Cover Picture: Indomethacin Polymorph δ Revealed To Be Two Plastically Bendable Crystal Forms by 3D Electron Diffraction: Correcting a 47‐Year‐Old Misunderstanding (Angew. Chem. Int. Ed. 7/2022)

Lightowler, Molly; Li, Shuting; Xiao, Ou; Zou, Xiaodong; Lü, Ming; Xu, Hongyi

doi:10.1002/anie.202200574

Cited by 13 publications

(18 citation statements)

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“…The crystal structure of indomethacin, a traditionally known crystal form that cannot be analyzed by single X-ray diffraction because of its slow crystal growth, was elucidated by MED analysis. 43 This showed that MED is useful for pharmaceutical crystal analysis. This study aimed to apply MED analysis to a novel multicomponent crystal of a P2X7 receptor antagonist to reveal its crystal structure and determine its crystal form as a salt/cocrystal.…”

Section: ■ Introductionmentioning

confidence: 99%

“…Electron diffraction analysis documented the crystal structures of the particles at the submicron level. − This technology can be considered as a desirable analytical method for samples with poor crystal growth. The crystal structure of indomethacin, a traditionally known crystal form that cannot be analyzed by single X-ray diffraction because of its slow crystal growth, was elucidated by MED analysis . This showed that MED is useful for pharmaceutical crystal analysis.…”

Section: Introductionmentioning

confidence: 99%

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Microelectron Diffraction Reveals Contamination of Polymorphs by Structure Analysis of Microscale Crystals in a Novel Pharmaceutical Cocrystal

Miyano,

Hirakawa,

Yamano

et al. 2023

Crystal Growth & Design

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A P2X7 receptor antagonist (basic nature) with possible amino/imino tautomeric forms was used as an active pharmaceutical ingredient (API). After the amorphous form was confirmed by powder X-ray diffraction (PXRD), crystallization was performed using various organic solvents. Crystal forms I−VI were obtained, and thermal and NMR analyses suggested the presence of solvate forms. A multicomponent crystal of form VII, containing succinic acid, was successfully obtained. Form VII was predicted to be a cocrystal based on the ΔpK a between the API and succinic acid. The stoichiometry of API and succinic acid was 2:1, as determined by TG−DTA and nuclear magnetic resonance analyses. Single-crystal XRD analysis was performed to determine the crystal tautomerism of form VII. However, no diffraction peaks were observed, owing to the streaky morphology. Hence, microelectron diffraction (MED) analysis was performed, and electron diffraction patterns were obtained, revealing unexpected polymorphic forms VII-A and VII−B. Similar dimer formation between the triazine and hydroxyl groups of the APIs was confirmed for both polymorphs, suggesting a tautomeric imino form. Intermolecular interactions were observed between the API imidazole group and the carboxylic acid group of succinic acid; however, these modes differed between forms VII-A and VII-B. Taken together, the MED analysis accurately revealed the crystal structures, particularly for isomeric and/or multicomponent crystals with poor growth.

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Section: ■ Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Microelectron Diffraction Reveals Contamination of Polymorphs by Structure Analysis of Microscale Crystals in a Novel Pharmaceutical Cocrystal

Miyano,

Hirakawa,

Yamano

et al. 2023

Crystal Growth & Design

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“…[25] Die Technik wurde auch bei der Charakterisierung anderer seit langem bekannter Polymorphe erfolgreich eingesetzt, deren Analyse zuvor große Herausforderung darstellte. [26] Eine Reihe von Studien hat gezeigt, dass die Strukturen von Wirkstoffen aus den Kristalliten von handelsüblichen Tabletten, Suspensionen und Salben bestimmt werden können. [3,11,27,28] Abbildung 1A, B).…”

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Levocetirizin‐Dihydrochlorid: Die Aufklärung einer lang verborgenen Struktur mittels Elektronenbeugung

KAROTHU¹,

Alhaddad²,

Göb

et al. 2023

Angewandte Chemie

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Levocetirizin ist ein oral verabreichtes Antihistaminikum der zweiten Generation, dass seit über 25 Jahren zur Behandlung von Allergiesymptomen und langanhaltender Nesselsucht eingesetzt wird. Trotz der weiten Verbreitung dieser Verbindung war ihre Kristallstruktur bisher unbekannt. Hier berichten wir über die Anwendung der 3D-Elektronenbeugung (3D ED)/Mikrokristallbeugung (MicroED) zur Bestimmung der Kristallstruktur von Levocetirizindihydrochlorid direkt aus kristallinen Pulvern, handelsüblicher Tabletten, die diese Verbindung enthalten. Weiterhin zeigen wir auch den Nutzen der dynamischen Verfeinerung zur eindeutigen Zuordnung der absoluten Konfiguration. Die Ergebnisse unterstreichen das immense Potenzial der 3D-ED/MicroED für die Strukturaufklärung von Komponenten mikrokristalliner Gemische, wodurch sich die Züchtung großer Einkristalle und der Einsatz ergänzender Analysetechniken erübrigt. Dies wird nicht nur dazu beitragen, dass die Methode für die Identifizierung, sondern auch für die primäre strukturelle Charakterisierung neuer Verbindungen in Zukunft an Bedeutung gewinnt.

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“…3,5–10 The technique has also been applied in the investigation of long-known polymorphs that were previously challenging to characterize. 11 Additionally, proof-of-concept studies have demonstrated that structures of APIs could be directly determined from small crystallites obtained from commercially available pills. 7,12…”

mentioning

confidence: 99%

“…3,[5][6][7][8][9][10] The technique has also been applied in the investigation of long-known polymorphs that were previously challenging to characterize. 11 Additionally, proof-of-concept studies have demonstrated that structures of APIs could be directly determined from small crystallites obtained from commercially available pills. 7,12 While the large majority of APIs are organic molecules, metallodrugs are found at the crossroads of pharmaceutical and inorganic compounds, being pharmaceutical formulations where a metal or metal cation is part of the API.…”

mentioning

confidence: 99%

Triple helix and rod structures of the antiseptic drug bibrocathol revealed by electron crystallography

2022

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Cover Picture: Indomethacin Polymorph δ Revealed To Be Two Plastically Bendable Crystal Forms by 3D Electron Diffraction: Correcting a 47‐Year‐Old Misunderstanding (Angew. Chem. Int. Ed. 7/2022)

Cited by 13 publications

References 0 publications

Microelectron Diffraction Reveals Contamination of Polymorphs by Structure Analysis of Microscale Crystals in a Novel Pharmaceutical Cocrystal

Microelectron Diffraction Reveals Contamination of Polymorphs by Structure Analysis of Microscale Crystals in a Novel Pharmaceutical Cocrystal

Levocetirizin‐Dihydrochlorid: Die Aufklärung einer lang verborgenen Struktur mittels Elektronenbeugung

Triple helix and rod structures of the antiseptic drug bibrocathol revealed by electron crystallography

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