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
Original languageEnglish
Publication statusPublished - 23 Jun 2019
EventGordon Research Conference on Crystal Growth and Assembly - Southern New Hampshire University in Manchester, Manchester, United States
Duration: 23 Jun 201928 Jun 2019

Conference

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

Keywords

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

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    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.