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Investigation of an Unusual Crystal Habit of Hydrochlorothiazide Reveals Large Polar Enantiopure Domains and a Possible Crystal Nucleation Mechanism
Author(s) -
Thomas Sajesh P.,
Grosjean Arnaud,
Flematti Gavin R.,
Karton Amir,
Sobolev Alexandre N.,
Edwards Alison J.,
Piltz Ross O.,
Iversen Bo B.,
Koutsantonis George A.,
Spackman Mark A.
Publication year - 2019
Publication title -
angewandte chemie
Language(s) - English
Resource type - Journals
eISSN - 1521-3757
pISSN - 0044-8249
DOI - 10.1002/ange.201905085
Subject(s) - enantiopure drug , crystal habit , chirality (physics) , crystallography , chemistry , crystal structure , nucleation , enantiomer , crystal (programming language) , materials science , crystallization , stereochemistry , chiral symmetry breaking , enantioselective synthesis , physics , organic chemistry , symmetry breaking , catalysis , programming language , quantum mechanics , computer science , nambu–jona lasinio model
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.