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.
Highlights
One particular scientific method is usually not enough to solve a challenging problem relating to solid matter for organic molecules, such as a moderately sized active pharmaceutical ingredient (API) organic molecule
Our study shows the power of combining experiments, namely differential scanning calorimetry (DSC), X-ray diffraction, and magic-angle spinning (MAS) NMR, with DFT calculations and crystal structure prediction (CSP) to probe and understand the solid-state landscape, and in particular the role of dynamics, for pharmaceutical molecules
We identify a polymorphic transformation at −40 °C that has not been reported by Gunnam et al Our paper applies a complementary multitechnique approach, employing 1D and 2D solid-state MAS NMR techniques, low- and roomtemperature X-ray diffraction measurements, and differential scanning calorimetry (DSC) as well as the DFT-based gauge-including projector-augmented wave (GIPAW) calculation of NMR chemical shifts and crystal structure prediction (CSP)
Summary
One particular scientific method is usually not enough to solve a challenging problem relating to solid matter for organic molecules, such as a moderately sized active pharmaceutical ingredient (API) organic molecule. Despite the fact that the CSP methodology explains the range of thermodynamically favored crystal packings very well, even the most robust algorithms still do not consider static or/and dynamic molecular disorder, commonly observed by experimental techniques These challenges have been discussed, in particular in relation to pharmaceutically important compounds.[40,41] On the other hand, solid-state NMR spectroscopy is readily applicable to systems exhibiting conformational flexibility and/or different intermolecular interactions. Scanning calorimetry (DSC) as well as the DFT-based GIPAW calculation of NMR chemical shifts and crystal structure prediction (CSP)
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