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Issue 21, 2013
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Powder crystallography of pharmaceutical materials by combined crystal structure prediction and solid-state 1H NMR spectroscopy

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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.

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

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Supplementary files

Article information


Submitted
05 Apr 2012
Accepted
18 Feb 2013
First published
19 Feb 2013

Phys. Chem. Chem. Phys., 2013,15, 8069-8080
Article type
Paper

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

M. Baias, C. M. Widdifield, J. Dumez, H. P. G. Thompson, T. G. Cooper, E. Salager, S. Bassil, R. S. Stein, A. Lesage, G. M. Day and L. Emsley, Phys. Chem. Chem. Phys., 2013, 15, 8069
DOI: 10.1039/C3CP41095A

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