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Pharmaceutical solid state 36

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Original research
Chemical and Pharmaceutical Bulletin

Rapid Structure Determination of Ranitidine Hydrochloride API in Two Crystal Forms Using Microcrystal Electron Diffraction

Hidetomo Yokoo; Yoshitaka Aoyama; Takashi Matsumoto; Eiichi Yamamoto; Nahoko Uchiyama; Yosuke Demizu

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.

MicroED structure determinationPharmaceutical solid state
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DOI: 10.1248/cpb.c23-00745

Original research
Advanced Biology

Polymorphic Structure Determination of the Macrocyclic Drug Paritaprevir by MicroED

Guanhong Bu; Emma Danelius; Lianne H.E. Wieske; Tamir Gonen

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.

MicroED structure determinationPharmaceutical solid state
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DOI: 10.1002/adbi.202300570

Original research
Angewandte Chemie International Edition

Phase Identification and Discovery of an Elusive Polymorph of Drug‐Polymer Inclusion Complex Using Automated 3D Electron Diffraction

Molly Lightowler; Shuting Li; Xiao Ou; Jungyoun Cho; Binbin Liu; Ao Li; Gerhard Hofer; Jiaoyan Xu; Taimin Yang; Xiaodong Zou; Ming Lu; Hongyi Xu

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.

MicroED structure determinationPharmaceutical solid state
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DOI: 10.1002/anie.202317695

Original research
Advanced Science

Distinct Conformations of Mirabegron Determined by MicroED

Jieye Lin; Johan Unge; Tamir Gonen

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.

MicroED structure determinationPharmaceutical solid state
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DOI: 10.1002/advs.202304476

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

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

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

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