Thesis
Spatially resolved spectroscopy for monitoring the solvent content in pharmaceutical drying
- Creator
- Rights statement
- Awarding institution
- University of Strathclyde
- Date of award
- 2024
- Thesis identifier
- T17081
- Person Identifier (Local)
- 202093993
- Qualification Level
- Qualification Name
- Department, School or Faculty
- Abstract
- The pharmaceutical drying process is critical to the quality of the activepharmaceutical ingredient or the drug product as it is often the final unitoperation. The non-uniformity of drying is particularly challenging as it rendersinaccurate the determined solvent content and drying endpoint, which is acritical quality attribute. As process analytical technology further develops,novel techniques are implemented to address process and product challenges.Spatially resolved spectroscopy is a technique in which spectra are collectedfrom spatially resolved distances from the incident light. This technique is usedfor the characterisation of non-uniform media. In this thesis, the use of spatiallyresolved spectroscopy for the monitoring of the drying of an activepharmaceutical ingredient is reported.Pharmaceutical drying of model systems was monitored using spatiallyresolved spectroscopy. In this work, three bespoke probes were used for thecollection of spatially resolved spectra. One probe allows the collection ofspatially and angularly resolved diffuse reflectance near-infraredmeasurements (SAR-DRM), while the other was developed for the collectionof spatially offset Raman spectroscopy (SORS) measurements. The thirdprobe combines both techniques and was developed for the collection of bothspatially resolved near-infrared spectra and spatially offset Raman spectra andis termed the combined probe. This thesis details the in-line and at-lineapplication for industrial process monitoring using these techniques, which toour knowledge were not applied in this setting.The drying of two grades of paracetamol, granular and powder, in the solventsn-heptane and methyl tert-butyl ether was monitored using SAR-DRM. Thedrying of granular and powder paracetamol in the solvents anisole and methyltert-butyl ether was monitored using SORS. Partial least squares regression(PLSR) analysis was used for the estimation of the solvent content using spectra from the individual signal collection configurations, in addition to acombination of the configurations. Results from both techniques suggest thatPLSR models of spectra collected from larger distances lead to more accurateviiestimations of the solvent content. This was attributed to the larger volume ofthe drying powder cake probed by those techniques. Since the drying ofparacetamol in methyl tert-butyl ether could be monitored using bothtechniques, the combined probe was used for monitoring this system, andmulti-block PLSR analysis was conducted using both near-infrared and Ramanspectra of combinations of the configurations. The multi-block PLSR modelperformance was similar to that of the individual SORS spectra, which wasattributed to the stronger signals and spectral features of the Raman signalcompared to the near-infrared measurements. Since the application of SORSfor the monitoring of pharmaceutical drying was demonstrated and showedimprovement in PLSR model performance and solvent content estimation,SORS was further used for the monitoring of the washing with methyl tert-butylether a paracetamol filter cake wet with anisole. The results similarly showedimproved estimations of the content of both solvents in the filter cake fromspectra from larger offset distances. The outcomes of the studies in this thesisdemonstrate the advantage of the application of spatially resolvedspectroscopy for monitoring the solvent content in pharmaceutical drying. Theuse of such novel process analytical technology offers potential for improvedprocess monitoring and accurate prediction of the process end point.
- Advisor / supervisor
- Chen, Yi-chieh
- Price, Chris
- Resource Type
- DOI
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