Rapid Structure Determination of Microcrystalline Molecular Compounds using Electron Diffraction

Several thousand bioactive molecules are only available as a sub-microcrystalline powder. The availability of sufficiently large, good quality single crystals is a requirement to elucidate the 3-dimensional structures by X-ray diffraction method. Crystals must have a side length of at least 5-10µm when using synchrotron radiation, and about 50 µm when the experiment is performed on laboratory diffraction. However, microcrystalline powders outnumber single crystal compounds by a factor of 3-4. This is true for biomolecules, in particular, those of pharmaceutical interests which may crystallize under different polymorphs ; these lead to different macroscopic properties which may affect many properties. Using electron diffraction instead of X-ray scattering the authors have set up a prototype of an electron diffractometer based on an EIGER detector and a transmission electron microscope. They illustrate the potential of their method, which opens the way to investigate the many unsolved cases in which submicron crystals were the limiting factor.