Abstract
Low-frequency Raman (LFR) spectroscopy was used to probe a variety of pharmaceutical systems within a framework of different analysis scenarios, including macro and bulk analysis, in-situ monitoring of solid-state transformations upon exposure to different environmental conditions (for example, temperature and/or relative humidity) and during the dissolution process, and spatial analysis of solid dosage forms. Better LFR data interpretation was facilitated by the use of chemometrics and complimentary analysis using other commonly used techniques such as powder X-ray diffractometry (PXRD), differential scanning calorimetry (DSC), thermogravimetric analysis (TGA), dynamic vapor sorption (DVS) as well as computational simulations employing molecular quantum mechanics.
The first chapter gives an in-depth background on the solid-state forms, including their structural, thermodynamic and kinetic descriptors. An overview on the LFR theory, instrumentation and (chemometric) data analysis employed in this thesis is also provided together with additional details related to the other aforementioned utilized complimentary analytical techniques. In the second chapter a series of pharmaceutically relevant entities with increasing molecular complexity were investigated using variable temperature LFR spectroscopy and computational simulations. The combination of these experimental and theoretical approaches allowed to elucidate the nature of various low-energy vibrational modes, and, ultimately, establish a protocol for the preliminary computational analysis of LFR spectral features of similar pharmaceuticals.
In the third chapter celecoxib (a popular anti-inflammatory agent) was used as a model compound to investigate compression-induced destabilization in melt-quenched amorphous drugs. Destabilization was assessed via the physical stability and dissolution performance of these phases using LFR spectroscopy among other complimentary techniques. Stability studies in the glassy and supercooled states as well as surface dissolution measurements allowed for the identification of the combined impact of preparation method and compression parameters on these properties. Most notably, although a slower cooling rate during the melt-quenching process gave an amorphous phase with a higher intrinsic physical stability, it also promoted increased sensitivity to compression-induced destabilization.
The fourth chapter further explored the compression-induced destabilization phenomenon in melt-quenched amorphous solid dispersions. Three different polymers (hydroxypropyl methylcellulose (HPMC), polyvinylpyrrolidone (PVP), and polyvinylpyrrolidone/vinyl acetate (PVP/VA)) in the concentration range of 1-10% w/w were used to formulate amorphous celecoxib systems with varied intermolecular interactions between the drug and polymer moieties. Dynamic LFR and DSC measurements in the supercooled state revealed the differences in the crystallization behavior. Polymer loading was found to significantly reduce the sensitivity to compression-induced destabilization within these samples with minimal differences observed between different polymer types.
In the fifth chapter development of a new Raman subtechnique - spatially/micro-spatially offset low frequency Raman spectroscopy (SOLFRS/micro-SOLFRS) is described with its main applications aimed toward the nondestructive spatial analysis of solid dosage forms. The capabilities of this technique was tested using several model formulations comprised of celecoxib and several excipients of crystalline and amorphous nature forming a variety of different (multi-layer/multi-component) tablets. In all of the explored scenarios, the LFR spectral domain was superior to more commonly used mid-frequency Raman (MFR) or fingerprint region, where it enhanced or enabled the determination of different layer (i.e., coating) thicknesses as well as the spatial analysis of solid-state form transformations.
Lastly, the final chapter gives a brief overview of the main findings as well as provides insight into potential future directions for the application of them in relation to both research and industry based pharmaceutical settings.