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Mitchell-Thurston, Charles (2024) Investigations Into Solvate forms of Naloxone using Solid-State NMR and Simulations. PhD thesis, University of Nottingham.

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Abstract

The aim of this work is to investigate solvate forms of a pharmaceutical compound using solid-state nuclear magnetic resonance (NMR) spectroscopy to be able to differentiate them and provide structural insight, such as the change in orientation of an aliphatic chain. This was done by a combination of two approaches, one using experimental techniques and the other using simulations. Naloxone was chosen as the model compound because of its pharmaceutical importance, as well as the fact that it possesses multiple solvate forms. For all three of the available forms of naloxone, both proton and carbon-13 NMR experiments were employed.

Using a refocused INADEQUTE experiment, and Dynamic Nuclear Polarization (DNP) allowed the carbon-13 NMR spectra of all three to be assigned. This allowed for differentiation between the available solvate forms based on their chemical shift peak positions. Symmetrybased recoupling techniques allowed for the reintroduction of the proton chemical shift anisotropy (CSA). This allowed for structural differences between the forms to be observed in experimental data. NMR analysis showed clear degradation, detected using carbon-13 analysis, of one of the samples from a purely anhydrous form to a mixed hydration form.

Comparison of experimental data with density functional theory (DFT) calculations of NMR parameters allowed for confirmation of carbon assignments as well as further insight into structural information such as the change in orientation of naloxone’s aliphatic tail. Experimental data was simulated using SIMPSON and by making use of code that broadened the 1D simulations along the isotropic axis to generate 2D simulations, this allowed for the direct comparison of experimental to simulated spectra. The code, which was written in MATLAB, functions via normal distribution broadening, while also automating SIMPSON simulations. Once 1D simulations are inserted at their isotropic values they are broadened along this axis for every anisotropic axis point.

This thesis shows the effectiveness of both DNP and recoupling techniques for analysis of diverse solvate forms of a compound. It also presents a novel way to make use of CASTEP data to produce 2D simulations of CSA recoupling experiments. These findings illustrate key structural differences between the forms and suggest similar differences could be seen in other pharmaceutical compounds

Item Type:	Thesis (University of Nottingham only) (PhD)
Supervisors:	Titman, Jeremy
Keywords:	naloxone, solvate forms, nuclear magnetic resonance
Subjects:	Q Science > QD Chemistry > QD 71 Analytical chemistry Q Science > QD Chemistry > QD241 Organic chemistry
Faculties/Schools:	UK Campuses > Faculty of Science > School of Chemistry
Item ID:	77478
Depositing User:	Mitchell-Thurston, Charles
Date Deposited:	24 Jul 2024 04:41
Last Modified:	24 Jul 2024 04:41
URI:	https://eprints.nottingham.ac.uk/id/eprint/77478

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