Journal
CRYSTAL GROWTH & DESIGN
Volume 21, Issue 6, Pages 3328-3343Publisher
AMER CHEMICAL SOC
DOI: 10.1021/acs.cgd.1c00123
Keywords
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Funding
- HOMING programme of the Foundation for Polish Science [04.04.00-00-4374/17-01 (Homing/2017 4/37)]
- European Union under the European Regional Development Fund
- EPSRC [EP/J014958/1, EP/J003840/1, EP/P022561/1, EP/P020194]
- BBSRC
- University of Warwick via partial funding through Birmingham Science City Advanced Materials Projects - Advantage West Midlands (AWM)
- European Regional Development Fund (ERDF)
- Eli Lilly
- EPSRC [EP/J014958/1, EP/J003840/1, EP/P022561/1] Funding Source: UKRI
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This work presents the X-ray diffraction crystal structure and spectral properties of a new, room-temperature polymorph of teriflunomide for the first time, along with insights into the thermal transitions and torsional angle differences between the low-temperature and room-temperature structures. The study demonstrates the combination of experiments, such as DSC, X-ray diffraction, and MAS NMR, with DFT calculations to probe and understand the solid-state landscape, particularly the role of dynamics, in pharmaceutical molecules.
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 degrees C. This reversible process is related to a change in Z' value, from 2 to 1, as observed by variable-temperature H-1-C-13 cross-polarization (CP) magic-angle spinning (MAS) solid-state NMR, while the crystallographic system is preserved (triclinic). Two-dimensional C-13-H-1 and H-1-H-1 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 degrees for the two Z' = 2 molecules, while in the room-temperature structure, there is disorder that is modeled with similar to 50% occupancy between torsion angles of -7.8 and 28.6 degrees. 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 degrees 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.
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