Lee, Para
(2023)
Predicting physical stability of pharmaceuticals and investigating use of Raman spectroscopy to interrogate molecular relaxation events.
PhD thesis, University of Nottingham.
Abstract
Poor water solubility and slow dissolution are common issues in pharmaceuticals. The pharmaceutical industry widely employs amorphous solid dispersion to enhance dissolution, accelerate it, and promote bioavailability.
Glass, unlike crystalline solids, lacks long-range order. The glass transition temperature (Tg) marks its shift from a glassy to a rubbery state, distinct from the melting point where solid turns to liquid. Understanding drug molecules in their amorphous state under varied conditions is crucial, warranting further investigation.
The widely held belief that amorphous drug stability is ensured below Tg - 50°C is questioned. Previous studies show crystal nucleation well below this temperature, such as in indomethacin at Tg - 55 K, 3,3'-dimethoxy-4,4'-bis(2,2-diphenylvinyl) biphenyl at Tg - 175 K, and amorphous naproxen at Tg - 89 K, challenging the reliability of Tg - 50 rule.
Amorphous compounds exhibit two types of molecular mobility: global mobility (primary alpha, α-relaxation) responsible for glass transition, and local mobility (secondary beta, β-relaxation). A specific form of β-relaxation, involving intermolecular rotations of whole molecules, is known as Johari-Goldstein (JG) beta secondary relaxation, serving as a precursor to global α-relaxation mobility.
Previous studies often empathized macroscopic properties of the materials such as alpha relaxation, mechanical or dielectric changes. The novelty of our study lies in using Raman spectroscopy and directly interrogating the molecular structure, conformation and inter-molecular bonding during temperature variation around alpha and beta transitions.
We conducted an in-depth Raman spectroscopy study of alpha and beta relaxation processes. In Chapter 3, paracetamol served as the model drug to explore spectral changes around alpha and beta transition temperatures for reproducibility. Chapters 4 and 5 continued this investigation with nifedipine and felodipine as model drugs, chosen due to their similar Tg values but contrasting crystallization tendencies.
In our study, no changes were detected near the glass transition temperature, contrary to literature. Unlike previous studies on polymers, we focused on small molecules, potentially explaining the lack of observed beta relaxation changes. Different relaxation time scales between polymers and small molecules might be a factor. Fast cooling in polymer systems may lead to excess enthalpy seen in DSC at the glass transition temperature. Previous DSC research showed annealing enables beta-relaxations. For future studies, a heat-cool-anneal-heat approach could explore sample enthalpic relaxation, diverging from our heat-cool-heat method.
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