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This standards article examines lessons from the growing body of refined MicroED structures and accessible diffraction data. It discusses quality indicators and proposes community best practices for assessing and reporting results. The recommendations provide a framework for critical evaluation rather than regulatory certification or a guarantee that every structure meets the same quality threshold.
DOI: 10.1107/s2053229625004875
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.
DOI: 10.1021/acs.molpharmaceut.5c00028
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.
DOI: 10.1107/s2052252524011898
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.
DOI: 10.1107/s2052252524008121
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.
DOI: 10.1021/acs.cgd.4c00951
This industry-linked evaluation examined 30 samples from Amgen process and medicinal chemistry groups. Fifteen crystal structures were elucidated using 40 hours of microscope time. For the chiral compounds whose structures were solved, dynamical refinement assigned the correct absolute stereochemistry. The study provides an observed sample-set outcome rather than a universal success rate for pharmaceutical materials.
DOI: 10.1021/acs.orglett.4c01865
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.
DOI: 10.1248/cpb.c23-00745
This community overview summarizes developments discussed at a MicroED symposium and workshop. It covers access to instrumentation, small-molecule and biomolecular applications, data collection, processing software, reporting, and validation. For pharmaceutical readers, it helps connect individual experimental demonstrations to the operational requirements of a complete workflow, without presenting an industrial validation study.
DOI: 10.1107/s2053229624004078
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.
DOI: 10.1002/adbi.202300570
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.
DOI: 10.1002/anie.202317695
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.
DOI: 10.1016/j.sbi.2023.102741
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.
DOI: 10.1002/advs.202304476
