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.
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.
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.
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.
Shuting Li; Molly Lightowler; Xiao Ou et al. Communications Chemistry · DOI 10.1038/s42004-022-00804-2
Researchers determined the structures of five vemurafenib polymorphs directly from compact spherulites using 3D electron diffraction. Three matched known single-crystal X-ray structures, while the method resolved a difficult delta form and a newly observed epsilon form. The work expands access to melt-grown polymorphs whose morphology or instability can frustrate conventional single-crystal analysis.
Why it is included: Multi-polymorph API demonstration including difficult and newly discovered forms.
Jieye Lin; Johan Unge; Tamir Gonen Advanced Science · DOI 10.1002/advs.202304476
MicroED analysis of mirabegron nanocrystals revealed two molecular conformers within the asymmetric unit and a hydrogen-bonded packing arrangement. The authors compared these solid-state conformations with a previously reported receptor-bound model and discussed differences. The two conformers are not, by themselves, evidence of two separate polymorphs; the study concerns molecular conformation within the observed crystal structure.
Why it is included: Direct powder-derived API structure with explicit conformational interpretation.
Guanhong Bu; Emma Danelius; Lianne H.E. Wieske; Tamir Gonen Advanced Biology · DOI 10.1002/adbi.202300570
Researchers determined two polymorphic crystal structures of the oral macrocyclic drug paritaprevir within the same MicroED experiment. The forms differed in macrocycle and substituent conformations. Docking suggested that one conformation could fit the viral protease binding pocket. The structural and computational results inform conformational analysis but do not establish a difference in clinical performance between polymorphs.
Why it is included: A direct macrocyclic-drug example connecting polymorphism with molecular conformation, useful for solid-form selection and interpretation of structural models.
Molly Lightowler; Shuting Li; Xiao Ou; Jungyoun Cho; Binbin Liu; Ao Li; Gerhard Hofer; Jiaoyan Xu; Taimin Yang; Xiaodong Zou; Ming Lu; Hongyi Xu Angewandte Chemie International Edition · DOI 10.1002/anie.202317695
An automated low-dose 3D electron diffraction workflow identified six phases in a melt-crystallized griseofulvin–polyethylene glycol system. More than 230 datasets were collected and processed in three days. The researchers resolved known drug polymorphs and inclusion complexes alongside an elusive new inclusion-complex phase, then related the two inclusion-complex polymorphs to their structural stability differences.
Why it is included: A strong pharmaceutical screening case showing how automated crystal-by-crystal analysis can uncover minor phases in complex, beam-sensitive crystallization products.
Hidetomo Yokoo; Yoshitaka Aoyama; Takashi Matsumoto; Eiichi Yamamoto; Nahoko Uchiyama; Yosuke Demizu Chemical and Pharmaceutical Bulletin · DOI 10.1248/cpb.c23-00745
Researchers used MicroED to determine the crystal structures of ranitidine hydrochloride Forms 1 and 2. The resulting structures agreed with previously reported X-ray diffraction structures. The work presents a focused pharmaceutical proof of applicability for small-quantity or microcrystalline API samples, while retaining the need to control crystal form, hydration, and residual solvents through complementary quality assessments.
Why it is included: A straightforward API polymorph comparison that helps readers evaluate MicroED against established X-ray structures rather than relying solely on novel discoveries.
Two previously unreported piroxicam polymorphs, Forms VIII and IX, emerged through polyethylene glycol-assisted melt crystallization. Their crystal structures were determined by 3D electron diffraction. Comparing the newly solved Form VIII with known Form IV allowed discussion of how differences in intermolecular hydrogen bonding contribute to melting behavior. The study concerns laboratory solid forms rather than validated drug-product performance.
Why it is included: Illustrates how polymer-assisted screening and 3D ED can jointly expand a well-studied API’s polymorph landscape and explain thermal-property differences.
Helen W. Leung; Royston C. B. Copley; Giulio I. Lampronti; Sarah J. Day; Lucy K. Saunders; Duncan N. Johnstone; Paul A. Midgley IUCrJ · DOI 10.1107/s2052252524008121
3D electron diffraction resolved the structure of the ninth reported indomethacin polymorph, designated sigma, from crystals found within an amorphous solid dispersion. Subsequent experiments produced the same form by solvent evaporation. The work demonstrates structure determination directly from a formulation-related sample containing an excipient; it does not establish improved dissolution or clinical performance for the new form.
Why it is included: A highly relevant formulation case linking unexpected crystallinity in an ASD with definitive structure determination and a follow-up crystallization route.
Agata Jeziorna; Maura Malinska; Isaac Sugden; Piotr Paluch; Rafał Dolot; Marta K. Dudek IUCrJ · DOI 10.1107/s2052252524011898
Three elusive meloxicam polymorphs required different structure-determination approaches. Single-crystal X-ray diffraction solved Form III, combined crystal structure prediction and NMR crystallography solved Form II, and electron diffraction resolved Form V, which contains four independent molecules in the asymmetric unit. The comparison highlights complementary strengths and limitations rather than establishing one universally superior crystallographic method.
Why it is included: A useful method-selection study for challenging drug polymorphs, illustrating why MicroED, CSP, solid-state NMR, and X-ray diffraction belong in one toolkit.
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.
