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.
| Date of Award | 19 Aug 2025 |
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| Original language | English |
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| Awarding Institution | - University Of Strathclyde
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| Supervisor | Alison Nordon (Supervisor) & John Robertson (Supervisor) |
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