posted on 2024-07-22, 05:29authored bySunil
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.