Development and application of high-resolution solid-state NMR methods for probing polymorphism of active pharmaceutical ingredients

The objective of the work presented in this thesis is to apply advanced high-resolution solid-state NMR methods for the structural characterisation of organic crystalline systems, specifically active pharmaceutical ingredients (APIs). The determination of the crystal packing is an important stage in the development of new APIs, and solid-state magic angle spinning (MAS) NMR is well suited to complement existing techniques. Improvements in spectral resolution in recent years have led to the development of homonuclear correlation experiments capable of identifying intermolecular proximities between 1H nuclei. These experiments provide a powerful probe of the local environment of each 1H nucleus in the three-dimensional structure, and the majority of the research presented in this thesis is focussed on the development of detailed analysis methods that may be used to extract more detailed structural information from 2D solid-state NMR correlation spectra. Throughout this thesis, experimental solid-state NMR results are analysed alongside computational data, including density matrix simulations of experiments and first principles calculations of shielding tensors. The results of simulations of a 1H DQ (double-quantum) correlation experiment are compared to experiment, in order to investigate the dependence of the DQ build-up (change in peak intensity as a function of the recoupling pulse duration) on the precise nature of the dipolar coupled proton network. It is found (for a simple dipeptide) that quantitative information on the relative H{H distance may be obtained by comparison of the maximum intensity reached in the corresponding 1H DQ build-up curves. This method is then applied to pharmaceutically relevant systems. It is shown that differences between two polymorphs of an API may be identified in the 1H DQ build-up of particular peaks, and, following the analysis for the dipeptide, this difference may be ascribed to differences in specific intermolecular distances. In the study of a second API, -indomethacin, it is shown that the standard 1H DQ experiment provides insufficient resolution to identify specific DQ peaks. A recently developed 1H(DQ){13C correlation experiment is used to exploit the higher resolution in the 13C dimension, hence allowing the extraction of DQ build-up curves which may be used, in conjunction with simulations, to obtain structural data. Finally, a recently discovered polymorph of the API ibuprofen is studied using 13C CPMAS (cross polarisation) solid-state NMR. Through the use of first-principles calculations, the 13C spectra of both the well known and new polymorphs are assigned, and the conversion of an amorphous solid to the new polymorph is monitored through the use of temperature-controlled solid-state NMR experiments