Thesis
Supramolecular amorphous systems : analysis and control of non-crystalline pharmaceutical systems
- Creator
- Rights statement
- Awarding institution
- University of Strathclyde
- Date of award
- 2022
- Thesis identifier
- T16229
- Person Identifier (Local)
- 201659355
- Qualification Level
- Qualification Name
- Department, School or Faculty
- Abstract
- Recent years have seen an increase in interest in amorphous pharmaceutical solids due to their solubility benefits when compared to their crystalline counterparts. This thesis reports approaches for reliable collection and analysis of X-ray pair distribution function (PDF) data to enable structural insights to amorphous pharmaceuticals to improve understanding of structure and properties in these systems. A number of factors are considered and assessed for enabling high-quality laboratory PDF, including sample handling and data collection methodologies, before applying to the amorphous systems indomethacin-polyvinylpyrrolidone (IND-PVP) and AZD5718, a small-molecule active pharmaceutical ingredient (API) currently under development at Astra Zeneca. High-throughput synchrotron X-ray PDF is applied to amorphous paracetamol (PCM) to understand structure and transformations in the amorphous solid. Optimisation of data collection, sample handling and data treatment procedures enabled laboratory PDF analysis of amorphous pharmaceuticals which compared favourably to benchmark synchrotron PDFs. This enabled in-house structural investigations including limit of detection of crystallinity and the impact of elevated humidity on the amorphous structure. PDF was found to be sensitive to both low levels of crystalline material and structural changes induced by moisture absorption. Investigations of amorphous AZD5718 revealed subtle structural changes as a result of preparation method, which were largely due to small differences in the water content in the two preparations, demonstrating again the sensitivity of PDF analysis to subtle structural changes. MD simulations revealed significant disruption of hydrogen bonds in the amorphous matrix by water. By extracting sample conformations from the MD simulations, the dominance of the intramolecular structure to features in the low-𝑟 region of the PDF was demonstrated. High-throughput synchrotron PDF analysis enabled tracking of structural transformations in amorphous PCM, where subtle differences were detected statistically through the 𝛽- and glass transitions, and upon crystallisation. MD simulations coupled with PDF allowed production of a structural model of amorphous PCM, and provided a possible explanation for the observed crystallisation behaviour of amorphous PCM.
- Advisor / supervisor
- Florence, Alastair
- Resource Type
- Note
- This thesis was previously held under moratorium from 12th May 2022 until 12th May 2025.
- DOI
- Date Created
- 2021
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