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Olanzapine crystal symmetry originates in preformed centrosymmetric solute dimers

Abstract

The symmetries of a crystal are notoriously uncorrelated to those of its constituent molecules. This symmetry breaking is typically thought to occur during crystallization. Here we demonstrate that one of the two symmetry elements of olanzapine crystals, an inversion centre, emerges in solute dimers extant in solution prior to crystallization. We combine time-resolved in situ scanning probe microscopy to monitor the crystal growth processes with all-atom molecular dynamics simulations. We show that crystals grow non-classically, predominantly by incorporation of centrosymmetric dimers. The growth rate of crystal layers exhibits a quadratic dependence on the solute concentration, characteristic of the second-order kinetics of the incorporation of dimers, which exist in equilibrium with a majority of monomers. We show that growth by dimers is preferred due to overwhelming accumulation of adsorbed dimers on the crystal surface, where it is complemented by dimerization and expedites dimer incorporation into growth sites.

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Fig. 1: The structure and growth of OZPN crystals.
Fig. 2: Potential mechanisms of observed accelerating step growth.
Fig. 3: Schematic of two alternative growth mechanisms.
Fig. 4: OZPN dimers in solution.
Fig. 5: Why is growth by dimers faster?
Fig. 6: The adsorption of monomers and dimers on the (002) OZPN face.

Data availability

The datasets generated during and/or analysed during the current study and the simulation and analysis codes used for these calculations are available with the manuscript files and/or from the corresponding authors upon reasonable request. Several hundred AFM files were used to determine step displacements and step velocities used in this work. Those needed to illustrate the presented results were output as images; they are included in the main and supplementary figures and are available in electronic format from the data repository of the University of Strathclyde at https://doi.org/10.15129/64d77d7f-d0e2-497e-84e5-3e201a677a75. Additional images are available from the corresponding authors upon reasonable request. Source data are provided with this paper.

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Acknowledgements

We thank M. Doherty, S. Price, E. Vlieg, D. Maes and J. Rimer for invaluable discussions and suggestions. This work was supported by the National Science Foundation (award no. DMR-1710354), NASA (award nos. NNX14AD68G and NNX14AE79G) and The Welch Foundation (Grant E-1882). We acknowledge the CMAC National Facility, housed within the University of Strathclyde’s Technology and Innovation Centre, and funded with a UK Research Partnership Investment Fund (UKRPIF) capital award, SFC ref H13054, from the Higher Education Funding Council for England (HEFCE). Computational resources were provided by the Hewlett Packard Enterprise Data Science Institute and the University of Houston and the Texas Advanced Computing Center at the University of Texas at Austin.

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Contributions

P.G.V., M.W. and A.J.F. conceived this work. P.G.V. and M.W. designed the experiments and M.W. performed all experiments and analysed data. B.F.J. and M.W. modelled the Raman spectra and adsorption on the OZPN crystal surface. P.G.V. developed kinetic and thermodynamic models. L.V. and J.C.P. carried out molecular dynamics simulations. P.G.V., M.W., L.V., J.C.P. and A.J.F. wrote the manuscript. All authors discussed the results and commented on the manuscript.

Corresponding authors

Correspondence to Jeremy C. Palmer, Alastair J. Florence or Peter G. Vekilov.

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Extended data

Extended Data Fig. 1 NMR study of self-association of OZPN molecules in solution.

a, concentration dependent 1H NMR spectra of OZPN in 1/1 (vol/vol) EtOD/D2O with assigned protons at listed concentrations. b, 1H NMR spectra of OZPN in CDCl3 with assigned protons at listed concentrations. Vertical dotted lines highlight shift evolution with increased concentration. c, Normalized changes in chemical shift observed for OZPN protons as a function of concentration in CDCl3 solution. Lines are guides for the eye. d, The C−H···π interactions stabilizing SC0 dimer illustrated using the Mercury software package.

Source data

Extended Data Fig. 2 Raman spectra of OZPN solutions.

a, b, Measured at listed concentrations in CHCl3 and EtOH/H2O. c, d, Simulated spectra of OZPN monomer in c and dimers, in d, in H2O, EtOH, and CHCl3.

Source data

Extended Data Fig. 3 Evaluation of the OZPN dimerization equilibrium constant.

a, In 1/1 (vol/vol) EtOH/H2O. b, In CHCl3. Root mean squared deviation (RMSD) of the intensity of the characteristic dimer Raman peak at 1517 cm−1 ID computed using Equation. 8 from the experimentally measured values at five OZPN concentrations in each solvent. The minima of these correlations indicate the values of KD that best fit the Raman spectra at different concentrations.

Extended Data Fig. 4 Predicted correlations between the step velocity and solute concentration.

Predicted correlations assuming four scenarios summarized in Extended Data Table 2. i. Monomers dominate in the solution and growth occurs by incorporation of monomers. ii. Monomers dominate in solution, but the growth occurs by incorporation of dimers. iii. Dimers dominate in solution but the growth occurs by monomers. iv. Dimers dominate in solution and growth occurs by the incorporation dimers.

Source data

Extended Data Fig. 5 The surface diffusion mechanism operates during growth of OZPN HE crystals.

a, The correlation between the step velocity v and the step separation ℓ at C = 2.38 mM. b, The correlation between v and ℓ in coordinates [σ/ν](1/ ℓ), where σ = (CCe)/Ce. In both plots, regions of depressed v enforced by step supply field overlap at ℓ < 250 nm are highlighted in gray. Error bars represent the standard deviation from the average of five independent measurements and are smaller than the symbol size for some data points.

Extended Data Fig. 6 Adsorption of OZPN monomers and dimers on the (002) face of 2OZPN·EtOH·2H2O crystals in contact with a 1/1 (vol/vol) EtOH H2O solution.

a, Schematic of dimerization in the solution bulk and on the crystal surface. \({\mathrm{\Delta }}H_D^0\) are the respective equilibrium enthalpies of dimerization in the bulk and at the surface and \({\mathrm{\Delta }}H_{ads}^0\), of adsorption of monomers and dimers. b, c, Structuring of the water, in b, and ethanol, in c, molecules at the crystal interface. Only the lattice water molecules are represented with their van der Waals surfaces, where red and white encode for O and H, respectively. In the solution, C atoms are shown in cyan, O and H in red. Hydrogen bonds between water molecules are depicted with dashed green lines in b. dg, OZPN monomers, in d and f, and dimers, in e and g, displace distinct numbers of solvent EtOH and H2O molecules in their various surface conformations. Only two confirmations for each species are shown, a dormant in d and e, and a rampant, in f and g.

Source data

Extended Data Fig. 7 X-ray identification of the crystal form of 2OZPN·EtOH·2H2O.

a, Power x-ray diffraction spectrum. b, Identification of the crystal faces by single-crystal X-ray diffraction.

Extended Data Fig. 8 Lack of interaction between the steps on the surface of OZPN HE during data collection for Fig. 1d and g.

a, The separation between steps ℓ at several OZPN concentrations during the measurements of v. Error bars correspond to standard deviations of about 30 measurements. b, The correlation between the step velocity v and ℓ for ℓ > 300 nm at C = 3.65 mM. Observed step separations during measurements of v were binned in 75 nm wide groups. Error bars correspond to standard deviations of 10 to 15 v data points in each group and are smaller than the symbol size for some data points.

Source data

Supplementary information

Supplementary Information

Supplementary text, references, tables and figures.

Source data

Source Data Fig. 1

CDX file for OZPN structure.

Source Data Fig. 1

Raw data for Fig. 1e–g.

Source Data Fig. 2

Raw data for Fig. 2a.

Source Data Fig. 4

Raw data for Fig. 4a–c.

Source Data Fig. 5

Raw data for Fig. 5d.

Source Data Extended Data Fig. 1

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Source Data Extended Data Fig. 6

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Source Data Extended Data Fig. 7

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Warzecha, M., Verma, L., Johnston, B.F. et al. Olanzapine crystal symmetry originates in preformed centrosymmetric solute dimers. Nat. Chem. 12, 914–920 (2020). https://doi.org/10.1038/s41557-020-0542-0

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