Received 8 July 2013
Binary co-crystals of the active pharmaceutical ingredient 1,4-bis(4-pyridyl)-2,3-diaza-1,3-butadiene and camphoric acid
aAnalytical Discipline and Centralized Instrument Facility, CSIR - Central Salt and Marine Chemicals Research Institute, Council of Scientific and Industrial Research, G. B. Marg, Bhavnagar 364 002, Gujarat, India,bAcademy of Scientific and Innovative Research (AcSIR), CSIR - Central Salt and Marine Chemicals Research Institute, Council of Scientific and Industrial Research, G. B. Marg, Bhavnagar 364 002, Gujarat, India, and cApplied Chemistry Department, Sardar Vallabhbhai National Institue of Technology (SVNIT), Surat 395007, Gujarat, India
Co-crystals comprising the active pharmaceutical ingredient 1,4-bis(4-pyridyl)-2,3-diaza-1,3-butadiene, C12H10N4, and the chiral co-formers (+)-, (-)- and (rac)-camphoric acid (cam), C10H16O4, have been synthesized. Two different stoichiometries of the API and co-former are obtained, namely 1:1 and 3:2. Crystallization experiments suggest that the 3:2 co-crystal is kinetically favoured over the 1:1 co-crystal. Single-crystal X-ray diffraction analysis of the co-crystals reveals N-HO hydrogen bonding as the primary driving force for crystallization of the supramolecular structures. The 1:1 co-crystal contains undulating hydrogen-bonded ribbons, in which the chiral cam molecules impart a helical twist. The 3:2 co-crystal contains discrete Z-shaped motifs comprising three molecules of the API and two molecules of cam. The 3:2 co-crystals with (+)-cam, (-)-cam (space group P21) and (rac)-cam (space group P21/n) are isostructural. The enantiomeric co-crystals contain pseudo-symmetry consistent with space group P21/n, and the co-crystal with (rac)-cam represents a solid solution between the co-crystals containing (+)-cam and (-)-cam.
Crystal engineering offers a rational approach to the design of new compositions and crystal structures, through manipulation of non-covalent interactions (Clarke et al., 2010; Sarma & Desiraju, 1984; Thakur & Desiraju, 2008). Co-crystals in particular are a class of crystalline materials that have attracted immense scientific and industrial interest in recent years (Bond, 2012; Aakeröy & Chopade, 2012; Aakeröy et al., 2008; Desiraju, 2012; Dastidar, 2000; Pedireddi, 2001; Aitipamula et al., 2012). Co-crystallization of active pharmaceutical ingredients (APIs) has proven to be a viable means to enhance the physical properties of drug substances, particularly when the chance of forming ionic complexes is limited and the inherent instability of the amorphous material is undesired (Schultheiss & Henck, 2012; Arora & Zaworotko, 2009). Co-crystallization of an API can improve not only physical properties like the melting point, but also several vital factors such as solubility (which is important during drug delivery), resistance to humidity, dissolution, bioavailability, moisture uptake, chemical stability etc. (Kawakami, 2012; Byrn & Henck, 2012; Upadhyay et al., 2011; Friscic & Jones, 2010; Chatterjee et al., 1998; Vinesha et al., 2013; Good & Rodríguez-Hornedo, 2010). Many binary and ternary co-crystals have been reported to date, and considerable success has been achieved when a carboxylic acid group is allowed to interact with a suitable N-heterocycle (Brittain, 2010, 2011, 2012).
Understanding of highly specific and mutually complementary non-covalent interactions between molecules is a basic requirement for crystal engineering. For carboxylic acids, the strength and directional nature of hydrogen bonding results frequently in dimeric homosynthon (I) and less frequently catemeric homosynthon (II). However, strong hydrogen-bond acceptors, for example pyridine, may disrupt these homosynthons, leading to heterosynthon (III) or (IV) (Santra et al., 2008; Sreekanth et al., 2007; Desiraju, 1996; Santra & Biradha, 2009; Merz & Vasylyeva, 2010). Thus, the design of co-crystals comprising two or more different molecules is based upon the perception of complementary intermolecular interactions which can preferentially lead to stable heteromeric assemblies (Miroshnyk & Mirza, 2010; Roy & Biradha, 2013; Elbagerma et al., 2010, 2011). Heterosynthons (III) and (IV) represent the end points of a `salt/co-crystal continuum' (Childs et al., 2007), and a judicious choice of API and co-former may lead to the synthesis of either a co-crystal [synthon (III)] or a salt [synthon (IV)]. Consideration of pKa values of the constituent molecules may help to select a suitable co-crystal former with the least possibility for salt formation (Rajbanshi et al., 2008; Aakeröy et al., 2007). In general, co-crystals and salts may be expected for pKa 0 and pKa 3, respectively. For pKa values in the range 0-3, the extent of proton transfer is largely unpredictable (Delori et al., 2013; Kathalikkattil et al., 2011).
The concepts of crystal engineering and supramolecular synthons can be applied to design new compositions of matter which are based upon existing APIs and complementary co-crystal formers. The new compositions hence generated can offer desirable structures and properties (Rajput et al., 2013; Thakuria & Nangia, 2013). Furthermore, due to the hydrogen-bond donor/acceptor sites typically present in API molecules, their solid-state properties can be tailored by exploiting the crystal engineering approach. The azine molecule (1) [systematic name: 1,4-bis(4-pyridyl)-2,3-diaza-1,3-butadiene] has been one of the popular choices among material chemists and crystal engineers as a supramolecular building block. The molecule has been extensively exploited for the synthesis of coordination polymers (CPs), and a variety of one-, two- and three-dimensional CPs comprising molecule (1) alone or in combination with polycarboxylate ligands are well documented in the literature (Kole et al., 2012; Aghabeygi et al., 2012; Ghazzali et al., 2011; Broker & Tiekink, 2011; Granifo et al., 2010; Diskin-Posner et al., 2002; Ikbal et al., 2012; Vajpayee et al., 2013; Verma et al., 2012). Owing to the presence of azine functionality, molecule (1) possesses NADPH oxidase inhibitor activity, which has been disclosed elsewhere (Ternansky et al., 1998). On the other hand, camphoric acid (cam) is derived from the natural product camphor. The bioavailability and non-toxic nature of cam makes it a suitable candidate for pharmaceutical preparations. It has been extensively studied and used as a precursor for coordination polymer/MOF synthesis (Smart et al., 2013; Thuery, 2009; Dybtsev et al., 2009; Blake et al., 2012; Chen et al., 2009; Wu et al., 2010). The physiological effects of cam are described and exploited in a few reports (Lima et al., 2012), which essentially indicate the potential of cam as a co-crystal former. There have also been a few reports where camphoric acid is employed in the design and synthesis of co-crystals with pharmaceutical and crystal engineering interests (Mohammad et al., 2011; Rager & Hilfiker, 2010; Edwards et al., 2010; Arenas-García et al., 2010; Zaworotko et al., 2008; Childs et al., 2008; Childs & Hardcastle, 2007; Zakaria et al., 2003; Moriuchi et al., 2003; Goswami et al., 2000).
The pharmaceutical activity of azine (1), non-toxicity of cam, and appealing crystal engineering prospects of both molecules prompted us to explore their solid-state compositions. We report in this paper that (1) forms two types of co-crystals when combined with the (+) or (-) forms of cam, with a 1:1 or 3:2 stoichiometry. It is further shown that (rac)-cam forms a 3:2 co-crystal that is isostructural with the corresponding enantiomeric structures. The paper describes the various co-crystallization experiments performed for (1) and cam, structural studies of the co-crystals by single-crystal X-ray diffraction, and other complementary physicochemical techniques.
Pyridine-4-carboxaldehyde, hydrazine hydrate and camphoric acids were purchased from Sigma-Aldrich. Organic solvents were obtained from SD Fine Chemicals, India. Distilled water was used in the crystallization experiments. All reagents and solvents were used as received without further purification. Molecule (1) was prepared by adopting a slightly modified literature method (Ciurtin et al., 2001), as described in the supporting information.1
CHNS analyses were carried out using a Perkin-Elmer 2400 CHNS/O analyzer. IR spectra were recorded using KBr pellets on a Perkin-Elmer GX FTIR spectrometer. For each IR spectrum, 10 scans were recorded at 4 cm-1 resolution. 1H NMR were recorded on a Bruker AX 500 spectrometer (500 MHz) at 298 K and were calibrated with respect to an internal TMS reference. X-ray powder diffraction data were collected using a PANalytical Empyrean (PIXcel three-dimensional detector) system with Cu K radiation. Solid-state UV-vis spectra and CD-UV-vis spectra were recorded using a Shimadzu UV-3101PC spectrometer and a JASCO J-851-150L CD spectrometer, respectively. Melting points, TGA and DSC analyses were carried out using Mettler Toledo instruments FP62, Star-SW8.10 and DSC822e, respectively.
The crystallographic data and details of data collection and structure refinement are given in Table 1. In each case, a crystal of suitable size was selected from the mother liquor and immersed in paratone oil, then mounted on the tip of a glass fibre. Intensity data for all three crystals were collected at low temperature using Mo K ( = 0.7107 Å) radiation on a Bruker SMART APEX CCD diffractometer. H atoms attached to C atoms were placed in geometric positions, while those on the OH groups of cam were located in difference Fourier maps. For CCP1:1 and CCR3:2 their positions were refined without restraint, while for CCP3:2 they were fixed in geometrically optimized positions during subsequent refinement. Both co-crystals CCP1:1 and CCP3:2 crystallize in non-centrosymmetric space groups, and in each case the absolute structure was assigned on the basis of the known (+) stereochemistry of cam. The chiral nature of the compounds is further supplemented by the CD spectroscopy. Single crystals of CCM3:2 were also obtained and analyzed, and their structure was confirmed to be equivalent to that of CCP3:2; only the structure of CCP3:2 is presented. In the case of co-crystal CCR3:2, crystallized from racemic cam, the camphoric acid molecule showed positional disorder. Two molecular components could be picked out, corresponding to (+) and (-)-cam, and refined without any restraints to produce satisfactory molecular geometries. The refined site occupancy factors were 0.641 (3):0.359 (3). The co-crystals CCP3:2 (and CCM3:2) and CCR3:2 are isostructural. The enantiomeric co-crystals CCP3:2 (and CCM3:2) thereby contain pseudo-symmetry consistent with space group P21/n, and co-crystal CCR3:2 represents a solid solution between CCP3:2 and CCM3:2.
CCP1:1: 60 mg (0.3 mmol) (+)-cam, 63 mg (0.3 mmol) of azine (1) and 3 ml methanol were taken in a 5 ml glass vial and the mixture was dissolved by sonication. The clear yellow-coloured solution obtained was kept for slow evaporation and block-shaped crystals suitable for single-crystal analysis were grown within 2 weeks (melting point: 456 K).
CCP3:2: 120 mg (0.6 mmol) (+)-cam and 190 mg (0.9 mmol) of (1) were separately dissolved in 5 ml methanol each, then mixed gradually with constant stirring at ambient temperature for 2 h. The clear solution thus obtained yielded plate-shaped crystals suitable for single-crystal analysis within 3-4 d (melting point: 434 K).
CCM3:2 (melting point: 434 K) and CCR3:2 (melting point: 466 K) were obtained using a similar procedure to CCP3:2 except that (-)-cam or (rac)-cam were used instead of (+)-cam.
Spectroscopic characterization of the products is provided in the supporting information.
From a crystal engineering viewpoint, molecule (1) is an interesting compound for co-crystal design owing to the presence of pyridine-N sites which are well known to form pyridine-carboxylic acid heterosynthons with carboxylic acids. We chose cam as a co-crystal former for (1), keeping in mind the probable heterosynthon (III). The exclusive formation of co-crystals rather than salts could be anticipated due to the marginal difference in the pKa values. These values are clearly fairly close to each other (pKa = 0.07) and suggest the minimal possibility of proton transfer between (1) and cam. Attempted co-crystallizations produced four co-crystals: CCP1:1 with 1:1 stoichiometry of (1) and (+)-cam, CCP3:2, CCM3:2 and CCR3:2 with 3:2 stoichiometry of (1) and (+)-cam, (-)-cam or (rac)-cam, respectively. The structure of CCM3:2 was determined and confirmed to be equivalent to that of CCP3:2. Attempts were also made to grow a 1:1 co-crystal of (1) and (-)-cam (CCM1:1), but we could not harvest crystals suitable for X-ray diffraction. The molecular structures of CCP1:1, CCP3:2 and CCR3:2 are presented in Fig. 1.
| || Figure 1 |
Asymmetric units of (a) CCP1:1, (b) CCP3:2 and (c) CCR3:2, with partial atom-numbering scheme and displacement ellipsoids shown at 50% probability. H atoms other than those of the carboxyl groups are omitted. Symmetry code: (i) 2-x,1-y,-z.
CCP1:1 crystallizes in space group P212121 and involves (1) and (+)-cam in a 1:1 stoichiometry (Fig. 1a). The C-O bond lengths of the carboxylic acid group of (+)-cam clearly indicate co-crystal formation (rather than a salt), and this was confirmed by the positions of the H atoms visible in difference Fourier maps. Details of the hydrogen-bonding parameters are given in Table 2. As depicted in Fig. 2, the molecules of (1) and (+)-cam are linked via synthon (III) to generate one-dimensional undulating ribbons extending along the c axis. Alternate cam molecules adopt opposite orientations, imparting a helical twist to the ribbons. The ribbons are cross-linked via C-H interactions involving the methyl H atom H20A from (+)-cam and the centroid of the pyridyl ring (Cg), generating a two-dimensional network involving the weak non-bonding interactions parallel to the (010) planes (Fig. 2). The parameters for the C-H interaction are H20ACg = 2.68 (3) Å; C20-H20ACg = 149° (symmetry code: ).
| || Figure 2 |
(a) Packing diagram of CCP1:1 viewed down the a axis, depicting sheets parallel to the (010) planes; (b) view down the b axis, showing undulating one-dimensional hydrogen-bonded ribbons formed via O-HN interactions between (1) and cam, cross-linked via C-H interactions.
The 3:2 co-crystal with enantiopure cam, CCP3:2, crystallizes in space group P21. The structural description of CCP3:2 is presented as a representative of the two enantiomers CCP3:2 and CCM3:2. The asymmetric unit of CCP3:2 (Fig. 1b) comprises three independent molecules of (1) and two (+)-cam molecules. As depicted in Fig. 3, the molecules are linked via heterosynthon (III) into discrete Z-shaped motifs comprising three molecules of (1) and two molecules of (+)-cam. Details of the hydrogen-bonding interactions are given in Table 2. These motifs are arranged into sheets parallel to the (103) planes, and they form an ABCABC-type pattern within each sheet, where the B and C strands are sandwiched between the A strands (Fig. 3). The pyridyl rings are stacked with Cg1Cg6 distance 3.68 Å and Cg2Cg5 distance 3.69 Å (where Cg1, Cg2, Cg5 and Cg6 are the centroids of the pyridyl rings C1-C5/N1, C8-C12/N4, C25-C29/N9 and C32-C36/N12, respectively). C-HO interactions involving the pyridyl H atoms and carboxyl O atoms bridge between the sheets.
| || Figure 3 |
(a) Packing diagram for CCP3:2 viewed down the b axis, showing sheets parallel to the (103) planes (horizontal); (b) view of one sheet, showing the ABCABC-type arrangement of the Z-shaped motifs. The molecules coloured red illustrate a complete Z-shaped motif with stoichiometry 3:2.
Co-crystal CCR3:2, comprising (1) and (rac)-cam, is isostructural with CCP3:2. It crystallizes in space group P21/n, with the asymmetric unit comprising one whole molecule of (1) and (rac)-cam, and another half molecule of (1) on a crystallographic inversion centre (Fig. 1c). The (rac)-cam molecule is disordered over two orientations, corresponding to an overlay of the (+) and (-)-cam enantiomers (Fig. 4). In the presented asymmetric unit, the majority component [site occupancy 0.641 (3)] corresponds to (+)-cam, while the minority component [site occupancy 0.359 (3)] corresponds to (-)-cam. Similar cases of structural resemblance in co-crystals derived from enantiopure and racemic forms of chiral substances with achiral co-crystal formers have previously been reported (Lemmerer et al., 2008; Eccles et al., 2011). In another relevant study, (S)- and (R/S)-ibuprofen were found to form almost isostructural co-crystals with nicotinamide; in that case, the (S) and (R/S) co-crystals crystallized in monoclinic (space group P21) and orthorhombic (space group Pca21) structures, respectively (Berry et al., 2008).
| || Figure 4 |
Overlay depicting the similarity between CCP3:2 (red) and CCR3:2 (blue). The origin shift of ¼c is due to the adoption of standard origin choices for space groups P21 (origin on 21) and P21/n (origin on ). For the cam molecules, it can be seen that one of the disorder components in CCR3:2 overlays the (+)-cam molecule in CCP3:2; the other disorder component corresponds to (-)-cam.
Full details of these supporting techniques are provided in the supporting information . All of the synthesized co-crystals were studied by FTIR spectroscopy, which indicates no proton transfer between the acid and N-donor ligand. All co-crystals exhibit a characteristic C=O stretching band at ca 1690 cm-1, which indicates the presence of hydrogen-bonded COOH. This is further supported by broad O-H stretching bands near ca 3500 cm-1. Other characteristic bands for aromatic and aliphatic functionalities were common in the co-crystals and their constituents. Proton NMR spectra in DMSO-d6 solutions were employed to establish adduct formation. Integration of well separated resonance signals for molecules (1) ( = 8.76, 8.69 and 7.82 p.p.m.) and camphoric acid ( = 2.74, 2.35, 1.95, 1.74, 1.72, 1.37, 1.20, 1.14 and 0.77 p.p.m.) confirmed the stoichiometry of the co-crystals. Powder XRD analyses of the bulk compounds corroborate well with those simulated from the single-crystal data for all co-crystals. All of the synthesized co-crystals are air-stable and retain their crystalline integrity under ambient conditions.
UV-vis absorption spectra were recorded for all co-crystals in solid as well as solution phases (Fig. 5a and supporting information ). In the solid state all co-crystals showed strong absorption bands at ca 238 and 376 nm which are attributable to the highly conjugated aromatic structure of azine (1). Slight differences in position and relative intensities of these bands may be attributed to the conformational differences of the molecule in the co-crystal phases. The absorption spectra recorded in methanol solutions (10-4 M) showed characteristic bands for camphoric acid and (1) at ca 215 and 275 nm, respectively.
| || Figure 5 |
(a) Solid-state UV-vis spectra; (b) CD spectra recorded in aqueous solution.
The chirality of the synthesized co-crystals was probed by means of circular dichroism (CD) spectroscopy (Fig. 5b and supporting information ). The CD signal from camphoric acid was relatively weaker and enveloped inside the noise observed for azine ligand (1). The experiments were carried out for different concentrations ranging from 10-3 to 10-7 M in methanol solution, but the signal-to-noise ratio did not improve. In order to eliminate the noisy signal of the azine component, (1) and cam were extracted into dichloromethane and water, respectively. Thus, 10 mg of each co-crystal was dissolved in a biphasic solvent mixture containing 2 ml of dichloromethane and 2 ml of water. The mixture was sonicated for 5 min, then the solutions were allowed to stand for 15 min and 1 ml of the aqueous layer was pipetted out and diluted to prepare 20 ml aqueous solution. The CD spectra recorded for the aqueous solutions showed clearly the signals for camphoric acid (Fig. 5b). Thus, CCP1:1 and CCP3:2 show a strong positive CD band near 220 nm, while a negative band is observed for CCM3:2 in the same region. The enantiomeric nature of CCP3:2 and CCM3:2 is evident from their mirror-like CD responses. The co-crystal derived from the racemic form of camphoric acid does not exhibit any dichroic signal.
There have been efforts to identify factors and conditions governing the formation and stability of co-crystals with different stoichiometry. In general, the varied stoichiometry of components in a particular solvent system or the variation of solvent composition for a given stoichiometry of co-crystal components has been studied. A few studies elaborating on ternary phase diagrams at differing temperatures and co-crystal eutectic constants (Keu) have also been exploited to obtain precise details about the selectivity and stability of possible co-crystal phases (Jayasankar et al., 2009; Ghazzali et al., 2011; Boyd et al., 2010; Seaton et al., 2009). Taking inspiration from these studies, we screened the crystallization conditions to achieve explicit formation of the 1:1 or 3:2 co-crystal phases. In the first set of experiments (Table 3), the reactants (1) and (+)-cam were taken in different stoichiometries, keeping other parameters constant. For each experimental set, reactants were separately dissolved in 5 ml methanol and mixed. The methanolic solution was then allowed to evaporate at ambient temperature. After evaporation of ca 70% volume of solvent, the first crop of crystalline material was isolated by filtration. PXRD patterns for the products with reactant ratio (1):(+)-cam ranging from 1:0.5 to 1:3 matched well with the simulated profile of co-crystal CCP3:2 (Fig. 6). Noticeably, when the ratio was as high as 1:4, only molecule (1) crystallized. 1H NMR spectra indicated the presence of precursors in small quantities beside CCP3:2 when the reactant ratio deviates from unity. Starting from an equimolar mixture of (1) and (+)-cam produced only CCP3:2.
| || Figure 6 |
(a) PXRD profiles of crystalline substances obtained with different ratios of (1) and (+)-cam; (b) PXRD profiles of crystalline substances obtained with different water-methanol ratios employed for the crystallization of (1) and (+)-cam in 1:1 stoichiometry.
The effect of solvent (water/methanol mixture) on co-crystal formation was studied with a 1:1 stoichiometry of reactants in a second set of experiments (Table 4). Water was added to methanol to achieve a mixed solvent with water content ranging from 0 to 100%, and the solid reactants were dissolved in the mixture by sonication. The solids obtained by evaporation after 24 h were characterized by means of PXRD and 1H NMR spectroscopy. It was observed that irrespective of the water/methanol ratio in a mixed solvent, the 1:1 ratio of reactants produces CCP3:2 when allowed to evaporate at ambient conditions. Interestingly, however, crystallization performed with pure water yielded exclusively the 1:1 co-crystal CCP1:1.
Co-crystals comprising the active pharmaceutical ingredient (1) and chiral co-crystal formers (+)-, (-)- and (rac)-cam have been prepared and characterized. The crystal structures and accompanying FTIR data confirm that there is no proton transfer between the carboxylic acid and pyridyl groups, which is consistent with the small difference in pKa values of the API and co-crystal formers. The co-crystal with 1:1 stoichiometry includes undulating one-dimensional hydrogen-bonded ribbons running parallel to each other and held together by means of C-H interactions. The co-crystals with 3:2 stoichiometry exhibit discrete Z-shaped supramolecular motifs comprising three molecules of (1) and two molecules of cam. The co-crystals with (+)-cam, (-)-cam and (rac)-cam are isostructural, and co-crystal CCR3:2 can therefore be viewed as a solid solution between CCP3:2 and CCM3:2. This study highlights an example of API co-crystals comprising the same components but with different stoichiometry.
The authors acknowledge CSIR India for financial support, Mr Batuk Bheel for NMR data, Mr Satyaveer Gothwal for TGA and DSC data, Mr V. K. Agrawal for IR data, Mr Viral Vakani for CHN analysis and Dr P. Paul for all-round analytical support. The authors are grateful to Director CSIR-CSMCRI and Dr Parimal Paul for approving the summer training program of PP at CSIR-CSMCRI. KKB and YR acknowledge CSIR (India) and UGC (India) for Senior and Junior Research Fellowships, respectively. The authors also gratefully acknowledge the reviewers of the paper for constructive suggestions and advice.
Aakeröy, C. B. & Chopade, P. D. (2012). Supramolecular Chemistry: From Molecules to Nanomaterials, edited by P. A. Gale & J. W. Steed, pp. 2975-2992. Chichester: John Wiley and Sons Ltd.
Aakeröy, C. B., Desper, J., Fasulo, M., Hussain, I., Levin, B. & Schultheiss, N. (2008). CrystEngComm, 10, 1816-1821.
Aakeröy, C. B., Fasulo, M. E. & Desper, J. (2007). Mol. Pharm. 4, 317-322.
Aghabeygi, S., Bigdeli, F. & Morsali, A. (2012). J. Inorg. Organomet. Polym. Mater. 22, 526-529.
Aitipamula, S. et al. (2012). Cryst. Growth Des. 12, 2147-2152.
Arenas-García, J. I., Herrera-Ruiz, D., Mondragón-Vásquez, K., Morales-Rojas, H. & Höpfl, H. (2010). Cryst. Growth Des. 10, 3732-3742.
Arora, K. K. & Zaworotko, M. J. (2009). Drugs Pharm. Sci. 192, 282-317.
Berry, D. J., Seaton, C. C., Clegg, W., Harrington, R. W., Coles, S. J., Horton, P. N., Hursthouse, M. B., Storey, R., Jones, W., Friscíc, T. & Blagden, N. (2008). Cryst. Growth Des. 8, 1697-1712.
Blake, K. M., Gandolfo, C. M., Uebler, J. W. & LaDuca, R. L. (2012). Cryst. Growth Des. 12, 5125-5137.
Bond, A. D. (2012). Pharmaceutial Salts and Co-crystals, edited by J. Wouters & L. Quéré, pp. 9-28. RSC Drug Discovery Series, Vol 16. Cambridge: Royal Society of Chemistry.
Boyd, S., Back, K., Chadwick, K., Davey, R. J. & Seaton, C. C. (2010). J. Pharm. Sci. 99, 3779-3786.
Brittain, H. G. (2010). Profiles of Drug Substances, Excipients, and Related Methodology, Vol. 35, pp. 373-390. Amsterdam: Elsevier Academic Press.
Brittain, H. G. (2011). Profiles of Drug Substances, Excipients, and Related Methodology, Vol. 36, pp. 361-381. Amsterdam: Elsevier Academic Press.
Brittain, H. G. (2012). Cryst. Growth Des. 12, 1046-1054.
Broker, G. A. & Tiekink, E. R. T. (2011). Acta Cryst. E67, m320-m321.
Bruker (2008). SMART, SAINT and SADABS. Bruker AXS Inc., Madison, Wisconsin, USA.
Byrn, S. R. & Henck, J.-O. (2012). Drug Discovery Today, 9, e73-e78.
Chatterjee, S., Pedireddi, V. & Rao, C. N. R. (1998). Tetrahedron Lett. 39, 2843-2846.
Chen, S., Zhang, J. & Bu, X. (2009). Inorg. Chem. 48, 6356-6358.
Childs, S. L. & Hardcastle, K. I. (2007). Cryst. Growth Des. 7, 1291-1304.
Childs, S. L., Rodríguez-Hornedo, N., Reddy, L. S., Jayasankar, A., Maheshwari, C., McCausland, L., Shipplett, R. & Stahly, B. C. (2008). CrystEngComm, 10, 856-864.
Childs, S. L., Stahly, G. P. & Park, A. (2007). Mol. Pharm. 4, 323-338.
Ciurtin, D. M., Dong, Y. B., Smith, M. D., Barclay, T. & zur Loye, H. C. (2001). Inorg. Chem. 40, 2825-2834.
Clarke, H. D., Arora, K. K., Bass, H., Kavuru, P., Ong, T. T., Pujari, T., Wojtas, L. & Zaworotko, M. J. (2010). Cryst. Growth Des. 10, 2152-2167.
Dastidar, P. (2000). CrystEngComm, 2, 49-52.
Delori, A., Galek, P. T. A., Pidcock, E., Patni, M. & Jones, W. (2013). CrystEngComm, 15, 2916-2928.
Desiraju, G. R. (1996). J. Am. Chem. Soc. 118, 4090-4093.
Desiraju, G. R. (2012). Pharmaceutial Salts and Co-crystals, edited by J. Wouters & L. Quéré, pp. 1-8. RSC Drug Discovery Series, Vol 16. Cambridge: Royal Society of Chemistry.
Diskin-Posner, Y., Patra, G. K. & Goldberg, I. (2002). Chem. Commun. pp. 1420-1421.
Dybtsev, D. N., Yutkin, M. P. & Fedin, V. P. (2009). Russ. Chem. Bull. 58, 2246-2249.
Eccles, K. S., Deasy, R. E., Fábián, L., Maguire, A. R. & Lawrence, S. E. (2011). J. Org. Chem. 76, 1159-1162.
Edwards, P. G., Knight, J. C. & Newman, P. D. (2010). Dalton Trans. 39, 3851-3860.
Elbagerma, M. A., Edwards, H. G. M., Munshi, T., Hargreaves, M. D., Matousek, P. & Scowen, I. J. (2010). Cryst. Growth Des. 10, 2360-2371.
Elbagerma, M. A., Edwards, H. G. M., Munshi, T. & Scowen, I. J. (2011). CrystEngComm, 13, 1877-1884.
Friscic, T. & Jones, W. (2010). J. Pharm. Pharmacol. 62, 1547-1559.
Ghazzali, M., Langer, V., Larsson, K. & Öhrström, L. (2011). CrystEngComm, 13, 5813-5817.
Good, D. J. & Rodríguez-Hornedo, N. (2010). Cryst. Growth Des. 10, 1028-1032.
Goswami, S., Mukherjee, R., Ghosh, K., Razak, I. A., Shanmuga Sundara Raj, S. & Fun, H.-K. (2000). Acta Cryst. C56, 477-478.
Granifo, J., Moreno, Y., Garland, M. T., Gaviño, R. & Baggio, R. (2010). J. Mol. Struct. 983, 76-81.
Ikbal, S. A., Brahma, S. & Rath, S. P. (2012). Inorg. Chem. 51, 9666-9676.
Jayasankar, A., Reddy, L. S., Bethune, S. J. & Rodríguez-Hornedo, N. (2009). Cryst. Growth Des. 9, 889-897.
Kathalikkattil, A. C., Damodaran, S., Bisht, K. K. & Suresh, E. (2011). J. Mol. Struct. 985, 361-370.
Kawakami, K. (2012). Adv. Drug Deliv. Rev. 64, 480-495.
Kole, G. K., Tan, G. K., Koh, L. L. & Vittal, J. J. (2012). CrystEngComm, 14, 6190-6195.
Lemmerer, A., Báthori, N. B. & Bourne, S. A. (2008). Acta Cryst. B64, 780-790.
Lima, B. G., Tietbohl, L. A. C., Fernandes, C. P., Cruz, R. A. S., Botas, G. S., Santos, M. G., Silva-Filho, M. V. & Rocha, L. (2012). Lat. Am. J. Pharm. 31, 152-155.
Macrae, C. F., Edgington, P. R., McCabe, P., Pidcock, E., Shields, G. P., Taylor, R., Towler, M. & van de Streek, J. (2006). J. Appl. Cryst. 39, 453-457.
Merz, K. & Vasylyeva, V. (2010). CrystEngComm, 12, 3989-4002.
Miroshnyk, I. & Mirza, S. (2010). Pharm. Technol. Eur. 22, 31-34.
Mohammad, M. A., Alhalaweh, A. & Velaga, S. P. (2011). Int. J. Pharm. 407, 63-71.
Moriuchi, T., Yoshida, K. & Hirao, T. (2003). J. Organomet. Chem. 668, 31-34.
Pedireddi, V. R. (2001). Cryst. Growth Des. 1, 383-385.
Rager, T. & Hilfiker, R. (2010). Cryst. Growth Des. 10, 3237-3241.
Rajbanshi, A., Aakeröy, C. B. & Desper, J. (2008). American Chemical Society, 42nd Midwest Regional Meeting.
Rajput, L., Sanphui, P. & Desiraju, G. R. (2013). Cryst. Growth Des. 13, 3681-3690.
Roy, S. & Biradha, K. (2013). Cryst. Growth Des. 13, 3232-3241.
Santra, R. & Biradha, K. (2009). Cryst. Growth Des. 9, 4969-4978.
Santra, R., Ghosh, N. & Biradha, K. (2008). New J. Chem. 32, 1673-1676.
Sarma, J. A. R. P. & Desiraju, G. R. (1984). J. Chem. Soc. Chem. Commun. pp. 145-147.
Schultheiss, N. & Henck, J.-O. (2012). Pharmaceutial Salts and Co-crystals, edited by J. Wouters & L. Quéré, pp. 110-127. RSC Drug Discovery Series, Vol 16. Cambridge: Royal Society of Chemistry.
Seaton, C. C., Parkin, A., Wilson, C. C. & Blagden, N. (2009). Cryst. Growth Des. 9, 47-56.
Sheldrick, G. M. (2008). Acta Cryst. A64, 112-122.
Smart, P., Mason, C. A., Loader, J. R., Meijer, A. J. H. M., Florence, A. J., Shankland, K., Fletcher, A. J., Thompson, S. P., Brunelli, M., Hill, A. H. & Brammer, L. (2013). Chem. Eur. J. 19, 3552-3557.
Sreekanth, B. R., Vishweshwar, P. & Vyas, K. (2007). Chem. Commun. pp. 2375-2377.
Ternansky, R. J., Valentino, K. L. & Karanewsky, D. S. (1998). Patent WO9801120A1.
Thakur, T. S. & Desiraju, G. R. (2008). Cryst. Growth Des. 8, 4031-4044.
Thakuria, R. & Nangia, A. (2013). Cryst. Growth Des. 13, 3672-3680.
Thuery, P. (2009). Cryst. Growth Des. 9, 4592-4594.
Upadhyay, N., Shukla, T. P., Mathur, A., Manmohana & Jha, S. K. (2011). Int. J. Pharm. Sci. Rev. Res. 8, 144-148.
Vajpayee, V., Lee, S., Kim, S. H., Kang, S. C., Cook, T. R., Kim, H., Kim, D. W., Verma, S., Lah, M. S., Kim, I. S., Wang, M., Stang, P. J. & Chi, K. W. (2013). Dalton Trans. 42, 466-475.
Verma, S., Vajpayee, V., Lee, S. M., Jung, H. J., Kim, H. & Chi, K. (2012). Inorg. Chim. Acta, 387, 435-440.
Vinesha, V., Sevukarajan, M., Rajalakshmi, R., Thulasi, C. G. & Haritha, K. (2013). Int. Res. J. Pharm. 4, 218-223.
Wu, J., Huang, S. & Chiang, M. (2010). CrystEngComm, 12, 3909-3919.
Zakaria, C. M., Ferguson, G., Lough, A. J. & Glidewell, C. (2003). Acta Cryst. B59, 118-131.
Zaworotko, M., Clarke, H., Kapildev, A., Kavuru, P., Shytle, R. D., Pujari, T., Marshall, L. & Ong, T. T. (2008). Patent WO2008153945A2.