title: Powder crystallography of pharmaceutical materials by combined crystal structure prediction and solid-state 1H NMR spectroscopy.
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 (1)H 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.
authors.affiliation: Université de Lyon, (CNRS/ENS-Lyon/UCB Lyon 1), Centre de RMN à Très Hauts Champs, 5 rue de la Doua, 69100 Villeurbanne, France.
authors.forename: Maria
authors.initials: M
authors.lastname: Baias
authors.forename: Cory M
authors.initials: CM
authors.lastname: Widdifield
authors.forename: Jean-Nicolas
authors.initials: JN
authors.lastname: Dumez
authors.forename: Hugh P G
authors.initials: HP
authors.lastname: Thompson
authors.forename: Timothy G
authors.initials: TG
authors.lastname: Cooper
authors.forename: Elodie
authors.initials: E
authors.lastname: Salager
authors.forename: Sirena
authors.initials: S
authors.lastname: Bassil
authors.forename: Robin S
authors.initials: RS
authors.lastname: Stein
authors.forename: Anne
authors.initials: A
authors.lastname: Lesage
authors.forename: Graeme M
authors.initials: GM
authors.lastname: Day
authors.forename: Lyndon
authors.initials: L
authors.lastname: Emsley
mesh_terms: D003042:Cocaine / Q000737:chemistry*; D003461:Crystallography / Q000379:methods; D005439:Flufenamic Acid / Q000737:chemistry*; D005485:Flutamide / Q000737:chemistry*; D009682:Magnetic Resonance Spectroscopy / Q000379:methods*; D008958:Models, Molecular; D011208:Powders; D011789:Quantum Theory; D013806:Theophylline / Q000737:chemistry*
chemical_list: D011208:Powders; D005439:Flufenamic Acid; D005485:Flutamide; D013806:Theophylline; D003042:Cocaine