Cocrystals and amorphous solid dispersions have generated interest in the pharmaceutical industry as an alternative to more established solid delivery forms. The identification of intermolecular hydrogen bonding interactions in a nicotinamide palmitic acid cocrystal and a 50% w/w acetaminophen-polyvinylpyrrolidone solid dispersion are reported using advanced solid-state magic-angle spinning (MAS) NMR methods. The application of a novel (14)N-(1)H HMQC experiment, where coherence transfer is achieved via through-space couplings, is shown to identify specific hydrogen bonding motifs. Additionally, (1)H isotropic chemical shifts and (14)N electric field gradient (EFG) parameters, both accessible from (14)N-(1)H HMQC experiments, are shown to be sensitive to changes in hydrogen bonding geometry. Numerous indicators of molecular association are accessible from this experiment, including NH cross-peaks occurring from intermolecular hydrogen bonds and changes in proton chemical shifts or electric field gradient parameters. First-principles calculations using the GIPAW approach that yield accurate estimates of isotropic chemical shifts, and EFG parameters were used to assist in assignment. It is envisaged that (14)N-(1)H HMQC solid state NMR experiments could become a valuable screening technique of solid delivery forms in the pharmaceutical industry.

We report the applications of two novel magic-angle spinning (MAS) solid-state NMR methods, 1 J 15N-1H spectral editing and 2D 14 N-1 H HMQC, to the characterisation of nitrogen functional groups in two pharmaceutical compounds, cimetidine and tenoxicam. The 1 J 15N-1H spectral editing method can readily differentiate the number of protons directly bonded to a nitrogen site and is not susceptible to motional effects. This enables confirmation of proton transfer, therefore proving or disproving amine salt formation, which is of high significance to the properties of a drug. The recently developed 2D 14 N-1 H HMQC method can demonstrate the presence of specific hydrogen bonding interactions and thus aid in identifying molecular association. First-principles calculations of NMR chemical shifts and quadrupolar parameters using the GIPAW method were combined with experimental data to assist with spectral assignment and the identification of the hydrogen bonding motifs.

NMR crystallographic techniques are used to validate a structure of -piroxicam determined from powder X-ray diffraction (PXRD) with a relatively poor R-factor. Geometry optimisation of PXRD-and singlecrystal XRD-derived structures results in convergence to the same energy of the structures, with minimal atomic displacements, and good agreement of gauge-included projector augmented wave (GIPAW) calculated and experimentally determined NMR 1 H, 13 C and 15 N chemical shifts and 14 N quadrupolar parameters. Calculations on isolated molecules combined with 2D magic-angle spinning (MAS) 1 H doublequantum (DQ) and 14 N-1 H NMR experiments confirm the 3D packing arrangement of -piroxicam. NMR crystallography is shown to be an effective means of validating crystal structures that might otherwise be considered sceptically on the basis of diffraction data alone.