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

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posted on 2024-07-22, 05:29 authored by Sunil K. Rai, Lokeswara Rao Potnuru, Nghia Tuan Duong, Toshio Yamazaki, Ashwini K. Nangia, Yusuke Nishiyama, Vipin Agarwal
Dabrafenib (DBF), an anticancer drug, exhibits isostructural properties in its hydrate (DBF⊃H2O) and perhydrate (DBF⊃H2O2) 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 H2O2/H2O in DBF⊃H2O2 (mixed hydrate/perhydrate). 1H–1H dipolar-coupling-based experiments were recruited to confirm the 3D molecular packing of solvent molecules in DBF⊃H2O and DBF⊃H2O2. 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⊃H2O2. 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.

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