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

Aneesa J. Al-Ani, Patrick M.J. Szell, Zainab Rehman, Helen Blade, Helen P. Wheatcroft, Leslie P. Hughes, Steven P. Brown, Chick C. Wilson

Research output: Contribution to journalArticlepeer-review

1 Citation (SciVal)

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 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 13C 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.

Original languageEnglish
Pages (from-to)4696-4707
Number of pages12
JournalCrystal Growth and Design
Volume22
Issue number8
Early online date20 Jul 2022
DOIs
Publication statusPublished - 3 Aug 2022

Bibliographical note

Funding Information:
This work was funded by Innovate UK and AstraZeneca (grant number: KTP11570) and the Engineering and Physical Sciences Research Council (EPSRC) through the Centre for Doctoral Training in Sustainable Chemical Technologies (Grant number: EP/L016354/1). Z.R. thanks the EPSRC and Pfizer for PhD funding. The authors thank Dinu Iuga for support with the NMR experiments. The UK High-Field Solid-State NMR Facility used in this research was funded by EPSRC and BBSRC (EP/T015063/1) and the University of Warwick including via part funding through Birmingham Science City Advanced Materials Projects 1 and 2, supported by Advantage West Midlands (AWM) and the European Regional Development Fund (ERDF). We thank Dr Andrew P. Howes and Patrick Ruddy for supporting the operation of the Millburn House Magnetic Resonance Laboratory. Data for this study are provided as a Supporting Information set from the University of the Warwick Research Dataset portal at https://wrap.warwick.ac.uk/167259 .

ASJC Scopus subject areas

  • General Chemistry
  • General Materials Science
  • Condensed Matter Physics

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