Papakostas, G
(2022)
Application and evaluation of Tip Enhanced Raman Spectroscopy in pharmaceutical analysis.
PhD thesis, University of Nottingham.
Abstract
Pharmaceutical analysis plays a crucial role in drug manufacturing, allowing the identification and exploration of the physio-chemical properties and interactions between active pharmaceutical ingredients (API) and excipients within a formulation. However, conventional microscopy instruments can be constrained in resolving chemical information below the micron-length scales. A newly arising nano-analytical technique is the Tip-Enhanced Raman Spectroscopy (TERS), which can obtain valuable spatio-chemical information from the sample of interest, at the length scales of tens of nanometres or less. TERS application has been reported on numerous carbon-based and biological samples, however to-date there are no records of TERS application on pharmaceutical formulations.
This thesis evaluates the application of TERS technique on individual pharmaceutical components or amorphous solid dispersions (ASDs). These include paracetamol, felodipine, nicotinamide, copovidone, polyvinyl alcohol (PVA) either alone or in combination as well as di-phenylalanine tubes. In these studies two microscopy systems were used to examine the samples of interest. One is the custom-built combined Atomic Force Microscopy - Confocal Raman Microscopy (AFM-CRM) system (located at the School of Physics and Astronomy - Chapter 2), equipped with silicon AFM probes and the second is the TERS system which is a combined AFM-CRM instrument of similar specifications (located at the National Physical Laboratory), equipped with Ag-coated TERS probes. Under the TERS equipment di-phenylalanine tubes were tested to evaluate the degree of signal enhancement and spatial resolution which can be obtained, followed by spectral evaluation of the ASDs, namely paracetamol/copovidone 50% w/w and felodipine/copovidone 50% w/w, in Ag-coated probe retracted and engaged positions (Chapter 3). With the intense photoluminescence background noise generated from the spectra in engaged probe position, two further studies were performed to identify the potential causes in individual pharmaceutical components (Chapters 4 and 5). In Chapter 4, each tested component was exposed under prolonged laser irradiation, with the AFM-CRM instrument, finding the threshold of sample photodegradation alongside with the association of photoluminescence occurrence in temperature rise. Moreover in Chapter 5, multiple spectra were acquired under the TERS instrument as a function to apex-to-focal spot distance across the XYZ directions, recording any changes in the spectra, including signal enhancement and sample photodegradation. After identifying paracetamol’s properties to withstand prolounged laser irradiation and provide adequate signal enhancement, AFM, CRM and TERS maps were obtained from both systems (Chapter 6). Specifically, paracetamol/PVA 30% w/w 2D-printed microdot was interrogated under the probe, detecting nano-meter length inhomogeneities at the sample surface.
Under the tested bottom-illumination TERS instrument equipped with 532 nm incident light, most pharmaceutical components and formulations showed low TERS signal enhancement. In all studies, felodipine displayed photodegradation, whereas paracetamol demonstrated small enhancement beneath the probe apex. With limited signal enhancement, it was feasible to demonstrate qualitatively ASD inhomogeneity at the surface of the formulation.
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