Probing intermolecular interactions and nitrogen protonation in pharmaceuticals by novel N-15-edited and 2D N-14-H-1 solid-state NMR

We report the applications of two novel magic-angle spinning (MAS) solid-state NMR methods, (1)J(15N-1H) spectral editing and 2D N-14-H-1 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 N-14-H-1 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.