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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.
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.
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.
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.
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.
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.
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.
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.
The authors incorporated multiple-scattering effects into continuous-rotation 3D electron diffraction refinement. Comparisons across 12 compounds improved structural models, and absolute-structure assignments were evaluated using 58 crystals of nine chiral compounds. The work provides a methodological basis for stereochemical assignment; its benchmark does not establish a universal success rate for pharmaceutical samples.
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.
This review connects advances in MicroED with examples spanning small molecules, peptides, and protein structures relevant to drug discovery. It explains how nanocrystalline material changes the range of accessible structural problems and surveys representative applications. The article is a guide to the evolving evidence base, rather than a new validation study or a general claim of routine success for every pharmaceutical sample.
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.
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.
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