Investigation of an Unusual Crystal Habit of Hydrochlorothiazide Reveals Large Polar Enantiopure Domains and a Possible Crystal Nucleation Mechanism

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DOI

  • Sajesh P. Thomas
  • Arnaud Grosjean, University of Western Australia
  • ,
  • Gavin R. Flematti, University of Western Australia
  • ,
  • Amir Karton, University of Western Australia
  • ,
  • Alexandre N. Sobolev, University of Western Australia
  • ,
  • Alison J. Edwards, Australian Nuclear Science and Technology Organisation
  • ,
  • Ross O. Piltz, Australian Nuclear Science and Technology Organisation
  • ,
  • Bo B. Iversen
  • George A. Koutsantonis, University of Western Australia
  • ,
  • Mark A. Spackman, University of Western Australia

The observation of an unusual crystal habit in the common diuretic drug hydrochlorothiazide (HCT), and identification of its subtle conformational chirality, has stimulated a detailed investigation of its crystalline forms. Enantiomeric conformers of HCT resolve into an unusual structure of conjoined enantiomorphic twin crystals comprising enantiopure domains of opposite chirality. The purity of the domains and the chiral molecular conformation are confirmed by spatially revolved synchrotron micro-XRD experiments and neutron diffraction, respectively. Macroscopic inversion twin symmetry observed between the crystal wings suggests a pseudoracemic structure that is not a solid solution or a layered crystal structure, but an unusual structural variant of conglomerates and racemic twins. Computed interaction energies for molecular pairs in the racemic and enantiopure polymorphs of HCT, and the observation of large opposing unit-cell dipole moments for the enantiopure domains in these twin crystals, suggest a plausible crystal nucleation mechanism for this unusual crystal habit.

Original languageEnglish
JournalAngewandte Chemie - International Edition
Volume58
Issue30
Pages (from-to)10255-10259
Number of pages5
ISSN1433-7851
DOIs
Publication statusPublished - Jul 2019

    Research areas

  • chiral resolution, crystal engineering, crystal growth, enantiomorphs, X-ray diffraction

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