Sensitivity and resolution in 19F and 15N solid-state NMR: applications to pharmaceutical systems

Abstract

This thesis describes a study into the improvement of solid-state NMR methods for the detection and characterisation of pharmaceutical compound.

Chapter 1 reviews the literature that are relevant to the techniques discussed within this thesis

Chapter 2 outlines the key experimental techniques employed within this work.

Chapter 3 investigates the usefulness of indirect detection as a method to detect and possibly quantify the ratio of 15N present for multiple 15N containing systems. The work highlights how for CP performed at fast MAS, there is a much greater sensitivity to the RF inhomogeneity of the probe, and how this be reduced by using ramped CP. The results showed that for routine detection of 15N it is advised to detect via routine CP, due to the more complex setup of indirect detection.

Chapter 4 discusses the potential of combining REDOR data and that of powder X-ray diffraction as a method to improve the efficiency of structural determination of powders. The investigation was performed on two pseudo-polymorphs with the aim of measuring differences in the 13C-19F couplings. The aim was that many ‘loose constraints’ could be used to improve efficiency when working with natural abundance 13C.


Chapter 5 for 19F, a large number of model compounds were selected to reflect the broad range of possible fluorine environments, ranging from per-fluorinated systems where the line-width is dominated by homonuclear coupling to systems dilute in 19F when the total line-width is found to be determined by the hetero-nuclear decoupling as well as in-homogenous contribution. Combining the data from the model compounds it has led to a better understanding the factors that determine 19F resolution. As such a suitable work scheme in order to achieve the best resolution for 19F containing compounds is presented.

Chapter 6 investigates the combination of NMR and calculated data in order to assign chemical shifts to specific crystal sites1. The results show that by combining ab initio calculations with 2D NMR data confident assignment of peaks is possible.

(1) Robbins, A. J.; Ng, W. T. K.; Jochym, D.; Keal, T. W.; Clark, S. J.; Tozer, D. J.; Hodgkinson, P. Phys. Chem. Chem. Phys. 2007, 9, 2389.