Dissecting the Behavior of a Promiscuous Solvate Former

Angewandte Chemie International EditionVolume 45, Issue 13 p. 2062-2066 Communication Dissecting the Behavior of a Promiscuous Solvate Former† Christopher P. Price, Christopher P. Price Department of Chemistry, University of Michigan, Ann Arbor, MI 48109–1055, USA, Fax: (+1) 734-615-8553Search for more papers by this authorGary D. Glick Prof., Gary D. Glick Prof. Department of Chemistry, University of Michigan, Ann Arbor, MI 48109–1055, USA, Fax: (+1) 734-615-8553Search for more papers by this authorAdam J. Matzger Prof., Adam J. Matzger Prof. [email protected] Department of Chemistry, University of Michigan, Ann Arbor, MI 48109–1055, USA, Fax: (+1) 734-615-8553Search for more papers by this author Christopher P. Price, Christopher P. Price Department of Chemistry, University of Michigan, Ann Arbor, MI 48109–1055, USA, Fax: (+1) 734-615-8553Search for more papers by this authorGary D. Glick Prof., Gary D. Glick Prof. Department of Chemistry, University of Michigan, Ann Arbor, MI 48109–1055, USA, Fax: (+1) 734-615-8553Search for more papers by this authorAdam J. Matzger Prof., Adam J. Matzger Prof. [email protected] Department of Chemistry, University of Michigan, Ann Arbor, MI 48109–1055, USA, Fax: (+1) 734-615-8553Search for more papers by this author First published: 13 March 2006 https://doi.org/10.1002/anie.200503533Citations: 67 † Supported in part by the National Institutes of Health Grant R01 AI47450. We thank GMP|Immunotherapeutics for samples of Bz-423 and Bz-430 and Jeff W. Kampf for the crystal structure determination. Read the full textAboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onEmailFacebookTwitterLinkedInRedditWechat Graphical Abstract Take any partner: Benzodiazepine derivative Bz-423 (see picture) can be described as an indiscriminate solvate former as it cocrystallizes with a diverse array of small molecules. This behavior was investigated by analysis of the packing efficiency of these crystal forms relative to that of unsolvated Bz-423 and an appropriate model compound. Supporting Information Supporting information for this article is available on the WWW under http://www.wiley-vch.de/contents/jc_2002/2006/z503533_s.pdf or from the author. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article. References 1For recent examples of studies that employ crystal engineering of pharmaceutical solvates/cocrystals, see: Google Scholar 1aI. D. H. Oswald, D. R. Allan, P. A. McGregor, W. D. S. Motherwell, S. Parsons, C. R. Pulham, Acta Crystallogr. Sect. B 2002, 58, 1057–1066; 10.1107/S0108768102015987 CASPubMedWeb of Science®Google Scholar 1bR. D. B. Walsh, M. W. Bradner, S. Fleischman, L. A. Morales, B. Moulton, N. Rodríguez-Hornedo, M. J. Zaworotko, Chem. Commun. 2003, 186–187; 10.1039/b208574g CASPubMedWeb of Science®Google Scholar 1cJ. F. Remenar, S. L. Morissette, M. L. 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Biol. 2005, 12, 485–496. 10.1016/j.chembiol.2005.02.012 CASPubMedWeb of Science®Google Scholar 11Crystal data: Google Scholar 11asolvent-free Bz-423; C27H21ClN2O2, colorless plate crystal of dimensions 0.28×0.20×0.04 mm was analyzed at 123(2) K, orthorhombic, space group Pbca (no. 61), a=14.835(3), b=14.999(3), c=19.901(4) Å, V=4528.4(14) Å3, Z=8, ρcalcd=1.323 g cm−3, μ(MoKα)=0.200 mm−1, F(000)=1840, 3789 unique reflections between 2.90°≤2θ≤24.81°, Tmax=0.99, Tmin=0.95, R1=0.0378, Rw=0.0780; Google Scholar 11bBz-430: C29H23ClN2O2 colorless plate crystal of dimensions 0.12×0.04×0.02 mm was analyzed at 123(2) K, monoclinic, space group P21/c (no. 14), a=9.7205(8), b=19.3671(17), c=12.8434(10), β=104.870(3)°, V=2336.9(3) Å3, Z=4, ρcalcd=1.327 g cm−1, μ(MoKα)=0.193 mm−1, F(000)=967, 2554 unique reflections between 3.02°≤2θ≤21.18°, R1=0.0424, Rw=0.0892; Google Scholar 11cBz-423/acetic acid solvate: C27H21ClN2O2⋅C2H4O2, colorless plate crystal of dimensions 0.36×0.24×0.10 mm was analyzed at 123(2) K, monoclinic, space group P21/c (no. 14), a=9.261(2), b=13.649(3), c=19.753(4) Å, β=97.623(4)°, V=2474.9(9) Å3, Z=4, ρcalcd=1.345 g cm−3, μ(MoKα)=0.193 mm−1, F(000)=1048, 4629 unique reflections between 2.97°≤2θ≤25.65°, Tmax=0.98, Tmin=0.93, R1=0.0428, Rw=0.0881; Google Scholar 11dBz-423/acetonitrile solvate: C27H21ClN2O2⋅C2H3N, colorless plate crystal of dimensions 0.25×0.14×0.05 mm was analyzed at 153(2) K, monoclinic, space group P21/c (no. 14), a=9.310(11), b=13.7802(17), c=19.082(2) Å, β=93.634(2)°, V=2443.2(5) Å3, Z=4, ρcalcd=1.310 g cm−3, μ(MoKα)=0.181 mm−1, F(000)=920, 5610 unique reflections between 1.82°≤2θ≤27.51°, Tmax=0.99, Tmin=0.96, R1=0.0352, Rw=0.0976; Google Scholar 11eBz-423/ethanol solvate: C27H21ClN2O2⋅C2H6O, colorless plate crystal of dimensions 0.32×0.18×0.08 mm was analyzed at 153(2) K, orthorhombic, space group Pbca (no. 61), a=14.7352(11), b=15.3206(11), c=22.1937(17) Å, V=5010.3(6) Å3, Z=8, ρcalcd=1.291 g cm−3, μ(MoKα)=0.186 mm−1, F(000)=2048, 5769 unique reflections between 1.84°≤2θ≤27.57°, Tmax=0.98, Tmin=0.96, R1=0.0901, Rw=0.2224; Google Scholar 11fBz-423/ethyl acetate solvate 2C27H21ClN2O2⋅C4H8O2: colorless block crystal of dimensions 0.50×0.26×0.14 mm was analyzed at 123(2) K, monoclinic, space group P21/n (no. 14), a=16.208(2) b=9.2803(12), c=16.937(2) Å, β=110.161(2)°, V=2391.5(5) Å3, Z=4, ρcalcd=1.347 g cm−3, μ(MoKα)=0.195 mm−1, F(000)=1020, 5930 unique reflections between 3.07°≤2θ≤28.30°, Tmax=0.97, Tmin=0.91, R1=0.0350, Rw=0.0933; Google Scholar 11gBz-423/fumaric acid cocrystal: 2C27H21ClN2O2⋅C4H4O4, colorless plate crystal of dimensions 0.30×0.24×0.08 mm was analyzed at 123(2) K, monoclinic, space group P21/c (no. 14), a=9.0653(13), b=13.7215(19), c=18.753(3) Å, β=93.236(3)°, V=2329.0(6) Å3, Z=4, ρcalcd=1.423 g cm−3, μ(MoKα)=0.205 mm−1, F(000)=1040, 5797 unique reflections between 2.86°≤2θ≤28.37°, Tmax=0.98, Tmin=0.94, R1=0.0412, Rw=0.0886; Google Scholar 11hBz-423/2-propanol solvate: C27H21ClN2O2⋅C3H8O, colorless plate crystal of dimensions 0.40×0.36×0.12 mm was analyzed at 123(2) K, orthorhombic, space group Pbca (no. 61), a=14.418(3), b=15.779(3), c=22.625(4) Å, V=5147.3(16) Å3, Z=8, ρcalcd=1.293 g cm−3, μ(MoKα)=0.183 mm−1, F(000)=2112, 4420 unique reflections between 2.11°≤2θ≤24.78°, Tmax=0.98, Tmin=0.93, R1=0.0339, Rw=0.0805; Google Scholar 11iBz-423/succinic acid cocrystal: 2C27H21ClN2O2⋅C4H6O4, colorless plate block of dimensions 0.44×0.22×0.20 mm was analyzed at 123(2) K, monoclinic, space group P21/c (no. 14), a=9.1098(14), b=13.834(2), c=18.715(2) Å, β=92.223(3)°, V=2356.8(6) Å3, Z=4, ρcalcd=1.409 g cm−3, μ(MoKα)=0.203 mm−1, F(000)=1044, 5860 unique reflections between 2.86°≤2θ≤28.40°, Tmax=0.96, Tmin=0.92, R1=0.0335, Rw=0.0882. Intensity data were collected on a Bruker SMART CCD-based X-ray diffractometer (MoKα=0.71073 Å). The structures were solved by direct methods and refined using the SHELXTL (v6.10 for structures (d) and (e) and v6.12 for all others) software package. All non-hydrogen atoms were refined anisotropically with hydrogen atoms generated at idealized positions and constrained to ride on their parent atoms. CCDC-285005–285013 contain the supplementary crystallographic data for this paper. These data can be obtained free of charge from The Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/data_request/cif. Google Scholar 12A. I. Kitaigorodskii, Organic Chemical Crystallography, Consultants Bureau, New York, 1961. Google Scholar 13Packing coefficient is calculated by using the following equation: Ck=Z Vmol Vcell−1, where Vmol is the molecular volume (Å3), Vcell is the volume of the unit cell (Å3), and Z is the number of molecules in the unit cell. Google Scholar 14Molecular volume was calculated with Spartan'04 (Wavefunction Inc.), which employs van der Waals radii in the calculation of molecular volume of 1.75 Å for carbon, 1.78 Å for chlorine, 1.30 Å for fluorine, 1.20 Å for hydrogen, 1.55 Å for nitrogen, 1.52 Å for oxygen, and 1.82 Å for sulfur atoms. For the packing efficiency of the crystal structures of sulfathiazole solvates not found in the CSD (see reference [16]) and for disordered solvate structures, models of sulfathiazole and the various solvent molecules were constructed in Spartan '04 and the equilibrium geometry for each was calculated by using molecular mechanics (MMFF). After geometric minimization, the CH, NH, and OH bonds were normalized to 1.083 Å for CH and 0.983 Å for OH and NH and the molecular volume was calculated. A list of the structures that possess disordered solvent molecules can be found in the Supporting Information. Google Scholar 15Crystal structures of two-component systems containing organic solvent molecules (liquid under ambient conditions) and possessing 3D coordinates were selected from the CSD for each compound. The CH, OH, and NH bonds in each structure were normalized and the molecular volume was calculated (see reference [14]). CSD reference codes for the structures used in the paper: sulfathiazole, SUTHAZ01, SUTHAZ02, SUTHAZ03, SUTHAZ04, SUTHAZ05, BABYIN, BABYOT, and FURDIF; gossypol, AWEXUV, BEMLOU03, BEMLOU12, CUVKEJ20, CUVKUZ20, CUVLAG10, DUBVUR, GOSPOL01, JEGWAT, JIDROD, JIDTIZ10, JIDTOF01, JIDTOF10, JIDVEX10, JIDWEY01, JINFAN, KIVCAT, LOQSEP, RIDNOH, RIDNUN, VAYJUA, VEVMOY, VEVNUF01, VEVRIX, VEVROD, VEVRUJ, VEVSEU, VEVTOF, VEVVUN01, VEVWUO, VEVXAV, VIGVUC, and YEWMUI; Dianin's compound, BEGSUC, DIANCH, DIANET, DIANHP13, HUSXOI, HUSXUO, HUSYAV, HUSYEZ, HUSYID, HUSYOJ, HUSYUP, HUSZAW, HUSZEA, HUSZIE, OBEQUH, PEPTIN, and SIHJEY01; references for these can be found in the Supporting Information. Google Scholar 16For a number of sulfathiazole solvates not found in the CSD, unit-cell constants, and stoichiometry have been reported; see the Supporting Information of reference [6]. 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