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Phase identification and discovery of an elusive polymorph of drug-polymer inclusion complex using automated 3D electron diffraction
Stockholm University, Faculty of Science, Department of Materials and Environmental Chemistry (MMK).ORCID iD: 0000-0002-9699-7794
Stockholm University, Faculty of Science, Department of Materials and Environmental Chemistry (MMK).
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Number of Authors: 122024 (English)In: Angewandte Chemie International Edition, ISSN 1433-7851, E-ISSN 1521-3773, Vol. 63, no 16, article id e202317695Article in journal (Refereed) Published
Abstract [en]

3D electron diffraction (3D ED) has shown great potential in crystal structure determination in materials, small organic molecules, and macromolecules. In this work, an automated, low-dose and low-bias 3D ED protocol has been implemented to identify six phases from a multiple-phase melt-crystallisation product of an active pharmaceutical ingredient, griseofulvin (GSF). Batch data collection under low-dose conditions using a widely available commercial software was combined with automated data analysis to collect and process over 230 datasets in three days. Accurate unit cell parameters obtained from 3D ED data allowed direct phase identification of GSF Forms III, I and the known GSF inclusion complex (IC) with polyethylene glycol (PEG) (GSF-PEG IC-I), as well as three minor phases, namely GSF Forms II, V and an elusive new phase, GSF-PEG IC-II. Their structures were then directly determined by 3D ED. Furthermore, we reveal how the stabilities of the two GSF-PEG IC polymorphs are closely related to their crystal structures. These results demonstrate the power of automated 3D ED for accurate phase identification and direct structure determination of complex, beam-sensitive crystallisation products, which is significant for drug development where solid form screening is crucial for the overall efficacy of the drug product. 

Place, publisher, year, edition, pages
2024. Vol. 63, no 16, article id e202317695
Keywords [en]
Polymorphism, automation, 3D electron diffraction (microED), phase analysis, structural analysis
National Category
Inorganic Chemistry
Identifiers
URN: urn:nbn:se:su:diva-228075DOI: 10.1002/anie.202317695ISI: 001179941000001PubMedID: 38380831Scopus ID: 2-s2.0-85186891241OAI: oai:DiVA.org:su-228075DiVA, id: diva2:1855920
Available from: 2024-05-03 Created: 2024-05-03 Last updated: 2025-04-02Bibliographically approved

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Lightowler, MollyCho, JungHofer, GerhardXu, JiaoyanYang, TaiminZou, XiaodongXu, Hongyi

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Lightowler, MollyOu, XiaoCho, JungHofer, GerhardXu, JiaoyanYang, TaiminZou, XiaodongXu, Hongyi
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Department of Materials and Environmental Chemistry (MMK)Inorganic and Structural Chemistry
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Inorganic Chemistry

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