Probing Short-Range Interactions in Isostructural Hydrate and Perhydrate of Dabrafenib by Magic-Angle Spinning Solid-State NMR.

Dabrafenib ( DBF ), an anticancer drug, exhibits isostructural properties in its hydrate ( DBF⊃H 2 O ) and perhydrate ( DBF⊃H 2 O 2 ) forms, as revealed by single-crystal X-ray diffraction. Despite the H 2 O and H 2 O 2 solvent molecules occupying identical locations, the two polymorphs have different thermal behaviors. In general, determination of stoichiometry of H 2 O in the perhydrate crystals is difficult due to the presence of both H 2 O and H 2 O 2 in the same crystal voids. This study utilizes magic-angle spinning (MAS) solid-state NMR (SSNMR) combined with gauge-included projector augmented wave calculations to characterize the influence of solvent molecules on the local environment in pseudopolymorphs. SSNMR experiments were employed to assign 1 H, 13 C, and 15 N peaks and identify spectral differences in the isostructural pseudopolymorphs. Proton spectroscopy at fast MAS was used to identify and quantify H 2 O 2 /H 2 O in DBF⊃H 2 O 2 (mixed hydrate/perhydrate). 1 H- 1 H dipolar-coupling-based experiments were recruited to confirm the 3D molecular packing of solvent molecules in DBF⊃H 2 O and DBF⊃H 2 O 2 . Homonuclear ( 1 H- 1 H) and heteronuclear ( 1 H- 14 N) distance measurements, in conjunction with diffraction structures and optimized hydrogen atom positions by density functional theory, helped decipher local interactions of H 2 O 2 with DBF and their geometry in DBF⊃H 2 O 2 . This integrated X-ray structure, quantum chemical calculations, and NMR study of pseudopolymorphs offer a practical approach to scrutinizing crystallized solvent interactions in the crystal lattice even without high-resolution crystal structures or artificial sample enrichment.