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The project has demonstrated the application of liquid chromatography coupled to mass spectrometry (LC-MS) for the characterisation of oligolactic acids (OLAs), employed as pharmaceutical excipients in metered dose inhalers. OLAs proved to be difficult to characterise because of their complexity, which was ascribed. to the presence of repeated structural monomeric units and a nonrepeating moiety (the head group). Furthermore, during the course of method development the potential presence of degradation products and impurities had to be considered for quality control purposes. Various LC-MS methods were developed to target both oligomeric distribution and head group functionalities of OLAs. Liquid chromatography at critical conditions (LCCC), aimed at addressing the head group distribution of OLAs, led to the separation of the cyclic impurities from the parent linear molecules. However, to successfully achieve a complete characterisation of OLAs, a second separation targeting the oligomeric distribution was investigated. Hydrophobic and polar interactions and possible solvation effects, which regulate RP-HPLC separation mechanisms, proved to be able to offer the selectivity necessary to resolve OLAs in terms of their size and their head groups, leading to the simultaneous separation between the linear molecules and their cyclic impurities and the determination of oligomeric distribution.

Acidic non-steroidal anti-inflammatory agents represent a large group of closely related compounds prescribed for the many patients suffering from rheumatic diseases. The mode of action of this group of drugs has been related to prostaglandin synthetase inhibition. This action is non- specific and may also be responsible for the gastric irritation and bleeding which constitute a major side effect. It is important therefore for patients being treated with such non-specific high dosing agents to be far better controlled than they are at present. Methods providing simple, rapid analysis of body fluids must be developed and adapted for routine use in clinical situations. These techniques are also necessary for an investigation into possible reasons for disparate drug activities observed in patients with rheumatic disease responding differently to different acidic drugs. The technique of High Pressure Liquid Chromatography (HPLC) has been explored as a means to these ends. The novel procedure of 'ionic suppression' in HPLC employing a reversed phase column and aqueous acidic solvent, based upon the physico-chemical properties of the acidic anti-inflammatory agents studied, has been developed for routine use. The procedure has been found to afford flexibility, selectivity, load capacity, sensitivity, speed and convenience over previously reported analytical methods. It is also capable of being exploited in the analysis of newly developed related drugs. The results obtained from the application of the HPLC procedure developed have been:- (1) the determination of ten non-steroidal anti-inflammatory agents in plasma and urine, (2) the application in a clinical trial of Benoxa-profen, (3) the assistance to clinicians at the Royal National Hospital for Rheumatic Diseases in providing rapid evaluation of patient compliance, (4) the simultaneous determination of four nonsteroidal anti-inflammatory agents and their metabolites in plasma and urine, (5) the profile study of levels of Sulindac and its metabolites in the plasma of a healthy volunteer after a single oral dose over 24 hours, (6) the examination of clinical urine and plasma samples of a patient treated with Clinoril and naproxen, (7) the separation of the glucuronide conjugates of ketoprofen and benoxaprofen, (8) the detection of hydroxyketoprofen as a metabolite of ketoprofen in rabbit. HPLC techniques have thus been established by this study as a most valuable aid to the modern therapy of rheumatic diseases. Improvements in detector technology will afford greater sensitivity and should extend the scope of its therapeutic applications.

This thesis is primarily concerned with the use and development of Porous Graphitic Carbon (PGC) for High Performance Liquid Chromatography (HPLC). Chromatographic studies carried out using PGC since its introduction in 1988 have shown it to posses quite unique separating properties. In particular the media has been shown to be very selective for the separation of closely related compounds such as geometric and diastereoisomers. It has also been shown to be very retentive towards compounds of increasing polarity. The magnitude of this interaction is considerable, we define it as the retention over and above that which might have been predicted if the polar functional group was replaced with a non polar group of similar size. We have called this effect, the Polar Retention Effect on Graphite (PREG). Previous attempts to correlate retention on graphite with energies associated with those molecular interactions associated with other chromatographic media have been largely unsuccessful. This has in part been due to the fact that there has been no attempt to measure in units of energy the magnitude of PREG. The main body of the thesis is then concerned with experiments, which provide information regarding the magnitude of PREG. We investigate a) the relative strength of analyte/graphite interactions to that of analyte/solvent interactions, b) the effect of coating discrete or polymeric molecules to the graphite surface on PREG and c) measure the energy associated with PREG for a range of analytes and correlate this energy with physical and calculated parameters associated with each analyte. In order to gain a measure of PREG we have developed a method which allows PREG to be measured and quantified. Based on our values of PREG we have put forward a hypothesis for the mechanism responsible for this interaction. Further work still needs to be done to strengthen this hypothesis, we therefore put forward a number of ideas and suggestions for future workers to which continue to investigate the mechanism associated with PREG.