The polymorphism of crystalline solids, particularly pharmaceuticals, is of great interest since different polymorphs often have distinctly different physical properties. However, it is not always experimentally possible to unambiguously determine the crystal structures of molecular crystals or to determine the presence of polymorphic forms. Crystal structure prediction (CSP) research has developed computational approaches that routinely sample hundreds of thousands of potential crystal structures for a given molecular solid, often ranking them by calculated energies and densities. The candidates are then typically validated as accurate reproductions of experimental structures through comparison of predicted and measured bulk powder X-ray diffraction (PXRD) data. In this work, a CSP methodology based on a broad force-field search of crystal structure space for rapid preliminary ranking, followed by more rigorous solid-state density functional theory (ss-DFT) analyses of the top candidates is demonstrated. Unique to this study is that the results are then verified by comparison to two types of experimental data, PXRD and low-frequency vibrational spectroscopy (both Raman and terahertz). Vibrational spectroscopy in the sub-200 cm-1 region probes the lattice vibrations of the molecular crystals and provides insights into the solid-state packing arrangements within the crystals. Only highly accurate crystal structure predictions can simultaneously reproduce both the observed vibrational spectra and the PXRD patterns. This method is demonstrated using the known trimorphic 2,2-dipyridylamine (DPA, C10H9N3) molecule as a test system with triclinic, monoclinic, and orthorhombic polymorphs each having distinctly identifying lattice vibrations. In this CSP approach, the final applied theory must both locate the minima on the crystal structure potential energy surface and accurately represent the curvature of the surface. Thus, the vibrational spectroscopy comparison not only aids in final structure selections from a vast CSP search, but also serves to verify that the applied ss-DFT functional and basis set choices provide acceptable speed and accuracy.

Testing crystal structure predictions with low-frequency vibrational spectroscopy

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