cocrystallization. Traditionally, the major modification of active pharmaceutical ingredients, API, to obtain good crystalline products has been the formation of salts. In contrast to the limited number of salt-forming counter ions in use today [1], cocrystallization provides extensive alternative solid-state modification possibilities through the groups of compounds approved as additives, and those classified as GRAS (generally regarded as safe) by the food and drug association [2]. Thus, with the inherent advantages of property improvement, pharmaceutical cocrystallization should play a significant role in the development of tomorrow’s medicines. J-Amino butyric acid, GABA, itself is an important substance as a major neurotransmitter inhibitor of the central nervous system. In addition the structural elements (strong hydrogen bond donor, strong hydrogen bond acceptor, and nonpolar region) of GABA are typical of small drug molecules, making GABA a good model compound for pharmaceutical cocrystallization studies. In this work GABA and oxalic acid, OX, were cocrystallized as part of a study on formation of cocrystals of pharmaceutically interesting molecules via hydrogen bonding. The material was previously reported by Wenger and Bernstein [3] in a study of fourcomponent synthons involving two amine donor groups and two carbonyl acceptor groups, but the supramolecular structure has not been analyzed in detail. 2. MATERIALS AND METHODS 2:1 GABA/Oxalic Acid was prepared by both solution crystallization and solid-state grinding. Single crystal X-ray diffraction quality 2GABA:OX cocrystals were grown from ethanol solution by slow evaporation Chiang Mai J. Sci. 2011; 38(3) at room temperature. The structure was determined by single crystal X-ray analysis. Intensity data were collected using the COLLECT software [4] on a Nonius Kappa CCD diffractometer equipped with a fine focus MoKD X-ray source, graphite monochromator, and 0.3 mm ifg capillary collimator. Data were reduced to structure factors using EvalCCD [5]. Crystallographic calculations utilized MaXus [6], SIR97 [7], SHELX-97 [8], and ORTEP-III [9] (4925 data collected, Rint = 0.0379, 1,606 unique data, 1,180 observed o data (Io > 2Ƴ(Io)), ƨmax = 26.37 ). In the final cycles of refinement, nonhydrogen atoms were included with anisotropic atomic displacement parameters; all hydrogen atoms were located and included in idealized geometrical positions with varied average distances d[X–H] for each type of hydrogen atom (d[C–H] = 0.97 Å, d[N–H] = 0.92 Å, d[O–H] = 0.85 Å); and a single refined isotropic atomic displacement parameter, U[H], (0.053(3) Å2) for CH2 hydrogen atoms, and another for NH and OH hydrogen atoms (0.062(4) Å2). A summary of crystal data and structure refinement parameters is given in Table 1. The crystallographic data for this paper has been deposited with The Cambridge Crystallographic Data Centre as deposition number CCDC 795844, and may be obtained free of charge via the link www. ccdc.cam.ac.uk/data_request/cif. 3. RESULTS AND DISCUSSION The compound crystallizes in ionic form in the monoclinic space group P21/c with GABA as protonated ammonium cation and oxalate dianions. Charge neutrality requires a 2:1 reaction ratio of GABA and oxalic acid. The crystal structure of the title compound was determined by single crystal X-ray diffraction. The asymmetric unit is shown in Figure 1. Chiang Mai J. Sci. 2011; 38(3) 407 Table 1. Crystal Data for 2GABA:OX. Chemical formula Chemical formula weight Crystal color Crystal system/Space group Unit cell a = b = c = Ƣ = V = Z = Temperature = dcalc = F000 = Radiation type = ƬMo = R1 = wR(F2) = Goodness of fit = Electron density Ʊmax = 2(C4H10NO2+)(C2O42î) 296.28 Transparent colorless Monoclinic P21/c 7.4153 (9) Å 10.2052 (13) Å 9.7584 (12) Å 108.396 (3)q 700.72(15) Å3 2 298 (2) K 1.404 Mg mî3 316 Mo Kơ 0.122 mmî1 0.0482 0.1141 1.141 0.18(4) e Åî3 Figure 1. A perspective view of the asymmetric unit of 2GABA:OX with atom labeling scheme indicated thereon. Thermal ellipsoids are drawn at the 50% probability level. 408 Chiang Mai J. Sci. 2011; 38(3) C(C=O)C, C(C=O)H, -NH3+, CNH2, NH4+, and NNH2. This survey clearly indicates that the highest incidence of participation in the R24(8) synthon is for carboxylate anion acceptors and ammonium cation donors. The supramolecular structure of 2GABA: OX contains extensive OHO, NHO, and CHO interactions leading to an elaborate three-dimensional hydrogen bonded network. The ammonium cation participates in three separate OHîNîHO motifs, one to each of the three crystallographically independent carboxylate C=O functional groups. Each of these motifs is half of the R42(8) synthon as shown in Figure 3 (d[CîH] = 2.887, 2.777, and 2.786 Å), but the R42(8) synthon itself is not found. Rather, the OHîNîHO motifs are strings in larger ring systems. The a and b hydrogen positions (upper left in Figure 3) participate in centrosymmetric R66(20) rings (Figure 4) that also include the carboxylic acid group of GABA and one carboxylate group of the oxalate dianion in local serpentine arrangements. While carboxylic acids generally form centrosymmetric R22(8) dimers (Figure 2), this robust synthon is unavailable to a combination of carboxylate with carboxylic acid. A common motif for carboxylate with carboxylic acid is An important part of the analysis of the structures of cocrystals is the supramolecular interconnectivity. A useful tool for this analysis is graph set theory, introduced by Etter et al. [10,11]. A typical graph set symbol is R22(8) which is used to represent the typical dimer formed in the solid state by two carboxylic acid molecules as shown in Figure 2a. A survey [2] of the Cambridge Structural Database, CSD, has identified over 12,000 instances of the NHO synthon, virtually all of which involve individual and nonconnected (but not necessarily chemically different) moieties in the solid state. Many of these cases involve four chemically different moieties, often resulting in the crystallographically centrosymmetric or pseudo centrosymmetric R42(8) pattern shown in Figure 2. Perhaps the most remarkable feature about this synthon in terms of cocrystal formation is that it potentially involves the intermolecular recognition of, and supramolecular synthesis from, four different molecules in its construction. The CSD survey gave 918 hits for structures utilizing the R42(8) synthon in which the donor is the amino group (NH2) and the acceptor is the carbonyl group (C=O).These are broken down into specific functional groups like (C=O)O, N(C=O), N(C=O)N, (C=O)OH, (a) (b) (c) Figure 2. Graph set notation for simple synthons relating to carboxylates. a. The R22(8) carboxylic acid dimer, b. the R42(8) synthon, and c. the R12(4) donor-carboxylate anion motif. D represents a hydrogen bond donor and A represents a hydrogen bond acceptor. Chiang Mai J. Sci. 2011; 38(3) 409 the R12(4) synthon (Figure 2) as seen in the O4HO3îC5 subrings in Figure 4. The strong hydrogen bond parameters are given in Table 2. Figure 3. The NH··· O hydrogen bonds of the ammonium cation. Thermal ellipsoids are drawn at the 50% probability level. Figure 4. The centrosymmetric R66(20) rings involving the a and b hydrogen positions of the ammonium cation. Thermal ellipsoids are drawn at the 25% probability level. Table 2. Strong hydrogen bonds. DH d(DH) d(HA) <DHA d(DA) A symmetry operator NHa 0.92 2.06 148.6 2.887 O1 [ -x, y+1/2, -z+1/2 ] NHa NHb NHc O2H2 0.92 0.92 0.92 0.86 2.56 1.91 1.89 1.68 113.5 156.5 164.8 171.3 3.042 2.777 2.786 2.534 O3 O3 O4 O4 [ x-1, -y+1/2, z-1/2 ] [ x-1, y, z ] [ -x, y-1/2, -z+1/2 ] [ x, -y+1/2, z+1/2 ] 410 The OHîNîHO motifs involving the a and c hydrogen positions (lower left in Figure 3) and the b and c hydrogen positions (right in Figure 3) are joined in the common R54(15) rings shown in Figure 5. One of the ammonium hydrogen atoms is also donated Chiang Mai J. Sci. 2011; 38(3) in a second (weaker) hydrogen bond connecting GABA and OX through carboxylate oxygen atoms. Additional strings and other concerted hydrogen bond motifs are also present, further augmented by a number of CîHO hydrogen bonds. Figure 5. The R54(15) rings involving the a and c, and the b and c hydrogen positions of the ammonium cation. Thermal ellipsoids are drawn at the 20% probability level. 4. CONCLUSIONS 5. ACKNOWLEDGEMENTS Strong OîHO and NîHO hydrogen bonded strings and concerted motifs supported by weaker CîHO hydrogen bonds from two J-ammonium butyric acid monocations and one oxalate dianion create an elaborate three-dimensional supramolecular network. While the ammonium ion features strongly in the supramolecular structure, the anticipated R42(8) synthon was not found. Instead, larger nonsymmetric R54(15) and centrosymmetric R55(20) rings connect adjacent ammonium ions, oxalate dianions, and carboxylic acid groups together. This work was supported by Suranaree University of Technology. 6. 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