3D Electron Diffraction / Micro-ED for Structural Characterization of beam sensitive API using Pixelated detectors
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3D-ED, Micro ED, Precession Electron Diffraction, Pharmaceuticals, Pixelated Detectors
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In recent years, the scientific community has shown a renewed interest in use of 3D Electron Diffraction (3D-ED) / Micro-ED for characterization of pharmaceutical compounds. For many API’s (active pharmaceutical ingredient), it is always challenging to grow suitable size crystals for single crystal X-ray diffraction or Powder X-ray Diffraction (PXRD). In those cases, 3D-ED/Micro-ED in Transmission Electron Microscope (TEM) could be a useful alternative for structural studies as crystals as small as 50 nm can be studied.
The principle of acquiring 3D-ED data consists of focusing the electron beam on a nm size crystal in TEM / STEM mode and sampling the reciprocal space in small steps (usually 1 degree tilt or less) using beam precession or using continuous rotation (Micro-ED with or without beam precession) of the crystal . As organic crystals are often very beam sensitive, data collection can be done either at room temperature and/or at cryo-conditions using pixelated detectors at low dose conditions (< 0.01e/Å2/sec) at STEM mode . The acquired 3D-ED data can be processed to determine ab-initio unit cell, space group, atomic positions and Hydrogen atom positions can also be determined.
Recently, we have reported determination of the crystal structure of an industrially important API Linagliptin. The compound has over 30 polymorphs reported in the literature where only 2 have crystal structure data available. We have used 3D-ED techniques to solve ab-initio the structure of a new Linagliptin polymorphic form (commercial reagent) using Pixelated detector (Medipix III, Amsterdam Scientific Instruments, Netherlands). The structure was then further refined using synchrotron PXRD data and optimized using density functional techniques. This structure is one of the largest structures ever solved by 3D-ED data .
Our results show that 3D-ED/Micro-ED techniques in combination with Direct Detection cameras can be used as a powerful tool for phase identification and structural characterization for nm size (50-500 nm) beam sensitive pharmaceutical materials.
 M. Gemmi, E. Mugnaioli, T. E. Gorelik, U. Kolb, L. Palatinus, P. Boullay, S. Hovmöller, J. P. Abrahams. ACS Central Science 2019, 5(8), 1315-1329.
 G. R. Woollam, P. P. Das, E. Mugnaioli, I. Andrusenko, A. Galanis, J-V. Streek, S. Nicolopoulos, M. Gemmi, T. Wagner, CrystEngComm, 2020, 22, 7490-7499.
 P. P. Das, I. Andrusenko, E. Mugnaioli, J. A. Kaduk, S. Nicolopoulos, M. Gemmi, N. C. Boaz, A. M. Gindhart, T. Blanton, Crystal Growth &Design, 2021, accepted.