Advances in solid-state NMR methodology and computational chemistry are applied to the (19)F NMR of solid octafluoronaphthalene. It is demonstrated experimentally, and confirmed by density functional theory (DFT) calculations, that the spectral resolution in the magic-angle spinning spectrum is limited by the anisotropy of the bulk magnetic susceptibility (ABMS). This leads to the unusual observation that the resolution improves as the sample is diluted. DFT calculations provide assignments of each of the peaks in the (19)F spectrum, but the predictions are close to the limits of accuracy and correlation information from 2-D NMR is invaluable in confirming the assignments. The effects of non-Gaussian lineshapes on the use of 2-D NMR for mapping correlations of spectral frequencies (e.g. due to the ABMS) are also discussed.
A combination of solid-state NMR techniques, including 13C/1H correlation, 2H magic-angle spinning NMR and first principles calculation are employed to characterise the role of water in different hydration states of sildenafil citrate.
The
manufacturing route toward verinurad, an amphoteric, class
II atropisomer that readily forms solvates, has proven to be highly
complex. This previously required the isolation of intermediates with
challenging physical properties and the application of cryogenic processes.
New processes were designed and optimized, enabling the manufacture
of 113 kg of verinurad in its desired polymorphic form. An interdisciplinary
approach involving the synthesis, high-throughput experimentation,
analytical chemistry, crystallization science, in silico modeling, and engineering was employed. Kinetic measurement of enantiomerically
enriched verinurad salts confirmed that racemization occurred within
the clearance time frame, thus mitigating safety concerns associated
with inherent axial chirality in verinurad.
The development of processes to produce the Bruton tyrosine kinase inhibitor, acalabrutinib 1, has resulted in improvements to the yield, cycle time, and operability, to realize a robust commercial manufacturing process. A highly accelerated clinical program meant that numerous key process challenges had to be resolved in a short timeframe. Issues are discussed, such as the uncontrolled epimerization of a chiral center and the control of the acalabrutinib 1 crystallization step, which was prone to oiling. Specifically, work to understand the complex polymorph landscape of a key intermediate (to facilitate resolution of a filtration issue) is described.
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