Search

Structural characterisation in the solid state is an important step in understanding\ud the physical and chemical properties of a material. In pharmaceuticals, an active\ud pharmaceutical ingredient (API) may be medicinally favourable, but have undesirable\ud physical properties, such as poor solubility, that potentially limit further development.\ud Solid delivery forms, such as pharmaceutical salts, cocrystals and solid amorphous\ud dispersions, potentially offer improvements in physical properties, whilst maintaining\ud favourable medicinal characteristics. Solid-state NMR is an extremely sensitive probe\ud of the local atomic environment and intermolecular interactions, for example hydrogen\ud bonding, and is therefore well suited to studies of pharmaceuticals.\ud Solid-state NMR techniques applied to solid delivery forms are presented as\ud an alternative to more established structural characterisation methods. The effect of\ud homonuclear decoupling upon heteronuclear couplings is investigated using a combination\ud of experimental and density-matrix simulation results acquired from a 13C-1H spinecho\ud pulse sequence, modulated by scalar couplings. It is found that third-order cross\ud terms under MAS and homonuclear decoupling contribute to strong dephasing effects\ud in the NMR signal. Density-matrix simulations allow access to parameters currently\ud unattainable in experiment, and demonstrate that higher homonuclear decoupling rf\ud nutation frequencies reduce the magnitude of third-order cross terms. 15N-1H spinecho\ud experiments were applied to pharmaceutically relevant samples to differentiate\ud between the number of directly attached protons. Using this method, proton transfer\ud in an acid-base reaction is proven in pharmaceutical salts.\ud The indirect detection of 14N lineshapes via protons obtained using 2D 14N-1H\ud HMQC experiments is presented, where coherence transfer is achieved via heteronuclear\ud through-space dipolar couplings. The importance of fast MAS frequencies is demonstrated,\ud and it is found that increasing the recoupling duration reveals longer range\ud NH proximities. The 2D 14N-1H HMQC method is used to demonstrate the presence\ud of specific hydrogen bonding interactions, and thus aid in identifying molecular association\ud in a cocrystal and an amorphous dispersion. In addition, hydrogen bonding\ud motifs were identified by observing the changes in the 14N quadrupolar parameters between\ud individual molecular components relative to the respective solid delivery form.\ud First-principles calculations of NMR chemical shifts and quadrupolar parameters using\ud the GIPAW method were combined with 14N-1H experimental results to assist with\ud spectral assignment and the identification of the hydrogen bonding interactions.