Design and characterisation of novel blends of poly(lactic acid)

This thesis is concerned with the effect of polymer structure on miscibility of the three component blends based on poly(lactic acid) (PLA) with using blending techniques. The examination of novel PLA homologues (pre-synthesised poly(a-esters)), including a range of aliphatic and aromatic poly(a-esters) is an important aspect of the work. Because of their structural simplicity and similarity to PLA, they provide an ideal system to study the effect of polyester structures on the miscibility of PLA polymer blends. The miscibility behaviour of the PLA homologues is compared with other aliphatic polyesters (e.g. poly(e-caprolactone) (PCL), poly(hydroxybutyrate hydroxyvalerate) (P(HB-HV)), together with a series of cellulose-based polymers (e.g. cellulose acetate butyrate (CAB)). The work started with the exploration the technique used for preliminary observation of the miscibility of blends referred to as “a rapid screening method” and then the miscibility of binary blends was observed and characterised by percent transmittance together with the Coleman and Painter miscibility approach. However, it was observed that symmetrical structures (e.g. a1(dimethyl), a2(diethyl)) promote the well-packing which restrict their chains from intermingling into poly(L-lactide) (PLLA) chains and leads the blends to be immiscible, whereas, asymmetrical structures (e.g. a4(cyclohexyl)) behave to the contrary. a6(chloromethyl-methyl) should interact well with PLLA because of the polar group of chloride to form interactions, but it does not. It is difficult to disrupt the helical structure of PLLA. PLA were immiscible with PCL, P(HB-HV), or compatibiliser (e.g. G40, LLA-co-PCL), but miscible with CAB which is a hydrogen-bonded polymer. However, these binary blends provided a useful indication for the exploration the novel three component blends. In summary, the miscibility of the three-component blends are miscible even if only two polymers are miscible. This is the benefit for doing the three components blend in this thesis, which is not an attempt to produce a theoretical explanation for the miscibility of three components blend system.

Skin delivery potency and antitumor activities of temozolomide ester prodrugs

Clinical trials have shown temozolomide to be an effective agent for treatment of malignant melanoma. In order to investigate its suitability for delivery via the skin, a series of temozolomide esters was synthesized as prodrugs. In vitro assays demonstrated temozolomide, temozolomide acid and the hexyl ester equi-effective against selected cancer cell lines. The susceptibility of the esters to enzyme hydrolysis and their effectiveness for application to the skin were investigated. The esters effectively diffuse through rat skin and the hexyl ester demonstrated profound potency for penetrating through skin. Topical application of 5% (w/v) hexyl ester in DMSO solution on a mouse model demonstrated a significant inhibition of tumor growth. These results suggest that temozolomide esters could be an effective alternative to temozolomide in the treatment of skin cancer. © 2005 Elsevier Ireland Ltd. All rights reserved.

Tear film lipids:dynamic composition and clinical performance

Purpose: Meibomian-derived lipid secretions are well characterised but their subsequent fate in the ocular environment is less well understood. Phospholipids are thought to facilitate the interface between aqueous and lipid layers of the tear film and to be involved in ocular lubrication processes. We have extended our previous studies on phospholipid levels in the tear film to encompass the fate of polar and non-polar lipids in progressive accumulation and aging processes on both conventional and silicone-modified hydrogel lenses. This is an important aspect of the developing understanding of the role of lipids in the clinical performance of silicone hydrogels. Method: Several techniques were used to identify lipids in the tear film. Mass-spectrometric methods included Agilent 1100-based liquid chromatography coupled to mass spectrometry (LCMS) and Perkin Elmer gas chromatography mass spectrometry (GCMS). Thin layer chromatography (TLC) was used for separation of lipids on the basis of increasing solvent polarity. Routine assay of lipid extractions from patient-worn lenses was carried out using a Hewlett Packard 1090 liquid chromatograph coupled to both uv and Agilent 1100 fluorescence detection. A range of histological together with optical, and electron microscope techniques was used in deposit analysis. Results: Progressive lipid uptake was assessed in various ways, including: composition changes with wear time, differential lipid penetrate into the lens matrix and, particularly, the extent to which lipids become unextractable as a function of wear time. Solvent-based separation and HPLC gave consistent results indicating that the polarity of lipid classes decreased as follows: phospholipids/fatty acids > triglycerides > cholesterol/cholesteryl esters. Tear lipids were found to show autofluorescence—which underpinned the value of fluorescence microscopy and fluorescence detection coupled with HPLC separation. The most fluorescent lipids were found to be cholesteryl esters; histological techniques coupled with fluorescence microscopy indicated that white spots (’’jelly bumps’’) formed on silicone hydrogel lenses contain a high proportion of cholesteryl esters. Lipid profiles averaged for 30 symptomatic and 30 asymptomatic contact lens wearers were compiled. Peak classes were split into: cholesterol (C), cholesteryl esters (CE), glycerides (G), polar fatty acids/phospholipids (PL). The lipid ratio for ymptomatic/symptomatic was 0.6 ± 0.1 for all classes except one—the cholesterol ratio was 0.2 ± 0.05. Significantly the PL ratio was no different from that of any other class except cholesterol. Chromatography indicated that: lipid polarity decreased with depth of penetration and that lipid extractability decreased with wear time. Conclusions: Meibomian lipid composition differs from that in the tear film and on worn lenses. Although the same broad lipid classes were obtained by extraction from all lenses and all patients studied, quantities vary with wear and material. Lipid extractability diminishes with wear time regardless of the use of cleaning regimes. Dry eye symptoms in contact lens wear are frequently linked to lipid layer behaviour but seem to relate more to total lipid than to specific composition. Understanding the detail of lipid related processes is an important element of improving the clinical performance of materials and care solutions.

Alcohols and other oxygenates in automotive fuels

The aim of this research was to assess the effect of oxygenated hydrocarbons on the knocking characteristics of an engine when blended with low-leaded gasoline. Alcohols, ethers, esters and ketones were tested individually and in various combinations up to an oxygen content of 4% wt/wt in a blend with Series F-7 gasoline of 90, 92, 94 and 96 RON. Tests were carried out at wide open throttle, constant speed and standard timing setting. Engine speed was varied using a dynamometer and knock was detected by two piezoelectric transducers, one on the cylinder head monitoring all four cylinders and one monitoring the cylinder most prone to knock. The engine speeds associated with trace and light knock of a continuous nature were noted. Curves were produced for each oxygenate blend of base RON used against engine speed for the two knock conditions which were compared with those produced using pure Series F-7 fuels. From this a suggested RON of the blend was derived. RON increase was less when using a higher RON base fuel in the blend. Most individual oxygenates showed similar effects in similar concentrations when their oxygen content was comparable. Blends containing more than one oxygenate showed some variation with methanol/MTBE/3 methylbutan-2-one and methanol/MTBE/4 methyl pentan-2-one knocking less than expected and methanol/MTBE/TBA also showing good knock resistance. Further tests to optimise initial findings suggested a blend of methanol and MTBE to be superior although partial replacement of MTBE by 4 methyl pentan-2-one resulted in a fuel of comparable performance. Exhaust emissions were tested for a number of oxygenated blends in 2-star gasoline. 2-star and 4-star fuels were also tested for reference. All oxygenate blends reduced carbon monoxide emissions as expected and hydrocarbon emissions were also reduced. The largest reduction in carbon monoxide occurred using a 14.5 % (1 : 1 : 1) methanol/MTBE/4 methyl pentan-2-one blend. Hydrocarbon emissions were most markedly reduced by a blend containing 25.5 % 4 methyl pentan-2-one. Power output was tested for the blends and indicated a maximum increase of about 5 % at low engine speeds. The most advantageous blends were methanol/4 methyl pentan-2-one (6 : 5) 11% in 2-star and methanol/MTBE/4 methyl pentan-2-one (6 : 3 : 2) 11% in 2-star. In conclusion methanol/MTBE (6 : 5) and (5 : 5), and various combinations of methanol/MTBE/4 methyl pentan-2-one, notably (6 : 3 : 2) gave good results in all tests conducted. CFR testing of these blends showed them to increase both RON and MON substantially.

Upgrading fast pyrolysis liquids:blends of biodiesel and pyrolysis oil

Fast pyrolysis liquid or bio-oil has been used in engines with limited success. It requires a pilot fuel and/or an additive for successful combustion and there are problems with materials and liquid properties. It is immiscible with all conventional hydrocarbon fuels. Biodiesel, a product of esterification of vegetable oil with an alcohol, is widely used as a renewable liquid fuel as an additive to diesel at up to 20%. There are however limits to its use in conventional engines due to poor low temperature performance and variability in quality from a variety of vegetable oil qualities and variety of esterification processes. Within the European Project Bioliquids-CHP - a joint project between the European Commission and Russia - a study was undertaken to develop small scale CHP units based on engines and microturbines fuelled with bioliquids from fast pyrolysis and methyl esters of vegetable oil. Blends of bio-oil and biodiesel were evaluated and tested to overcome some of the disadvantages of using either fuel by itself. An alcohol was used as the co-solvent in the form of ethanol, 1-butanol or 2-propanol. Visual inspection of the blend homogeneity after 48 h was used as an indicator of the product stability and the results were plotted in a three phase chart for each alcohol used. An accelerated stability test was performed on selected samples in order to predict its long term stability. We concluded that the type and quantity of alcohol is critical for the blend formation and stability. Using 1-butanol gave the widest selection of stable blends, followed by blends with 2-propanol and finally ethanol, thus 1-butanol blends accepted the largest proportion of bio-oil in the mixture. © 2013 Elsevier Ltd. All rights reserved.

The effect of antifoams upon recombinant protein production in yeast

Foaming during fermentation reduces the efficiency of the process leading to increased costs and reduced productivity. Foaming can be overcome by the use of chemical antifoaming agents, however their influence upon the growth of organisms and protein yield is poorly understood. The objective of this work was to evaluate the effects of different antifoams on recombinant protein production. Antifoam A, Antifoam C, J673A, P2000 and SB2121 were tested at different concentrations for their effect on the growth characteristics of Pichia pastoris producing GFP, EPO and A2aR and the yield of protein in shake flasks over 48 h. All antifoams tested increased the total GFP in the shake flasks compared to controls, at higher concentrations than would normally be used for defoaming purposes. The highest yield was achieved by adding 1 % P2000 which nearly doubled the total yield followed by 1 % SB2121, 1 % J673A, 0.6 % Antifoam A and lastly 0.8 % Antifoam C. The antifoams had a detrimental effect upon the production of EPO and A2aR in shake flasks, suggesting that their effects may be protein specific. The mechanisms of action of the antifoams was investigated and suggested that although the volumetric mass oxygen transfer coefficient (kLa) was influenced by the agents, their effect upon the concentration of dissolved oxygen did not contribute to the changes in growth or recombinant protein yield. Findings in small scale also suggested that antifoams of different compositions such as silicone polymers and alcoxylated fatty acid esters may influence growth characteristics of host organisms and the ability of the cells to secrete recombinant protein, indirectly affecting the protein yield. Upon scale-up, the concentration effects of the antifoams upon GFP yield in bioreactors was reversed, with lower concentrations producing a higher yield. These data suggest that antifoam can affect cells in a multifactorial manner and highlights the importance of screening for optimum antifoam types and concentrations for each bioprocesses.

Enzyme catalysed modification of polymers

The aim of this project was to investigate the enzyme catalysed modification of synthetic polymers. It was found that an immobilised lipase from Candida antartica (Novozyme 435) catalysed the selective epoxidation of poly(butadiene) in the presence of hydrogen peroxide and catalytic quantities of acetic acid. The cis and trans double bonds of the backbone were epoxidised in yields of up to 60 % whilst the pendent vinyl groups were untouched. The effect of varying a number of reaction parameters was investigated. These studies suggested that higher yields of epoxide could not be obtained because of the conformational properties of the partially epoxidised polymer. Application of this process to the Baeyer-Villiger reaction of poly(vinyl phenyl ketone) and poly(vinyl methyl ketone) were unsuccessful. The lack of reactivity was found to be a property of the polymer rather than the enzymatic system employed. Attempts to modify hydroxyl containing polymers and polymers bearing active esters close to the polymer backbone were unsuccessful. Steric factors appear to be the most important influence on the outcome of the reactions.

Synthesis and evaluation of novel polymer modifiers for biodegradable polymers

The effects of ester plasticizers and copolymers on the mechanical properties of the natural biodegradable polymers, poly(3-hydroxybutyrate) [PHB] and poly(lactic acid) [PLA] have been studied after subjecting to melt processing conditions. Ester plasticizers were synthesized from citric, tartaric and maleic acids using various alcohols. A variety of PLA copolymers have also been prepared from poly(ethylene glycol) derivatives using stannous octanoate catalysed ring opening polymerisations of DL-lactide. A novel PLA star copolymer was also prepared from an ethoxylated pentaerythritol. The structures of these copolymers were determined by NMR spectroscopy. The plasticizing effect of the synthesised additives at various concentrations was determined. While certain additives were capable of improving the mechanical properties of PLA, none were effective in PHB. Moreover, it was found that certain combinations of additives exhibited synergistic effects. Possible mechanisms are discussed. Biotic and abiotic degradation studies showed that the plasticizers (esters and copolymers) did not inhibit the biodegradability of PHB or PLA in compost at 60°C. Simple toxicity tests carried out on compost extract and its ability to support the growth of cress seeds was established. PLA was found to be susceptible to limited thermal degradation under melt processing conditions. Conventional phenolic antioxidants showed no significant effect on this process, suggesting that degradation was not predominantly a free radical process. PLA also underwent photo-oxidative degradation with UV light and the process could be accelerated in the presence of a photoactivator such as iron (III) diisononyl dithiocarbamate. The mechanisms for the above processes are discussed. Finally, selected compounds were prepared on a pilot plant scale. Extruded and blown films were prepared containing these additives with conventional polymer processing equipment. The mechanical properties were similar to those obtained with laboratory produced compression moulded films.

Environmental degradation of polyethylene-based plastics

The criteria involved in the degradation of polyethylene-based degradable polymer samples have been investigated, with a view to obtaining a clearer mechanism of photo-biodegradation. The compatibility of degradable polymer samples during materials recycling was also studied. Commercial and laboratory prepared degradable polymer samples were oxidised in different environments and the oxidation products formed were studied using various analytical chromatographic and spectroscopic techniques such as HPLC, FT-IR and NMR. It was found that commercial degradable polymer samples which are based on the ECO systems, degrade predominantly via the Norrish II process, whereas the other degradable systems studied (starch-filled polyethylene systems, transition metal systems, including metal carboxylate based polyethylene systems and the photoantioxidant-activator systems) photodegrade essentially via the Norrish I process. In all cases, the major photoxidation products extracted from the degradable polymer samples were found to be carboxylic acids, although, in the polymer itself a mixture of carbonyl containing products such as esters, lactones, ketones and aldehydes was observed. The study also found that the formation of these hydrophilic carbonyl products causes surface swelling of the polymer, thus making bioerosion possible. It was thus concluded that environmental degradation of LDPE is a two step process, the initiation stage being oxidation of the polymer which gives rise to bioassimilable products, which are consequently bioeroded in the second stage, (the biodegradation step). Recycling of the degradable polymer samples as 10% homogeneous and heterogeneous blends was carried out using a single screw extruder (180°C and 210°C) and an internal mixer (190°C). The study showed that commercial degradable polymer samples may be recycled with a minimal loss in their properties.

Novel materials for membrane separation processes

The aim of this work was to synthesise a series of hydrophilic derivatives of cis-1,2-dihydroxy-3,5-cyclohexadiene (cis-DHCD) and copolymerise them with 2-hydroxyethyl methacrylate (HEMA), to produce a completely new range of hydrogel materials. It is theorised that hydrogels incorporating such derivatives of cis-DHCD will exhibit good strength and elasticity in addition to good water binding ability. The synthesis of derivatives was attempted by both enzymatic and chemical methods. Enzyme synthesis involved the transesterification of cis-DHCD with a number of trichloro and trifluoroethyl esters using the enzyme lipase porcine pancreas to catalyse the reaction in organic solvent. Cyclohexanol was used in initial studies to assess the viability of enzyme catalysed reactions. Chemical synthesis involved the epoxidation of a number of unsaturated carboxylic acids and the subsequent reaction of these epoxy acids with cis-DHCD in DCC/DMAP catalysed esterifications. The silylation of cis-DHCD using TBDCS and BSA was also studied. The rate of aromatisation of cis-DHCD at room temperature was studied in order to assess its stability and 1H NMR studies were also undertaken to determine the conformations adopted by derivatives of cis-DHCD. The copolymerisation of diepoxybutanoate, diepoxyundecanoate, dibutenoate and silyl protected derivatives of cis-DHCD with HEMA, to produce a new group of hydrogels was investigated. The EWC and mechanical properties of these hydrogels were measured and DSC was used to determine the amount of freezing and non-freezing water in the membranes. The effect on EWC of opening the epoxide rings of the comonomers was also investigated

The polymerization of lactic acid anhydrosulphite by anionic initiators

This thesis is primarily concerned with the synthesis and polymerization of 5-methyl-1;3, 2-dioxathiolan-4-one-2-oxide (lactic acid anhydrosulphite (LAAS)) using anionic initiators under various conditions. Poly(lactic acid) is a biodegradable polymer which finds many uses in biomedical applications such as drug-delivery and wound-support systems. For such applications it is desirable to produce polymers having predictable molecular weight distributions and crystallinity, The use of anionic initiators offers a potential route to the creation of living polymers. The synthesis of LAAS was achieved by means of an established route though the procedure was modified to some extent and a new method of purification of the monomer using copper oxides was introduced, Chromatographic purification methods were also examined but found to be ineffective. An unusual impurity was discovered in some syntheses and this was identified by means of 1H and 13C NMR, elemental analysis and GC-MS. Since poly-α-esters having hydroxyl-bearing substituents might be expected to have high equilibrium water contents and hence low surface tension characteristics which might aid bio-compatibility, synthesis of gluconic acid anhydrosulphite was also attempted and the product characterised by 1H and 13C NMR. The kinetics of the decomposition of lactic acid anhydrosulphite by lithium tert-butoxide in nitrobenzene has been examined by means of gas evolution measurements. The kinetics of the reaction with potassium tert-butoxide (and also sec-butyl lithium) in tetrahydrofuran has been studied using calorimetric techniques. LAAS was block co-polymerized with styrene and also with 1,3-butadiene in tetrahydrofuran (in the latter case a statistical co-polymer was also produced).

The use of enzyme catalysts in organic media for the synthesis of biodegradable polyesters

The enzyme catalysed polytransesterification of diesters with diols was investigated under various conditions. The most consistent results were obtained using crude porcine pancreatic lipase (PPL) suspended in anhydrous diethyl ether. Addition of molecular sieve to the above system gave higher molecular weight products. The PPL catalysed reaction of bis(2,2,2-trichlorethyl) adipate and glutarate with butane-1,4-diol in anhydrous ether with and without molecular sieve was investigated over a range of times from 8 to 240 hours. The 72 hour adipate reaction with molecular sieve gave the highest molecular weight polymer (Mn 6,500 and Mw 9,400). The glutarate gave the maximum molecular weight polyester after 24 hours (Mn 5,700 and Mw 9,500). Occasionally the glutarate reaction produced very high molecular weight polyester-enzyme complexes. Toluene generally gave lower molecular weight products than diethyl ether. Dichloromethane and tetrahydrofuran gave mainly dimers and trimers. Alternative enzyme and diol systems were also investigated. These yielded no polymeric products. The molecular weights of the polyesters were determined by 1H NMR end-group analysis and by GPC. The molecular weights determined by NMR were on average about twice as great as those determined by GPC. The synthesis of the following diesters is described: i)Bis(2,2,2-trichloroethyl) succinate, glutarate, adipate, trans-3-hexenedioate, and trans-3,4-epoxyadipate. ii) Diphenyl glutarate and adipate.iii)Bis(2,2,2-fluoroethyl) glutarate and trans-3-hexendioate.iv) Divinyl glutarate. v) N,N'Glutaryl dicyclohexanone oxime.The polytransesterification of all the above esters with diols was investigated. The easily synthesised bis(2,2,2-trichloroethyl) glutarate and adipate gave the best results and the work was concentrated on these two esters.

Cyclodextrin complexes of antimicrobial agents

Poorly water-soluble drugs show an increase in solubility in the presence of cyclodextrins (CyD) due to the formation of a water-soluble complex between the drug and dissolved CyD. This study investigated the interactions of -Cyd and hydroxypropyl--CyD (HP--CyD, M.S. = 0.6) with antimicrobial agents of limited solubility in an attempt to increase their microbiological efficacy. The agents studied were chlorhexidine dihydrochloride (CHX), p-hydroxybenzoic acid esters (methyl, ethyl, proply and butyl) and triclosan. The interactions between the antimicrobials and CyDs were studied in solution and solid phases. Phase solubility studied revealed an enhancement in the aqueous drug solubility in the presence of the CyD and also gave an indication of the complex stability constant (Ks). The temperature-dependence of the stability constant of the complex was modelled by the van't Hoff plot which yielded the thermodynamic parameters for complexation. Further confirmation of the inclusion of the antimicrobials within the cavity of the CyDs in aqueous solution was obtained from proton magnetic resonance and ultraviolet absorption spectroscopies. The former method indicated that the chlorophenyl moiety of the CHX was included within the -CyD cavity and the stoichiometry of the complex formed was 1:1. The solid-phase complexes were prepared by freeze-drying. The inclusion complex of triclosan with HP--CyD was obtained from aqueous solution with the addition of ammonia. Evidence to confirm complex formation was obtained from DSC, IR and X-ray powder diffraction studies. Dissolution studies of the solid inclusion complexes using the dispersed powder technique illustrated their superior solubilities as compared to the equimolar physical mix of the guest and CyD. It was shown that these solutions of the complex were supersaturated with respect to the free guest. This was further demonstrated by diffusion studies which showed the flux of free drug from donor solutions of the antimicrobial-CyD complex to be significantly greater than the flux from donor suspensions of drug alone.

Synthesis and cytotoxity of oxysterols:studies on the A,B ring polyoxygenated sterols

Oxysterols (OS), the polyoxygenated sterols, represent a class of potent regulatory molecules for important biological actions. Cytotoxicity of OS is one of the most important aspects in studies of OS bioactivities. However, studies, the structure-activity relationship (SAR) study in particular, have been hampered by the limited availability of structurally diverse OS in numbers and amounts. The aim of this project was to develop robust synthetic methods for the preparation of polyhydroxyl sterols, thereof, evaluate their cytotoxicity and establish structure-activity relationship. First, we found hydrophobicity of the side chain is essential for 7-HC's cytotoxicity, and a limited number of hydroxyl groups and a desired configuration on the A, B ring are required for a potent cytotoxicity of an OS, after syntheses and tests of a number of 7-HC's analogues against cancer cell lines. Then polyoxygenation of cholesterol A, B rings was explored. A preparative method for the synthesis of four diastereomerically pure cholest-4-en-3,6-diols was developed. Epoxidation on these cholest-4-en-3,6-diols showed that an allyl group exerts an auxiliary role in producing products with desired configuration in syntheses of the eight diastereomerically pure 45-epoxycholestane-3,6-diols. Reduction of the eight 45-epoxycholestane-3,6-diols produced all eight isomers of the cytotoxic 5α-acholestane 3β,5,6β-triol (CT) for the first time. Epoxide ring opening with protic or Lewis acids on the eight 45-epoxycholestane-3,6-diols are carefully studied. The results demonstrated a combination of an acid and a solvent affected the outcomes of a reaction dramatically. Acyl group participation and migration play an important role with numbers of substrates under certain conditions. All the eight 4,5-trans cholestane- 3,4,5,6-tetrols were synthesised through manipulation of acyl participation. Furthermore these reaction conditions were tested when a number of cholestane-3,4, 5,6,7-pentols and other C3-C7 oxygenated sterols were synthesised for the first time. Introduction of an oxygenated functional group through cholest-2-ene derivatives was studied. The elimination of 3-(4-toluenesulfonate) esters showed the interaction between the existing hydroxyls or acyls with the reaction centre often resulted in different products. The allyl oxidation, epoxidation and Epoxide ring opening reactions are investigated with these cholest-2-enes.

The percutaneous absorption of ionisable compounds

The effects of ionisation on transdermal drug delivery using excised human epidermis (HS) and silastic rubber (SR) as model permeation barriers were investigated in vitro using Franz-type absorption cells. Suspensions and solutions of salicylic acid (SA), the model ionogenic permeant, were used as donors and the variables studied were vehicle pH and trans-membrane pH-gradients. For solutions, the pH effect was related to the level of ionisation of the drug and the degree of saturation of the solution. With suspensions, the observed permeation rate was unaffected by pH. The penetration profiles through HS and SR were similar, although the overall flux through HS was about 70% of that observed through SR. Pretreatment of the membranes with various enhancer regimens, including oleic acid, Azone and N, N-dimethylamides in propylene glycol (PG) and isopropyl myristate (IPM) promoted the penetration of SA. SR was not a suitable model for enhancer pretreatment using IPM as a vehicle as the membrane was significantly disrupted by this vehicle. The results from comparable experiments with and without a trans-membrane pH-gradient did not have a significant effect upon flux or flux enhancement after pretreatment with the above enhancers. A theoretical model for the extraction coefficients of weak acids was derived using the partition coefficients of the ionised and unionised species, pH and pKa. This model was shown to account for the variation in overall partition of salicylic acid dependent upon pH and pKa. This model was shown to account for the variation in overall partition of salicylic acid dependent upon pH and pKa. The distribution of this solute between aqueous and oily phases, with and without added enhancer, was measured as a function of pH. The extraction coefficients determined were consistent with the model and showed that the behaviour of the system can be explained without referral to ion-pair mechanisms. Phosphonoacetate is an effective antiviral agent. However, as it is charged at physiological pH, its permeation across cell membranes is limited. To assess the improvement of the transport properties of this molecule, mono-, di- and tri-ester prodrugs were examined. These were assessed for stability and subsequent breakdown with respect to pH by HPLC. In vitro percutaneous absorption was observed using the triester, but not the ionic mono- or di-esters. The triester absorption could be potentiated using a range of enhancers with oleic acid being the most effective. Cyclodextrins (CD) have a role as absorption enhancers for peptide compounds across nasal epithelium. One potential mode of action is that CDs include these compounds, protect them from enzymic attack and thereby increase their residence time in the nasal epithelium. This study investigated the potential of CDs to protect ester prodrugs from enzymatic breakdown and prevent production of poorly transportable ionic species. Using a range of CD to ester molar ratios (10:1 to 2500:1) a small, but measurable, protection for the model esters (parabens) against esterase attack was observed. Possible mechanisms for this phenomenon are that CDs include the ester, making it unavailable for hydrolysis, the CDs may also affect the esterase in some way preventing access for the ester into the active site.