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.
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.
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.
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.
Alison Haymaker; Brent L. Nannenga Current Opinion in Structural Biology · DOI 10.1016/j.sbi.2023.102741
The review describes MicroED methodology and recent advances across small organic molecules, materials, and biological structures. It explains how diffraction from very small crystals extends the experimental toolkit. Pharmaceutical readers can use it for broader methodological context, while recognizing that its cross-disciplinary examples do not constitute a dedicated benchmark of routine API polymorph screening.
Why it is included: Provides background for readers entering the field and places pharmaceutical applications within the broader development of electron crystallography.
