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.

ABSTRACT:The crystal structure of Form 4 of the drug (4-[4-(2-adamantylcarbamoyl)-5-ter-butyl-pyrazol-1-yl] benzoic acid) is determined using a protocol for NMR powder crystallography at natural isotopic abundance combining solid-state 1 H NMR spectroscopy, crystal structure prediction, and DFT chemical shift calculations. This is the first example of NMR structure determination for a molecular compound of previously unknown structure, and at 422 g/mol this is the largest compound to which this method has been applied so far.