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Doxycycline hydrate and doxycycline hydrochloride dihydrate – crystal structure and charge density analysis

  • Daniel Tchoń , Anna Makal EMAIL logo , Matthias Gutmann and Krzysztof Woźniak EMAIL logo
Published/Copyright: June 12, 2018

Abstract

High-resolution low-temperature X-ray diffraction experiments for doxycycline monohydrate and hydrochloride dihydrate have been performed. Translation-Libration-Screw (TLS) analysis for both crystal forms as well as the data from neutron diffraction experiment for hydrochloride combined with the Hansen-Coppens formalism resulted in precise charge density distribution models for both the zwitterionic monohydrate and a protonated hydrochloride crystal forms. Their detailed topological analysis suggested that the electron structure of doxycycline’s amide moiety undergoes significant changes during protonation due to formation of a very strong resonance-assisted hydrogen bond. A notably increased participation of amide nitrogen atom and hydrogen-accepting oxygen atom in the resonance upon doxycycline protonation was observed. A comparison of TLS- and neutron data-derived hydrogen parameters confirmed the experimental neutron data to be vital for proper description of intra- and inter-molecular interactions in this compound. Finally, calculated lattice and interaction energies quantified repulsive Dox-Dox interactions in the protonated crystal form of the antibiotic, relating with a good solubility of doxycycline hydrochloride relative to its hydrate.


Dedicated to: Prof. Peter Luger on the occasion of his 75-th birthday.


Acknowledgement

D. T., A. M. and K. W. thank the Polish National Science Centre (NCN) for financial support, decision DEC-2012/04/A/ST5/00609, as well as the Wrocɬaw Centre for Networking and Super-computing (WCSS) for resources used to perform the computations under Grant 115.

References

[1] M. O. Griffin, E. Fricovsky, G. Ceballos, F. Villarreal, Tetracyclines: a pleitropic family of compounds with promising therapeutic properties. Review of the literature. Am. J. Physiol. Cell Physiol.2010, 299, C539.10.1152/ajpcell.00047.2010Search in Google Scholar PubMed PubMed Central

[2] D. M. Elston, Tick bites and skin rashes. Curr. Opin. Infect. Dis.2010, 23, 132.10.1097/QCO.0b013e328335b09bSearch in Google Scholar PubMed

[3] R. Mokabberi, A. Haftbaradaran, K. Ravakhah, Doxycycline vs. levofloxacin in the treatment of community-acquired pneumonia. J. Clin. Pharm. Ther.2010, 35, 195.10.1111/j.1365-2710.2009.01073.xSearch in Google Scholar PubMed

[4] B. A. Cunha, New uses for older antibiotics: nitrofurantoin, amikacin, colistin, polymyxin B, doxycycline, and minocycline revisited. Med. Clin. North Am.2006, 90, 1089.10.1016/j.mcna.2006.07.006Search in Google Scholar PubMed

[5] J. J. Stezowski, Chemical-structural properties of tetracycline antibiotics. 4. Ring A tautomerism involving the protonated amide substituent as observed in the crystal structure of α-6-deoxyoxytetracycline hydrohalides. J. Am. Chem. Soc.1977, 99, 1122.10.1021/ja00446a025Search in Google Scholar PubMed

[6] Alexandre O. Legendre, Laila R. R. Silva, Douglas M. Silva, I. M. L. Rosa, L. C. Azarias, P. J. de Abreu, M. B. de Araújo, P. P. Neves, C. Torres, F. T. Martins, A. C. Doriguetto, Solid state chemistry of the antibiotic doxycycline: structure of the neutral monohydrate and insights into its poor water solubility. CrystEngComm.2012, 14, 2532.10.1039/C1CE06181JSearch in Google Scholar

[7] F. W. Heinemann, C. F. Leypold, C. R. Roman, M. O. Schmitt, S. Schneider, X-ray crystallography of tetracycline, doxycycline and sancycline. J. Chem. Crystallogr.2013, 43, 213.10.1007/s10870-013-0407-0Search in Google Scholar

[8] O. M. M. Santos, D. M. Silva, F. T. Martins, A. O. Legendre, L. C. Azarias, I. M. L. Rosa, P. P. Neves, M. B. de Araújo, A. C. Doriguetto, Protonation pattern, tautomerism, conformerism, and physicochemical analysis in new crystal forms of the antibiotic doxycycline. Cryst. Growth Des.2014, 14, 3711.10.1021/cg500877zSearch in Google Scholar

[9] J. Morgan, A. Greenberg, J. F. Liebman, Paradigms and paradoxes: O- and N-protonated amides, stabilization energy, and resonance energy. Struct. Chem.2012, 23, 197.10.1007/s11224-011-9851-7Search in Google Scholar

[10] W. F. Sanjuan-Szklarz, A. A. Hoser, M. Gutmann, A. Ø. Madsen, K. Woźniak, Yes, one can obtain better quality structures from routine X-ray data collection. IUCrJ 2016, 3, 61.10.1107/S2052252515020941Search in Google Scholar PubMed PubMed Central

[11] M. Woińska, D. Jayatilaka, M. A. Spackman, A. J. Edwards, P. M. Dominiak, K. Woźniak, E. Nishibori, K. Sugimoto, S. Grabowsky, Hirshfeld atom refinement for modelling strong hydrogen bonds. Acta Cryst. A2014, 70, 483.10.1107/S2053273314012443Search in Google Scholar PubMed

[12] N. K. Hansen, P. Coppens, Testing aspherical atom refinements on small-molecule data sets. Acta Cryst. A1978, 34, 909.10.1107/S0567739478001886Search in Google Scholar

[13] Agilent Technologies. Agilent Technologies UK Ltd., SuperNova CCD system, CrysAlisPro Software system, version 1.171.37.35, Oxford, UK, 2014.Search in Google Scholar

[14] R. H. Blessing, An empirical correction for absorption anisotropy. Acta Cryst. A1995, 51, 33.10.1107/S0108767394005726Search in Google Scholar PubMed

[15] L. J. Farrugia, WinGX and ORTEP for Windows: an update. J. Appl. Cryst.2012, 45, 849.10.1107/S0021889812029111Search in Google Scholar

[16] L. Krause, R. Herbst-Irmer, D. Stalke, An empirical correction for the influence of low-energy contamination. J. Appl. Cryst.2015, 48, 1907.10.1107/S1600576715020440Search in Google Scholar

[17] D. A. Keen, M. J. Gutmann, C. C. Wilson. SXD – the single-crystal diffractometer at the ISIS spallation neutron source. J. Appl. Cryst.2006, 39, 714.10.1107/S0021889806025921Search in Google Scholar

[18] F. H. Allen, O. Kennard, D. G. Watson, L. Brammer, A. G. Orpen, R. Taylor, Tables of bond lengths determined by X-ray and neutron diffraction. Part 1. Bond lengths in organic compounds. J. Chem. Soc. Perkin Trans.1987, 2, S1.10.1039/p298700000s1Search in Google Scholar

[19] S. Parsons, H. D. Flack, T. Wagner, Use of intensity quotients and differences in absolute structure refinement. Acta Cryst. B2013, 69, 249.10.1107/S2052519213010014Search in Google Scholar PubMed PubMed Central

[20] P. Munshi, A. Ø. Madsen, M. A. Spackman, S. Larsen, R. Destro, Estimated H-atom anisotropic displacement parameters: a comparison between different methods and with neutron diffraction results. Acta Cryst. A2008, 64, 465.10.1107/S010876730801341XSearch in Google Scholar PubMed

[21] G. M. Sheldrick, A short history of SHELX. Acta Cryst. A2008, 64, 112.10.1107/S0108767307043930Search in Google Scholar PubMed

[22] G. M. Sheldrick, Crystal structure refinement with SHELXL. Acta Cryst. C2015, 71, 3.10.1107/S2053229614024218Search in Google Scholar PubMed PubMed Central

[23] O. V. Dolomanov, L. J. Bourhis, R. J. Gildea, J. A. K. Howard, H. Puschmann, OLEX2: a complete structure solution, refinement and analysis program. J. Appl. Cryst.2009, 42, 339.10.1107/S0021889808042726Search in Google Scholar

[24] B. Guillot, L. Viry, R. Guillot, C. Lecomte, C. Jelsch, Refinement of proteins at subatomic resolution with MOPRO. J. Appl. Cryst.2001, 34, 214.10.1107/S0021889801001753Search in Google Scholar

[25] S. Domagała, B. Fournier, D. Liebschner, B. Guillot, C. Jelsch, An improved experimental databank of transferable multipolar atom models – ELMAM2. Construction details and applications. Acta Cryst. A2012, 68, 337.10.1107/S0108767312008197Search in Google Scholar PubMed

[26] A. A. Hoser, K. N. Jarzembska, Ł. Dobrzycki, M. J. Gutmann, K. Woźniak, Differences in charge density distribution and stability of two polymorphs of benzidine dihydrochloride. Cryst. Growth Des.2012, 12, 3526.10.1021/cg300337aSearch in Google Scholar

[27] A. Ø. Madsen, SHADE web server for estimation of hydrogen anisotropic displacement parameters. J. Appl. Cryst.2006, 39, 757.10.1107/S0021889806026379Search in Google Scholar

[28] T. S. Koritsanszky, P. Coppens, Chemical applications of X-ray charge-density analysis. Chem. Rev.2001, 101, 1583.10.1021/cr990112cSearch in Google Scholar PubMed

[29] P. R. Mallinson, T. Koritsanszky, E. Elkaim, N. Li, P. Coppens, The Gram-Charlier and multipole expansions in accurate X-ray diffraction studies: can they be distinguished? Acta Cryst. A1988, 44, 336.10.1107/S0108767387012558Search in Google Scholar PubMed

[30] R. F. W. Bader, Atoms in Molecules: A Quantum Theory. International Series of Monographs on Chemistry. Oxford University Press, Oxford, New York, 1994.Search in Google Scholar

[31] R. Kamiński, S. Domagała, K. N. Jarzembska, A. A. Hoser, W. F. Sanjuan-Szklarz, M. J. Gutmann, A. Makal, M. Malińska, J. M. Bąk, K. Woźniak, Statistical analysis of multipole-model-derived structural parameters and charge-density properties from high-resolution X-ray diffraction experiments. Acta Crystallogr. A Found. Adv.2014, 70, 72.10.1107/S2053273313028313Search in Google Scholar PubMed

[32] C. Gatti, L. Bertini, The local form of the source function as a fingerprint of strong and weak intra- and intermolecular interactions. Acta Crystallogr. A2004, 60, 438.10.1107/S0108767304017258Search in Google Scholar PubMed

[33] A. Volkov, P. Macchi, L. J. Farrugia, C. Gatti, P. Mallinson, T. Richter, T. Koritsanszky, XD-2006. XD-2006: A computer program package for multipole refinement and topological analysis of charge densities and evaluation of intermolecular energies from experimental or theoretical structure factors, Version 5, 2007. Available at: http://www.chem.gla.ac.uk/~louis/xd-home/docs/xd2006manual.pdf.Search in Google Scholar

[34] K. Meindl, J. Henn, Foundations of residual-density analysis. Acta Crystallogr. A2008, 64, 404.10.1107/S0108767308006879Search in Google Scholar

[35] R. Dovesi, V. R. Saunders, C. Roetti, R. Orlando, C. M. Zicovich-Wilson, F. Pascale, B. Civalleri, M. Doll, I. J. Bush, P. D’Arcp, M. Llunell, CRYSTAL09 User’s Manual, University of Torino, Torino, Italy, 2009.Search in Google Scholar

[36] B. Civalleri, C. M. Zicovich-Wilson, L. Valenzano, P. Ugliengo, B3LYP augmented with an empirical dispersion term (B3lyp-D*) as applied to molecular crystals. CrystEngComm.2008, 10, 405.10.1039/B715018KSearch in Google Scholar

[37] R. Prewo, J. J. Stezowski, Chemical-structural properties of tetracycline derivatives. 3. The integrity of the conformation of the nonionized free base. J. Am. Chem. Soc.1977, 99, 1117.10.1021/ja00446a024Search in Google Scholar

[38] C. F. Macrae, I. J. Bruno, J. A. Chisholm, P. R. Edgington, P. McCabe, E. Pidcock, L. Rodriguez-Monge, R. Taylor, J. van de Streek, P. A. Wood, Mercury CSD 2.0-new features for the visualization and investigation of crystal structures. J. Appl. Cryst.2008, 41, 466.10.1107/S0021889807067908Search in Google Scholar

[39] I. J. Bruno, J. C. Cole, M. Kessler, J. Luo, W. D. S. Motherwell, L. H. Purkis, B. R. Smith, R. Taylor, R. I. Cooper, S. E. Harris, A. Guy Orpen, Retrieval of crystallographically-derived molecular geometry information. J. Chem. Inf. Comput. Sci.2004, 44, 2133.10.1021/ci049780bSearch in Google Scholar

[40] W. Beichel, N. Trapp, C. Hauf, O. Kohler, G. Eickerling, W. Scherer, I. Krossing, Charge-scaling effect in ionic liquids from the charge-density analysis of N,N′-dimethylimidazolium methylsulfate. Angew. Chem. Int. Ed.2014, 53, 143.10.1002/anie.201308760Search in Google Scholar

[41] M. Stachowicz, M. Malińska, J. Parafiniuk, K. Woźniak, Experimental observation of charge-shift bond in fluorite CaF2. Acta Crystallogr. Sect. B-Struct. Sci. Cryst. Eng. Mat.2017, 73, 643.10.1107/S2052520617008617Search in Google Scholar

[42] A. Parkin, K. Woźniak, C. C. Wilson, From proton disorder to proton migration: a continuum in the hydrogen bond of a proton sponge in the solid state. Cryst. Growth Des.2007, 7, 1393.10.1021/cg0606848Search in Google Scholar

[43] M. C. Etter, J. C. MacDonald, J. Bernstein, Graph-set analysis of hydrogen-bond patterns in organic crystals. Acta Cryst. B1990, 46, 256.10.1107/S0108768189012929Search in Google Scholar

[44] W. Hummel, J. Hauser, H. B. Bürgi, PEANUT: computer graphics program to represent atomic displacement parameters. J. Mol. Graph1990, 8, 214.10.1016/0263-7855(90)80006-2Search in Google Scholar

[45] A. Aleksandrov, J. Proft, W. Hinrichs, T. Simonson, Protonation patterns in tetracycline:tet repressor recognition: simulations and experiments. ChemBioChem.2007, 8, 675.10.1002/cbic.200600535Search in Google Scholar PubMed

[46] M. A. Spackman, J. J. McKinnon, Fingerprinting intermolecular interactions in molecular crystals. CrystEngComm.2002, 4, 378.10.1039/B203191BSearch in Google Scholar

[47] M. A. Spackman, D. Jayatilaka, Hirshfeld surface analysis. CrystEngComm.2009, 11, 19.10.1039/B818330ASearch in Google Scholar


Supplementary Material

The online version of this article offers supplementary material (https://doi.org/10.1515/zkri-2018-2058).


Received: 2018-02-05
Accepted: 2018-04-30
Published Online: 2018-06-12
Published in Print: 2018-09-25

©2018 Walter de Gruyter GmbH, Berlin/Boston

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