Researchers have integrated whole structure analysis by electron diffraction and local structure analysis by solid-state NMR to observe microcrystals of 0.1–1 μm
Selected ED patterns of the L-histidine microcrystal during continuous rotation. The number of each frame represents a starting rotation angle of each ED patterns. The diffraction patterns were obtained every 1.18°
Researchers at the RIKEN-JEOL Collaboration Center and the Kyoto University iCeMS (Material-Cell Integrated System Center) have developed a nuclear magnetic resonance (NMR) crystallography method for observing crystal structure in detail, including the position of hydrogen atoms.
Single crystal X-ray diffraction (SCXRD) analysis of low-molecular-weight active pharmaceutical ingredient (API) crystal structures requires a single crystal of 10 μm or more, making microcrystal analysis challenging. The collaborative research group has integrated whole structure analysis by electron diffraction (ED) and local structure analysis by solid-state NMR (SSNMR), utilising first-principles quantum chemical calculations, to observe microcrystals of 0.1 to 1 μm.
With this method, it was also possible to analyse substances in mixtures, which are often found in general preparations and usually pose a challenge for XRD techniques.
Dr Michael Frey, Analytical Instruments Product Manager at JEOL USA, said: “Using this new electron and NMR crystallography technique, we could confirm the structure of the model system L-histidine, and succeeded in the structural analysis of the drug cimetidine (crystal form B), whose structure was previously unknown. The advanced capabilities of the JEOL JNM-ECZ600R spectrometer and 3.2 mm double-resonance magic angle spinning (MAS) Probe for SSNMR measurements, and the JEM-2200FS transmission electron microscope for ED measurements, have helped further our understanding of the hydrogen-bonding network in these microcrystals.”
The results of this research have demonstrated the importance of accurately determining both the structure and the hydrogen positions in microcrystals, and are expected to contribute to the quality improvement of small molecule drugs to treat conditions such as lifestyle-related diseases and hay fever.
These methods may contribute to future quality assurance of pharmaceuticals, and lead to the discovery of more unknown crystal forms.
The collaboration centre, established jointly by RIKEN and JEOL, opened in November 2014 with the aim of creating unique technologies in the field of analytical and diagnostic instruments. You can view the full results of this research in Nature Communications.