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

Powder crystallography of pharmaceutical materials by combined crystal structure prediction and solid-state 1H NMR spectroscopy
Powder crystallography of pharmaceutical materials by combined crystal structure prediction and solid-state 1H NMR spectroscopy
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.
1463-9076
8069-8080
Baias, Maria
36ef2b00-6865-43b9-b49e-88a2ce339364
Widdifield, Cory M.
731f9ea0-147f-40ca-8bd8-7ade1bbe867a
Dumez, Jean-N.
09230715-ba4f-4183-a481-d9b278b129cc
Thompson, Hugh P.G.
be3bf8ed-7503-4b64-9851-5116134859c3
Cooper, Timothy G.
c0804dd3-e795-40c2-a1f8-afce188715b5
Salager, Elodie
8776b252-7c73-487d-aac7-11e482c5f12a
Bassil, Sirena
c6527cbb-0fe7-4ea1-baef-b9a698f0f7c6
Stein, Robin S.
e093e861-84ad-49b6-975e-564c74fbbdc9
Lesage, Anne
bf3518dc-c688-4b8b-ab85-62ce2d6cbae0
Day, Graeme M.
e3be79ba-ad12-4461-b735-74d5c4355636
Emsley, Lyndon
3234816a-24e9-44a0-b134-70c09de78257
Baias, Maria
36ef2b00-6865-43b9-b49e-88a2ce339364
Widdifield, Cory M.
731f9ea0-147f-40ca-8bd8-7ade1bbe867a
Dumez, Jean-N.
09230715-ba4f-4183-a481-d9b278b129cc
Thompson, Hugh P.G.
be3bf8ed-7503-4b64-9851-5116134859c3
Cooper, Timothy G.
c0804dd3-e795-40c2-a1f8-afce188715b5
Salager, Elodie
8776b252-7c73-487d-aac7-11e482c5f12a
Bassil, Sirena
c6527cbb-0fe7-4ea1-baef-b9a698f0f7c6
Stein, Robin S.
e093e861-84ad-49b6-975e-564c74fbbdc9
Lesage, Anne
bf3518dc-c688-4b8b-ab85-62ce2d6cbae0
Day, Graeme M.
e3be79ba-ad12-4461-b735-74d5c4355636
Emsley, Lyndon
3234816a-24e9-44a0-b134-70c09de78257

Baias, Maria, Widdifield, Cory M., Dumez, Jean-N., Thompson, Hugh P.G., Cooper, Timothy G., Salager, Elodie, Bassil, Sirena, Stein, Robin S., Lesage, Anne, Day, Graeme M. and Emsley, Lyndon (2013) Powder crystallography of pharmaceutical materials by combined crystal structure prediction and solid-state 1H NMR spectroscopy Physical Chemistry Chemical Physics, 15, (21), pp. 8069-8080. (doi:10.1039/C3CP41095A). (PMID:23503809).

Record type: Article

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.

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e-pub ahead of print date: 19 February 2013
Published date: 7 June 2013
Organisations: Computational Systems Chemistry

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Local EPrints ID: 351758
URI: http://eprints.soton.ac.uk/id/eprint/351758
ISSN: 1463-9076
PURE UUID: 0698adcf-1eb3-4662-a4aa-53cd6f1252a4
ORCID for Graeme M. Day: ORCID iD orcid.org/0000-0001-8396-2771

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Date deposited: 30 Apr 2013 12:26
Last modified: 18 Jul 2017 04:23

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Contributors

Author: Maria Baias
Author: Cory M. Widdifield
Author: Jean-N. Dumez
Author: Hugh P.G. Thompson
Author: Timothy G. Cooper
Author: Elodie Salager
Author: Sirena Bassil
Author: Robin S. Stein
Author: Anne Lesage
Author: Graeme M. Day ORCID iD
Author: Lyndon Emsley

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