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. 2019 Jan 11;5(1):eaau3338.
doi: 10.1126/sciadv.aau3338. eCollection 2019 Jan.

Reliable and practical computational description of molecular crystal polymorphs

Johannes Hoja  1 , Hsin-Yu Ko  2 , Marcus A Neumann  3 , Roberto Car  2 , Robert A DiStasio Jr  4 , Alexandre Tkatchenko  1
Affiliations

Reliable and practical computational description of molecular crystal polymorphs

Johannes Hoja et al. Sci Adv. .

Abstract

Reliable prediction of the polymorphic energy landscape of a molecular crystal would yield profound insight into drug development in terms of the existence and likelihood of late-appearing polymorphs. However, the computational prediction of molecular crystal polymorphs is highly challenging due to the high dimensionality of conformational and crystallographic space accompanied by the need for relative free energies to within 1 kJ/mol per molecule. In this study, we combine the most successful crystal structure sampling strategy with the most successful first-principles energy ranking strategy of the latest blind test of organic crystal structure prediction methods. Specifically, we present a hierarchical energy ranking approach intended for the refinement of relative stabilities in the final stage of a crystal structure prediction procedure. Such a combined approach provides excellent stability rankings for all studied systems and can be applied to molecular crystals of pharmaceutical importance.

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Figures

Fig. 1
Fig. 1. General overview of a CSP protocol.
Starting with the 2D chemical formula for each molecule, this procedure generates molecular crystal structures and (free) energy rankings for all thermodynamically relevant polymorphs. In this work, we combine the crystal structure sampling strategy provided by the GRACE software package with the highly accurate (free) energy ranking strategy provided by the first principles–based DFT + MBD framework.
Fig. 2
Fig. 2. Obtained polymorphic energy landscapes.
Relative stabilities for all steps in the present CSP stability ranking procedure for systems: (A) XXII, (B) XXIII, (C) XXIV, (D) XXV, and (E) XXVI. For each ranking, the energy of the most stable crystal structure defines the zero of the energy. Experimentally observed structures are highlighted in color, while all other structures are in gray. The final ranking for each system corresponds to the Helmholtz free energies at the PBE0 + MBD + Fvib level, computed at the corresponding experimental temperatures: 150 K for XXII, 240 K for XXIV, and 300 K for XXIII, XXV, and XXVI. All relative energies are reported per chemical unit, i.e., for XXII, XXIII, and XXVI, the energies are normalized per molecule, and for XXIV and XXV, the energies are given per trimer and dimer, respectively. (F) Unit cells for all highlighted structures.
Fig. 3
Fig. 3. Accuracy of structures.
Overlay between the experimentally determined structures (element-specific colors) and the corresponding PBE + TS–optimized structures (green) for systems: (A) XXII, (B) XXIII-A, (C) XXIII-B, (D) XXIII-C, (E) XXIII-D, (F) XXIII-E, (G) XXIV, (H) XXV, and (I) XXVI. These overlays are shown for the molecules constituting the respective unit cell.
Fig. 4
Fig. 4. Stability rankings for thermally expanded structures.
Energetic rankings for all experimentally observed (forms A, B, C, D, and E) and theoretically predicted (N18, N31, N42, and N70) structures for system XXIII. All energies were evaluated using thermally expanded PBE + TS structures optimized at 300 K with the QHA. The last two rankings include harmonic (Fvib) and Morse anharmonic (F~vib) vibrational free energy contributions.
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References

    1. Cruz-Cabeza A. J., Reutzel-Edens S. M., Bernstein J., Facts and fictions about polymorphism. Chem. Soc. Rev. 44, 8619–8635 (2015). - PubMed
    1. Bučar D. K., Lancaster R. W., Bernstein J., Disappearing polymorphs revisited. Angew. Chem. Int. Ed. 54, 6972–6993 (2015). - PMC - PubMed
    1. Price S. L., Predicting crystal structures of organic compounds. Chem. Soc. Rev. 43, 2098–2111 (2014). - PubMed
    1. Reilly A. M., Cooper R. I., Adjiman C. S., Bhattacharya S., Boese A. D., Brandenburg J. G., Bygrave P. J., Bylsma R., Campbell J. E., Car R., Case D. H., Chadha R., Cole J. C., Cosburn K., Cuppen H. M., Curtis F., Day G. M., DiStasio R. A. Jr., Dzyabchenko A., van Eijck B. P., Elking D. M., van den Ende J. A., Facelli J. C., Ferraro M. B., Fusti-Molnar L., Gatsiou C.-A., Gee T. S., de Gelder R., Ghiringhelli L. M., Goto H., Grimme S., Guo R., Hofmann D. W. M., Hoja J., Hylton R. K., Iuzzolino L., Jankiewicz W., de Jong D. T., Kendrick J., de Klerk N. J. J., Ko H.-Y., Kuleshova L. N., Li X., Lohani S., Leusen F. J. J., Lund A. M., Lv J., Ma Y., Marom N., Masunov A. E., McCabe P., McMahon D. P., Meekes H., Metz M. P., Misquitta A. J., Mohamed S., Monserrat B., Needs R. J., Neumann M. A., Nyman J., Obata S., Oberhofer H., Oganov A. R., Orendt A. M., Pagola G. I., Pantelides C. C., Pickard C. J., Podeszwa R., Price L. S., Price S. L., Pulido A., Read M. G., Reuter K., Schneider E., Schober C., Shields G. P., Singh P., Sugden I. J., Szalewicz K., Taylor C. R., Tkatchenko A., Tuckerman M. E., Vacarro F., Vasileiadis M., Vazquez-Mayagoitia A., Vogt L., Wang Y., Watson R. E., de Wijs G. A., Yang J., Zhu Q., Groom C. R., Report on the sixth blind test of organic crystal structure prediction methods. Acta Crystallogr. B Struct. Sci. Cryst. Eng. Mater. 72, 439–459 (2016). - PMC - PubMed
    1. Beran G. J. O., Modeling polymorphic molecular crystals with electronic structure theory. Chem. Rev. 116, 5567–5613 (2016). - PubMed