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Pharmaceutical solid state 36

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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

Original research
International Journal of Pharmaceutics

Structure determination, thermal stability and dissolution rate of δ-indomethacin

Iryna Andrusenko; Victoria Hamilton; Arianna E. Lanza et al.

Researchers solved a previously unresolved indomethacin form by three-dimensional electron diffraction and related its packing to infrared and Raman observations. They measured faster dissolution than the better-characterized alpha and gamma forms and observed a solid-state transition to alpha. This is a solid-form structure–property study; laboratory dissolution results do not by themselves establish improved human bioavailability.

MicroED structure determinationPharmaceutical solid state
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DOI: 10.1016/j.ijpharm.2021.121067

Methods
Frontiers in Molecular Biosciences

Small Molecule Microcrystal Electron Diffraction for the Pharmaceutical Industry–Lessons Learned From Examining Over Fifty Samples

Jessica F. Bruhn; Giovanna Scapin; Anchi Cheng et al.

Researchers described a pharmaceutical MicroED service workflow after examining more than fifty client-submitted small-molecule samples. Most yielded diffraction data suitable for structure solution, and validation examples included common reference compounds and teniposide. The paper documents preparation, collection, processing, and typical obstacles; its selected service cohort does not establish a universal success rate.

MicroED structure determinationPharmaceutical solid state
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DOI: 10.3389/fmolb.2021.648603

Original research
RSC Advances

Selecting a stable solid form of remdesivir using microcrystal electron diffraction and crystal structure prediction

Sivakumar Sekharan; Xuetao Liu; Zhuocen Yang et al.

This study combined MicroED with crystal structure prediction to support solid-form selection for remdesivir. Experimentally determined structural information was evaluated alongside computational crystal-energy analysis, demonstrating a joint experimental and modeling approach when conventional large-crystal growth is difficult. The work concerns solid-state characterization and selection, not a new assessment of antiviral efficacy or clinical performance.

MicroED structure determinationPharmaceutical solid state
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DOI: 10.1039/d1ra03100g

Original research
CrystEngComm

Structural analysis of metastable pharmaceutical loratadine form II, by 3D electron diffraction and DFT+D energy minimisation

Grahame R. Woollam; Partha P. Das; Enrico Mugnaioli; Iryna Andrusenko; Athanassios S. Galanis; Jacco van de Streek; Stavros Nicolopoulos; Mauro Gemmi; Trixie Wagner

Researchers combined room-temperature, limited-resolution three-dimensional electron diffraction with density-functional energy minimization to determine metastable loratadine Form II. Direct methods were insufficient because of resolution, disorder, and possible beam-induced amorphization. Simulated annealing generated candidate models, and computational validation selected the correct structure, illustrating a complementary experimental and computational workflow for challenging pharmaceutical polymorphs.

MicroED structure determinationPharmaceutical solid state
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DOI: 10.1039/d0ce01216e

Methods
IUCrJ

Polymorph evolution during crystal growth studied by 3D electron diffraction

Edward T. Broadhurst; Hongyi Xu; Max T. B. Clabbers; Molly Lightowler; Fabio Nudelman; Xiaodong Zou; Simon Parsons

Combining cryogenic specimen preparation with three-dimensional electron diffraction, researchers followed glycine crystallization from water. Different samples captured the sequential appearance of its three ambient-pressure polymorphs, including a short-lived beta form before alpha became dominant. Structures could be obtained from very small crystallites, demonstrating how diffraction can reveal phases missed by slower bulk measurements.

MicroED structure determinationPharmaceutical solid state
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DOI: 10.1107/s2052252519016105

Original research
Angewandte Chemie International Edition

The Crystal Structure of Orthocetamol Solved by 3D Electron Diffraction

Iryna Andrusenko; Victoria Hamilton; Enrico Mugnaioli; Arianna Lanza; Charlie Hall; Jason Potticary; Simon R. Hall; Mauro Gemmi

Researchers solved the previously unknown crystal structure of orthocetamol, a pharmaceutical compound that had not yielded single crystals suitable for X-ray diffraction. The approach combined low-dose three-dimensional electron-diffraction acquisition with a single-electron detector. The case illustrates structure determination from challenging small crystals rather than requiring successful growth of larger specimens first.

MicroED structure determinationPharmaceutical solid state
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DOI: 10.1002/anie.201904564

Original research
Science

Electron diffraction determines molecular absolute configuration in a pharmaceutical nanocrystal

Petr Brázda; Lukáš Palatinus; Martin Babor

A complete structure analysis of a sofosbuvir–L-proline pharmaceutical cocrystal used electron diffraction from a highly beam-sensitive nanocrystal. Collecting data at multiple positions and using improved intensity extraction enabled structure solution. Dynamical diffraction effects then distinguished the absolute structure despite the sample containing light atoms, establishing an important route to stereochemical assignment.

MicroED structure determinationPharmaceutical solid state
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DOI: 10.1126/science.aaw2560

Original research
ACS Central Science

The CryoEM Method MicroED as a Powerful Tool for Small Molecule Structure Determination

Christopher G. Jones; Michael W. Martynowycz; Johan Hattne; Tyler J. Fulton; Brian M. Stoltz; Jose A. Rodriguez; Hosea M. Nelson; Tamir Gonen

Researchers demonstrated atomic-resolution structure determination of small organic molecules from nanocrystals present in ordinary powders, using minimal specimen preparation. The study included pharmaceutical and natural-product examples and showed that individual compounds could be analyzed from a mixed specimen. It established a practical route around the need to grow crystals large enough for conventional single-crystal X-ray diffraction.

MicroED structure determinationPharmaceutical solid state
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DOI: 10.1021/acscentsci.8b00760

Original research
Angewandte Chemie International Edition

Rapid Structure Determination of Microcrystalline Molecular Compounds Using Electron Diffraction

Tim Gruene et al.

A prototype electron diffractometer combined a transmission electron microscope with a hybrid pixel detector. Researchers determined a methylene blue derivative and identified the crystal structure of paracetamol within a commercial medicine containing crystalline and noncrystalline components. The work demonstrated chemical crystallography from crystals too small for standard X-ray workflows, while emphasizing the need for appropriate structural validation.

MicroED structure determinationPharmaceutical solid state
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DOI: 10.1002/anie.201811318

Original research
Organic Process Research & Development

Crystal Structures of Two Important Pharmaceuticals Solved by 3D Precession Electron Diffraction Tomography

Partha P. Das; Enrico Mugnaioli; Stavros Nicolopoulos; Camilla Tossi; Mauro Gemmi; Athanasios Galanis; Gheorghe Borodi; Mihaela M. Pop

Researchers determined crystal structures of ramelteon and tolvaptan using three-dimensional precession electron diffraction tomography on approximately 500-nanometer crystals. Structures from subsequently grown, much larger crystals were measured by single-crystal X-ray diffraction for comparison. Agreement in molecular conformation, packing, and unit-cell parameters supported the electron-diffraction workflow for these two pharmaceutical materials.

MicroED structure determinationPharmaceutical solid state
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DOI: 10.1021/acs.oprd.8b00149

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