Phosphorylcholine (PC) based materials have been shown to have increased biocompatibility when compared to more established bio-implantable materials. This has been attributed to the ability of PC to mimic the cell lipid bilayer membrane, resulting in reduced protein adhesion and cellular interaction / activation. PC research has previously focused on the areas of contact lens formulation and medical device coating. This project sought to harness the biomimetic properties of PC to develop novel systems for drug delivery, with the emphasis being focused on microparticulate drug delivery.

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Background: Pharmacovigilance (PV) is the science and activities involved in monitoring and developing the safety profile of all marketed medicines. Adverse drug reactions (ADRs) for medicinal products can be identified through postmarketing studies by methods of signal detection. Traditional, qualitative methods involve clinical review of cases, and coupled with modem, quantitative methods which have evolved as PV has grown, may help surveillance of the large number of medicinal products on the market today. This research aimed to investigate combining traditional and modern methods of signal detection by adding statistical weighting to adverse event telms identified as requiring further monitoring pre-marketing, to improve identification and evaluation of ADRs post -marketing. Methods: Four anti-diabetic drugs currently marketed were chosen to model the concept: gliclazide, pioglitazone, rosiglitazone and vildagllptin. Review of pre-marketing information for safety concerns highlighted two medical concepts: cardiac failure and acute pancreatitis. The Delphi method was adapted to identify and pliolitise terms for these concepts to add statistical weighting to. The weightings were applied to two datasets, both from the UK Yellow Card. Scheme (YCS): a two-year dataset (2005-2007) and a ten-year dataset (2000- 2010).

The need for software tools to support decision-making relating to biomanufacture is becoming increasingly critical in order to accelerate the time-to-market and reduce costs. The main objective of this thesis is the design and implementation of a decision-support tool that integrates both the business and process perspectives of biopharmaceutical manufacture to aid the evaluation of manufacturing alternatives. The tool, designated BioPharmKit, was built on the platform of the simulation package Extend Industrial Suite (Imagine That Inc., San Jose, USA). As an illustration, the tool was used to evaluate manufacturing alternatives for the production of monoclonal antibodies derived from mammalian-based processes. The functionalities of such a tool to model cost summation, perform mass balance calculations, simulate resource handling, and incorporate uncertainties are demonstrated via two industrial-related case studies. The first case study was based upon the assessment of pooling strategies in perfusion culture of mammalian cells to deliver a therapeutic protein for commercial use. The analysis in this study addressed the trade-offs between investing in a plant with a smaller downstream process (DSP) capacity and employing more frequent pooling of the broth for purification or opting for a plant with a larger DSP capacity and less frequent pooling of broth. The feasibility of each manufacturing option was evaluated based on the annual throughput, resource utilisation profiles and cost of goods per gram (COG/g). Project appraisal was based on expected output values and the likelihood of achieving or exceeding critical threshold indicators generated using Monte Carlo simulations. Critical drivers that may affect the decision were identified through scenario analyses to improve the robustness of the decision-making process. In the second case study, the decision-support tool developed was employed to evaluate the economic feasibility of fed-batch and perfusion cultures. The trade-offs between the relative simplicity and high titres of fed-batch systems and the high productivity but greater complexity of perfusion processes were analysed. The study aimed to investigate the relative economics of the two operational modes by examining key performance metrics such as the COG/g and the net present value (NPV). Another major objective of this study was to compare the relative usefulness and limitations of the decision tree and Monte Carlo simulations, which are typical tools used for risk analysis to aid decision-making in situations subject to uncertainty. Although the decision tree analysis provided a simple approach for decision-making based on the expected values of performance metrics, it does not explicitly consider the underlying uncertainty in each contributory estimate. The Monte Carlo simulation method was more time-consuming but provided a more complete estimation of process uncertainties subject to fluctuating product titres and process yields. The examples illustrate the benefits of using the tool to investigate the cost effectiveness of different manufacturing alternatives and may assist the process of decision-making in the context of both business and process drivers. It is envisaged that such a tool might be employed in early process development, hence contributing to transparent planning and project management decisions.

This thesis is concerned with the development of a predictive model for batch cooling suspension pharmaceutical crystallizations, with a focus on product performance. A major challenge involved in the design of industrial pilot plant pharmaceutical crystallizers, is to predict the influence of crystallizer geometry, scale and operating conditions on the process behaviour and crystal size distribution (CSD). The design of industrial crystallizers is hindered by the lack of scale-up rules due to the absence of reliable predictive process models. Currently no reliable predictive or 'dial up a particle size' tool exists for scale-up predictions. The research involves the development of a novel predictive compartmental modelling framework for the scale-up of an organic fine chemical. A new approach of using compartments is developed in order to facilitate scale-up design and process modelling by separating crystallization kinetic and hydrodynamic phenomena. Application of this technique involves determining key process engineering information on a laboratory scale, which is critical for technology transfer, and combining this data with hydrodynamic information on transfer to large scale for predictive scale-up purposes. The key process engineering information required for predictive modelling includes the determination of solubility characteristics, thermodynamic properties and crystallization kinetics of the organic fine chemical. Attenuated Total Reflectance Ultra-Violet (ATR-UV) spectroscopy is used as an 'in-situ' measurement technique to measure solute concentration. A modified continuous Mixed Suspension Mixed Product Removal (MSMPR) crystallizer is designed specifically for innovative drug candidates available in limited quantities to derive steady state crystallization kinetics with minimal influence from hydrodynamic phenomena. Batch attrition experiments were carried out to determine the effects of specific power input on the CSD using Lasentec Focussed Beam Reflectance Monitoring (FBRM) to monitor the process on-line and to develop an attrition rate model. Computational Fluid Dynamics (CFD) is a simulation tool that is also introduced to provide valuable insight into mixing, heat transfer and hydrodynamic phenomena within agitated batch cooling suspension crystallization vessels including investigating the effects of scale-up. CFD is used to aid the development of the compartmental modelling framework. The design of the compartmental structure is based on high spatial resolution CFD simulations of internal flow, mixing and heat transfer within crystallizers upon scale-up. The great advantage of using a compartmental modelling framework is that the spatial resolution is reduced and the full population balance with kinetic models can be implemented. The detailed compartmental framework is based on the overall flow pattern, local energy dissipation rate, solids concentration and temperature distribution obtained from CFD. The number, location, cross-sectional area and volume of compartments are determined from CFD results based on the physical crystallizer dimensions. The compartments are selected such that they have approximately uniform temperature, local energy dissipation and solids concentration. Each dynamic compartment has a mass, concentration, enthalpy and population balance combined with MSMPR crystallization kinetic models. The compartments are therefore well mixed and physically connected via interconnecting flows determined from CFD. A general process modelling tool, gPROMS (Process Systems Enterprises) that supports both steady state and dynamics simulations is used to solve sets of ordinary differential and algebraic equations in each compartment. A single compartmental modelling approach is used initially as a first approach without taking into account local variations in process conditions. Predictions on a laboratory scale for an MSMPR and batch cooling crystallizer were satisfactory but upon scale-up the effects of mixing and hydrodynamics is not taken into account and therefore the predictions become less reliable. A compartmentalization approach can be introduced into gPROMS whereby the compartments are modelled as individual units with input and output streams using CFD hydrodynamic information.

The synthesis of a series of peptides from the processing region of interleukin-1-β precursor (IL-1-β-pre) has been carried out using automated solid-phase methods. The subpeptide comprising residues 102-138 was found to possess inhibitory activity towards the cleavage of IL-1-β-pre in studies using human monocyte cell lines. Attempts have been made to define more closely the region of the peptide responsible for this activity. Overlapping dodecapeptides have been prepared which cover this region of the precursor. The highest level of residual biological activity was found to reside in the subpeptide 111-122, comprising six residues on either side of the site of processing. Various derivatives of this peptide have been prepared in order to enhance this activity. Several of these peptides have been investigated by high-field nuclear magnetic resonance (NMR). Computer assignment of the spectra of most of the dodecapeptides has been achieved. The NMR spectra of an analogue of IL-1-β-pre 102-138 where cysteine-124 has been replaced by alanine (Ala-124-IL-1-β-pre 102-138) have been obtained and partially assigned. Analysis of through-space interactions indicated that these peptides adopt random conformations. A survey of protecting groups for the side-chain amide functional groups of asparagine and glutamine in solid-phase peptide synthesis has been carried out. Novel dibenzosuberenyl-type derivatives have been prepared and successfully applied to the preparation of a series of peptides. A comparison between these derivatives and commonly used alternatives (unprotected amide, trityl and 4,4'dimethoxybenzhydryl) indicated that the trityl group was the most generally suitable means of incorporating these amino acids.

The endothelins were discovered in 1988 and are known to be the most active pressor molecules in the mammalian vascular system. Endothelin-1, which shows potent and long-lasting vasoconstricting activity has been isolated from the culture medium of porcine aortic endothelial cells and implicated in a novel cardiovascular control system. The first member of endothelin family, Endothelin-1, is a 21 amino acid peptide whose structure is constrained by two disulphide bridges between residues 1-15 and 3-11. Increasing evidence for the involvement of endothelins in human disease has prompted a major effort in drug design, pharmacological evolution and structure elucidation. In this thesis, the three dimensional solution structures of Endothelin-1 and modified linear Endothelin-1 derivatives are presented using one- and two-dimensional NMR methods followed by structure calculations DIANA, DSA and MD. This is the first report of solution structures of modified linear Endothelin-1 derivatives. The Panax family plants (<I>P.ginseng</I> and <I>P.notoginseng</I>) are well known in traditional Chinese medicine with the popular name "ginseng". Major compounds isolated from the Panax family plans are saponins and the most of the saponins are also biologically active. The last chapter of this thesis presents the elucidation by one- and two-dimensional NMR methods of the structure and steriochemistry of a compound isolated from the roots of <I>Panax notoginseng</I> shown to release tissue plasminogen activator (tPA) from hemi-pituitary glands <I>in vitro</I>. The compound was identified as the saponin, ginsenoside-Rd, and its NMR spectra fully assigned for the first time.

A novel disulphide containing phosphotriester monomer has been synthesised which possesses oligonucleotide coupling efficiencies which are superior to those obtained from existing disulphide monomers. This dipropyl disulphide linker, which should be stable outside the cell but vulnerable to disulphide cleavage by thiols contained in the cell, has been introduced between the lipophilic groups and oligonucleotides. The oligonucleotides should thus be released from the lipophilic groups once endocytosis has occurred. Similarly, the dipropyl disulphide linker has been introduced between a biotin group and an oligonucleotide. Quantitative disulphide cleavage can be achieved by the addition of dithiothreitol. Thus oligonucleotides bearing cleavable biotin moieties have been synthesised, employing a far more facile and high yielding process than the current method of choice. This approach has been extended to the synthesis of a novel amino functionalised disulphide linker for the production of the first cleavable aminolink oligonucleotides. Cleavage of the disulphide bond in the dipropyl disulphide linker produces a propyl thiol group at the 5'-end of an oligonucleotide. A diethyl disulphide linker has been synthesised which produces an ethyl thiol group on the oligonucleotide after disulphide cleavage. Under basic conditions, the oligonucleotide can eliminate mercaptoethanol to give a 5'-phosphate group. Thus a simple, high-yielding method for the synthesis of terminal thiol and terminal phosphate functionalised oligonucleotides has been developed, offering a viable alternative to existing routes to these functionalities.

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