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.
The study examined API crystals directly in Allegra, Clarith, and Ibrance tablets using selected-area 3D ED/MicroED. Fexofenadine hydrochloride Form I and clarithromycin Form II retained their polymorphs, while palbociclib Form A showed slight lattice shrinkage. The results demonstrate formulation-level structural analysis and emphasize that a lattice change and a new polymorph are different findings.
Why it is included: Direct tablet measurements make this a particularly useful reference for formulation development, manufacturing comparisons, and investigating API form changes in finished products.
Hidetomo Yokoo; Tatsuo Koide; Tamaki Miyazaki; Yoshitaka Aoyama; Yutaro Ogaeri; Eiichi Yamamoto; Yosuke Demizu; Nahoko Uchiyama Chemical and Pharmaceutical Bulletin · DOI 10.1248/cpb.c25-00377
This study characterized indomethacin–nicotinamide cocrystals using MicroED together with solid-state NMR, Raman spectroscopy, and powder X-ray diffraction. MicroED supplied the crystal structure, while NMR helped examine molecular interactions. The combined approach addressed properties that individual methods could not establish alone, offering a pharmaceutical cocrystal workflow relevant to API powders and formulations containing excipients.
Why it is included: A concrete cocrystal example showing how electron diffraction and spectroscopic evidence can complement each other in pharmaceutical structural characterization.
3D ED/MicroED determined casopitant mesylate Forms 1 and 3 from one batch of fine powder containing an inseparable polymorphic mixture. Their structures differed through a small packing shift, explaining their very similar powder X-ray diffraction patterns. The work demonstrates how selecting individual microcrystals can resolve structurally similar phases that remain difficult to separate or distinguish in bulk measurements.
Why it is included: A directly relevant pharmaceutical mixture case for polymorph investigations, showing why similar PXRD patterns need not imply identical crystal structures.
Jieye Lin; Orel Paz; Johan Unge; Tamir Gonen ChemMedChem · DOI 10.1002/cmdc.202500601
MicroED identified two polymorphic structures of oxyacanthine dihydrochloride monohydrate in samples mislabeled as berbamine dihydrochloride. The forms differed principally in the conformation of a tetrahydroisoquinoline ring. Structural, energetic, and packing analyses suggested a thermodynamic preference between them. The study demonstrates how crystallographic analysis can expose both identity problems and polymorphism in complex natural-product samples.
Why it is included: A relevant identity-and-polymorph case for natural-product materials, emphasizing that resolving a crystal structure can reveal mislabeled inputs as well as solid-form differences.
Luca Iuzzolino; Andrew W. Kelly; Mohammad T. Chaudhry; Cristian Jandl; Danny Stam; Alfred Y. Lee Communications Chemistry · DOI 10.1038/s42004-025-01814-6
Revisiting ritonavir’s polymorph landscape, the authors examined whether crystal structure prediction could have flagged the risk posed by the less soluble Form 2. They also solved the previously unresolved Form 4 structure using 3D electron diffraction, modeling, and powder X-ray diffraction, finding disorder and thermodynamic instability. The retrospective analysis informs risk assessment rather than guaranteeing future polymorph prediction.
Why it is included: Connects a classic pharmaceutical polymorphism failure with modern structure determination and computational risk assessment, making the technical implications especially accessible.
Jieye Lin; Orel Paz; Johan Unge; Tamir Gonen Small · DOI 10.1002/smll.202511875
Researchers reported MicroED structures for nine chemically diverse natural products whose three-dimensional structures had remained unavailable. The work used microgram quantities and avoided the need to grow large single crystals. It supports MicroED as a practical route for difficult natural-product samples, although the selected examples do not define a universal success rate across all natural products.
Why it is included: Broadens the pharmaceutical-relevant compound range beyond common API standards and offers useful examples for scarce or difficult-to-crystallize natural products.
Saleem Iqbal; Bairong Shen Journal of Applied Crystallography · DOI 10.1107/s1600576726003250
The authors reported a cryo-MicroED structure of cefadroxil, characterizing its molecular geometry, stereochemistry, and intermolecular packing. The crystallographic model also supported complementary molecular-dynamics analysis. This is a structural case study of an established beta-lactam antibiotic; the accompanying computational work should not be interpreted as clinical evidence of a new neurotherapeutic benefit or a general performance guarantee.
Why it is included: A relevant antibiotic structure example, useful for evaluating what MicroED establishes experimentally and what remains an interpretation from downstream computational models.
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.
Helen W. Leung; Royston C. B. Copley; Stephanie Lam; Luca Russo; Simon Fairclough; Duncan N. Johnstone; Paul A. Midgley Molecular Pharmaceutics · DOI 10.1021/acs.molpharmaceut.6c00365
This study applied multidimensional electron diffraction to cabotegravir nanocrystals within a long-acting injectable formulation. 3D electron diffraction confirmed a structure consistent with the known X-ray model, while imaging and diffraction linked particle shape to crystal structure and revealed dislocations. The results describe nanoscale structural features that may guide formulation work; improved product performance was not demonstrated.
Why it is included: A strong finished-formulation example connecting crystal structure, morphology, and defects in an injectable nanocrystal system rather than studying isolated API powder alone.
Delbert S. Botes; Mikaela I. Aleman; Alyssa M. Anderson; Pierre Le Maguerès; Kristin M. Hutchins RSC Advances · DOI 10.1039/d6ra07954g
Electron diffraction established the previously unresolved structure of buspirone hydrochloride Form 2. The study also prepared 15 multicomponent solids, including cocrystals, an ionic cocrystal, and salts, and compared conformations and thermal behavior. This expands structural knowledge of a long-marketed drug and provides a solid-form exploration example without demonstrating improved clinical performance for the newly prepared materials.
Why it is included: Demonstrates that long-established APIs can still have unresolved polymorph structures, and links electron diffraction to a broader multicomponent solid-form development program.
Edward T. Broadhurst; Hongyi Xu; Max T. B. Clabbers; Molly Lightowler; Fabio Nudelman; Xiaodong Zou; Simon Parsons IUCrJ · DOI 10.1107/s2052252519016105
Combining cryogenic specimen preparation with three-dimensional electron diffraction, researchers followed glycine crystallization from water. Different samples captured the sequential appearance of its three ambient-pressure polymorphs, including a short-lived beta form before alpha became dominant. Structures could be obtained from very small crystallites, demonstrating how diffraction can reveal phases missed by slower bulk measurements.
Why it is included: A mechanistic bridge from nanocrystal structure solution to time-resolved polymorph discovery.
Jessica F. Bruhn; Giovanna Scapin; Anchi Cheng et al. Frontiers in Molecular Biosciences · DOI 10.3389/fmolb.2021.648603
Researchers described a pharmaceutical MicroED service workflow after examining more than fifty client-submitted small-molecule samples. Most yielded diffraction data suitable for structure solution, and validation examples included common reference compounds and teniposide. The paper documents preparation, collection, processing, and typical obstacles; its selected service cohort does not establish a universal success rate.
Why it is included: An early multi-sample account of industrial MicroED implementation.
