University of Cambridge
Investigating the Variations in Molecular Mobility within Amorphous Formulations using Terahertz Spectroscopy
Abstract
dc:description.abstractNumerous promising drug candidates are discontinued during development due to their poor aqueous solubility, a common challenge encountered by crystalline drugs. This challenge can be overcome by formulating such drugs into amorphous solid dispersions (ASDs). ASDs can load higher doses of drugs, but they are at a higher energy state than their crystalline counterparts, which leads to recrystallisation over time. In this thesis, terahertz time-domain spectroscopy (THz-TDS) was used to probe variations in molecular mobility within different amorphous systems, with the aim of predicting physical stability based on these changes. The investigation began with a basic polymer-water binary system, representing the simplest case of hygroscopic amorphous formulations. Subsequently, the study progressed to more complex systems involving drug-polymer interactions. Finally, the most complex system investigated included the drug, polymer, residual water, and other additives. Polyvinylpyrrolidone/vinyl acetate copolymer (PVPVA), used to formulate poorly water-soluble drugs, was used as the polymer for all investigations. PVPVA exhibits hygroscopic behaviour and will absorb water over time. The residual water inherently present in the PVPVA backbone is often overlooked by the research community, but THz-TDS demonstrates that even this minimal water significantly influences changes in mobility. For the drug component of the investigation, indomethacin (IMC) was selected due to its Class III classification in the Glass Forming Ability (GFA) scale, indicating a low tendency to recrystallise. This characteristic makes IMC an ideal candidate for studying changes in molecular mobility without interference from additional factors such as crystallisation. The initial study of PVPVA-water demonstrates the significant impact of water on mobility, a consistent finding across various amorphous systems studied. While DSC and XRD can confirm the amorphous state of samples, they have limitations in detecting trace water content and struggle to measure solubility temperatures at low drug loadings. To overcome these challenges, THz-TDS emerges as a promising tool for assessing mobility changes in the presence of trace water. Notably, THz-TDS can predict the tendency for amorphous formulations to recrystallise, even at low drug loadings, a capability beyond DSC. These findings demonstrate the potential of THz-TDS in detecting trace water and predicting physical stability in pharmaceutical formulations.
Degree
thesis:*- Name dc:type.qualificationname
- Doctor of Philosophy (PhD)
- Level dc:type.qualificationlevel
- Doctoral
- Grantor dc:publisher.institution
- University of Cambridge
- Year dc:date.issued
- 2024
Author and committee
dc:creator, dc:contributor.*- Author dc:creator
-
- Santitewagun, Supawan
- Advisor dc:contributor.advisor
-
- Zeitler, Axel
Subjects
dc:subject × 8Rights
dc:rightsIdentifiers
dc:identifier.*- DOI dc:identifier.doi
- https://doi.org/10.17863/CAM.112565
- OAI identifier oai:identifier
- oai:www.repository.cam.ac.uk:1810/374525