Thesis

Predictive design of stable polymer-based amorphous solid dispersions

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Awarding institution
  • University of Strathclyde
Date of award
  • 2025
Thesis identifier
  • T17397
Person Identifier (Local)
  • 201772507
Qualification Level
Qualification Name
Department, School or Faculty
Abstract
  • The potential of amorphous solid dispersions (ASDs) solving current aqueous solubility challenges within the pharmaceutical industry has been extensively reported. Nonetheless, the difficulty of ensuring long-term physical stability has limited its translation into commercial drug products. One of the main factors that determines ASD physical stability is the solubility of the API in the polymeric carrier. However, there is a scarcity of reliable methods available for its determination. In this thesis, this was directly addressed by developing a novel empirical method to determine the saturated solubility of crystalline API in polymer matrices. Hot melt extrusion and low-frequency Raman (LFR) spectroscopy were combined for the first time for real-time API-polymer solubility determination. This approach enabled construction of solubility phase diagrams that inform safe processing windows to avoid residual API crystallinity, inform maximum drug loadings and aid polymer selection for maximum API solubility and ASD physical stability. The solid-liquid equilibrium depicting the API solubility curve was also compared to state of the art DSC-based methods, including the Flory-Huggins and Kyeremateng modelling approaches, among others. Equilibrium assumptions and potential shortfalls leading to under or overestimations were discussed. In addition, the impact of drug loading and processing temperature on the ASD internal microstructure was investigated by means of synchrotron phase-contrast micro tomography (Sync-PC-μCT). Furthermore, the local distribution evolution of the API and polymer on the ASD surface was investigated through time-of-flight secondary ion mass spectrometry (ToF-SIMS) chemical mapping. Surface phase-separation and crystallisation kinetics were determined and compared to bulk crystallisation phenomena. A close link was established between the coordinates of the solubility phase diagram and ASD properties such as the degree of structural heterogeneity and the crystallisation induction time and rate. Overall, these results suggest the API saturated solubility determined by the LFR method could be used as a physical stability predictor for the design, development and manufacture of stable polymer-based ASDs with desired structure and performance.
Advisor / supervisor
  • Halbert, Gavin
  • Robertson, John
Resource Type
DOI
Date Created
  • 2023

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