MicroED structure determination · Industry updates · Page 2
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MICROED / 3D ELECTRON DIFFRACTION
Pharmaceutical structures and polymorphs: the literature library
Explore significant papers from 2018 onward by year, author, DOI, and application. Historical papers retain their original publication dates.
An integrated workflow combined MicroED with high-resolution mass spectrometry, database searches, solution and solid-state NMR, and computational calculations. Demonstrations used a pyridoxine–N-acetyl-L-cysteine salt and the peptide fMLF. The approach addressed molecular identity, crystal packing, light-atom assignment, and hydrogen positions, illustrating how complementary measurements can resolve ambiguities that electron diffraction alone may leave in nanocrystalline powders.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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