Combining X-ray and NMR Crystallography to Explore the Crystallographic Disorder in Salbutamol Oxalate

Salbutamol is an active pharmaceutical ingredient commonly used to treat respiratory distress and is listed by the World Health Organization as an essential medicine. Here, we establish the crystal structure of its oxalate form, salbutamol oxalate, and explore the nature of its crystallographic disorder by combined X-ray crystallography and 13C cross-polarization (CP) magic-angle spinning (MAS) solid-state NMR. The *C-OH chiral center of salbutamol (note that the crystal structures are a racemic mixture of the two enantiomers of salbutamol) is disordered over two positions, and the tert-butyl group is rotating rapidly, as revealed by C-13 solid-state NMR. The impact of crystallization conditions on the disorder was investigated, finding variations in the occupancy ratio of the *C-OH chiral center between single crystals and a consistency across samples in the bulk powder. Overall, this work highlights the contrast between investigating crystallographic disorder by X-ray diffraction and solid-state NMR experiment, and gauge-including projector-augmented-wave (GIPAW) density functional theory (DFT) calculations, with their combined use, yielding an improved understanding of the nature of the crystallographic disorder between the local (i.e., as viewed by NMR) and longer-range periodic (i.e., as viewed by diffraction) scale.

Automated summary

This study presents the crystal structure of salbutamol oxalate and investigates its crystallographic disorder using X-ray crystallography and solid-state NMR. The study reveals that the chiral center of salbutamol is disordered over two positions and the tert-butyl group is rotating rapidly. The impact of crystallization conditions on the disorder is also explored.