4.0 Article

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

Journal

ZEITSCHRIFT FUR KRISTALLOGRAPHIE-CRYSTALLINE MATERIALS
Volume 233, Issue 9-10, Pages 649-661

Publisher

WALTER DE GRUYTER GMBH
DOI: 10.1515/zkri-2018-2058

Keywords

charge density; doxycycline; neutron diffraction; QTAIM analysis; theoretical calculations

Funding

  1. Polish National Science Centre (NCN) [DEC-2012/04/A/ST5/00609]
  2. Wroclaw Centre [115]

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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.

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