Synergy of Solid-State NMR, Single-Crystal X-ray Diffraction, and Crystal Structure Prediction Methods: A Case Study of Teriflunomide (TFM)

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 1 H– 13 C cross-polarization (CP) magic-angle spinning (MAS) solid-state NMR, while the crystallographic system is preserved (triclinic). Two-dimensional 13 C– 1 H and 1 H– 1 H 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.

Solid-State Study of the Structure, Dynamics, and Thermal Processes of Safinamide Mesylate─A New Generation Drug for the Treatment of Neurodegenerative Diseases

“…However, the average dipolar coupling value of ca. 10.4 kHz allows to assign it as a low-amplitude wobbling of aromatic rings. ,,− …”

Crystal structure prediction of N-halide phthalimide compounds: halogen bonding synthons as a touchstone

“…10,11 Polymorphism in organic compounds also complicates the CSP calculations, where molecules adopt different crystal structures that can be assessed experimentally. [12][13][14][15][16][17][18] If an experimental compound is thermodynamically stable ("thermodynamic polymorph"), it can be found as the global energy minimum, as opposed to metastable polymorphs that correspond to local energy minima. To find all possible polymorphs of a compound among the produced crystal structures, it is necessary to consider both kinetic and thermodynamic factors.…”

Combining X-ray and NMR Crystallography to Explore the Crystallographic Disorder in Salbutamol Oxalate

“…Solid-state NMR can be used to gain insights into crystallographic disorder occurring in bulk pharmaceuticals ,− and can be combined with gauge-including projector-augmented-wave (GIPAW) calculations to verify and refine the crystal structure, that is, NMR crystallography. ,,,− As a technique that observes the bulk sample, solid-state NMR can be used to validate the occurrence of crystallographic disorder and determine its nature. ,, The disorder caused by dynamics can be investigated by solid-state NMR, − offering qualitative information through line-shape analysis, chemical shift measurement, and dipolar coupling measurements. , In addition, quantitative information on the thermodynamic parameters of the dynamics can be obtained through relaxation time measurements. ,,, There are limits to the ability of solid-state NMR to investigate disorder, which may arise due to the nature of the technique. Examples of this may arise from an insufficient resolution required to adequately resolve the crystallographic disorder, the disorder involving unreceptive nuclei or potentially missing the presence of dynamics occurring at a timescale distinct from that of the one-dimensional NMR experiment.…”

“…21,25,71 The disorder caused by dynamics can be investigated by solid-state NMR, 71−80 offering qualitative information through line-shape analysis, chemical shift measurement, 21 and dipolar coupling measurements. 61,81 In addition, quantitative information on the thermodynamic parameters of the dynamics can be obtained through relaxation time measurements. 61,71,72,75 There are limits to the ability of solid-state NMR to investigate disorder, which may arise due to the nature of the technique.…”