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.
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.
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.
Bo Wang; Yiqing Lin Chemical Communications · DOI 10.1039/d2cc05218k
Researchers analyzed micron-sized powders of SMTP-7 and its diastereomer to resolve stereochemical assignments. Kinematical refinement combined with additional chiral information and dynamical refinement provided complementary routes. The work demonstrates absolute-configuration analysis for complex, hard-to-crystallize drug candidates with limited material, while distinguishing what can be inferred from conventional refinement and what requires dynamical treatment.
Why it is included: Pharmaceutical example testing dynamical refinement on a challenging stereochemical problem.
Harsh S. Shah; Jiuchuang Yuan; Tian Xie et al. Chemistry – A European Journal · DOI 10.1002/chem.202203970
This study combined virtual screening of chiral probes, experimental cocrystal screening, and MicroED structure determination to assign absolute configuration for two marketed API molecules. Known probe stereochemistry anchors the assignment. The workflow offers a route around difficult large-crystal growth while retaining an experimental screening step; computational propensity predictions alone do not establish absolute configuration.
Why it is included: Integrated prediction-and-cocrystal workflow demonstrated on marketed API molecules.
Durga Prasad Karothu; Zainab Alhaddad; Christian R. Göb et al. Angewandte Chemie International Edition · DOI 10.1002/anie.202303761
The crystal structure of levocetirizine dihydrochloride was determined by 3D ED/MicroED from crystalline powder extracted from commercially available tablets. Dynamical refinement also supported its absolute configuration. The study provides an example of identifying and characterizing an API within a microcrystalline mixture, without requiring the growth of large single crystals or implying that every formulated product is equally accessible.
Why it is included: Solves a long-used API directly from tablet-derived crystalline material.
Jae Ho Shim; Pooreum Lim; Sangwoo Woo; Jihye Han; Hyeon Soo Kim Journal of Medicinal Chemistry · DOI 10.1021/acs.jmedchem.6c02422
A medicinal-chemistry study developed a chiral quinazoline-based Nav1.7 inhibitor and used MicroED to confirm the lead compound’s absolute configuration. The report combined structure–activity studies with pharmacokinetic and pain-model experiments in rodents. Its pharmaceutical relevance is the stereochemical assignment within a drug-discovery program; the animal findings do not establish analgesic efficacy or safety in patients.
Why it is included: Shows MicroED contributing a specific stereochemical decision in medicinal chemistry, while keeping that structural evidence separate from preclinical pharmacology and clinical claims.
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.
