Powder crystallography of pharmaceutical materials by combined crystal structure prediction and solid-state 1H NMR spectroscopy

Maria Baias, Cory M. Widdifield, Jean Nicolas Dumez, Hugh P.G. Thompson, Timothy G. Cooper, Elodie Salager, Sirena Bassil, Robin S. Stein, Anne Lesage, Graeme M. Day, Lyndon Emsley

Research output: Contribution to journalArticle

Abstract

A protocol for the ab initio crystal structure determination of powdered solids at natural isotopic abundance by combining solid-state NMR spectroscopy, crystal structure prediction, and DFT chemical shift calculations was evaluated to determine the crystal structures of four small drug molecules: cocaine, flutamide, flufenamic acid, and theophylline. For cocaine, flutamide and flufenamic acid, we find that the assigned 1H isotropic chemical shifts provide sufficient discrimination to determine the correct structures from a set of predicted structures using the root-mean-square deviation (rmsd) between experimentally determined and calculated chemical shifts. In most cases unassigned shifts could not be used to determine the structures. This method requires no prior knowledge of the crystal structure, and was used to determine the correct crystal structure to within an atomic rmsd of less than 0.12 Å with respect to the known reference structure. For theophylline, the NMR spectra are too simple to allow for unambiguous structure selection.

Original languageEnglish (US)
Pages (from-to)8069-8080
Number of pages12
JournalPhysical Chemistry Chemical Physics
Volume15
Issue number21
DOIs
StatePublished - Jun 7 2013

ASJC Scopus subject areas

  • Physics and Astronomy(all)
  • Physical and Theoretical Chemistry

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    Baias, M., Widdifield, C. M., Dumez, J. N., Thompson, H. P. G., Cooper, T. G., Salager, E., Bassil, S., Stein, R. S., Lesage, A., Day, G. M., & Emsley, L. (2013). Powder crystallography of pharmaceutical materials by combined crystal structure prediction and solid-state 1H NMR spectroscopy. Physical Chemistry Chemical Physics, 15(21), 8069-8080. https://doi.org/10.1039/c3cp41095a