Development of novel biodegradable polymers from renewable resources has attracted attention due to the limitations associated with polymers obtained from petroleum resources. The objective of the work presented in this thesis was to develop various novel biodegradable amphiphilic block copolymers from commercially available sustainable feedstocks for drug delivery applications. Synthesis was performed using a reported method under mild reaction conditions. Renewable δ-decalactone was chosen as a key monomer to synthesise novel amphiphilic block copolymers via ROP using PEG as initiator. A diblock (i.e. mPEG-b-PDL) and a triblock (i.e. PDL-b-PEG-b-PDL) copolymer of poly(decalactone) (PDL) was synthesised and purified successfully. Additionally, a novel triblock copolymer (i.e. mPEG-b-PDL-b-PPDL) was synthesised using ω-pentadecalactone as monomer and mPEG-b-PDL as initiator via ROP to generate a copolymer with different physical properties. Further, a di-block copolymer of ε-caprolactone (i.e. mPEG-b-PCL) was synthesised for comparative studies with novel block copolymers. Micelles of synthesised block copolymers were fabricated using a reported nanoprecipitation method. Micelles fabricated from these novel block copolymers were of sizes <200nm and possessed low critical micelle concentration (CMC) values. Curcumin and Amphotericin B were successfully encapsulated in the novel block copolymer micelles via nanoprecipitation method. The results obtained from curcumin loading and release studies suggested that these novel PDL block copolymers could perform in similar fashion when compared with poly(caprolactone) (PCL) block copolymer micelles. However, in subsequent study micelle of mPEG-b-PDL gave high loading content compared to mPEG-b-PCL micelles when amphotericin B was used as a drug. Further, a preliminary in vitro degradation study of mPEG-b-PDL micelles was performed and the results proposed that the ester linkage of PDL chain were susceptible to hydrolytic degradation in physiological condition. Additionally, in vitro cytotoxicity studies performed on HCT-116 human colon cancer cells revealed that the novel mPEG-b-PDL micelles have similar toxicity profiles when compared to the well-established mPEG-b-PCL micelles. Ligand mediated targeting efficiency of novel diblock copolymer micelles was also studied for potential future applications in cancer therapy. Amphiphilic block copolymers using PEG and PDL were synthesised via click chemistry to generate functionalised block copolymers. Folic acid and rhodamine B were used as targeting ligand and tracker dye respectively. Mixed micelles fabricated from functionalised block copolymers (i.e. FA-PEG-b-PDL, RhB-PEG-b-PDL and mPEG-b-PDL) were tested on folate receptor positive (MCF-7 FR+ve) and folate receptor negative (A549 FR-ve) human cancer cell lines for receptor mediated endocytosis. The acquired confocal images demonstrated the nonspecific uptake of the PEG-b-PDL micelles formulations (targeted and non-targeted) in both cell lines selected in current study. The results obtained from this thesis study suggested that the synthesised novel PDL block copolymer micelles have potential to act as a novel drug delivery system. However, further studies have been proposed to explore the possible applications of these renewable block copolymers.

Studies on electronic patient medication record (ePMR) systems that are used in community pharmacy in England have focused primarily on the ability of these systems to highlight potentially hazardous co-prescriptions and prevent clinical hazards and harm to patients. As such, there is a scarcity of literature on the use of ePMR systems, other safety functionality of the systems and user responses to alerts. This thesis aims to fill this gap by examining the functionality of ePMR systems used in community pharmacy in England, focusing on safety features and alerts. This research was conducted in England between July 2010 and July 2013. Evidence for the effectiveness of safety features and alerts in ePMR systems during the dispensing process was evaluated through a systematic review of the literature. Stakeholder perspectives of ePMR systems’ functionality were then obtained through qualitative interviews. The performance of ePMR systems licensed for the electronic prescription service (release 2) in the community pharmacy setting were then assessed using a simulated observational testing approach. Ethnographically informed observations in community pharmacies were subsequently used to study how community pharmacy professionals use ePMR systems and manage alerts in practice. The systematic review included five studies - three randomised controlled trials and two before-after studies, with drug-drug interaction (1), drug-laboratory (2), drug-pregnancy (1) and drug-age (1) alerts. The review revealed that ePMR systems in conjunction with embedded safety features are effective in picking up clinical hazards at the point of dispensing. However, there are problems of false alerts and inconsistencies in alert management. Empirical findings indicate that there are significant issues with the way ePMR systems and alerts are designed and used. Thirty participants took part in the qualitative interviews - community pharmacy professionals (13), health care policy makers (5), legal practitioners specialising in pharmacy (3), ePMR systems’ software vendors (4) and ePMR systems’ software knowledgebase creators (5). Participants attributed alert ineffectiveness in community pharmacy practice to factors such as lack of harmonisation of alert severity levels in systems, poor alert design, over-presentation of alerts and absence of management advice in alerts. Five unique ePMR systems were evaluated in eight participating pharmacies with a sixth ePMR system assessed in a demonstration setting. The systems’ performance was variable and sub-optimal. The ethnographically informed observations took place in the eight pharmacies where system assessment was conducted. The observations revealed that the current design of ePMR systems and presentation of alerts are limiting the quality of support provided to pharmacists and their support staff. This research is part of a growing body of work on the functionality of ePMR systems, their safety features and alerts indicating that ePMR systems require improvements if they are to effectively support patient safety and consistently deliver better patient outcomes. The findings highlight the need to incorporate patient context into alerting to increase alert relevance. In addition, system vendors need to make use of the evidence in the literature to design effective ePMR systems, alerts and user interfaces. An authoritative body should set the minimum specifications for ePMR systems and alerts, and identify the critical alerts that pharmacy professionals should evaluate at the point of dispensing. Additionally, training of pharmacy professionals in health information and communication technology is required to improve patient safety. This should cover areas such as informatics, human factors, safety culture, clinical decision-making, alert management, risk management and communication. Many of the findings are likely to be relevant to similar medication record systems in ambulatory pharmacies around the world; however, further work is required to understand fully the extent of the issues identified in this research.

Ink-jet printing is a precise and versatile technique that accurately deposits small volumes of solutions (pico litres) in specific locations. Recently inkjet printing has attracted increasing attention in the pharmaceutical industry because of its ability to deliver low adjustable doses, variable drug release profiles and drug combinations suitable for the paradigm of personalised medicines. The significant growth in the aging population and the rise in the number of patients suffering from multiple chronic diseases are the key drivers. The current traditional tablet compression methods are largely limited in terms of flexibility and complexity of dosage form. There is a need for new innovative technologies that can produce bespoke medicines in a relatively cheap and efficient manner at the point of care. 3D inkjet printing (3DIJP) provides a platform with the potential to address the above need. This thesis investigates the capability of 3DIJP as a tool for manufacturing solid dosage forms. In chapter 3, a piezoelectric drop on demand printer was used. The chapter focuses on two solvent based inkjet printing methods. In the first solvent based method, excipients including hydroxypropyl methylcellulose (HPMC), poly (vinyl pyrrolidone) (PVP) and Eudragit RL were investigated for printability. PVP (K10) which showed the best printability behaviour was loaded with digoxin or carbamazepine (CBZ) and printed to obtain films. In the second solvent based method, a solution containing CBZ dissolved in a mixture of of polyethylene glycol diacrylate (PEGDA) and with poly(caprolactone dimethyl acrylate) (PCLDMA) was printed and polymerised in situ using ultraviolet light to form films. The printed drug loaded films were investigated using time of flight secondary ion mass spectroscopy (ToF SIMS), atomic force microscopy (AFM), scanning electron microscopy (SEM) and differential scanning microscopy (DSC). PVP formulations were homogeneous, with no evidence of crystallisation PEGDA/PCLDA/CBZAFM images showed a clear phase separation at the micron scale and no drug was detected at the surface. In this chapter, the production of adjustable doses was also evaluatedusing UV-VIS spectrophotometry. In chapters 4 and 5, a solvent-free hot-melt 3D inkjet printing method suitable for manufacturing solid dosage forms was developed. Excipients including beeswax, carnuba wax, gelucire 44/14 and trimyristin were examined for printability. Beeswax a naturally derived and FDA approved material showed the best printability behaviour and was selected as the drug carrier. Traditional circular shaped tablets and cylindrical implants loaded with 5% w/w fenofibrate were successfully fabricated. The printed tablets and implants were well-defined, smooth surfaced and with no apparent defects. The architecture of the tablets was investigated using 3D micro X-ray computed tomography (μCT), revealing well defined and ordered honeycomb channels in the interior of the tablets. The distribution of the drug was evaluated at the macro scale level using DSC and at the micro scale level using ToF - SIMS and Raman spectroscopy. The drug was homogenously distributed within the drug carrier (beeswax matrix ) at the microscale level. At the micron scale level, the drug was heterogeneously distributed. ToF - SIMS studies also revealed that the drug was depleted from the upper most top surfaces. Production of solid dosage forms with intricate and adaptable geometries was demonstrated by printing honeycomb architecture tablets with predetermined variable cell diameters. The diamater of the honeycomb cells was varied, in order to achieve controlled variable drug release profiles. The ablity to control drug release was only applicable above an established critical cell diameter of 0.5 mm. An analytical model describing Fickian diffusion from a slab geometry was developed to allow for the prediction of drug release from the honeycomb tablets. The predicted drug release profiles varied slightly from the experimental data, but the trends for the two data set were identical. For both data sets the rate of drug release increased with increase in the surface area to volume ratio. The findings and the developments demonstrated in this thesis provide an insight into the potential application of 3DIJP as a tool for manufacturing solid dosage forms with bespoke properties for controlled drug release but also highlights some limitations.

Transition metal coordination complexes show great promise as novel therapeutic agents with new mechanisms of action, but their characterisation, and identification of their target sites present significant challenges. In this thesis a variety of new analytical methods is explored for the study of platinum, ruthenium, osmium and iridium anticancer complexes. High performance liquid chromatography (HPLC) was used to determine the relative hydrophobicity of a series of photoactivatable Pt(IV) diazido complexes of the general type trans,trans,trans-[Pt(N3)2(OH)2(R)(F11]. Interestingly the hydrophobicities did not follow trends based on literature Log P values of individual ligands and did not correlate with the cellular uptake or antiproliferative activity of the drugs. Other factors such as the quantum yield of the complex, and the type of DNA adducts appear to be more important for their efficacy. Chromatography and high-resolution mass spectrometry were used to study the formation of platinum adducts on DNA when the most active complex trans,trans,trans-[Pt(N3)2(OH)2(PYridine)2], 8 was irradiated in the presence of short single strand oligonucleotides 14 bases in length. Complex 8 was found to bind to the oligonucleotides as a {Pt(pyridine)2}2+ adduct. Modifying the wavelength of activation from UVA to 420 nm had no effect on the type of adduct formed, but the higher energy irradiation achieved maximum levels of DNA platination more quickly. Changing the sequence of the oligonucleotide suggested that the photoactivated form of 8 does not favour the formation of the 1,2-(GpG) bisadduct formed by cisplatin and other clinically approved platinum based drugs, but may form 1,3-(GpNpG) or 1,3-(ApNpG) adducts, as is the case with other trans-platinum complexes. Chiral chromatography using cellulose- and amylose-based stationary phases successfully separated the enantiomers of a series of organometallic 'piano stool' anticancer complexes. This appears to be the first successful separation of facially chiral Ru(II) arene complexes, the enantiomers of which were stable in solution for over 3 h. In contrast, separated cyclopentadienyl WI) complexes with chiral metal centres epimerized within 2 h in solution at ambient temperature. Under similar conditions the enantiomers of the Os(II) arene complex [Os(n6-p-cym)(4-(2-pyridylazo)-N,N-dimethylaniline)Ir remained stable, as did those of the ruthenium-based complex [Ru(9,10- diydrophenanthrene)(en)C1r. It was shown that it is possible to separate the diasteriomers of [Ru(t)6-para-cymene)(iminopyridine)I], that can also be resolved by crystallisationtechniques, and hence, decrease the time required to separate the enantiomers. This work will therefore allow exploration of the biological properties of some of these enantiomers A novel technique for the rapid irradiation and detection of light¬senstive species was developed. Photonic crystal fibers (PCFs) were coupled to a mass spectrometer using HPLC tubing and fittings. This continuous flow method of analysis was validated using the photaquation of cyanocobalamin. The PCF system was compared to the conventional cuvette-based approach. No significant difference in the species detected by MS could be found, but the PCF system had the advantage of requiring 20 times less sample (25 pL), and only 15 min of irradiation compared to 10 h by conventional methods. The new PCF-MS system was then used to study the interaction of the photoactivateable ruthenium-based drug [{(e-indan)RuC1}201-2,3-dPa2+ with a range of small molecules that acted as models for intracellular components, e.g. 5'GMP for DNA. The nucleobase binding properties were consistent with those previously reported with plasmid DNA by Magennis et al: a small amount of binding took place in the dark in view of the aquation of the mondentate leaving groups but this dramatically increased upon photoactivation and loss of the arene ligands. The complex was also found to bind to glutathione (GSH), which is known to detoxify metal-based drugs, an observation possibly explaining its poor anticancer activity.

The presence of organic salts as drug counter-ions and buffers in hydroxypropylmethylcellulose (HPMC) matrices is often overlooked. This study investigates their potential to influence polymer solution properties and matrix drug release kinetics. A homologous series of aliphatic organic salts influenced solution and matrix properties in rank order of hydrocarbon chain length. Monovalent salts containing 1to4 C-atoms had little effect on polymer surface activity, but lowered sol:gel transition temperatures (SGTT), and accelerated matrix drug release in comparison with a dextrose control. Divalent salts were more potent. These observations are consistent with Hofmeister effects in which anions restructure water in the polymer hydration sheath, induce 'salting-out' and suppressing particle swelling and matrix gel layer formation. Organic salts with StoB C-atoms increasingly influenced polymer surface activity, elevated SGTT, and retarded matrix drug release. This suggests these salts enhance HPMC hydration, possibly through interaction with hydrophobic regions. The effects of these salts on matrix drug release show that these ions impact on water:polymer interactions important to gel layer formation and diffusion barrier properties. HPMC matrices containing SOS and its homologues were also investigated. Turbidimetric, tensiometric and rheological studies supported a mechanism in which these surfactants solubilise HPMC at post-micellar concentrations. Incorporating 10% SOS into HPMC matrices was shown to increase the resistance of HPMC matrices to sucrose medium up to 2.0M, suggesting a role for surfactants in avoiding food solute effects. This study shows that organic salts incorporated in HPMC matrices have the potential to influence drug release in a rank order that reflects their modulation of the HPMC polymer hydration sheath in solution. SOS and its homologous series could retard drug release from HPMC matrices only when their critical aggregation concentration (CAC) was reached. However, it suggests this excipient may have uses as an excipient for improving HPMC matrix release performance.

This study is a natural follow on from previous work by M. T. Anderson and I. Fiebrig. The goal of those latter and of the present study is to find a mucoadhesive system for improving the oral bioavailability of a number of drugs, for example bioactive peptides and proteins. This current work evaluates the adhesive properties of a cationic polymer and a cationic protein to mucus glycoproteins as a step towards the future development of a mucoadhesive drug delivery system. Four different mucin populations were analysed in solution (a freshly purified sample PGM-MD, and three purified from different regions of the porcine stomach cardiac, antrum and fundus). Their interaction with two groups of chitosans differing in degree of deacetylation (FA = 0.11 and 0.25) and a protein purified from the foot of the blue mussel Mytilus edulis foot protein-1 (Mefp-1) were studied. Interaction was determined using analytical ultracentrifugation and with the chitosan/mucin interaction specifically atomic force microscopy. The influence of ionic strength on the interaction was studied in detail studied as was the effect of the oligosaccharide composition of the mucin population on the interaction. It was found that both groups of chitosans (FA = 0.11 and 0.25) formed a large complex with a freshly purified mucin population (PGM-MD). Ionic strengths above 0.2 M were found to inhibit the interaction. The three mucin species differed in terms of their net charge, with cardiac being the most negatively charged and antrum the least negative. It was found that the cardiac species interacted the most and antrum the least, as would be expected for an ionic interaction. Increasing ionic strength was found to inhibit the interaction. There was also evidence for a hydrophobic interaction at high ionic strengths. The atomic force microscopy results allowed the complex to be visualised under atmospheric conditions and to get away from the harsh sample preparation techniques employed by electron microscopy. Large spherical complexes were seen as entanglements of mucin and chitosan strands.

The weight variation of gelatin capsules filled by a dosator-type machine has several possible causes, one of which, the presence of density variations within the powder feed bed, has been evaluated, using a number of particle size fractions of material. Existing theories suggested that the bulk density, or porosity of a powder bed depends on the velocity and intensity of deposition of the particles, together with the properties of the powder. Experiments with lactose confirmed this, indicating in particular that low velocity deposition encourages the formation of regions of relatively high porosity. The application of vibration, especially in a vertical direction, proved effective in reducing the porosity of powder packings, and optimum frequency and acceleration appeared to be largely independent of particle size. A system was developed for detecting porosity variations within powder beds, using the technique of gamma-ray attenuation, the principle being that the reduction in intensity of a Gamma-ray beam traversing a powder bed is a function of local porosity. The observed linear attenuation coefficient of lactose was found to be a function of porosity, for reasons not fully established, hence a calibration expression for the attenuation coefficient was proposed, and was used in subsequent local porosity determinations. The radial distribution of porosity within cylindrical samples of lactose, prepared under various conditions, was studied, and a means of presenting such distributions pictorially was developed. The influence of deposition method, and applied vibration, on the uniformity, of such packings, was clearly demonstrated. A semi-automatic dosator-type capsule filling machine was used to evaluate the relationship between powder feed bed porosity variations and capsule fill weight variation. The results indicated that in the case of lactose, the influence of porosity variations, of the order of magnitude encountered, tends to be masked by other phenomena affecting the filling process.

Protein-based therapeutics play an increasingly important role in medicine, and the exquisite bio-recognition properties exhibited by antibodies has also led the their use in a number of other fields apart from medicine. The increasing use of these molecules requires more efficient methods of purification. A review of the current purification strategies was conducted. Of all the purification methods studied, peptide epitope/mimotope affinity chromatography proved to be the method of choice - resulting in antibodies exhibiting high specific immunoreactivity. The need to tailor unique affinity ligands for each antibody to be purified by peptide epitope/ mimotope affinity chromatography was identified as the major problem with this technique. A review of the technologies available to regulate the antibody-antigen interaction was conducted. Little was published on the use of phage display for the discovery of peptide ligands for use in peptide mimotope affinity chromatography. Experiments were conducted using a polyvalent phage display library to identify novel peptide ligands for the purification of the therapeutic monoclonal antibody C595. A novel peptide was isolated which demonstrated improved chromatographic performance compared to the standard epitope peptide used to purify mAb C595 from biological supernatants. Circular dichroism showed that the novel peptide had a more highly ordered structure at 4oC and room temperature than the epitope peptide, and fluorescence quenching revealed a higher equilibrium association constant. A method for the optimisation of peptide mimotopes derived from phage display, cross-reactive with an anti-steroid antibody was investigated. Improvements relating to the selection of lead peptide sequences are described, and the use of mimotopes in an assay to determine concentrations of steroid in solution has been demonstrated. The optimised mimotope was used as an effective paratope-specific affinity ligand. A novel method for selecting high affinity antibody fragments in vivo is described. The C595 scFv gene was fused to a gene encoding green fluorescent protein and incorporated into the phagemid vector pCANTAB 5E. The fusion protein could not be expressed at high levels and could only be detected using epitope affinity chromatography in combination with ELISA.

The chemistry and structure of Poly (glycerol adipate) facilitate its substitution with various pendant functional groups leading to modifications of the physicochemical properties of the polymer. Modified backbones then can be selected based upon the properties of the compound to be incorporated. Thus, this could be explored as a drug delivery system without many of the limitations of commercially available polymers. The aim of this study was investigate whether various polymers and drugs interact in a specific manner and whether the nature of these interactions influence the physicochemical characteristics of the particles and their drug loading and release profile. By investigating drugs belonging to various classes and with different properties it has been possible to correlate properties associated with drugs and pendant functional groups of the polymer which are ultimately responsible for the drug loading and release characteristics. For some drug polymer formulations, good loading and controlled release rates have been achieved. Compared to various conventional polymer systems reported for nanoparticle formulations, poly (glycerol adipate) polymers have also demonstrated the ability to control rate of release of highly water soluble drugs, even from the most hydrophilic polymer backbone in its unsubstituted form. From the various drug loading and release profiles it has been demonstrated that, unlike reported literature, particle size is not the primary factor influencing drug release over the relatively small range of particle sizes seen in this study. Neither is the water solubility of either the drug or the polymer alone responsible for the rapid and uncontrolled release profile from nanoparticles. Thus, Drug polymer interactions are more likely to influence drug loading and release and unlike common reports in the literature, hydrophilicity, molecular weight or concentration of polymer / drug are less likely to affect these parameters in isolation.

Some of the colloidal aspects of perfluorochemical emulsions have been investigated. Particular attention was given to the influence of the nature of the oil phase on emulsion stability. Bulk emulsion stability was measured by an electron micrographic technique. Interfacial and single droplet rest-time data were also collected. A range of surfactants and perfluorochemicals were investigated. It was found that emulsion stability depends on the chemical nature of the oil phase and the emulsifier. The differences in stability could be rationalized in terms of the intermolecular forces between oil molecules, and oil and surfactant molecules. The effect on stability of a small amount of an additive incorporated into the oil phase was also investigated. It is postulated that although coalescence is the main mechanism by which fluorocarbon emulsions coarsen, molecular diffusion (Ostwald Ripening), in the more stable systems, is also important. Most stable emulsions were obtained by utilizing an emulsifier system comprising a small and a large molecular weight emulsifier. Accelerated stability testing and optimum storage conditions were also investigated. About 40C was found to be the optimum storage temperature. The problem of the fluoride ion production during emulsification could be minimised by sonicating in a carbon dioxide atmosphere. The oxygen uptake and release by fluorocarbon emulsions was rapid, reaching equilibrium within half a second. The in-vitro phagocytosis experiments showed that the phagocytosis rate of fluorocarbon emulsions was dependent on the droplet diameter and its surface characteristics. Investigation of methods to sterilize the fluorocarbon emulsions showed that filtration of constituents before emulsification coupled with autoclaving had the minimum effect on stability. A qualitative correlation between single droplet stability and bulk emulsion stability was found and it is concluded that the method could be a useful screening procedure to find an optimum system.