Investigating the role of cholesterol in the formation of non-ionic surfactant based bilayer vesicles:thermal analysis and molecular dynamics

The aim of this research was to investigate the molecular interactions occurring in the formulation of non-ionic surfactant based vesicles composed monopalmitoyl glycerol (MPG), cholesterol (Chol) and dicetyl phosphate (DCP). In the formulation of these vesicles, the thermodynamic attributes and surfactant interactions based on molecular dynamics, Langmuir monolayer studies, differential scanning calorimetry (DSC), hot stage microscopy and thermogravimetric analysis (TGA) were investigated. Initially the melting points of the components individually, and combined at a 5:4:1 MPG:Chol:DCP weight ratio, were investigated; the results show that lower (90 C) than previously reported (120-140 C) temperatures could be adopted to produce molten surfactants for the production of niosomes. This was advantageous for surfactant stability; whilst TGA studies show that the individual components were stable to above 200 C, the 5:4:1 MPG:Chol:DCP mixture show ∼2% surfactant degradation at 140 C, compared to 0.01% was measured at 90 C. Niosomes formed at this lower temperature offered comparable characteristics to vesicles prepared using higher temperatures commonly reported in literature. In the formation of niosome vesicles, cholesterol also played a key role. Langmuir monolayer studies demonstrated that intercalation of cholesterol in the monolayer did not occur in the MPG:Chol:DCP (5:4:1 weight ratio) mixture. This suggests cholesterol may support bilayer assembly, with molecular simulation studies also demonstrating that vesicles cannot be built without the addition of cholesterol, with higher concentrations of cholesterol (5:4:1 vs 5:2:1, MPG:Chol:DCP) decreasing the time required for niosome assembly. © 2013 Elsevier B.V.

The effect of pH on PAMAM dendrimer-siRNA complexation:endosomal considerations as determined by molecular dynamics simulation

Intracellular degradation of genes, most notably within the endo-lysosomal compartment is considered a significant barrier to (non-viral) gene delivery in vivo. Previous reports based on in vitro studies claim that carriers possessing a mixture of primary, secondary and tertiary amines are able to buffer the acidic environment within the endosome, allowing for timely release of their contents, leading to higher transfection rates. In this report, we adopt an atomistic molecular dynamics (MD) simulation approach, comparing the complexation of 21-bp siRNA with low-generation polyamidoamine (PAMAM) dendrimers (G0 and G1) at both neutral and acidic pHs, the latter of which mimics the degradative environment within maturing 'late-endosomes'. Our simulations reveal that the time taken for the dendrimer-gene complex (dendriplex) to reach equilibrium is appreciably longer at low pH and this is accompanied by more compact packaging of the dendriplex, as compared to simulations performed at neutral pH. We also note larger absolute values of calculated binding free energies of the dendriplex at low pH, indicating a higher dendrimer-nucleic acid affinity in comparison with neutral pH. These novel simulations provide a more detailed understanding of low molecular-weight polymer-siRNA behavior, mimicking the endosomal environment and provide input of direct relevance to the "proton sponge theory", thereby advancing the rational design of non-viral gene delivery systems.

Living cationic polymerization of styrene monomers

This thesis describes an experimental investigation of synthesis of polystyrene under various polymerization conditions such as solvent polarity, temperature, initial concentrations of initiator, catalyst, monomer and added salts or co-catalyst, which was achieved using the living cationic polymerization technology in conjunction with gel permeation chromatography (GPC) and NMR spectroscopy. Polymerizations of styrene were conducted using 1-phenyl ethylchloride (1-PEC) as an initiator and tin tetrachloride (SnCI4) as a catalyst in the presence of tetra-n-Butylammonium chloride (nBu4NCI). Effects of solvent polarity varied by mixing dichloromethane (DCM) and less polar cyclohexane (C.hex), temperature, initial concentrations of SnC14, 1-PEC and nBu4NCI on the polymerizations were examined, and the conditions under which a living polymerization can be obtained were optimised as: [styrene]o ~ 0.75 - 2 M; [1-PEC]o ~ 0.005 - 0.05 M; [SnCI4Jo ~ 0.05 - 0.4 M; [nBu4NCIJo ~ 0.001 - 0.1 M; DCM/C.hex ~ 50/0 - 20/30 v/v; T ~ 0 to -45°C. Kinetic studies of styrene polymerization using the Omnifit sampling method showed that the number average molecular weight (Mn) of the polymers obtained increased in direct proportion to monomer conversion and agreed well with the theoretical Mn expected from the concentration ratios of monomer to initiator. The linearities of both the 1n([MJoI[M]) vs. time plot and the Mn vs. monomer conversion plot, and the narrow molecular weight distribution (MWD) measured using GPC demonstrated the livingness of the polymerizations, indicating the absence of irreversible termination and transfer within the lifetimes of the polymerizations. The proposed 'two species' propagation mechanism was found to apply for the styrene polymerization with 1-PEC/SnCI4 in the presence of nBu4NCl. The further kinetic experiments showed that living styrene polymerizations were achieved using the 1-PEC/SnCI4 initiating system in mixtures of DCM/C.hex 30/20 v/v at -15°C in the presence of various bromide salts, tetra-n-butylammonium bromide, tetra-n-pentylammonium bromide, tetra-n-heptylammonium bromide, and tetra-n-octylammonium bromide, respectively. The types of the bromide salts were found to have no significant effect on monomer conversion, Mn, polydispersity and initiation efficiency. Living polymerizations of styrene were also achieved using titanium tetrachloride (TiCI4) as a catalyst and 1-PEC as an initiator in the presence of a small amount of 2,6-di-tert-butylpyridine or pyridine instead of nBu4NCl. GPC analysis showed that the polymers obtained had narrow polydispersities (P.D. < 1.3), and the linearities of both the In([MJo/[MJ) vs. time plot and the Mn vs. monomer conversion plot demonstrated that the polymerizations are living, when the ratio of DCM and C.hex was less than 40 : 10 and the reaction temperature was not lower than -15°C. The reaction orders relative to TiCl4 and 1-PEC were estimated from the investigations into the rate of polymerization to be 2.56 and 1.0 respectively. lH and 13C NMR analysis of the resultant polystyrene would suggest the end-functionality of the product polymers is chlorine for all living polymerizations.

Atom transfer radical polymerisation - towards the synthesis of a fully-functional photorefractive polymer

Atom transfer radical polymerisation (ATRP) of styrene in xylene solution initiated with 1-phenylethyl bromide and mediated by CuBr/N-propyl-2- pyridinemethanimine catalyst complex was studied. The polymerisation was ill-controlled, yielding polymers with broad molecular weight distributions and values of number average molecular weight considerably higher than the theoretical values calculated from 100% initiator efficiency. The degree of control afforded over the polymerisation was enhanced by use of a more soluble catalyst complex, CuBr/N-octyl-2-pyridinemethanimine. Furthermore, the use of a more polar solvent, diglyme, generated a homogeneous catalyst complex that facilitated the production of polymers having narrow molecular weight distributions (1.10 < PDi < 1.20). The kinetics of the atom transfer radical polymerisation of methyl methacrylate at 90°C in diglyme solution initiated with ethyl-2-bromoisobutyrate and mediated by CuBr/N-octyl-2-pyridinemethanimine was studied and the orders of the reaction were established. The effect on the rate of polymerisation of the ratio of CuBr:N-octyl-2-pyridinemethanimine was also determined. The temperature dependencies of the rate of polymerisation of methyl methacrylate in diglyme solution and xylene solution were studied, and were found to be non-linear and dependent upon the polarity of the solvent. The use of highly polar aprotic solvents, such as N,N-dimethylformamide and dimethylsulphoxide, was found to be detrimental to the degree of control afforded over the polymerisation of methyl methacrylate. This was circumvented by use of a 5-fold excess, over that conventionally used, of catalyst complex. The atom transfer radical polymerisation of (4-nitrophenyl)-[3-[N-[2- (methacryloyloxy)ethyl]carbazolyl]]diazene in dimethyl sulphoxide solution was studied. Although homopolymerisation yielded only oligomers, copolymerisation of this monomer with methyl methacrylate was found to be readily achievable. Keywords: ATRP, Styrene; Methyl methacrylate; Polar solvents; Fully-functional photorefractive polymer. 2

Investigation of the oxidative degradation mechanisms and melt stabilisation of a new generation metallocene polytehylene

The two main objectives of the research work conducted were firstly, to investigate the processing and rheological characteristics of a new generation metallocene catalysed linear low density polyethylene (m-LLDPE), in order to establish the thermal oxidative degradation mechanism, and secondly, to examine the role of selected commercial stabilisers on the melt stability of the polymers. The unstabilised m-LLDPE polymer was extruded (pass I) using a twin screw extruder, at different temperatures (210-285°C) and screw speeds (50-20rpm) and was subjected to multiple extrusions (passes, 2-5) carried out under the same processing conditions used in the first pass. A traditional Ziegler/Natta catalysed linear low density polyethylene (z-LLDPE) produced by the same manufacturer was also subjected to a similar processing regime in order to compare the processability and the oxidative degradation mechanism (s) of the new m-LLDPE with that of the more traditional z-LLDPE. The effect of some of the main extrusion characteristics of the polymers (m-LLDPE and z-LLDPE) on their melt rheological behaviour was investigated by examining their melt flow performance monitored at two fixed low shear rate values, and their rheological behaviour investigated over the entire shear rates experienced during extrusion using a twin-bore capillary rheometer. Capillary rheometric measurements, which determine the viscous and elastic properties of polymers, have shown that both polymers are shear thinning but the m-LLDPE has a higher viscosity than z-LLDPE and the extent of reduction in viscosity of the former when the extrusion temperature was increased from 210°C to 285°C was much higher than in the case of the z-LLDPE polymer. This was supplied by the findings that the m-LLDPE polymer required higher power consumption under all extrusion conditions examined. It was fUliher revealed that the m-LLDPE undergoes a higher extent of melt fracture, the onset of which occurs under much lower shear rates than the Ziegler-based polymer and this was attributed to its higher shear viscosity and narrower molecular weight distribution (MWD). Melt flow measurements and GPC have shown that after the first extrusion pass, the initial narrower MWD of m-LLDPE is retained (compared to z-LLDPE), but upon further multiple extrusion passes it undergoes much faster broadening of its MWD which shifts to higher Mw polymer fractions, paliicularly at the high screw speeds. The MWD of z-LLDPE polymer on the other hand shifts towards the lower Mw end. All the evidence suggest therefore the m-LLDPE undergoes predominantly cross-linking reactions under all processing conditions whereas z-LLDPE undergoes both cross-linking and chain scission reactions with the latter occurring predominantly under more severe processing conditions (higher temperatures and screw speeds, 285°CI200rpm). The stabilisation of both polymers with synergistic combinations of a hindered phenol (Irganox 1076) and a phosphite (Weston 399) at low concentrations has shown a high extent of melt stabilisation in both polymers (extrusion temperatures 210-285°C and screw speeds 50-200rpm). The best Irganox 1076/Weston 399 system was found to be at an optimum 1:4 w/w ratio, respectively and was found to be most effective in the z-LLDPE polymer. The melt stabilising effectiveness of a Vitamin E/Ultranox 626 system used at a fraction of the total concentration of Irganox 1076/Weston 399 system was found to be higher in both polymers (under all extrusion conditions). It was found that AOs which operate primarily as alkyl (Re) radical scavengers are the most effective in inhibiting the thermal oxidative degradation of m-LLDPE in the melt; this polymer was shown to degrade in the melt primarily via alky radicals resulting in crosslinking. Metallocene polymers stabilised with single antioxidants of Irganox HP 136 (a lactone) and Irganox E201 (vitamin E) produced the highest extent of melt stability and the least discolouration during processing (260°C/1 OOrpm). Furthermore, synergistic combinations of Irganox HP I 36/Ultranox 626 (XP-60) system produced very high levels of melt and colour stability (comparable to the Vitamin E based systems) in the mLLDPE polymer. The addition of Irganox 1076 to an Irganox HP 136/Ultranox 626 system was found not to result in increasing melt stability but gave rise to increasing discolouration of the m-LLDPE polymer. The blending of a hydroxylamine (lrgastab FS042) with a lactone and Vitamin E (in combination with a phosphite) did not increase melt stability but induced severe discolouration of resultant polymer samples.

The synthesis of novel biodegradable polyesters and copolyesters from anhydrosulfites

This thesis was concerned primarily with the synthesis and the ring-opening polymerisation of anhydrosulfites (1,3,2-dioxa-thiolan-4-one-2-oxides), and secondly with the copolymerisation of anhydrosulfites with -caprolactone. The polyesters and copolyesters synthesised are of considerable interest in medical applications and also for use as environmental friendly packaging. A range of anhydrosulfites were prepared according to an established method. Aliphatic anhydrosulfites were obtained with a level of purity satisfactory for polymerisation whereas aromatic anhydrosulfites decomposed during distillation and purification by chromatographic techniques. Aliphatic anhydrosulfites with a substituent, such as methyl, isopropyl, n-butyl and isobutyl were studied by NMR spectroscopy. Analysis of these spectra revealed that the five-membered anhydrosulfite ring was puckered and that when the substituent was bulky, rotations about the alkyl chains were restricted. A wide range of anionic initiators may be used to initiate anhydrosulfites. Lithium alkyls turned out to be more successful than alkali metal alkoxides and amides. The molecular weights were found to depend on the basicity of the initiator, the monomer-to-initiator ratio, the nature of the solvent and the polymerisation temperature. The molecular weight M0 of poly(L-lactic acid) ranged from (0.5 to 6)x104. Highly crystalline and purely isotactic poly(lactic acid) was synthesised from L-lactic acid anhydrosulfite (L-LAAS) whereas DL-LAAS led to an amorphous polymer with randomly distributed D-and L-lactic units. This indicated that this polymerisation was not stereoselective. However, the bulkiness of the substituent in the anhydrosulfites molecule was found to influence the stereoselectivity of the polymerisation, thus polyesters with isobutyl or n-butyl pendant group were preferentially isotactic. Block-copolymers of ε-caprolactone and several anhydrosulfites were successfully produced. Block-copolymers of LAAS with ε-caprolactone were also synthesised, but the incorporation of caprolactone units was rather small. In contrast, random copolymerisation of LAAS and ε-caprolactone led to polymers with blocky structures similar to those obtained in the block-copolymerisation of LAAS with  ε-caprolactone.

Liquid-phase adsorption of n-paraffins on type 5A molecular sieves

As a basis for the commercial separation of normal paraffins a detailed study has been made of factors affecting the adsorption of binary liquid mixtures of high molecular weight normal paraffins (C12, C16, and C20) from isooctane on type 5A molecular sieves. The literature relating to molecular sieve properties and applications, and to liquid-phase adsorption of high molecular weight normal paraffin compounds by zeolites, was reviewed. Equilibrium isotherms were determined experimentally for the normal paraffins under investigation at temperatures of 303oK, 323oK and 343oK and showed a non-linear, favourable- type of isotherm. A higher equilibrium amount was adsorbed with lower molecular weight normal paraffins. An increase in adsorption temperature resulted in a decrease in the adsorption value. Kinetics of adsorption were investigated for the three normal paraffins at different temperatures. The effective diffusivity and the rate of adsorption of each normal paraffin increased with an increase in temperature in the range 303 to 343oK. The value of activation energy was between 2 and 4 kcal/mole. The dynamic properties of the three systems were investigated over a range of operating conditions (i.e. temperature, flow rate, feed concentration, and molecular sieve size in the range 0.032 x 10-3 to 2 x 10-3m) with a packed column. The heights of adsorption zones calculated by two independent equations (one based on a constant width, constant velocity and adsorption zone and the second on a solute material balance within the adsorption zone) agreed within 3% which confirmed the validity of using the mass transfer zone concept to provide a simple design procedure for the systems under study. The dynamic capacity of type 5A sieves for n-eicosane was lower than for n-hexadecane and n-dodecane corresponding to a lower equilibrium loading capacity and lower overall mass transfer coefficient. The values of individual external, internal, theoretical and experimental overall mass transfer coefficient were determined. The internal resistance was in all cases rate-controlling. A mathematical model for the prediction of dynamic breakthrough curves was developed analytically and solved from the equilibrium isotherm and the mass transfer rate equation. The experimental breakthrough curves were tested against both the proposed model and a graphical method developed by Treybal. The model produced the best fit with mean relative percent deviations of 26, 22, and 13% for the n-dodecane, n-hexadecane, and n-eicosane systems respectively.

Continuous chromatographic biochemical reaction-separation

Combined bioreaction separation studies have been carried out for the first time on a moving port semi-continuous counter-current chromatographic reactor-separator (SCCR-S1) consisting of twelve 5.4cm id x 75cm long columns packed with calcium charged cross-linked polystyrene resin (KORELA V07C). The inversion of sucrose to glucose and fructose in the presence of the enzyme invertase and the biochemIcal synthesis of dextran and fructose from sucrose in the presence of the enzyme dextransucrase were investigated. A dilute stream of the appropriate enzyme in deionised water was used as the eluent stream. The effect of switch time, feed concentration, enzyme activity, eluent rate and enzyme to feed concentration ratio on the combined bioreaction-separation were investigated. For the invertase reaction, at 20.77% w/v sucrose feed concentrations complete conversions were achieved. The enzyme usage was 34% of the theoretical enzyme amount needed to convert an equivalent amount of sucrose over the same time period when using a conventional fermenter. The fructose rich (FRP) and glucose rich (GRP) product purities obtained were over 90%. By operating at 35% w/v sucrose feed concentration and employing the product splitting and recycling techniques, the total concentration and purity of the GRP increased from 32% w/v to 4.6% and from 92.3% to 95% respectively. The FRP concentration also increased from 1.82% w/v to 2.88% w/v. A mathematical model was developed for the combined reaction-separation and used to simulate the continuous inversion of sucrose and product separation using the SCCR-S1. In the biosynthesis of dextran studies, 52% conversion of a 2% w/v sucrose concentration feed was achieved. An average dextran molecular weight of 4 millIon was obtained in the dextran rich (DRP) product stream. The enzyme dextransucrase was purifed successfully using centrifugation and ultrafiltration techniques.

The ring opening polymerization of ring strained cyclic ethers

The kinetics and mechanisms of the ring-opening polymerization of oxetane were studied using cationic and coordinated anionic catalysts. The cationic initiators used were BF30Et2!/ethanol, BF30Et2!/ethanediol and BF30Et2/propantriol. Kinetic determinations with the BF30Et2/diol system indicated that a 1: 1 BF3:0H ratio gave the maximum rate of polymerization and this ratio was employed to detenmne the overall rates of polymerization. An overall second-order dependence was obtained when the system involved ethanediol or propantriol as co-catalyst and a 3/2-order dependence with ethanol, in each case the monomer gave a first-order relationship. This suggested that two mechanisms accounted for the cationic polymerization. These mechanisms were investigated and further evidence for these was obtained from the study of the complex formation of BF30Et2 and the co-catalysts by 1H NMR. Molecular weight studies (using size-exclusion chromatography) indicated that the hydroxyl ion acted as a chain transfer reagent when the [OH] > [BF3]. A linear relationship was observed when the number average molecular weight was plotted against [oxetane] at constant [BF3:0H], and similarly a linear dependency was observed on the BF3:0H 1:1 adduct at constant oxetane concentration. Copolymerization of oxetane and THF was carried out using BF30Et2/ethanol system. The reactivity ratios were calculated as rOXT = 1.2 ± 0.30 and rTHF = 0.14 ± 0.03. These copolymers were random copolymers with no evidence of oligomer formation. The coordinated anionic catalyst, porphinato-aluminium chloride [(TPP)AICl], was used to produce a living polymerization of oxetane. An overall third-order kinetics was obtained, with a second-order with respect to the [(TPP)AICl] and a first-order with respect to the [oxetane] and a mechanism was postulated using these results. The stereochemistry of [(TPP)AlCl] catalyst was investigated using cyclohexene and cyclopentene oxide monomers, using extensive 1H NMR, 2-D COSY and decoupling NMR techniques it was concluded that [(TPP)AlCl] gave rise to stereoregular polymers.

The sustained delivery of antisense oligodeoxynucleotides using biodegradable polymer microspheres

Antisense technology is a novel drug discovery method, which provides an essential tool for directly using gene sequence information to rationally design specific inhibitions of mRNA, to treat a wide range of diseases. The efficacy of naked oligodeoxynucleotides (ODNs) is relatively short lived due to rapid degradation in vivo. The entrapment of ODNs within biodegradable sustained-release delivery systems may improve ODN stability and reduce dose required for efficacy. Biodegradable polymer microspheres were evaluated as delivery devices for ODNs and ribozymes. Poly(lactide-co-glycolide) polymers were used due to their biocompatibility and non toxic degradation products. Microspheres were prepared using a double emulsion-deposition method and the formulations characterised. In vitro release profiles were characterised by an initial burst effect during the first 48 hours of release followed by a more sustained release. The release profiles were influenced by microsphere size, copolymer molecular weight, copolymer ratio, ODN loading, ODN length, and ODN chemistry. The serum stability of ODNs was significantly improved when entrapped within polymer microspheres. The cellular association of ODNs entrapped within small spheres (1-2μm) was improved by approximately 20-fold in A431 carcinoma cells compared with free ODNs. Fluorescence microscopy studies showed a more diffuse subcellular distribution when delivered as a microsphere formulation compared with free ODNs, which exhibited the characteristic punctate periplasmic distribution. For in vivo evaluation, polymer microspheres containing fluorescently-labelled ODNs were stereo-taxically administered to the neostriatum of the rat brain. Free ODN resulted in a punctate cellular distribution after 24 hours. In comparison ODN delivered using polymer microspheres were intensely visible in cells 48 hours post administration, and fluorescence appeared to be diffuse covering both cytosolic and nuclear regions. Whole-body autoradiography was also used to evaluate the biodistribution of free tritium labelled ODN and ODN entrapped microspheres, following subcutaneous administration to Balb-C mice. Polymer entrapped ODN gave a similar biodistribution to free ODN. Free ODN was distributed within 24 hours, whereas polymer released ODN was observed still presented in organs and at the site of administration seven days post administration.

Reduced metal transferrin binding in neurological diseases

By employing G75 gel-filtration chromotography, it has been demonstrated that human plasma gallium speciation (and by implication, Al speciation) is bimodal. Normally, gallium was predominantly bound to a high molecular weight fraction which was presumably transferrin. Literature reviews and experimental work throughout this thesis provided evidence to support this idea. An aluminium-transferrin species was assumed to be relatively non-toxic and a protective function for this complex has been suggested. A second, low molecular weight species of gallium was observed and its identity has been suggested to be citrate. The results of this thesis support the concept citrate was a gallium binding ligand present in the plasma, but there was another species (tentatively identified as phosphate) which bound gallium to a much greater degree than did citrate in the majority of samples studied. The consequence of a low molecular weight species of aluminium is the possibility that this leads to a more rapid, uncontrolled deposition of the metal in the brain compared to a transferrin mediated mechanism. Plasma speciation studies in Alzheimer's disease, Parkinson's disease, Down's syndrome, and neonates has revealed an altered ratio of the two gallium species found in control subjects. In all groups there was an increase in the potentially more neurotoxic low molecular weight species. These observations have led to a suggested mechanism of accumulation of metals in the brain, which is known to occur in the first three groups. Possible pathogenic mechanisms are described. The results can also offer an explanation to the reported increased sensitivity to the toxic effects of aluminium in the neonate. Speciation studies on normal plasma has shown the balance between high and low molecular weight species of gallium to be influenced by many physiological factors. There appears to be a fine equilibrium between both species which can be altered without any great difficulty. Therefore, in the diseased groups studied, it is possible that there are subtle biochemical changes within the circulatory system to affect the equilibrium which results in an increased low molecular weight species of aluminium. Furthermore, it has been demonstrated that there is a group of normal controls with no clinical signs of Alzheimer's or Parkinson's disease which have reduced transferrin binding. This indicates there is a population of healthy people who are at risk to the development of either disease.

Investigating the molecular structures of solid dispersions by the simulated annealing method

Knowledge of the molecular structures of solid dispersions is vital, yet, despite thousands of reports in this area, it remains unclear. The aim of this research is to investigate the molecular structure of solid dispersions with hot melt preparation method by the simulated annealing method. Simulation results showed linear polymer chains form the random coils under heat and the drug molecules stick on the surface of polymer coils, while drug molecules are dispersed molecularly but irregularly within the amorphous low molecular weight carriers. This research presents more reasonable molecular images of solid dispersions than the existed theory.

Strategic development and physicochemical analysis of oral preparations for unstable drugs

Oral liquid formulations are ideal dosage forms for paediatric, geriatric and patient with dysphagia. Dysphagia is prominent among patients suffering from stroke, motor neurone disease, advanced Alzheimer’s and Parkinson’s disease. However oral liquid preparations are particularly difficult to formulate for hydrophobic and unstable drugs. Therefore current methods employed in solving this issue include the use of ‘specials’ or extemporaneous preparations. In order to challenge this, the government has encouraged research into the field of oral liquid formulations, with the EMEA and MHRA publishing list of drugs of interest. The current work investigates strategic formulation development and characterisation of select API’s (captopril, gliclazide, melatonin, L-arginine and lansoprazole), each with unique obstacles to overcome during solubilisation, stabilisation and when developing a palatable dosage from. By preparing a validated calibration protocol for each of the drug candidates, the oral liquid formulations were assessed for stability, according to the ICH guidelines along with thorough physiochemical characterisation. The results showed that pH and polarity of the solvent had the greatest influence on the extent of drug solubilisation, with inclusion of antioxidants and molecular steric hindrance influencing the extent of drug stability. Captopril, a hydrophilic ACE inhibitor (160 mg.mL-1), undergoes dimerisation with another captopril molecule. It was found that with the addition of EDTA and HP-β-CD, the drug molecule was stabilised and prevented from initiating a thiol induced first order free radical oxidation. The cyclodextrin provided further steric hindrance (1:1 molar ratio) resulting in complete reduction of the intensity of sulphur like smell associated with captopril. Palatability is a crucial factor in patient compliance, particularly when developing a dosage form targeted towards paediatrics. L-arginine is extremely bitter in solution (148.7 g.L-1). The addition of tartaric acid into the 100 mg.mL-1 formulation was sufficient to mask the bitterness associated with its guanidium ions. The hydrophobicity of gliclazide (55 mg.L-1) was strategically challenged using a binary system of a co-solvent and surfactant to reduce the polarity of the medium and ultimately increase the solubility of the drug. A second simpler method was developed using pH modification with L-arginine. Melatonin has two major obstacles in formulation: solubility (100 μg.mL-1) and photosensitivity, which were both overcome by lowering the dielectric constant of the medium and by reversibly binding the drug within the cyclodextrin cup (1:1 ratio). The cyclodextrin acts by preventing UV rays from reaching the drug molecule and initiated the degradation pathway. Lansoprazole is an acid labile drug that could only be delivered orally via a delivery vehicle. In oral liquid preparations this involved nanoparticulate vesicles. The extent of drug loading was found to be influenced by the type of polymer, concentration of polymer, and the molecular weight. All of the formulations achieved relatively long shelf-lives with good preservative efficacy.