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

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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

Author

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. / Investigation of an Unusual Crystal Habit of Hydrochlorothiazide Reveals Large Polar Enantiopure Domains and a Possible Crystal Nucleation Mechanism. In: Angewandte Chemie - International Edition. 2019 ; Vol. 58, No. 30. pp. 10255-10259.

Bibtex

@article{af757675a89440238489689a2fc34751,

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

abstract = "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.",

keywords = "chiral resolution, crystal engineering, crystal growth, enantiomorphs, X-ray diffraction",

author = "Thomas, {Sajesh P.} and Arnaud Grosjean and Flematti, {Gavin R.} and Amir Karton and Sobolev, {Alexandre N.} and Edwards, {Alison J.} and Piltz, {Ross O.} and Iversen, {Bo B.} and Koutsantonis, {George A.} and Spackman, {Mark A.}",

year = "2019",

month = jul,

doi = "10.1002/anie.201905085",

language = "English",

volume = "58",

pages = "10255--10259",

journal = "Angewandte Chemie International Edition",

issn = "1433-7851",

publisher = "Wiley-VCH",

number = "30",

}

RIS

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

C2 - 31136063

AN - SCOPUS:85068168258

VL - 58

SP - 10255

EP - 10259

JO - Angewandte Chemie International Edition

JF - Angewandte Chemie International Edition

SN - 1433-7851

IS - 30

ER -