Thesis

Real-time determination of active pharmaceutical ingredient solubility in polymer matrices and solid-state monitoring using in situ terahertz (THz)-Raman spectroscopy during extrusion

Creator
Rights statement
Awarding institution
  • University of Strathclyde
Date of award
  • 2025
Thesis identifier
  • T17453
Person Identifier (Local)
  • 201986596
Qualification Level
Qualification Name
Department, School or Faculty
Abstract
  • This thesis aimed to develop and demonstrate the application of in situ terahertz (THz)-Raman spectroscopy as a real-time monitoring tool for determining active pharmaceutical ingredient (API) solubility in a polymer matrix during extrusion. Initially, a qualitative analysis was conducted to assess API solubility during the extrusion of a ternary system consisting of mefenamic acid, sorbitol, and Soluplus. A solubility diagram was constructed using preprocessed in situ THz-Raman spectra, and off-line characterisation techniques confirmed the absence of crystallinity in the extrudates. The maximum API solubility was established at 15% w/w. Building on these findings, the thesis progressed to semi-quantitative analyses using multivariate curve resolution-alternating least squares (MCR-ALS) to quantify the ratios of amorphous and crystalline API components during extrusion. MCR-ALS was applied successfully to two binary systems and a more complex ternary system. The optimised MCR parameters derived from the first binary system were transferable to the subsequent systems, providing chemically meaningful results. Moreover, use of reference spectra as a constraint did not show any advantage, confirming the effectiveness of MCR-ALS as a calibration-free method for resolving in situ THzRaman spectra obtained during extrusion. Notably, the high sensitivity of MCR-ALS to crystalline content was demonstrated by the close match between experimental and reconstructed spectra at higher drug loadings. Finally, the insights from earlier chapters were applied to the case study in collaboration with Eli Lilly and company. The high drug-loaded amorphous solid dispersions (HASDs) containing evacetrapib were successfully formulated with 50% w/w API in the most suitable polymer, i.e., Soluplus. Off-line characterisation confirmed the absence of crystallinity in both fresh and 3-month-old extrudates, indicating the successful formulation of stable HASDs. The in situ and off-line characterisation techniques were largely in agreement. In conclusion, this research highlights the impact of in situ THz-Raman spectroscopy and MCR-ALS in pharmaceutical manufacturing, enabling real-time solid-state monitoring, formulation design, and process control. These findings establish a foundation for broader applications of process analytical technology, with potential benefits beyond extrusion in drug development and production efficiency.
Advisor / supervisor
  • Nordon, Alison
  • Halbert, Gavin
  • Robertson, John
Resource Type
Note
  • Previously held under moratorium from 3 September 2025 until 3 March 2026.
DOI
Funder
Embargo Note
  • This thesis is restricted to Strathclyde users only until 3 September 2030

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