MicroED and 3D Electron Diffraction: Pharmaceutical Literature, 2018–2026
Selected MicroED and 3D electron diffraction publications on pharmaceutical crystal structures, polymorphs, salts, cocrystals, solvates, drug products, and absolute configuration.
Selected for pharmaceutical relevance, methodological contribution, industrial evidence, and review value. This is an editorial collection, not a citation-count ranking or an exhaustive bibliography. Foundational 2018 studies are included.
Tim Gruene et al. Angewandte Chemie International Edition · DOI 10.1002/anie.201811318
A prototype electron diffractometer combined a transmission electron microscope with a hybrid pixel detector. Researchers determined a methylene blue derivative and identified the crystal structure of paracetamol within a commercial medicine containing crystalline and noncrystalline components. The work demonstrated chemical crystallography from crystals too small for standard X-ray workflows, while emphasizing the need for appropriate structural validation.
Why it is included: Early instrument-and-application milestone demonstrating an API structure directly from a commercial medicine.
Christopher G. Jones; Michael W. Martynowycz; Johan Hattne; Tyler J. Fulton; Brian M. Stoltz; Jose A. Rodriguez; Hosea M. Nelson; Tamir Gonen ACS Central Science · DOI 10.1021/acscentsci.8b00760
Researchers demonstrated atomic-resolution structure determination of small organic molecules from nanocrystals present in ordinary powders, using minimal specimen preparation. The study included pharmaceutical and natural-product examples and showed that individual compounds could be analyzed from a mixed specimen. It established a practical route around the need to grow crystals large enough for conventional single-crystal X-ray diffraction.
Why it is included: Foundational small-molecule MicroED demonstration directly connecting nanocrystal analysis with pharmaceutical and natural-product structure determination.
Petr Brázda; Lukáš Palatinus; Martin Babor Science · DOI 10.1126/science.aaw2560
A complete structure analysis of a sofosbuvir–L-proline pharmaceutical cocrystal used electron diffraction from a highly beam-sensitive nanocrystal. Collecting data at multiple positions and using improved intensity extraction enabled structure solution. Dynamical diffraction effects then distinguished the absolute structure despite the sample containing light atoms, establishing an important route to stereochemical assignment.
Why it is included: Direct pharmaceutical demonstration of absolute-structure discrimination using dynamical electron diffraction.
Lee Joon Kim; Mengzhao Xue; Xin Li et al. Journal of the American Chemical Society · DOI 10.1021/jacs.1c01729
MicroED analysis of lomaiviticin C prompted revision of its molecular connectivity and stereochemical assignments. High-field NMR and computational analysis supported the revised interpretation, with implications for related lomaiviticins. This is a natural-product structure-elucidation landmark rather than a pharmaceutical-polymorph study, demonstrating the value of complementary methods when complex, sparsely protonated molecules resist confident NMR assignment.
Why it is included: Landmark natural-product structure revision supported by MicroED and orthogonal evidence.
Partha P. Das; Enrico Mugnaioli; Stavros Nicolopoulos; Camilla Tossi; Mauro Gemmi; Athanasios Galanis; Gheorghe Borodi; Mihaela M. Pop Organic Process Research & Development · DOI 10.1021/acs.oprd.8b00149
Researchers determined crystal structures of ramelteon and tolvaptan using three-dimensional precession electron diffraction tomography on approximately 500-nanometer crystals. Structures from subsequently grown, much larger crystals were measured by single-crystal X-ray diffraction for comparison. Agreement in molecular conformation, packing, and unit-cell parameters supported the electron-diffraction workflow for these two pharmaceutical materials.
Why it is included: One of the early direct pharmaceutical benchmarks validating nanocrystal electron diffraction against X-ray crystallography.
Iryna Andrusenko; Victoria Hamilton; Enrico Mugnaioli; Arianna Lanza; Charlie Hall; Jason Potticary; Simon R. Hall; Mauro Gemmi Angewandte Chemie International Edition · DOI 10.1002/anie.201904564
Researchers solved the previously unknown crystal structure of orthocetamol, a pharmaceutical compound that had not yielded single crystals suitable for X-ray diffraction. The approach combined low-dose three-dimensional electron-diffraction acquisition with a single-electron detector. The case illustrates structure determination from challenging small crystals rather than requiring successful growth of larger specimens first.
Why it is included: An application milestone solving an unknown pharmaceutical-related molecular crystal from very small, challenging crystals.
Grahame R. Woollam; Partha P. Das; Enrico Mugnaioli; Iryna Andrusenko; Athanassios S. Galanis; Jacco van de Streek; Stavros Nicolopoulos; Mauro Gemmi; Trixie Wagner CrystEngComm · DOI 10.1039/d0ce01216e
Researchers combined room-temperature, limited-resolution three-dimensional electron diffraction with density-functional energy minimization to determine metastable loratadine Form II. Direct methods were insufficient because of resolution, disorder, and possible beam-induced amorphization. Simulated annealing generated candidate models, and computational validation selected the correct structure, illustrating a complementary experimental and computational workflow for challenging pharmaceutical polymorphs.
Why it is included: Direct metastable API polymorph application showing how computation can complement limited-resolution diffraction data.
Sivakumar Sekharan; Xuetao Liu; Zhuocen Yang et al. RSC Advances · DOI 10.1039/d1ra03100g
This study combined MicroED with crystal structure prediction to support solid-form selection for remdesivir. Experimentally determined structural information was evaluated alongside computational crystal-energy analysis, demonstrating a joint experimental and modeling approach when conventional large-crystal growth is difficult. The work concerns solid-state characterization and selection, not a new assessment of antiviral efficacy or clinical performance.
Why it is included: Direct API case linking MicroED with crystal structure prediction.
Iryna Andrusenko; Victoria Hamilton; Arianna E. Lanza et al. International Journal of Pharmaceutics · DOI 10.1016/j.ijpharm.2021.121067
Researchers solved a previously unresolved indomethacin form by three-dimensional electron diffraction and related its packing to infrared and Raman observations. They measured faster dissolution than the better-characterized alpha and gamma forms and observed a solid-state transition to alpha. This is a solid-form structure–property study; laboratory dissolution results do not by themselves establish improved human bioavailability.
Why it is included: API structure–property case with dissolution and phase-transition measurements.
Molly Lightowler; Shuting Li; Xiao Ou et al. Angewandte Chemie International Edition · DOI 10.1002/anie.202114985
Three-dimensional electron diffraction showed that solution-grown and melt-grown materials previously grouped as delta-indomethacin have different crystal structures. The authors retained delta for the solution-grown form and proposed theta for the melt-grown form. Both displayed plastic bending associated with molecular slip. This case demonstrates how structural measurements can resolve longstanding ambiguity in polymorph identity.
Why it is included: Corrects a decades-old ambiguity in an extensively studied pharmaceutical polymorph system.
Bo Wang; Jessica F. Bruhn; Asmerom Weldeab et al. Chemical Communications · DOI 10.1039/d2cc00221c
The authors determined the absolute configuration of a preclinical API by forming a salt with a chiral reference and analyzing its microcrystalline powder using MicroED. This approach transfers known stereochemical information from the salt former to the API. It addresses situations where large crystals cannot be obtained, but depends on a suitable, well-characterized chiral reference.
Why it is included: Early real-world API absolute-configuration demonstration through chiral salt formation.
Erik Svensson Grape; Victoria Rooth; Mathias Nero et al. Nature Communications · DOI 10.1038/s41467-022-29566-0
Three-dimensional electron diffraction and scanning transmission electron microscopy resolved the layered structure and stacking variations of bismuth subsalicylate, a long-used pharmaceutical ingredient. Clustering compatible diffraction datasets helped obtain the ordered structural model, while imaging exposed disorder. The paper shows why complementary electron-crystallography techniques can be valuable when small crystals and structural defects obstruct conventional characterization.
Why it is included: Resolves longstanding structural uncertainty for a widely used pharmaceutical ingredient.
