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Data for Synergy of solid-state NMR, single-crystal X-ray diffraction, and crystal structure prediction methods : a case study of teriflunomide (TFM)
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Pawlak, Tomasz, Sudgen, Isaac, Bujacz, Grzegorz, Iuga, Dinu, Brown, Steven P. and Potrzebowski, Marek J. (2021) Data for Synergy of solid-state NMR, single-crystal X-ray diffraction, and crystal structure prediction methods : a case study of teriflunomide (TFM). [Dataset]
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WRAP.zip - Published Version Available under License Creative Commons Attribution 4.0. Download (2674Kb) |
Official URL: http://wrap.warwick.ac.uk/152054/
Abstract
In this work, for the first time, we present the X-ray diffraction crystal structure and spectral properties of a new, room-temperature polymorph of teriflunomide (TFM), CSD code 1969989. As revealed by DSC, the low-temperature TFM polymorph recently reported by Gunnam et al. undergoes a reversible thermal transition at −40 °C. This reversible process is related to a change in Z’ value, from 2 to 1, as observed by variable-temperature 1H–13C cross-polarization (CP) magic-angle spinning (MAS) solid-state NMR, while the crystallographic system is preserved (triclinic). Two-dimensional 13C–1H and 1H–1H double-quantum MAS NMR spectra are consistent with the new room-temperature structure, including comparison with GIPAW (gauge-including projector augmented waves) calculated NMR chemical shifts. A crystal structure prediction procedure found both experimental teriflunomide polymorphs in the energetic global minimum region. Differences between the polymorphs are seen for the torsional angle describing the orientation of the phenyl ring relative to the planarity of the TFM molecule. In the low-temperature structure, there are two torsion angles of 4.5 and 31.9° for the two Z’ = 2 molecules, while in the room-temperature structure, there is disorder that is modeled with ∼50% occupancy between torsion angles of −7.8 and 28.6°. These observations are consistent with a broad energy minimum as revealed by DFT calculations. PISEMA solid-state NMR experiments show a reduction in the C–H dipolar coupling in comparison to the static limit for the aromatic CH moieties of 75% and 51% at 20 and 40 °C, respectively, that is indicative of ring flips at the higher temperature. Our study shows the power of combining experiments, namely DSC, X-ray diffraction, and MAS NMR, with DFT calculations and CSP to probe and understand the solid-state landscape, and in particular the role of dynamics, for pharmaceutical molecules.
Item Type: | Dataset | |||||||||||||||
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Subjects: | Q Science > QD Chemistry | |||||||||||||||
Divisions: | Faculty of Science, Engineering and Medicine > Science > Physics | |||||||||||||||
Library of Congress Subject Headings (LCSH): | Crystals -- Structure, Crystal growth, X-ray crystallography, Polymorphism (Crystallography), Multiple sclerosis -- Treatment -- Research, Pharmaceutical chemistry, Nuclear magnetic resonance spectroscopy, Drug development -- Research | |||||||||||||||
Publisher: | University of Warwick, Department of Physics | |||||||||||||||
Official Date: | 7 May 2021 | |||||||||||||||
Dates: |
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Status: | Not Peer Reviewed | |||||||||||||||
Publication Status: | Published | |||||||||||||||
Media of Output (format): | .cif .magres | |||||||||||||||
Access rights to Published version: | Open Access (Creative Commons) | |||||||||||||||
Copyright Holders: | University of Warwick | |||||||||||||||
Description: | The NMR-850MHz folder contains: 1H -> 13C CP MAS NMR spectra of TFM recorded at a spinning rate of 12 kHz at 20 oC (1) and -80 oC (2) and a 1H Larmor frequency of 850.2 MHz. The NMR-600MHz contains: 1H -> 13C CP MAS NMR spectrum (1) of TFM recorded at a spinning rate of 12 kHz, 13C-1H invHETCOR spectra (2 and 3) and 1H-1H DQ-SQ MAS NMR spectrum (4) recorded at a spinning rate of 62.5 kHz and a 1H Larmor frequency of 600.1 MHz and at 20 oC. The DSC folder contains the binary output file of DSC measurment recorded with Mettler Toledo software. The CASTEP folder contains the appropriate output magres and cif files. The Structures folder contains cif files for the CSP outputs. |
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Date of first compliant deposit: | 7 May 2021 | |||||||||||||||
Date of first compliant Open Access: | 7 May 2021 | |||||||||||||||
RIOXX Funder/Project Grant: |
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