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Structural Dynamics of Amorphous Solid-State Macromolecular Materials at Terahertz Frequencies 10.17863/CAM.50234 Shmool, Talia Amira 0000000204153050 Zeitler, Jochen Axel 0000000249580582 Structural Dynamics of Amorphous Solid-State Macromolecular Materials at Terahertz Frequencies Talia Amira Shmool The aim of this thesis is to investigate the ability of terahertz time-domain spectroscopy (THz-TDS) to study complex amorphous solid-state systems. THz-TDS is a vibrational optical spectroscopy technique which can probe the intermolecular librations and vibrations of materials. Previous work has explored the use of THz-TDS in probing crystalline systems and amorphous small organic molecules, and uniquely this thesis focuses on studying amorphous macromolecular systems. In addition to contributing to the literature and increasing the understanding of the fundamental properties of amorphous macromolecular solid-state systems, this thesis provides a framework and methodology for assessing the stability of amorphous biological systems using THz-TDS. This thesis is organised as follows: Chapter 1 includes an introduction to terahertz spectroscopy and the theoretical framework relevant for understanding the behaviour of the biological systems investigated in the following chapters. Chapter 2 first provides a detailed explanation to THz-TDS data acquisition and analysis. Then, sample preparation methods for THz-TDS experiments are described and formulation fabrication is outlined. Finally, the methodologies used for each experiment conducted in this thesis are detailed. Chapter 3 introduces a qualitative physical interpretation of the dynamic motions of polymers that contribute to the β- and α-relaxation processes identified by THz-TDS and dynamic mechanical analysis data. These processes are then related to the combined contributions of temperature and free volume effects. Chapter 4 investigates the interactions between peptides and polymers at terahertz frequencies, with an emphasis on the molecular mobility behaviour leading to the glass transition temperature of lyophilised polymeric microspheres. Chapter 5 utilises THz-TDS to study the vibrational dynamic properties of lyophilised protein formulations complemented with Fourier-transform infrared (FTIR), circular dichroism (CD), and solid-state nuclear magnetic resonance (ssNMR) spectroscopy experiments to further investigate the structural changes observed for the formulations. Chapter 6 explores the extent to which THz-TDS can be used to track thermally induced conformational changes of spray-dried formulations. Extending this work, Chapter 7 examines a series of spray-dried formulations and connects the THz-TDS results to the trends observed in the storage stability study conducted for these formulations. Finally, Chapter 8 summarises the findings and contributions of this thesis and considers future experiments which would be interesting to perform as an extension of this work. University of Cambridge 2020-04-25 Thesis Doctoral Doctor of Philosophy (PhD) en AstraZeneca UK Limited (MedImmune Limited) AJA-Ian Karten Charitable Trust AIA-Kenneth Lindsay Scholarship Trust https://www.repository.cam.ac.uk/handle/1810/303159 https://apollo8-f-pro.lib.cam.ac.uk/bitstreams/c98d8902-c0ef-4ac2-a327-09a67a6e0e9f/download f2a05b28536a793c674c8bbe3cc12c5e https://apollo8-f-pro.lib.cam.ac.uk/bitstreams/79b8b514-962b-4d62-8365-ba0cff3f614f/download 87eda9de84448d1f82354d60eee3eb5f https://www.rioxx.net/licenses/all-rights-reserved/ Please see page ii of the thesis: 'Collaborations'. terahertz spectroscopy solid state amorphous macromolecules polymers peptides microspheres α‐ and β‐relaxation processes glass transition temperature local- and large-scale mobility vibrational dynamics pharmaceutical formulations antibodies stabilising matrix excipients lyophilisation spray drying storage stability degradation aggregation energy landscape