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.
Toshiyuki Sasaki; Takanori Nakane; Akihiro Kawamoto et al. CrystEngComm · DOI 10.1039/d2ce01522f
MicroED determined a powder-derived cocrystal of 2-aminopyrimidine and succinic acid prepared by solid-state grinding. The mechanically generated phase was not accessible through the solution-crystallization route examined. This is a model organic cocrystal rather than an API efficacy study, illustrating how electron diffraction can characterize crystal-engineering products without first recreating them as large solution-grown crystals.
Why it is included: Demonstrates direct structure analysis of a mechanically accessible organic crystal form.
Paul B. Klar; Yaşar Krysiak; Hongyi Xu; et al. Nature Chemistry · DOI 10.1038/s41557-023-01186-1
The authors incorporated multiple-scattering effects into continuous-rotation 3D electron diffraction refinement. Comparisons across 12 compounds improved structural models, and absolute-structure assignments were evaluated using 58 crystals of nine chiral compounds. The work provides a methodological basis for stereochemical assignment; its benchmark does not establish a universal success rate for pharmaceutical samples.
Why it is included: A key methods paper for pharmaceutical stereochemistry, showing why dynamical refinement should be distinguished from conventional kinematical refinement.
Lygia Silva de Moraes; Jessica E. Burch; David A. Delgadillo; Isabel Hernandez Rodriguez; Huanghao Mai; Austin G. Smith; Seb Caille; Shawn D. Walker; Ryan P. Wurz; Victor J. Cee; Jose A. Rodriguez; Dan Gostovic; Kyle Quasdorf; Hosea M. Nelson Organic Letters · DOI 10.1021/acs.orglett.4c01865
This industry-linked evaluation examined 30 samples from Amgen process and medicinal chemistry groups. Fifteen crystal structures were elucidated using 40 hours of microscope time. For the chiral compounds whose structures were solved, dynamical refinement assigned the correct absolute stereochemistry. The study provides an observed sample-set outcome rather than a universal success rate for pharmaceutical materials.
Why it is included: A practical industrial benchmark for feasibility, instrument time, and absolute-configuration workflows, with an unusually useful denominator for interpreting success claims.
Johan Unge; Brent L. Nannenga; Allen G. Oliver; Tamir Gonen Acta Crystallographica Section C · DOI 10.1107/s2053229625004875
This standards article examines lessons from the growing body of refined MicroED structures and accessible diffraction data. It discusses quality indicators and proposes community best practices for assessing and reporting results. The recommendations provide a framework for critical evaluation rather than regulatory certification or a guarantee that every structure meets the same quality threshold.
Why it is included: Useful for setting vendor deliverables and internal review criteria, including what evidence should accompany a reported pharmaceutical crystal structure.
An integrated workflow combined MicroED with high-resolution mass spectrometry, database searches, solution and solid-state NMR, and computational calculations. Demonstrations used a pyridoxine–N-acetyl-L-cysteine salt and the peptide fMLF. The approach addressed molecular identity, crystal packing, light-atom assignment, and hydrogen positions, illustrating how complementary measurements can resolve ambiguities that electron diffraction alone may leave in nanocrystalline powders.
Why it is included: Provides a realistic multi-technique strategy for salts and unknown powders where a plausible electron-diffraction model still requires chemical and spectroscopic validation.
Adam Thibodeaux; Guanhong Bu; Lael C. Edwards; Emma Rova Danelius IUCrJ · DOI 10.1107/s2052252526002095
An automated molecular-replacement workflow solved the electron-diffraction structure of corilagin, a macrocyclic gallotannin that resisted ab initio phasing. Validation used known paritaprevir and grazoprevir structures across several resolution cutoffs. The results suggest an alternative route for flexible or lower-quality small-molecule datasets, with the important condition that chemically appropriate trial conformations must be available.
Why it is included: An application-enabling method for pharmaceutical macrocycles, useful when direct methods fail but molecular connectivity and credible conformations can guide structure solution.
Niko W. Vlahakis; Krzysztof Konieczny; Cameron W. Flowers; Miguel A. Garcia-Garibay; Jose A. Rodriguez ACS Central Science · DOI 10.1021/acscentsci.6c00603
Liquid cells made from paired carbon grids retained a thin solution layer around microcrystals for room-temperature MicroED. The study obtained atomic structures from solvated organic molecules and pharmaceutical hydrates while using low-dose, rapid, multi-crystal acquisition to limit beam damage. It extends access to hydrated or solvated states, but sample-specific radiation sensitivity and preparation remain important constraints.
Why it is included: Addresses a central pharmaceutical concern: vacuum and drying can alter solvated crystal states, so room-temperature liquid-cell measurements may reveal otherwise inaccessible forms.
Brent L. Nannenga; Tamir Gonen Nature Methods · DOI 10.1038/s41592-019-0395-x
This review explains MicroED and compares its role with other structure-determination methods. It surveys example structures and practical considerations for prospective users, including the progression from specimen preparation to diffraction acquisition and analysis. Its value for pharmaceutical readers is methodological orientation across sample classes, rather than evidence that a specific API screening workflow has been validated.
Why it is included: An accessible methods overview by early MicroED developers, useful for interpreting later pharmaceutical studies.
Mauro Gemmi; Enrico Mugnaioli; Tatiana E. Gorelik; Ute Kolb; Lukas Palatinus; Philippe Boullay; Sven Hovmöller; Jan Pieter Abrahams ACS Central Science · DOI 10.1021/acscentsci.9b00394
This outlook places three-dimensional electron diffraction within the wider development of nanocrystallography. It discusses acquisition and analysis approaches, the treatment of diffraction from very small crystals, and applications spanning organic, inorganic, and biological materials. Pharmaceutical examples help connect the methodological landscape with molecular crystal analysis, while the article remains a synthesis rather than a new API validation study.
Why it is included: Broad methodological outlook connecting major 3D ED acquisition traditions and representative applications.
Emma Danelius; Steve Halaby; Wilfred A. van der Donk; Tamir Gonen Natural Product Reports · DOI 10.1039/d0np00035c
Covering work from 2013 through 2020, this highlight reviews how MicroED expanded from protein crystallography into natural products and small organic molecules. It discusses examples obtained from extremely small crystals and outlines progress in specimen handling, data collection, and structural analysis. The article offers historical context and practical possibilities, not a prospective pharmaceutical success-rate benchmark.
Why it is included: A focused overview of the transition from protein MicroED to natural-product and small-molecule structure elucidation.
Max T. B. Clabbers; Hongyi Xu Drug Discovery Today: Technologies · DOI 10.1016/j.ddtec.2020.12.002
Clabbers and Xu review the properties of electron diffraction and early MicroED developments relevant to pharmaceutical chemistry and structural biology. The discussion spans small-molecule structure determination, fragment screening, and structure-guided discovery. It is a historical perspective on opportunities and limitations, rather than new experimental proof of performance across a pharmaceutical sample collection.
Why it is included: An early pharmaceutical-facing review that helps explain why MicroED complements existing structural methods rather than replacing every crystallographic approach.
Xuelang Mu; Cody Gillman; Chi Nguyen; Tamir Gonen Annual Review of Biochemistry · DOI 10.1146/annurev-biochem-081720-020121
This review introduces the development and scope of MicroED, from small molecules and peptides to proteins and larger complexes. It explains how nanocrystalline samples extend crystallographic opportunities and summarizes the method’s trajectory. Its value for pharmaceutical materials is conceptual orientation; readers should use dedicated API studies to evaluate solid-form identification and industrial performance.
Why it is included: A broad entry point for understanding the technique before moving to pharmaceutical polymorph, formulation, and stereochemistry case studies.
