Olanzapine Crystal Symmetry Originates in Preformed Centrosymmetric Solute Dimers

Monika Warzecha, Lakshmanji Verma, Jeremy Palmer, Alastair Florence, Peter G. Vekilov

Research output: Contribution to conferencePoster

Abstract

The symmetry of crystals is a central quality that determines their function and allure. Given the uncorrelated symmetries of a crystal and its constituent molecules, the symmetry breaking that begets a crystal phase has been thought to ensue during nucleation. Here we combine time-resolved in situ scanning probe microscopy to monitor the crystal growth processes with all-atom molecular dynamics simulations and demonstrate that the one of the two symmetry elements of olanzapine crystals, an inversion center, emerges in solute dimers extant in solution prior to crystallization. We show that crystals grow nonclassically, exclusively by incorporation of dimers. This growth mode has been speculated and inferred from crystal and solute structures, but never experimentally observed. The growth rate of crystal layers exhibits a quadratic dependence on the solute concentration, characteristic of the second-order kinetics of dimer incorporation. The olanzapine dimers constitute a minority solution component. We show that growth by dimers is preferred not owing to their greater activation entropy or faster dissociation of attached solvent molecules. The enthalpies of monomer and dimer adsorption on the crystal surface suggest overwhelming accumulation of adsorbed dimers and additional dimerization at the surface, which expedites dimer incorporation into growth sites. The proposed outlook on the cooperative creation of crystal symmetry illuminates analyses of structure selection, polymorph transformations, chiral separation, and crystal properties of natural and engineered crystals

Conference

ConferenceGordon Research Conference on Crystal Growth and Assembly
CountryUnited States
CityManchester
Period23/06/1928/06/19

Fingerprint

solutes
dimers
symmetry
crystals
minorities
dimerization
crystal surfaces
crystal growth
molecules
broken symmetry
monomers
enthalpy
nucleation
activation
dissociation
crystallization
entropy
inversions
molecular dynamics
microscopy

Keywords

  • crystallisation
  • crystal growth
  • olanzapine
  • olanzapine solvates
  • atomic force microscopy
  • symmetry-breaking
  • dimers

Cite this

Warzecha, M., Verma, L., Palmer, J., Florence, A., & Vekilov, P. G. (2019). Olanzapine Crystal Symmetry Originates in Preformed Centrosymmetric Solute Dimers. Poster session presented at Gordon Research Conference on Crystal Growth and Assembly , Manchester, United States.
Warzecha, Monika ; Verma, Lakshmanji ; Palmer, Jeremy ; Florence, Alastair ; Vekilov, Peter G. . / Olanzapine Crystal Symmetry Originates in Preformed Centrosymmetric Solute Dimers. Poster session presented at Gordon Research Conference on Crystal Growth and Assembly , Manchester, United States.
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abstract = "The symmetry of crystals is a central quality that determines their function and allure. Given the uncorrelated symmetries of a crystal and its constituent molecules, the symmetry breaking that begets a crystal phase has been thought to ensue during nucleation. Here we combine time-resolved in situ scanning probe microscopy to monitor the crystal growth processes with all-atom molecular dynamics simulations and demonstrate that the one of the two symmetry elements of olanzapine crystals, an inversion center, emerges in solute dimers extant in solution prior to crystallization. We show that crystals grow nonclassically, exclusively by incorporation of dimers. This growth mode has been speculated and inferred from crystal and solute structures, but never experimentally observed. The growth rate of crystal layers exhibits a quadratic dependence on the solute concentration, characteristic of the second-order kinetics of dimer incorporation. The olanzapine dimers constitute a minority solution component. We show that growth by dimers is preferred not owing to their greater activation entropy or faster dissociation of attached solvent molecules. The enthalpies of monomer and dimer adsorption on the crystal surface suggest overwhelming accumulation of adsorbed dimers and additional dimerization at the surface, which expedites dimer incorporation into growth sites. The proposed outlook on the cooperative creation of crystal symmetry illuminates analyses of structure selection, polymorph transformations, chiral separation, and crystal properties of natural and engineered crystals",
keywords = "crystallisation, crystal growth, olanzapine, olanzapine solvates, atomic force microscopy, symmetry-breaking, dimers",
author = "Monika Warzecha and Lakshmanji Verma and Jeremy Palmer and Alastair Florence and Vekilov, {Peter G.}",
year = "2019",
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note = "Gordon Research Conference on Crystal Growth and Assembly ; Conference date: 23-06-2019 Through 28-06-2019",

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Warzecha, M, Verma, L, Palmer, J, Florence, A & Vekilov, PG 2019, 'Olanzapine Crystal Symmetry Originates in Preformed Centrosymmetric Solute Dimers' Gordon Research Conference on Crystal Growth and Assembly , Manchester, United States, 23/06/19 - 28/06/19, .

Olanzapine Crystal Symmetry Originates in Preformed Centrosymmetric Solute Dimers. / Warzecha, Monika; Verma, Lakshmanji ; Palmer, Jeremy ; Florence, Alastair; Vekilov, Peter G. .

2019. Poster session presented at Gordon Research Conference on Crystal Growth and Assembly , Manchester, United States.

Research output: Contribution to conferencePoster

TY - CONF

T1 - Olanzapine Crystal Symmetry Originates in Preformed Centrosymmetric Solute Dimers

AU - Warzecha, Monika

AU - Verma, Lakshmanji

AU - Palmer, Jeremy

AU - Florence, Alastair

AU - Vekilov, Peter G.

PY - 2019/6/23

Y1 - 2019/6/23

N2 - The symmetry of crystals is a central quality that determines their function and allure. Given the uncorrelated symmetries of a crystal and its constituent molecules, the symmetry breaking that begets a crystal phase has been thought to ensue during nucleation. Here we combine time-resolved in situ scanning probe microscopy to monitor the crystal growth processes with all-atom molecular dynamics simulations and demonstrate that the one of the two symmetry elements of olanzapine crystals, an inversion center, emerges in solute dimers extant in solution prior to crystallization. We show that crystals grow nonclassically, exclusively by incorporation of dimers. This growth mode has been speculated and inferred from crystal and solute structures, but never experimentally observed. The growth rate of crystal layers exhibits a quadratic dependence on the solute concentration, characteristic of the second-order kinetics of dimer incorporation. The olanzapine dimers constitute a minority solution component. We show that growth by dimers is preferred not owing to their greater activation entropy or faster dissociation of attached solvent molecules. The enthalpies of monomer and dimer adsorption on the crystal surface suggest overwhelming accumulation of adsorbed dimers and additional dimerization at the surface, which expedites dimer incorporation into growth sites. The proposed outlook on the cooperative creation of crystal symmetry illuminates analyses of structure selection, polymorph transformations, chiral separation, and crystal properties of natural and engineered crystals

AB - The symmetry of crystals is a central quality that determines their function and allure. Given the uncorrelated symmetries of a crystal and its constituent molecules, the symmetry breaking that begets a crystal phase has been thought to ensue during nucleation. Here we combine time-resolved in situ scanning probe microscopy to monitor the crystal growth processes with all-atom molecular dynamics simulations and demonstrate that the one of the two symmetry elements of olanzapine crystals, an inversion center, emerges in solute dimers extant in solution prior to crystallization. We show that crystals grow nonclassically, exclusively by incorporation of dimers. This growth mode has been speculated and inferred from crystal and solute structures, but never experimentally observed. The growth rate of crystal layers exhibits a quadratic dependence on the solute concentration, characteristic of the second-order kinetics of dimer incorporation. The olanzapine dimers constitute a minority solution component. We show that growth by dimers is preferred not owing to their greater activation entropy or faster dissociation of attached solvent molecules. The enthalpies of monomer and dimer adsorption on the crystal surface suggest overwhelming accumulation of adsorbed dimers and additional dimerization at the surface, which expedites dimer incorporation into growth sites. The proposed outlook on the cooperative creation of crystal symmetry illuminates analyses of structure selection, polymorph transformations, chiral separation, and crystal properties of natural and engineered crystals

KW - crystallisation

KW - crystal growth

KW - olanzapine

KW - olanzapine solvates

KW - atomic force microscopy

KW - symmetry-breaking

KW - dimers

M3 - Poster

ER -

Warzecha M, Verma L, Palmer J, Florence A, Vekilov PG. Olanzapine Crystal Symmetry Originates in Preformed Centrosymmetric Solute Dimers. 2019. Poster session presented at Gordon Research Conference on Crystal Growth and Assembly , Manchester, United States.