Crystallography mainly relies on diffraction techniques and the most recent of them, electron diffraction, is gaining increasing attention. Dr Eric Hovestreydt discusses why nanocrystallography using electron radiation to achieve atomic resolution will drive innovation
Knowing the crystal or molecular structure is a crucial step in the development of a compound for pharmaceutical, industrial, or technological applications.
Hodgkin, Laue, Bragg, Pauling; resounding laureates in one of the most ‘Nobel’ and multidisciplinary fields of science: crystallography - the experimental determination of atom arrangements in crystalline solids. For over 100 years, researchers have been working to decipher the atomic structures of molecules and materials and make them available for further processing in the form of drugs, agrochemicals, catalysts, batteries, and any kind of novel materials. Electron diffraction results when electrons interact with crystalline materials. By using electron radiation, it is now possible to investigate nanosized solids with atomic resolution, and this new technique – nanocrystallography - is the analytical breakthrough that will drive innovations in many crucial fields.
Drawing an analogy with other crystallographic techniques, the basic principle of electron diffraction is to irradiate a crystalline sample with a high-energy beam and measure the diffracted patterns. From the position and intensity of the diffraction peaks, the molecular and crystal structure can be derived based on well-known mathematical relations. The use of an electron beam instead of X-rays is now the game changer in crystallography, allowing particles sized tens of nanometres to be characterised with the same accuracy as larger crystals. Knowing the crystal or molecular structure is a crucial step in the development of a compound for pharmaceutical, industrial, or technological applications.
Accelerated drug development
In the pharmaceutical industry, it is critical to know exactly the spatial structure of a chemical compound. For instance, understanding the right three-dimensional arrangement is essential to develop and approve active pharmaceutical ingredients (API). The substances can be examined in detail with the help of X-ray diffraction (the established technology at the present time) only when they are in the form of individual large crystals. However, most compounds come in the form of powders, and growing crystals large enough for X-ray experiments needs weeks, months or even years. This proves to be an expensive process for drug development. For drug discovery alone, a strong acceleration is expected, as many more crystalline compounds could be rapidly screened for their scientific or commercial potential. With electron diffraction, conclusive and complete structural characterisation can be achieved directly from nano-sized batches of nanocrystalline products without the need for time-consuming purification, scale-up or recrystallisation. In this sense, it supports crucial steps like polymorph screening, and allows identification of new solid forms and detection of impurities, while saving time and resources. Any level of detail, ranging from mere phase identification to molecular connectivity, interactions in the solid state and even absolute configuration, becomes accessible by incorporating electron diffraction analysis in the workflow.
Improving structure investigation at the nanoscale would also stir up the status-quo in many other fields of chemical research and industry, among which are agrochemistry, energy conversion and storage or environmental remediation. Many active materials making up catalysts, absorbents, batteries, sensors etc. are effectively polycrystalline or nanostructured, and their structure characterisation can be a bottleneck in new material discovery and optimisation.
Safer batteries and shorter charging times
Carbon dioxide reduction plays an important role within international sustainability goals (i.e.: a 60% reduction in the transport sector by year 2050). At the present time, 30% of the CO2 emissions are coming from the mobility industry. Within the scope of environmental responsibility, zero CO2 emission batteries for electrical vehicles (EVs) are geared towards the ‘green’ energy transition.
For the electrical vehicles industry, Li-ion batteries play a crucial role, however, there are limitations for structural research. Therefore, new materials and new battery systems are needed to improve performance in terms of density, range, power, charging times and safety. In this context, a new class of batteries - solid state batteries (SSB) - have gained increased visibility. Additionally, the search for better cathodic materials, polyelectrolytes, and the understanding of such systems at the molecular level is key in achieving the transition towards zero CO2 emissions.
To more precisely understand and tailor the structure-properties relationship, material scientists and engineers need to visually access the nano-scale. Electron diffraction is crucial for energy storage since it allows scientists to obtain precise and accurate structural information of nano-crystalline particles, while providing enough information to even ‘see’ those light atoms like hydrogen or lithium moving within the frame of the heavier atoms.
Electron diffraction has, until recently, been a specialist procedure carried out on customised transmission electron microscopes and requiring hard- and/or software add-ons. Now, the technique is becoming more well-established. Recently, the first dedicated instrumentation for electron diffraction was unveiled. With this innovation, any lab may soon be able to perform routine crystallographic analysis on samples that have so far been considered prohibitive, including nanocrystalline powders, minute quantities and phase mixtures.
Author: Dr Eric Hovestreydt, CEO, ELDICO Scientific eldico-scientific.com
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 Bruhn, Jessica F. et al: Front. Mol. Biosci., 2021, 354, https://doi.org/10.3389/fmolb.2021.648603
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