(600e) Olanzapine Crystal Symmetry Originates in Preformed Centrosymmetric Solute Dimers

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 demonstrate that the one of the two symmetry element of olanzapine crystals, an inversion center, emerges in solute dimers extant in the solution prior to crystallization. Time resolved in situ atomic force microscopy monitoring of growth steps reveals 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. Olanzapine dimers constitute a minority solution component. We show that growth by dimers is preferred not owing to greater activation entropy or faster dissociation of attached solvent molecules. The monomer and dimer adsorption energies on the crystal surface, evaluated in all-atom molecular dynamics simulations, suggest overwhelming accumulation of adsorbed dimers, which expedites their 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.