Communication pubs.acs.org/crystal
A Tale of Two Stoichiometrically Diverse Cocrystals Published as part of the Crystal Growth & Design Margaret C. (Peggy) Etter Memorial virtual special issue Heba Abourahma,*,† Dhaval D. Shah,† Jesus Melendez,† Elizabeth J. Johnson,† and K. Travis Holman‡ †
Department of Chemistry, The College of New Jersey, 2000 Pennington Road, Ewing, New Jersey 08628, United States Department of Chemistry, Georgetown University, 37th and O Street NW, Washington, D.C. 20057, United States
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S Supporting Information *
ABSTRACT: Liquid-assisted grinding of an equimolar amount of pyrazinamide and p-nitrobenzoic acid yields two stoichiometric cocrystals in a 1:1 and 2:1 ratio, respectively. The 2:1 cocrystal was found to be the thermodynamically stable cocrystal based on solid stoichiometric interconversion, solvent-mediated conversion, and solubility studies.
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the supramolecular synthons10 likely to sustain the resulting cocrystal.
echanochemistry1,2 is one of the go-to methods for the synthesis and screening of cocrystals. A technique that goes back to the early 19th Century3 was pioneered in the context of engineering cocrystals by the late Margaret Etter.4−6 She demonstrated through a series of studies that cocrystals can be formed by grinding two components together in the solid state. Since then, synthesis of cocrystals by mechanochemistry has become widely popular. Mechanochemistry is particularly attractive because it can produce cocrystals not readily accessible by solution or melt synthesis. Moreover, it has been shown to afford control over the polymorphic outcome and stoichiometric composition of cocrystals.7,8 The technique produces microcrystalline materials, which are primarily characterized by powder X-ray diffraction (PXRD). A unique PXRD pattern that is different from the starting materials generally indicates the formation of a new product. However, unlike in the case of a single component system where variation in the PXRD pattern of the product can be attributed to polymorphism, in a two-component system stoichiometric variation is an additional possibility that has to be taken into consideration. Differentiating between polymorphs and stoichiometrically diverse cocrystals by PXRD alone is not an easy task, and misinterpreting PXRD data can easily confuse polymorphs and stoichiometric cocrystals. A case in point is presented herein with a pair of pyrazinamide (PZA)·pnitrobenzoic acid (pNBA) cocrystals. The relative thermodynamic stability based on solvent-mediated conversion, solid state stoichiometric interconversion and solubility studies is also discussed. pNBA is a suitable coformer for PZA that was selected to complement our previous study9 on the effect of electronwithdrawing/-donating substituents on cocrystal formation. Figure 1 depicts the molecular structure of PZA and pNBA and © XXXX American Chemical Society
Figure 1. Molecular structures of pyrazinamide (PZA) and pnitrobenzoic acid (pNBA) and the possible supramolecular synthons that could sustain the two in a cocrystal.
Equimolar amounts of PZA and pNBA were reacted by liquid-assisted grinding (LAG) in the presence of various solvents. The resulting microcrystalline product was analyzed by PXRD and differential scanning calorimetry (DSC). PXRD data revealed the formation of a new phase, as indicated by a unique PXRD pattern that is different from either of the starting materials. DSC data showed two endotherms at ca. 171 and 183 °C suggesting that two phases existed. Influenced by Received: March 15, 2015 Revised: May 4, 2015
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DOI: 10.1021/acs.cgd.5b00357 Cryst. Growth Des. XXXX, XXX, XXX−XXX
Crystal Growth & Design
Communication
Figure 2. PZA amide homodimer is retained in the (PZA)2·pNBA cocrystal, while pNBA hydrogen bonds to the pyrazine ring (top left); π stacking interactions sustain the crystal structure in the ab-plane (top right); short CH···O and NH···O contacts (in white) sustain the structure in the bcplane (bottom).
the perceived notion that mechanochemistry provides control over the stoichiometric outcome and in the absence of a crystal structure, we believed that the cocrystal was dimorphic. Single crystals11 suitable for X-ray crystallography were isolated from an acetonitrile (MeCN) solution upon standing for months and revealed that the cocrystal is in fact (PZA)2·pNBA. Figure 2 shows the crystal structure of (PZA)2·pNBA. The asymmetric unit contains two PZA molecules and one pNBA molecule. The carboxylic acid forms a hydrogen bond to the pyrazine ring of PZA, while the amide moiety of PZA hydrogen bonds to the other PZA forming R22(8) homodimer. The C−O bond length for the carboxylic acid of pNBA was significantly different (1.224, 1.328 Å) indicating no proton transfer has occurred and that the cocrystal is neutral and is not a salt. The observed hydrogen bonding pattern is consistent with Etter’s Rules12,13 of hydrogen bonding and Aakeröy’s findings14 where the strongest hydrogen bond donor hydrogen bonds to the strongest hydrogen bond acceptor (acid··· pyrazine), and the second best donor hydrogen bonds to the second best acceptor (amide···amide). Short CH···O and NH··· O contacts ( 2σ(I) (refinement of F2), 291 parameter, 1 restraint, μ = 0.124 mm−1. Data were collected on a Bruker APEXII system equipped with a CCD area-detector using Mo Kα radiation (λ = 0.71073 Å) at T = 100(2) K. Structure solution and refinement were performed with SHELXL.18 N−H and O−H hydrogen atoms were located in difference Fourier maps, and their positions and isotropic thermal parameters were refined; other hydrogen atoms were placed in calculated positions and were refined using a riding model with coordinates and isotropic displacement parameters being dependent upon the atom to which they are attached. All non-hydrogen atoms were refined with anisotropic displacement parameters. Structure visualization and molecular graphics were performed using XSEED.19 (12) Etter, M. C. Acc. Chem. Res. 1990, 23, 120−126. (13) Etter, M. C. J. Phys. Chem. 1991, 95, 4601−4610. (14) Aakeroy, C. B.; Hussain, I.; Forbes, S.; Desper, J. CrystEngComm 2007, 9, 46−54. (15) Karki, S.; Frišcǐ ć, T.; Jones, W. CrystEngComm 2009, 11, 470− 481. (16) Loots, L.; Wahl, H.; van der Westhuizen, L.; Haynes, D. A.; le Roex, T. Chem. Commun. 2012, 11507−11509. (17) Glomme, A.; März, J.; Dressman, J. J. Pharm. Sci. 2005, 1, 1−16. (18) Sheldrick, G. M. Acta Crystallogr., Sect. A 2007, 1, 112−122. (19) Barbour, L. J. J. Supramol. Chem. 2001, 1, 189−191.
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DOI: 10.1021/acs.cgd.5b00357 Cryst. Growth Des. XXXX, XXX, XXX−XXX
