Atomic-level structure determination of amorphous molecular solids by NMR

Manuel Cordova, Pinelopi Moutzouri, Sten O. Nilsson Lill, Alexander Cousen, Martin Kearns, Stefan T. Norberg, Anna Svensk Ankarberg, James McCabe, Arthur C. Pinon, Staffan Schantz () and Lyndon Emsley ()
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Manuel Cordova: École Polytechnique Fédérale de Lausanne (EPFL)
Pinelopi Moutzouri: École Polytechnique Fédérale de Lausanne (EPFL)
Sten O. Nilsson Lill: Pharmaceutical Sciences, R&D, AstraZeneca
Alexander Cousen: Pharmaceutical Sciences, R&D, AstraZeneca
Martin Kearns: Pharmaceutical Sciences, R&D, AstraZeneca
Stefan T. Norberg: Pharmaceutical Technology & Development, Operations, AstraZeneca
Anna Svensk Ankarberg: Pharmaceutical Technology & Development, Operations, AstraZeneca
James McCabe: Pharmaceutical Sciences, R&D, AstraZeneca
Arthur C. Pinon: University of Gothenburg
Staffan Schantz: Pharmaceutical Technology & Development, Operations, AstraZeneca
Lyndon Emsley: École Polytechnique Fédérale de Lausanne (EPFL)

Nature Communications, 2023, vol. 14, issue 1, 1-12

Abstract: Abstract Structure determination of amorphous materials remains challenging, owing to the disorder inherent to these materials. Nuclear magnetic resonance (NMR) powder crystallography is a powerful method to determine the structure of molecular solids, but disorder leads to a high degree of overlap between measured signals, and prevents the unambiguous identification of a single modeled periodic structure as representative of the whole material. Here, we determine the atomic-level ensemble structure of the amorphous form of the drug AZD4625 by combining solid-state NMR experiments with molecular dynamics (MD) simulations and machine-learned chemical shifts. By considering the combined shifts of all 1H and 13C atomic sites in the molecule, we determine the structure of the amorphous form by identifying an ensemble of local molecular environments that are in agreement with experiment. We then extract and analyze preferred conformations and intermolecular interactions in the amorphous sample in terms of the stabilization of the amorphous form of the drug.

Date: 2023
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DOI: 10.1038/s41467-023-40853-2

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