Temperature-dependent Terahertz Time-domain Spectroscopy as a Tool to Assess the Crystallisation Tendencies of Amorphous Drug-Polymer Systems
Amorphous solid dispersions (ASDs) represent a widely adopted strategy to enhance the solubility and bioavailability of poorly water-soluble drugs. However, their inherent thermodynamic instability poses a major formulation challenge due to the tendency of amorphous drugs to recrystallise over time. This thesis explores the use of temperature-dependent terahertz time-domain spectroscopy (THz-TDS) as a sensitive, non-destructive tool to probe molecular mobility and predict the physical stability of amorphous drug-polymer systems. Specifically, the work investigates how molecular properties – such as hydrogen bonding capacity and conformational flexibility – as well as polymer grade and drug loading, influence relaxation dynamics and the crystallisation tendency of ASDs. ASDs of three model drugs – indomethacin, felodipine, and clotrimazole – were prepared with the polymer HPMCAS across a range of drug loadings and polymer substitution grades. Differential scanning calorimetry (DSC) was used to determine glass transition temperatures, while THz-TDS provided insight into temperature-dependent absorption behaviour. A three-region quadratic model was fitted to the absorption coefficient data at 0.7 THz, enabling the identification of both primary (α) and secondary (β) relaxations. The results revealed that the molecular mobility and thermal properties of these ASDs are predominantly governed by the strength of drug-polymer interactions, with hydrogen bonding being the most critical factor. With the absence of hydrogen bond donors, clotrimazole-HPMCAS exhibited elevated sub-Tg mobility, correlating with a greater crystallisation risk. Indomethacin and felodipine, meanwhile, formed strong, stabilising interactions due to their hydrogen bond donor groups. Additionally, the influence of polymer hydrophilicity was shown to modulate water uptake and relaxation behaviour. In the strongly interacting systems of indomethacin and felodipine, the evaporation of tightly bound water caused sharp changes in mobility, particularly in the most hydrophobic polymer. However, in the case of clotrimazole, higher polymer hydrophilicity led to greater mobility as – in the absence of strong interactions – the hydrophilicity of the polymer dictates water retention. This research establishes THz-TDS as a powerful tool for the rational design of stable ASDs, enabling a deeper understanding of relaxation phenomena and guiding polymer selection. The methodological framework developed – combining systematic sample preparation, thermal control, and analytical modelling – lays the foundation for future studies seeking to bridge the gap between molecular-level mobility and bulk physical stability in amorphous formulations.
Terahertz, Spectroscopy, Amorphous, Crystallisation, Drugs, Polymers
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