Salt/cocrystal/continuum: While single crystal X-ray diffraction (SCXRD) is widely used for structure determination of crystalline materials, it is not straightforward to determine the hydrogen positions due to small scattering power of hydrogens. This is problematic especially to distinguish salt and cocrystals, where hydrogen positions play a key role. On the other hand, solid-state NMR (SSNMR) is able to directly observe 1H (proton) with the aid of technical and methodological progress of very fast MAS. The combination of XRD for structural determination and SSNMR for hydrogen observation gives whole structural picture of small organic molecules. We demonstrate this approach to distinguish salt/cocrystals/ continuum in multi-component systems including co-drugs. Crystalline polymorphs: The same molecule can be packed in crystals with different manners. The different molecular packing results in different 1H chemical shift anisotropy (CSA) which gives additional insight of molecular structure with a help of quantum chemical calculations. We also demonstrate parallel and anti-parallel arrangement of beta-sheet can be distinguished by 3D 14N/1H double quantum (DQ)/1H single qunatum (SQ) correlation experiments. Since both 14N and 1H are naturally abundant nuclei, it provides high-throughput measurements (several hours for each samples). We also demonstrate the use of electron diffraction (ED) for crystalline form determination. Since electron interact to materials 4-5 orders stronger than X-ray, sub-micro to nano-meter sized single-crystals can be used for SCED. This allow us to determine the crystalline form from micro-crystalline samples.

NMR, X-ray and electron crystallography for crystalline polymorphs and salt/cocrystal/continuum issues at natural abundance

255th National Meeting (2018)

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