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.
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.
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.
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.
Diptajyoti Gogoi; Toshiyuki Sasaki; Takanori Nakane et al. Crystal Growth & Design · DOI 10.1021/acs.cgd.3c00432
The authors combined liquid-assisted grinding with MicroED to characterize olanzapine molecular salts that had resisted suitable single-crystal growth. The approach also identified minor impurity structures within bulk solids. This pharmaceutical example links mechanochemical preparation to structure determination, while showing that crystallinity alone does not guarantee success with conventional single-crystal X-ray analysis.
Why it is included: Direct pharmaceutical salt and minor-component characterization with mechanochemistry plus MicroED.
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.
