Temperature-dependent Terahertz Time-domain Spectroscopy as a Tool to Assess the Crystallisation Tendencies of Amorphous Drug-Polymer Systems
type: CreativeWork
description: 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 …
abstract: 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 …
author: Mahmood, Haseeb
language: eng
keywords: Terahertz, Spectroscopy, Amorphous, Crystallisation, Drugs, Polymers
license: https://www.repository.cam.ac.uk/bitstreams/5fb7c1da-3107-4643-a948-c4fbbac542f2/download
license: http://purl.org/NET/rdflicense/allrightsreserved
date published: 2025-11-07
date modified: 2026-07-24T01:33:13Z
provider: Cambridge University
publisher: Networked Digital Library of Theses and Dissertations
type: WebPage
source organization: University of Cambridge

PropertyValue
property ID: DOI
value: 10.17863/CAM.132124