Breast cancer chemotherapy often damages rapidly reproducing cells without discerning between those which are healthy and those which are neoplastic. In this project the design, synthesis and evaluation of novel tumour targeting conjugates were investigated. Polyamines are an attractive tool in targeted cancer therapy since their transport system (PAT) can be used to facilitate the cellular uptake of cytotoxic drugs conjugated to them. Furthermore the PAT is upregulated in many cancer cells because of their high demand for them. Consequently, synthetic analogues which contain a cytotoxic moiety linked with a polyaminic portion could be transported in higher concentrations into cancer cells than into those which are normal. Additionally, polyamines exhibit a high affinity for nucleic acids; therefore drugs containing an antineoplastic moiety which targets DNA and a polyaminic portion may exhibit a bifunctional mode of binding to the nucleic acid and hence an higher cytotoxicity. In order to improve selectivity, a trifunctional conjugate was designed composed of an oestrogenic ligand and an acridinic moiety, linked by an amido bond to the polyamine spermine. The acridine is expected give rise to the main cytotoxic action via DNA intercalation, whereas the oestrogenic portion is predicted to provide an additional selectivity against those breast cancer cells which are oestrogen receptor positive (ER+). Synthetic studies towards the target molecule were partly successful with the two halves of the conjugate, the functionalised oestrogen and polyamine linked acridine (PAC), being made. However time prevented the final step, linking these moieties, from being achieved. The cytotoxicity of PAC and the controls mitoxantrone (MTO) and 9-aminoacridine (AMAC) was found against four ER+ cell lines (MCF7, T 47D, 5637, ZR-75-1) and one ER- (Hs 578T). PAC had μM IC50 values in each cell line and was more cytotoxic than AMAC, but less than MTO. To optimise the activity of the synthetic polyamine conjugate, DFMO, an irreversible inhibitor of a key enzyme in the synthesis of endogenous polyamines, was co-administered during cytotoxicity assays. Depletion of the endogenous polyamine pool by inhibition of biosynthetic enzymes has been shown to upregulate PAT and hence leads to enhanced uptake of polyamine analogues. The resulting IC50 values were in the nM range suggesting that the PAC is transported by PAT. The Chinese Hamster Ovary (CHO) cell line is known to strongly express PAT whilst the mutant CHO-MG is devoid of it. The IC50 values for PAC were similar (μM) for both cell types suggesting that PAC is not transported predominantly by PAT and that DFMO acts synergistically via an alternative mechanism. Interestingly the cytotoxicity of MTO was increased by a similar order upon co-administration with DFMO. Spectrophotometric analysis of mixtures of PAC with calf thymus DNA showed clear isosbestic points indicating that PAC has a single mode of binding. This is consistent with base pair intercalation, typical of widely used chemotherapics including MTO.

Cryptolepine is a tetracyclic, aromatic natural product, isolated from West African shrubs of the Cryptolepis species, consisting of fused indole and quinoline rings. Due to its polyaromatic character it is able to intercalate into DNA showing a unique selectivity for non-alternating GC base pairs. Cryptolepine, and especially its halogenated analogues, have been investigated for their anti-malarial and anti-cancer activity, the latter being the area of interest of this thesis. A number of novel halogenated indoloquinoline cryptolepine analogues were synthesised in order to determine their abilities to interact with DNA, and to inhibit topoisomerase II activity. In vitro cytotoxicity testing was carried out using human tumor cell lines MCF-7 (breast cancer), 5637 (bladder cancer), DLD-1 (colon cancer) and A-549 (lung cancer) via the MTT assay. The halogenated cryptolepine analogues were allowed to bind to calf thymus DNA and the melting points of these complexes measured. An increase in melting temperature between 4.5 and 12°C was seen when compared to naked DNA. Inhibition of topoisomerase II was seen at concentrations between 0.5 and 0.020 μM compared to 5 μM for cryptolepine. All compounds showed cytotoxic activity in the range 0.07 to 73.87 μM against the tumor cell lines after 96 hr exposure. 11-lodocryptolepine was found to be the most potent on all of the cell lines tested, with IC₅₀ values down to sub micro molar levels. This analogue was also one of the most potent at topoisomerase II inhibition (0.5 μM) and had a ΔTm of 12.0°C. However, despite 11-chlorocryptolepine being the most potent at inhibiting topoisomerase II (0.02 μM), it was found to be the least potent in vitro and had one of the lowest ΔTm values (5.0°C). Cellular incorporation of the analogues was investigated by using laser confocal microscopy which showed that 11-iodo and 11-bromocryptolepines had nuclear localisation, whereas, the 11-chlorocryptolepine analogues remain in the cell membrane.

A high proportion of prostate cancer and benign prostatic hyperplasia (BPH) have been shown to be dependent on androgen biosynthesis. The biosynthesis of androgens is undertaken by a number of important enzymes such as 17a-hydroxylase/17,20-lyase and 17[beta]-hydroxysteroid dehydrogenase. Through the inhibition of these enzymes it is possible to. reduce the amount of androgens present, which in turn reduces the stimulation of androgen-dependent prostatic diseases. Within the current study, we have undertaken the biochemical evaluation of a number of compounds of varying structural features and which were synthesised within our group as potential enzyme inhibitors in the tretament of androgen-dependent diseases. In general, the results from the current study show that the compounds evaluated against the enzyme complex 17a-hydroxylase/17,20-lyase possessed good inhibitory activity. In particular, the imidazole-based inhibitors were found to be more potent against 17,20-lyase in comparison to 17a-hydroxylase, and were more potent than the triazole-based compounds. The most potent compounds within the current study include: 1-(7-phenyl-heptyl)-1H-imidazole (171) (lC50=98.5±15.6nM, K¡=55.3±3AnM against 17,20-lyase and IC50=O.32±O.05I-lM, K¡=O.21±O.01¡.¡M against 17a-hydroxylase), 1-[7 -(4-fluoro-phenyl)-heptyl]-1 H-imidazole (179) (IC50=57.5±1.5nM, K¡=21.5±O.1nM against 17,20-lyase and IC50=173.62±7.00nM, K¡=77.5±2.5nM against 17 a-hydroxylase) and 1-[5-(4-bromo-phenyl)-pentyl]-1 H-imidazole (187) (IC50=58.1±5.2nM against 17,20-lyase and IC50=O.50±O.04I-lM against 17a-hydroxylase), these compounds were all potent inhibitors compared to the standard inhibitor ketoconazole (1) (lC50=1.66±O.15¡.JM, K¡=O.67±O.02¡.¡M against 17,20-lyase and IC50=3.76±O.01I-lM, K¡=1.24±O.01¡.¡M against 17a-hydroxylase). In an effort to discover lead compounds in the inhibition of the 17[beta]-hydroxysteroid dehydrogenase (17[beta]-HSD) family of enzymes, a range of commercially available compounds based on phenyl ketones were initially evaluated against type 1 (17[beta]-HSD1) and 3 (17[beta]-HSD3) of 17[beta]-HSD which are responsible for the reduction of estrone and androstenedione to estradiol and testosterone respectively. The majority of these compounds were found to possess weak inhibitory activity, however, some were found to possess good inhibitory activity. As such, a number of compounds were synthesised within our group as potential inhibitors of 17[beta]-HSD1 and 17[beta]-HSD3. The results show that the 4-hydroxyphenyl ketone-based compounds were found to be . highly potent against type 3 in comparison to type 1. For example, 1-(4-hydroxy-phenyl)-nonan-1-one (254) was found to possess (against type 3) inhibitory activity of 83.53±OA8% (at [1]=100¡.¡M) (IC5o of 2.86 ± O.03¡.¡M). Under similar conditions, 254 was found to possess 36.32±O.33% (at [1]=100¡.¡M) inhibitory activity against type1. A range of compounds were also synthesised based on the biphenyl ketones, however, these were found to be weaker inhibitors of type 3 in comparison to the 4- hydroxyphenyl ketones although they possessed greater inhibitory activity against type 1. In an effort to determine the selectivity of these compounds against the overall class of HSD enzymes, all inhibitors were evaluated for 3[beta]-hydroxysteroid dehydrogenase (3[beta]-HSD) inhibitory activity. We discovered that in general, all of the synthesised compounds possessed weak inhibitory activity against this enzyme at inhibitor concentration of 100¡.¡M and 500¡.¡M, as such, these synthesised compounds could be considered to be good lead compounds for the inhibition of 17[beta]-HSD.

The present study was designed to investigate the effect of lipid lowering therapy, using lovastatin or simvastatin (HMG-CoA reductase inhibitors), on coronary or aortic atherosclerotic lesion development in the St. Thomas' Hospital strain of genetically hyperlipidaemic rabbit. The primary aim of this study was to investigate the effects of lovastatin treatment on the development and regression of coronary atherosclerotic lesions in St Thomas' hospital rabbits (n=40). Light microscopic (LM) and scanning electron microscopic (SEM) examinations were carried out on the coronary arteries from lovastatin treated (12mg/Kg/day, for varying time periods) and control animals. No coronary lesions were found in lovastatin treated animals. However, coronary lesions were evident in a number of the untreated rabbits. Detailed histopathological examination demonstrated that the left septal (LSP) coronary arteries were most severely affected compared to the left circumflex LCX), left anterior descending (LAD) and right coronary arteries (RCA). There was no evidence of myocardial lesions present in either treated or control rabbits. To investigate the effect of simvastatin on established aortic atherosclerotic lesions, St. Thomas' rabbits (8 months old) (n=24) were treated with simvastatin (I0mg/Kg/day) for 12 months. Biochemical analysis of the treated animals revealed a 58% and 73% reduction in total plasma cholesterol and LDL cholesterol respectively. This decrease in LDL cholesterol led to a significant reduction of 82% (p<0.05) in the percentage area of fatty streaking and a reduction of 63% (p<0.05) in the intima to media ratio. A cholesterol exposure index was calculated based on plasma cholesterol levels and time. It was found that there was a highly significant linear relationship between cholesterol exposure index and fatty streaking (r[sup]2 =0.73) (p<0.001), and also between cholesterol exposure index and intima to media ratio (r[sup]2=0. 72) (p<0.001). The effect of lovastatin therapy on the macrophage foam cell population and the intercellular adhesion molecule-1 (ICAM-1) were studied in aortic atherosclerotic lesions of St Thomas' hospital rabbits using immunohistochemical techniques. Treatment with lovastatin led to a decrease in the number of macrophage foam cells in lesions. There was a 82% and 92% reduction after 6 and 10 months of treatment respectively. Moreover, there was significant increase in the ICAM-1 expression in the control animal group compared with the lovastatin treated group (p<0.001). It is concluded that in St. Thomas' rabbits development of coronary artery atherosclerotic lesions begins later than aortic lesions. However, early treatment with the lipid lowering 'statins ' can prevent the development of coronary atherosclerotic lesions. Later intervention may help to slow aortic lesion progression and may induce regression of established lesions. Interestingly, hypercholesterolemia and atherosclerosis were more pronounced in female than male St. Thomas' rabbits and the effect of 'statins ' were more prominent on the female rabbits. Lipid lowering therapy by 'statins' not only lowers total plasma cholesterol level, but may also aid to stabilise lesions and reduce the risk of plaque rupture through changes in plaque composition and adhesion molecule expression.

Androgen-dependent prostate cancer (PC) and benign prostate hyperplasia (BPH) can be treated either by surgical resection or through the use of drugs that produce androgen deprivation. Inhibition of the enzyme 5[alpha]-reductase (5[alpha]R), which is a membrane-bound NADPH-dependent protein and which metabolises testosterone to dihydrotestosterone (DHT) within androgen-dependent target cells, has been under investigation as a possible chemotherapeutic target for the treatment of BPH, and possibly of PC, although the correlation between the two diseases has yet to be determined. Due to the localisation of this protein within the membrane, attempts to gain information regarding the active site of 5[alpha]R have been slow. As such, a molecular modeling study of both steroidal and non-steroidal inhibitors of 5[alpha]R was undertaken in order to elucidate the essential requirements needed for the design of novel non¬steroidal inhibitors. It suggests that: (i) there is a requirement for groups to mimic the carbonyl group at the C3-position of the steroid substrate A-ring; (ii) the area about the C3, C4, CS and C6-positions of testosterone appears to be sterically hindered, presumably due to the binding of the NADPH moiety; (iii) the area of the active site about the C17-0H position of the substrate does not appear to possess hydrogen bonding groups and is unrestricted. Using the modeling data, a number of steroidal and non-steroidal compounds based upon N- and 3-substituted pyrrolidine-2,S-diones has been designed and their synthesis attempted using a number of reaction schemes.

This work describes the preparation of an immobilised ephedrine silica supported catalyst and its application in asymmetric synthesis. (1R,2S)-(-)-Ephedrine is a controlled substance, whose use in synthesis is closely monitored by a licence regulated by the Medicines and Healthcare products Regulatory Agency (MHRA). One way of reducing the demand for controlled substances as catalysts is to tether them onto a support medium so that afier use they may be recovered by filtration, washed and reactivated, if necessary, dried and then reused. In this project, (IR,ZS)-(-)-cphedrine was tethered onto a functionalised silica support and tested for its use in asymmetric alkynylation reactions involving a range of aromatic aldehydes and a terminal alkyne, phenylacetylene. The loading of the ephedrine on the supported catalyst was characterised by both elemental analysis and thermogravimetric analysis (TGA) due to the nature of the support material. The immobilised ephedrine catalyst was evaluated in asymmetric alkynylation reactions and was shown to provide good enantioselectivity (up to 92% for (R)-(+)- l ,3-diphenylprop-2-yn-l-ol) and high yields for the secondary propargylic alcohols (up to 97%). The use of the immobilised ephedrine catalyst in asymmetric alkynylation reactions was assumed to be novel. The results of the newly formed secondary propargylic alcohols proved to be comparable to those achieved by homogeneous systems. The secondary propargylic alcohols were analysed using a wide range of spectroscopic techniques such as nuclear magnetic resonance (NMR) spectroscopy, gas chromatography- mass spectrometry (GC-MS), optical rotation and high performance liquid chromatography (HPLC). Due to the restrictions placed on ephedrine, it was important to test the recyclability of the tethered catalyst to reduce the amount of the regulated drug in circulation. The catalyst demonstrated the ability to be recovered quantitatively from the reaction mixture using a simple filtration and then recycled in further asymmetric alkynylation reactions for three cycles before the yield was affected. In addition to the study, a novel tethering of ephedrine derivatives onto a silica support was investigation and its use in asymmetric alkynylation reactions explored. This was undertaken in an effort to optimise and improve upon the results obtained from N-methylcphedrine alone. Our initial results showed that it is possible to tether ephedrine derivatives onto a silica support and then employ them in asymmetric synthesis, thus opening up the possibility to use controlled ephedrine more efficiently.

The research described in this thesis is based on novel analytical approaches to develop new methods for determining psychoactive and therapeutic drugs in biological matrices. All the analytical methods developed were according to Food and Drug Administration (FDA) guidelines. The first project involved development and validation of an analytical method for quantification of psychoactive drug mephedrone and its two metabolites 4- methylephedrine and 4-methylnorephedrine in human hair using liquid chromatography tandem mass spectrometry (LC-MS/MS). Recent abuse of designer drugs such as mephedrone has presented a requirement for sensitive, reliable and reproducible analytical methods for the detection of these controlled drugs in different matrices. Based on the similar structure of mephedrone to other methcathinones and amphetamines, the study also proposed a similar metabolic pathway for mephedrone. The method developed can be of great value for the future detection of mephedrone and its two metabolites in human hair. Having completed the above, another analytical method was developed capable of detecting 0.6 ng/mg abacavir and tenofovir in human hair using LC-MS/MS. The method was successfully validated for the intraday precision, interday precision, and limit of detection, accuracy and extraction recovery. This is the first full report of a method for the simultaneous determination of these two key antiretroviral drugs in hair. The newly developed method is useful for future routine analysis of tenofovir and abacavir in human hair and could be used in therapeutic drug monitoring and adherence to medicines studies, which would be helpful in decision making regarding treatment change in combination anti-retroviral therapies. The last project focused on analysing dietary substances such as green and white tea, fruit juices along with catechins present in tea and corticosteroids in order to investigate potential inhibitory effects on the glucuronidation of B2" agonists clenbuterol and formoterol. [3;- agonists are frequently prescribed for the treatment of asthma in athletes. Due to performance-enhancing effects, these [3;- agonists have been subjected to restrictions in sport. A glucuronidation method using human liver microsomes (HLM) and uridine 5'-diphospho-glucuronosyltransferase (UGT2B17) has been used. The study shows that common dietary products and the catechins present in tea inhibit the glucuronidation activity of forrnoterol which effects/alters the actual drug concentration when testing in human body/urine and may help in masking formoterol misuse therefore having implications on current doping control in sport.

Introduction: Cloudiness of the eye-lens -cataract- is part of the eye lens aging process. Cataract is known to be the leading cause of blindness worldwide as it contributes towards 51% of all blindness cases. A cararact formation has been associated with reduced levels of glutathione (GSH) in the eye. Recent work showed that cystine-glutamine exchangers are expressed in the lens nucleus which suggests that these exchangers could be targeted to increase the cysteine (GSH precursor) that plays a vital role in the GSH lenticular biosynthesis. L-2-oxothiazolidine-4-carboxylic acid (OTZ) is a cysteine pro-drug that is believed to increase intracellular GSH levels. Hypothesis: Ocular supplementation of cysteine or OTZ (cysteine prodrug) would increase the lenticular level of GSH, this is likely to prevent or delay the formation of cataract. Experimental: Preformulation studies were conducted to assess OTZ aqueous solubility and permeation through excised bovine cornea and sclera. A new analytical method based on hydrophilic interaction liquid chromatography (HILIC) was developed and validated following FDA guidelines to separate and quantify OTZ in different biological matrices. Four different nanoparticle delivery systems, namely chitosan, modified chitosan, poly (lactic-co-glycolic acid) -PLGA- and cerium oxide nanoparticles were formulated. The formation of chitosan nanoparticles was optimised using experimentally design chitosan nanoparticles. Considered responses include particle size, polydispersity index, [Zeta] potential, entrapment efficiency and release profile. Optimised chitosan nanoparticles loaded with OTZ were formulated using an ionotropic gelation method. A short alkyl glycerol group was added ti the chitosan backbone at the N-position to ofm N-acyl glycerol chitosan, formation of N-modified chitosan was investigated using several analytical and spectroscopic tecniques. N-modified chitosan nanoparticles were fabricated by ionic gelation. A double emulsion solvent diffusion (DES-D) method was used to formulate OTZ-loaded PLGA nanoparticles. HPMC-coated cerium oxide nanoparticles were fabricated in two steps: first, double emulsion formation to entrap OTZ into HPMC; second, homogenous precipitation to formulate cerium oxide nanoparticles. Particle size, [Zeta] potential, entrapment efficiency, particle morphology and in vitro release were measured for all the formulated nanoparticle systems. Further, permeation studies for all the formulated nanoparticles were performed on excised bovine sclera and cornea. Ocular tolerability was assessed using bovine corneal opacity and permeability followed by histological examination, Red Blodd Cell hemolysis and Hen's Eggs Test Chorioallantoic Membrane test. Different concentrations of the four nanoparticulate systems were used to assess the cytotoxicity to a lens epithelium cell line using the neutral red uptake (NRU) and suforhodamine B colorimetric (SRB) assays. The effect of those systems on the lens epithelium cell line was monitored using real time imaging techniques; this allows monitoring of the cell morphology and shape in addition to calculating the cell growth in real time. The effect of cystine on the ceulluar level of GSH was invetigated. Monochlorobimane (MCB) dye was used to quantify the GSH levels of cysteine treated HLEC-B3 cells. Results: The HILIC developed method was found to accurate and precise wiht LLOD and LOOQ on 100 and 200 ng/mL respectively. The optimisation process revelaed that the two most important variables in the formulation of chitosan nanoparticles were chitosan and TPP concentration. These optimised conditions were chosen to produce the chitosan nanoparticles. The optimised nanoparticles had a size and [Zeta] potential of 133.0 nm and 28 mV repectively. Using chitosan nanoparticles, the permeation of OTZ thriugh excised bovine cornea and sclera was higher than the OTZ simple solution. This increase may be attributed to the permeation enhancing properties of chitosan. The analytical and spectroscopic techniques confirmed the success of the N-acyle glycerol modification on the chitosan backbone. Both NMR and IR showed the modification peaks, gel permeation chromatography (GPC) showed an increase in the molecular weight of the modified chitsan (197.8 kDa) compared to the unmodified (151.4 kDa). The modified chitosan nanoparticles had a size of 176.7 nm and [Zeta] potential of 24.2 mV. Although the entrapment efficiency of the modified chitosan nanoparticles was less compared to the unmodified form (73.3 and 86.9% respectively), the permeation of OTZ from modified chitosan nanoparticles was comparable to the unmodified one, this indicates that the modification had improved the ocular permeation of OTZ from the nanoparticles. The formulated PLGA nanoparticles had a particle size, and [Zeta] potential of 92.9nm, and -8.6mV respectively, with an entrapment efficiencey of 68.4%. The mechanical properties of the formulated PLGA nanoparticles were investigated using atomic force microscopy (AFM), the results showed uniform and non-porous nanoparticles. Trans-scleral permeation of OTZ was 6 times that through the cornea using PLGA nanoparticles. Nanoceria were formulated and coated with hydroxypropyl methylcellulose (HPMA). The X-Ray diffractograms of coated nanoceris confirmed the formation of an HPMC coat. FT-IR spectra further confirmed the presence of polymer coatung on the surface of the nanoceria by showing peaks representing hydroxypropyl and epoxy groups of HPMC. Particle size and zeta potential of HPMC coated nanoceria were 15 [plus or minus] 1.19 nm and -1.67 [plus or minus] 0.2 mV respectively. Scanning electron microscopy and transmission electron microscopy revealed the formation of uniform well dispersed spherical nanoparticles. Furthermore, certain oxide nanotparticles showed [zeta] potential of -1.67 [plus or minus] 2.07 mV with HPMC and -34.67 [plus or minus] 2.33 mV without HPMC coating. This reduction in [Zeta] potential after coating which is attributed to the ability of the HPMC coat to mask the negative charge of cerium oxide. The ex-vivo permeation studies revealed that the scleral permeation of OTZ is 10 times higher than the corneal permeation. OTZ is a hydrophilic molecule, and as such is expected to show better permeation through the sclera over the cornea for all the permeation studies. The results obtained from the BCOP, HET-CAM and RBC haemolysis assays alongside with the histological examination illustrated the, the formulated nanoparticulate systems were wll endured by the ocular surface and dveoid of any irritation effect on the ocular surfaces. Additionally, NRU and SRB cytoxic assays showed no cytoxic effect from modified chitosan, PLGA nanoparticles and HPMC coated nanoceria on the HLEC-B3 cell line. However, these assays revealed that chitosan nanoparticles were mild irritantsto the HLEC-B3 cell line at a higher concetration. Real time imaging was used to study and evaluate the cell morpholology and growht before, during and after exposure to the nanoparticulate systems. The imaging technology confirmed that those cells were grown normally without any abnormality. HLEC-B3 cells treated with cyctine for 24 hours showed an increase in GSH levels. Cystenine is a GSH precursor and it is the rate limiting step in GSH biosynthesis. As such, it would be expected that, supplementing the cell with cyctine will enhance the GSH level. Conclusion: Formulation of OTZ (cysteine prodrug) has been fine-tuned through incorporation into various nanoparticulate systems. These nanoparticulate systems have the potential to prolong OTZ residence time, control the release and ocular permeation of OTZ. Cysteine has been shown to increase the GSH cellular levels in HLEC-B3 cell line. These findings warrant further studies on the possible use of these nanoparticulate systems for cataract prophylaxis as an alternative to surgery.

The synthesis, stability and properties of two particular processible conducting polymer types, polyaniline and polythiothene have been investigated. Those two classes of polymers have great commercial potential but their properties can be difficult to control. Polythiophene was evaluated as potentially useful in a photolithographic process. When polymers are involved in image formation, changing the solubility of the exposed polymer is usually required. Photodegradation was chosen as a way to render crosslinked polythiophene soluble. The photodegradation study was divided in two parts; in solution and in the solid state. Methylene blue was used in both cases as a generator of singlet oxygen. The polymer effectively underwent photodegradation under irradiation at 670nm. It could not be determined from our studies whether this effect was due to methylene blue or spontaneous photodecomposition of the polymer itself. This line of work was then discontinued and we focused on the polyanilines. The synthesis of various polymers of the polyaniline family was performed and different modes of polymerisation evaluated. In particular the parameters of the emulsion polymerisation of PANI-DBSA (dodecylbenzene sulfonic acid doped polyaniline) were evaluated and a new process was formulated. The doping on heating of polyaniline base (EB) with two dopants DBSA and toluene sulfonic acid (TSA) was studied using differential scanning calorimetry (DSC). Polymers with a molar ratio of base unit/dopant of 1 presented the good thermal stability and solubility expected from sulfonic acid doped polyanilines. The conductivity of the samples obtained was up to 15 Scm[sup]-1 and was improved by annealing polymer films, which led to conductivities of up to 25 Scm[sup]-1. Finally, a comprehensive study of the thermal stability of the various polyanilines produced is presented. The good stability of polyaniline was demonstrated by DSC and thermogravimetric (TGA) studies. The initial degradation stages were allocated to the loss or decomposition of dopants. Some degradation products were identified by gas chromatography coupled with mass spectrometry (GC-MS) and correlate with loss and decomposition of the dopants. The kinetic parameters of the decomposition of the polymers were calculated using a computer package and a tailored logarithmic method. Those parameters were then used in mathematical models of the TGA decomposition curves. They showed good agreement with the experimental results therefore proving the accuracy of the kinetic parameters. Attempts at stabilisation of the polymer using commercially available antioxidants showed that it is possible to enhance polyaniline stability even further. The secondary antioxidants used (trivalent phosphorus and divalent sulphur containing compounds) demonstrated a more positive effect on the stability of the polymers than the primary antioxidants (hindered phenols). However, even in the best conditions only a minor reduction in weight loss of the polymers can be obtained.

Purpose: There is interest in targeting the ileo-colonic region of the gastro-intestinal tract either to treat colonic disorders, or take advantage of the low enzymatic activity and relatively high residence time. Four main approaches have been proposed for ileo-colonic delivery; pH triggered, time-dependent and bacterial degradable release systems, and prodrug formation. pH triggered systems are commonly used although there are inherent problems with such systems. Researchers have ascribed failures of disintegration with enteric coated tablets in the colon to the low volume of fluid content and high viscosity in the local environment. The aim of this work is to target the ileo-colonic region with a solid dispersion technique using polyvinylpyrrolidone (PVP) to maximise dissolution, and a methacrylic acid-methacrylate copolymer (Eudragit S/L 100) to trigger release. Methods: Solid dispersions were produced using two model drugs; indomethacin (a poorly-soluble weak acid) and atenolol (a soluble weak base). The optimisation of drug polymer ratio and effect of order of mixing the constituents to the feed solution for spray drying were investigated with indomethacin and subsequently performed with atenolol. Differential scanning calorimetry (DSC) and X-ray diffraction (XRD) were used to examine the polymorphic form of the drug in the dispersion. The molecular interactions in the dispersion were studied by using infrared (IR) spectroscopy. Dissolution studies were performed across a range of pH. Results: DSC and XRD confirmed the formation of amorphous solid dispersions when drug (atenolol or indomethacin) was spray dried with the polymers. IR spectra showed peak-shifts indicative of molecular interactions between drug and polymer. Carrier controlled release was achieved with solid dispersions containing 10 % drug loading with 80:20 PVP- Eudragit S/L 100 contents. The alteration in dissolution rate of solid dispersions was ascribed to a mixture of particle size reduction, conversion to the amorphous form of the drug, the polymer characteristics, drug-polymer molecular interactions and particle surface morphological properties. Conclusion: pH-triggered drug release was successfully demonstrated in vitro with solid dispersions. The presence of strong molecular interactions and the high glass transition temperature of the resultant dispersions ensured they remained amorphous at least for six months under accelerated conditions.