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Investigation of an Unusual Crystal Habit of Hydrochlorothiazide Reveals Large Polar Enantiopure Domains and a Possible Crystal Nucleation Mechanism. / 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.
In: Angewandte Chemie - International Edition, Vol. 58, No. 30, 07.2019, p. 10255-10259.Research output: Contribution to journal/Conference contribution in journal/Contribution to newspaper › Journal article › Research › peer-review
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TY - JOUR
T1 - Investigation of an Unusual Crystal Habit of Hydrochlorothiazide Reveals Large Polar Enantiopure Domains and a Possible Crystal Nucleation Mechanism
AU - Thomas, Sajesh P.
AU - Grosjean, Arnaud
AU - Flematti, Gavin R.
AU - Karton, Amir
AU - Sobolev, Alexandre N.
AU - Edwards, Alison J.
AU - Piltz, Ross O.
AU - Iversen, Bo B.
AU - Koutsantonis, George A.
AU - Spackman, Mark A.
PY - 2019/7
Y1 - 2019/7
N2 - 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.
AB - 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.
KW - chiral resolution
KW - crystal engineering
KW - crystal growth
KW - enantiomorphs
KW - X-ray diffraction
UR - http://www.scopus.com/inward/record.url?scp=85068168258&partnerID=8YFLogxK
U2 - 10.1002/anie.201905085
DO - 10.1002/anie.201905085
M3 - Journal article
VL - 58
SP - 10255
EP - 10259
JO - Angewandte Chemie International Edition
JF - Angewandte Chemie International Edition
SN - 1433-7851
IS - 30
ER -