Small Crystals, Big Insights: How Electron Diffraction is Transforming Materials, Life Science, and Chemistry Research #4. Solving Pharma’s Toughest Solid Form Challenges with Electron Diffraction

In your drug development process, do you ever have to deal with very small amounts of highly imperfect and impure samples, where you are required to determine some structural information related to connectivity, polymorphism, disorder state?

If so, then electron diffraction may be the tool you have been waiting for.

Within the drug development process, especially with more complex molecular entities, there are many stages where the solids requiring characterization might be sub-milligram in weight, be impure and imperfect from a crystalline perspective, and exhibit nanometer sized particles. In many cases, these solids are ideal for Micro Electron Diffraction (MicroED, 3DED).

At the initial crystallization step in late discovery / early development, you may have small amounts of material with a multitude of crystalline polymorphs driven by the impurity profile. These crystals will likely be very small and imperfect. MicroED can provide the only realistic characterization tool for determining connectivity and crystal form. In addition, with automated crystal identification and measurement protocols, polymorph screens can be performed on these very first solids.

After milling or processing to reduce particle size (enhance flow characteristics and solubility) the crystal will again be very small and highly disorder. As disorder as well as size play a significant role in solubility, being able to characterize the level and type of disorder induced by processing can be critical in optimizing scale up and manufacturing. MicroED is able to characterize induced disorder through automated analysis of individual particles.

The application of MicroED to characterize these types of samples will be discussed along with examples of measurements on nanoparticle delivery systems.

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• “High-Throughput Identification of Crystalline Natural Products from Crude Extracts Enabled by Microarray Technology and microED”, Delgadillo et al, ACS Cent. Sci., 2024, 10(1), 176-183 https://doi.org/10.1021/acscentsci.3c01365
  
  
• “Atomic-level structural responsiveness to environmental conditions from 3D electron diffraction”, Ling et al, Nat. Comm., 2022, 13, 6625 https://doi.org/10.1038/s41467-022-34237-1
  
  
• “Making the Most of 3D Electron Diffraction: Best Practices to Handle a New Tool”, Truong et al, Symmetry 2023, 15(8), 1555 https://doi.org/10.3390/sym15081555
  
  
• “The Elusive Structure of Levocetirizine Dihydrochloride Determined by Electron Diffraction”, Karothu et al, Angewandte Chemie Int. Ed. 2023, 62(26), e202303761 https://doi.org/10.1002/anie.202303761
  
  
• “Detection of Hydrogen Atoms Using Only 3D ED/MicroED and Contribution to Structure Determining Salts or Cocrystals”, Keiyo Nakai, Kuniyoshi Miki, Takashi Kikuchi, and Mitsuhisa Yamano, Cryst. Growth Des. 2025, 25(1), 129-135 https://doi.org/10.1021/acs.cgd.4c01421 
  
  
• “Furfural-Derived Diacid Prepared by Photoreaction for Sustainable Materials Synthesis”, Wang et al, ACS Sustainable Chem. Eng. 2018, 6(7), 8136-8141https://doi.org/10.1021/acssuschemeng.8b02415