This thesis sets out to evaluate the application of Inverse Gas Chromatography (lGC) in the context of being a Process Analytical Technique (PAT) for the characterisation of pharmaceutical materials. It reviews the literature as it relates to the use of chromatography to determine physico-chemical properties and discusses how this has been applied to assessing surface characteristics of powders, particularly those used for pharmaceutical purposes. The review section considers the strengths and limitations of IGC based characterisation, especially where it was intended to distinguish between batches of material that might differ only subtly. Working from this base, a study was devised that would give a better appreciation of the capability of IGC to make these distinctions. A number of materials were viewed as being suitable to study, and their selection is justified on the basis of physical and chemical properties, and the extent of their use in the pharmaceutical sector. Two approaches were used in the evaluation. Firstly, IGC was carried out on materials crystallised under carefully controlled conditions, and then following milling (size-reduction) and granulation (size-enlargement). These processes are widely used in the industry. The capability of IGC to evaluate materials thus prepared is discussed. The second approach uses a variant of molecular modelling known as systematic grid based searching. This identifies low energy locations on a crystal surface where molecules may favourably attach. This has been used to study crystal growth and appeared be analogously useful in evaluating adsorption. It is concluded that IGC is valuable in a PAT context, but mainly in a complementary role. The modelling is shown to give very good correlations between the availability of low energy sites and chromatographic retention. Recommendations are made as to how IGC can be used most effectively, and how the modelling approach can be developed further.

The use of comprehensive two-dimensional gas chromatography (GC x GC) for the analysis of volatile organic compounds in the atmosphere will be presented. Three different systems have been used and developed each suited to a particular aspect of atmospheric VOC analysis. A method for the offline analysis of whole air samples using a commercial GC x GC system coupled to a time-of-flight mass spectrometer (TOFMS) has been developed and has been used during an aircraft campaign. Calibration and precision data for 60 hydrocarbon species are presented, with %RSD ranging from 0.56 to 14.78 % and LOD ranging from 0.01 - 0.61 pptv for a l L sample. The developed method was used during the RONOCO campaign and data for 39 hydrocarbon species re- ported. The system allowed for an investigation into the aromatic complexity of the samples and the effect of these aromatic species on atmospheric reactivity was also investigated. Further investigation into the VOC complexity in the atmosphere was also performed. The development of a portable valve based GC x GC system is also presented. The system uses total transfer methodology to allow for sensitive cryogen free modula- tion. Analysis of gasoline and tea tree was performed and the performance of the system was assessed using gasoline. The instrument was coupled to a thermal des- orption unit for the analysis of atmospheric VOCs and gave LODs of between 2-4 pptv for selected hydrocarbons in a l L sample. Further development of the system making it suitable for fieldwork is also presented. A third miniaturised GC x GC system has been developed, particularly suited for the analysis of biogenic VOCs. The system is compact, low power and cryogen free, with the large GC oven replaced with a novel direct column heating method. The small footprint, power and consumable requirement make this system suitable for deployment for analysis in remote locations.

Quality control monitoring analysis and original pattern recognition studies involving coupled chromatography were presented in this thesis. A number of methods had been developed for the quality control analysis, which is extremely important in biological studies that were described in this thesis.

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Emerging contaminants (EC) are unregulated substances that have entered the environment for as long as they have been produced through human activities. Within the ECs family, pharmaceuticals and personal-care products (PPCPs) is a class of the most common pollutants employed in everyday urban activities. Current regulatory approaches are inadequate to address these contaminants and the presence of such chemicals in the aquatic environment and their potential deleterious effects has received an increasing attention from the public and scientific community. Influent and effluent wastewater from Daspoort Waste Water Treatment Works (WWTW), which treats wastewater from the central Pretoria area, were sampled and analysed from January to December 2015 for pharmaceuticals and personal care products by gas chromatography time of flight mass spectrometry (GC/TOF-MS). Thirteen pharmaceuticals were selected for focused study in wastewater which include; (acetaminophen, bisphenol A, carbamazepine, diclofenac, 17α-estradiol, 17β-estradiol, estriol, famciclovir, fenoprofen, ibuprofen, primidone, progesterone and testosterone) based on the criteria of their prescription volumes in both private and public health sector in South Africa. The development of a sensitive and reliable analytical method for the simultaneous determination of PPCPs in aquatic samples was carried out; using a combined solid-phase extraction (SPE) isolation and clean-up, followed by derivatization prior to GC/TOFMS determination. A seven points concentration levels linear calibration curve with correlation coefficient (R2) ranged from 0.9988 to 0.9999 was obtained. The limits of detection (LOD) and the limit of quantification (LOQ) ranged from 0.01-0.27 μg L-1 and 0.03-0.91 μg L-1 respectively for target PPCPs. Repeatability studies gave % RSD within 3.41 – 11.72 % for peak area. The % RSD values for reproducibility studies were 2.88 – 9.91% for peak area over the three concentrations (ibuprofen: 0.4, 2 and 8 μg L-1) evaluated during 5 days. These results indicated that the proposed method has excellent precision as evidenced by very stable peak area for the analytes. The recovery testing carried out, exhibited recoveries ranging from at least 82-115% and 81-115 % in tap water and Milli-Q water respectively, with % RSD less than 12%, showing that the overall PPCPs determination method including the extraction procedure was a repeatable method.. The method was applied to target PPCPs from Daspoort influent and effluent wastewater in Pretoria (South Africa). Natural hormones and antiviral drug were not detected in all the samples analysed by this method. Bisphenol A, acetaminophen, carbamazepine, ibuprofen and diclofenac were detected at low concentrations, ranging from 0.052-135.42 μg L-1 in wastewater. The level of bisphenol A, primidone, carbamazepine, ibuprofen and diclofenac in effluent wastewater were found to be lower in comparison to the influent. Several other non-target compounds, such as benzophenone, caffeine, methocarbamol, efavirenz, atrazine, dioxaphetyl butyrate, nevirapine, androsta-1,4-diene-3,17-dione, cis-tramadol, batyl alcohol, paredrine, 7-acetyl-6-ethyl-1,1,4,4-tetramethyltetralin, propylparaben, eugenol, cholesterol, stigmasterol, guaifenesin, benzyl benzoate, 4-tert-octylphenol, diethyltoluamide, dicyclomine, terbuthylazine, spiroxamine, bis(2-ethylhexyl) phthalate, bumetrizole , were also detected in the wastewater sample using the developed method. / Chemistry / M. Sc. (Chemistry)