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

Abstract

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 13 C 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 13 C 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.

Organic NMR crystallography: enabling progress for applications to pharmaceuticals and plant cell walls

“…52 Working together with scientists at AstraZeneca and Pfizer, Brown and co-workers have presented NMR crystallography studies of a range of pharmaceutical molecules. 4,33,[53][54][55][56] Together with Dracinsky, Hodgkinson has advocated for bringing together of molecular dynamics and nuclear quantum effects in the path-integral molecular dynamics (PIMD) approach. 57 This proves important for predicting salt or co-crystal formation corresponding to the transfer or not of a proton, as evidenced by the 1 H chemical shift.…”

Polymorph Identification for Flexible Molecules: Linear Regression Analysis of Experimental and Calculated Solution- and Solid-State NMR Data

“…The integration of solid-state NMR data and ab initio calculations of NMR parameters in NMR crystallography presents a valuable approach for determining crystal structures. − ,− Requiring a good starting structural model that is geometry optimized before the calculation of NMR parameters, NMR crystallography is now widely employed in academia and increasingly in industry, particularly to refine and improve the quality of structures derived from both single-crystal and powder X-ray diffraction data. − ,− ,,, NMR crystallography can also be used to determine crystal structures de novo without X-ray diffraction data by finding the model from a CSP ,,− campaign whose calculated properties are most consistent with the experimental NMR data. ,− ,,,,− Chemical shifts for proposed model structures are calculated, usually using the gauge-including projector augmented wave (GIPAW) method, − and compared directly with experimentally measured solid-state NMR chemical shifts, with only the correct model expected to pass the given thresholds of agreement for the root mean squared error (RMSE). ,,, …”