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Discovering the solid-state secrets of Lorlatinib by NMR crystallography : to hydrogen bond or not to hydrogen bond
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Rehman, Zainab, Franks, W. Trent, Nguyen, Bao, Schmidt, Heather Frericks, Scrivens, Garry and Brown, Steven P. (2023) Discovering the solid-state secrets of Lorlatinib by NMR crystallography : to hydrogen bond or not to hydrogen bond. Journal of Pharmaceutical Sciences, 112 (7). pp. 1915-1928. doi:10.1016/j.xphs.2023.02.022 ISSN 0022-3549.
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WRAP-Discovering-solid-state-secrets-Lorlatinib-NMR-crystallography-hydrogen-bond-23.pdf - Accepted Version - Requires a PDF viewer. Available under License Creative Commons Attribution 4.0. Download (1930Kb) | Preview |
Official URL: http://doi.org/10.1016/j.xphs.2023.02.022
Abstract
Lorlatinib is an active pharmaceutical ingredient (API) used in the treatment of lung cancer. Here, an NMR crystallography analysis is presented whereby the single-crystal X-ray diffraction structure (CSD: 2205098) determination is complemented by multinuclear (1H, 13C, 14/15N, 19F) magic-angle spinning (MAS) solid-state NMR and gauge-including projector augmented wave (GIPAW) calculation of NMR chemical shifts. Lorlatinib crystallises in the P21 space group, with two distinct molecules in the asymmetric unit cell, Z′ = 2. Three of the four NH2 hydrogen atoms form intermolecular hydrogen bonds, N30-H…N15 between the two distinct molecules and N30-H…O2 between two equivalent molecules. This is reflected in one of the NH2 1H chemical shifts being significantly lower, 4.0 ppm compared to 7.0 ppm. Two-dimensional 1H-13C, 14N-1H and 1H (double-quantum, DQ)-1H (single-quantum, SQ) MAS NMR spectra are presented. The 1H resonances are assigned and specific H-H proximities corresponding to the observed DQ peaks are identified. The resolution enhancement at a 1H Larmor frequency of 1 GHz as compared to 500 or 600 MHz is demonstrated.
Item Type: | Journal Article | ||||||||||||||||||
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Subjects: | Q Science > QD Chemistry Q Science > QP Physiology R Medicine > RC Internal medicine |
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Divisions: | Faculty of Science, Engineering and Medicine > Science > Physics | ||||||||||||||||||
Library of Congress Subject Headings (LCSH): | Lungs -- Cancer -- Treatment, Solid state chemistry, Hydrogen bonding, Crystallography, Nuclear magnetic resonance | ||||||||||||||||||
Journal or Publication Title: | Journal of Pharmaceutical Sciences | ||||||||||||||||||
Publisher: | John Wiley & Sons, Inc. | ||||||||||||||||||
ISSN: | 0022-3549 | ||||||||||||||||||
Official Date: | July 2023 | ||||||||||||||||||
Dates: |
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Volume: | 112 | ||||||||||||||||||
Number: | 7 | ||||||||||||||||||
Page Range: | pp. 1915-1928 | ||||||||||||||||||
DOI: | 10.1016/j.xphs.2023.02.022 | ||||||||||||||||||
Status: | Peer Reviewed | ||||||||||||||||||
Publication Status: | Published | ||||||||||||||||||
Access rights to Published version: | Open Access (Creative Commons) | ||||||||||||||||||
Date of first compliant deposit: | 6 March 2023 | ||||||||||||||||||
Date of first compliant Open Access: | 6 March 2023 | ||||||||||||||||||
RIOXX Funder/Project Grant: |
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