Characterization of the structural and dynamic properties of two polymorphs of leflunomide by solid-state NMR

Solid-state Nuclear Magnetic Resonance (ssNMR) spectroscopy is a powerful tool for the structural and dynamic characterization of polymorphs, whose pharmaceutical properties can differ in terms of solubility, stability, and bioavailability. In this study, we present the first ssNMR characterization of the two polymorphs α and β of leflunomide, a Disease Modifying Anti-Rheumatic Drug. A multinuclear ( 1 H, 19 F, 13 C, 15 N) NMR approach using spectral and relaxation data confirmed distinct structural and dynamic differences between the two polymorphs. In particular, the reorientational motions of the methyl, phenyl, and trifluoromethyl groups are at least two orders of magnitude faster in the β form. • Nuclear Magnetic Resonance explores differences between polymorphs of Leflunomide. • Study of spin relaxation allows characterization of motions of molecular fragments. • Motions are much faster and less activated in the β than in the α polymorph. • 1D and 2D spectra of 1 H, 19 F, 13 C, 15 N nuclei give details on molecular structure.