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

Dabrafenib (DBF), an anticancer drug, exhibits isostructural properties in its hydrate (DBF⊃HO) and perhydrate (DBF⊃HO) forms, as revealed by single-crystal X-ray diffraction. Despite the H₂O and H₂O₂ solvent molecules occupying identical locations, the two polymorphs have different thermal behaviors. In general, determination of stoichiometry of H₂O in the perhydrate crystals is difficult due to the presence of both H₂O and H₂O₂ 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 ¹H, ¹³C, and ¹⁵N peaks and identify spectral differences in the isostructural pseudopolymorphs. Proton spectroscopy at fast MAS was used to identify and quantify HO/HO in DBF⊃HO (mixed hydrate/perhydrate). ¹H-¹H dipolar-coupling-based experiments were recruited to confirm the 3D molecular packing of solvent molecules in DBF⊃HO and DBF⊃HO. Homonuclear (¹H-¹H) and heteronuclear (¹H-¹⁴N) distance measurements, in conjunction with diffraction structures and optimized hydrogen atom positions by density functional theory, helped decipher local interactions of H₂O₂ with DBF and their geometry in DBF⊃HO. 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.