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MicroED structure determination 52

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Original research
Crystal Growth & Design

Structure Elucidation of Olanzapine Molecular Salts by Combining Mechanochemistry and Micro-Electron Diffraction

Diptajyoti Gogoi; Toshiyuki Sasaki; Takanori Nakane et al.

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.

MicroED structure determinationPharmaceutical solid state
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DOI: 10.1021/acs.cgd.3c00432

Methods
Nature Chemistry

Accurate structure models and absolute configuration determination using dynamical effects in continuous-rotation 3D electron diffraction data

Paul B. Klar; Yaşar Krysiak; Hongyi Xu; et al.

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.

MicroED structure determination
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DOI: 10.1038/s41557-023-01186-1

Original research
Angewandte Chemie International Edition

The Elusive Structure of Levocetirizine Dihydrochloride Determined by Electron Diffraction

Durga Prasad Karothu; Zainab Alhaddad; Christian R. Göb et al.

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.

MicroED structure determinationPharmaceutical solid state
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DOI: 10.1002/anie.202303761

Reviews & perspectives
Current Opinion in Structural Biology

MicroED in drug discovery

Emma Danelius; Khushboo Patel; Brenda Gonzalez et al.

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.

MicroED structure determination
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DOI: 10.1016/j.sbi.2023.102549

Original research
Chemistry – A European Journal

Absolute Configuration Determination of Chiral API Molecules by MicroED Analysis of Cocrystal Powders Formed Based on Cocrystal Propensity Prediction Calculations

Harsh S. Shah; Jiuchuang Yuan; Tian Xie et al.

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.

MicroED structure determinationPharmaceutical solid state
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DOI: 10.1002/chem.202203970

Original research
Communications Chemistry

Direct structure determination of vemurafenib polymorphism from compact spherulites using 3D electron diffraction

Shuting Li; Molly Lightowler; Xiao Ou et al.

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.

MicroED structure determinationPharmaceutical solid state
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DOI: 10.1038/s42004-022-00804-2

Methods
CrystEngComm

Microcrystal electron diffraction (MicroED) structure determination of a mechanochemically synthesized co-crystal not affordable from solution crystallization

Toshiyuki Sasaki; Takanori Nakane; Akihiro Kawamoto et al.

MicroED determined a powder-derived cocrystal of 2-aminopyrimidine and succinic acid prepared by solid-state grinding. The mechanically generated phase was not accessible through the solution-crystallization route examined. This is a model organic cocrystal rather than an API efficacy study, illustrating how electron diffraction can characterize crystal-engineering products without first recreating them as large solution-grown crystals.

MicroED structure determinationPharmaceutical solid state
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DOI: 10.1039/d2ce01522f

Original research
Chemical Communications

Absolute configuration determination of SMTP-7 via microcrystal electron diffraction (MicroED)

Bo Wang; Yiqing Lin

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.

MicroED structure determinationPharmaceutical solid state
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DOI: 10.1039/d2cc05218k

Reviews & perspectives
WIREs Nanomedicine and Nanobiotechnology

3D electron diffraction for structure determination of small‐molecule nanocrystals: A possible breakthrough for the pharmaceutical industry

Iryna Andrusenko; Mauro Gemmi

This review examines three-dimensional electron diffraction for beam-sensitive small-molecule nanocrystals, with a pharmaceutical-industry perspective. It discusses experimental strategies, diffraction completeness, dynamical scattering, and structural applications that extend beyond conventional large-crystal requirements. It provides a methods-oriented framework for interpreting published demonstrations; it does not establish a universal preparation method or replace sample-specific feasibility assessment.

MicroED structure determinationPharmaceutical solid state
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DOI: 10.1002/wnan.1810

Original research
Nature Communications

Structure of the active pharmaceutical ingredient bismuth subsalicylate

Erik Svensson Grape; Victoria Rooth; Mathias Nero et al.

Three-dimensional electron diffraction and scanning transmission electron microscopy resolved the layered structure and stacking variations of bismuth subsalicylate, a long-used pharmaceutical ingredient. Clustering compatible diffraction datasets helped obtain the ordered structural model, while imaging exposed disorder. The paper shows why complementary electron-crystallography techniques can be valuable when small crystals and structural defects obstruct conventional characterization.

MicroED structure determinationPharmaceutical solid state
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DOI: 10.1038/s41467-022-29566-0

Original research
Chemical Communications

Absolute configuration determination of pharmaceutical crystalline powders by MicroED via chiral salt formation

Bo Wang; Jessica F. Bruhn; Asmerom Weldeab et al.

The authors determined the absolute configuration of a preclinical API by forming a salt with a chiral reference and analyzing its microcrystalline powder using MicroED. This approach transfers known stereochemical information from the salt former to the API. It addresses situations where large crystals cannot be obtained, but depends on a suitable, well-characterized chiral reference.

MicroED structure determinationPharmaceutical solid state
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DOI: 10.1039/d2cc00221c

Original research
Angewandte Chemie International Edition

Indomethacin Polymorph δ Revealed To Be Two Plastically Bendable Crystal Forms by 3D Electron Diffraction: Correcting a 47‐Year‐Old Misunderstanding

Molly Lightowler; Shuting Li; Xiao Ou et al.

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.

MicroED structure determinationPharmaceutical solid state
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DOI: 10.1002/anie.202114985

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