Development of solid-state NMR techniques for the characterisation of pharmaceutical compounds

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Abstract

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

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