Methods to Aid Robust Structural Characterisation Using Nuclear Magnetic Resonance Spectroscopy

Abstract

The structural assignment of organic molecules in spectroscopy underpins our understanding of their related physical and chemical properties. This is particularly prominent for pharmaceuticals, where understanding the behaviour of a material in both solution and solid can dictate its applicability for future developments. Nuclear Magnetic Resonance (NMR) spectroscopy can play a critical role given its ability to elucidate local environment information whilst providing insight to conformation, polymorphism, dynamics, and exchange.

In this thesis, organic materials have been probed using both solid and solution state NMR methods with the aim of providing comprehensive and robust structural characterisation. This has been demonstrated through the determination of the correct structural model of indapamide using an NMR crystallographic approach alongside the evaluation of possible multiple-quantum-based pulse sequences to probe carbon connectivity both indirectly and directly. A Bayesian probability-based workflow has also been presented as a method to evaluate a proposed experimental assignment of a material where its proof of concept is discussed.

In the final chapter, the solution state behaviour of the pharmaceutical, ritonavir, has been revisited where the assignment, exchange behaviour and conformation has been evaluated. This has led to the extraction of kinetic information directly from 1H-1H exchange spectroscopy (EXSY) spectra to comprehensively understand the interconversion of conformers in the solution state.