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Purpose: The aim of this thesis was to investigate a novel method of preparing crosslinked alginate matrices. Current methods use large quantities of water and hence are not suitable for large scale manufacturing of drug alginate particulate systems. Moreover, the current processes offer little scope for control of the crosslinking process. The aim was to overcome these problems through studies of paracetamol alginate granular matrices prepared by the novel method and to explore if these granules could be used to improve the taste of paracetamol. Methods: The novel method involves preparation of dried drug alginate granules (moisture content: <5-6 %) using conventional granulation followed by crosslinking treatment of the dried granules with calcium chloride or a combination of calcium and magnesium ion solution in a crosslinking bath. The effect of the process (shear rate, binder quantity) to prepare untreated granules, composition of the raw materials (drug particle size and type of alginate) and subsequently the crosslinking treatment process variables (Ca�⁺ ion concentration, agitation rate, time and temperature of Ca�⁺ solution) on the physicochemical properties of granule systems were studied using factorial designs together with supporting studies. The granules were characterized using sodium and calcium content analysis, drug release studies (mainly sub-60s release) matrix swelling rate and equilibrium swelling studies, tensile strength studies, ion permeation studies, SEM and X Ray analysis and gravimetric studies. Sensory studies correlating sub-60 s drug release (determined using a specially designed apparatus) and human taste scores (measured using an analogue scale) were then undertaken. Selected formulations were evaluated for taste improvement and to determine if mucoadhesion led to an increased unpalatability of paracetamol. Results: Of the crosslinking treatment factors, the calcium concentration had the greatest effect on crosslinked granules. Although other treatment factors also affected the granule properties, alteration of the salt concentration allowed considerable control over the crosslinking process (not possible in the conventional method) in addition to providing a mechanistic understanding of the crosslinking process in the dried state. The use of low calcium concentrations (< 20 mg/ml, CaCl₂. 2H₂O) during treatment led to granule erosion (hence drug loss) due to overall incomplete crosslinking but led to a reduction in the short-term drug release compared to the granules treated with intermediate (100- 250 mg/ml) or high calcium concentrations (>400 mg/ml) due to reduction in the granule porosity after crosslinking. Although intermediate calcium concentrations led to complete crosslinking and longer release times (T 85 %: 25 min) high calcium crosslinking restricted the crosslinking to the surface of the granules leading to faster drug release (T 85 %: 8 min) with low calcium granules showing intermediate crosslinking and drug release rates (T 85 %: 18 min). High calcium treatment limited drug loss during crosslinking (95 % recovered compared to 83 % recovery at intermediate calcium concentration) without affecting the short-term drug release much. Low calcium granules showed the lowest drug recovery (< 70 %) and slowest sub-60s drug release followed closely by intermediate and high calcium treated granules. The granule preparation factors (shear rate, binder quantity) and type of alginate used, considerably affected the sub-60s drug release by affecting surface porosity especially when a low shear rate was used. However, these factors only slightly reduced the drug loss during crosslinking treatment phase (about 4 % increase in drug recovery). Smaller drug particle size had a slightly larger incremental effect on drug recovery (about 8 % increase in the drug recovery) during crosslinking treatment due to better embedding of the drug particles inside the untreated granule matrix. This was true as long as the particle size of the drug was > 98 [mu]m. Below this size drug recovery remained unaffected by changes in drug particle size. Although granule surface porosity considerably affected the sub-60s drug release, its effect on drug release (long-term) was much less. A linear correlation was observed between the sub-60s drug release and sensory scores despite high individual variability. Both granule formulations evaluated showed taste improvement and mucoadhesion did not lead to an increase in the bitter taste of the uncrosslinked paracetamol alginate granules. Conclusions: Unlike the traditional method, the new technique of preparation of crosslinked drug alginate particulate systems uses very little water and allows greater control over the the crosslinking process compared to the swollen state crosslinking. The novel process of preparation is versatile, and should be scalable. It offers the formulator a platform to prepare a matrix, reservoir or a combination of these two systems using alginates and other drugs and polymers as well. Adequate short-term control over paracetamol release, very little loss of paracetamol during treatment (< 5 % loss), reduction in mucoadhesion of the granules and lastly improvement of the taste of paracetamol is possible using alginate based systems especially if high calcium is used during the crosslinking treatment. Hence, it is likely that these taste-improved granules could be used to prepare tablets without the need for a protective film coating to improve taste. Finally, this research established the utility of short-term drug release in taste improvement research and characterization of solid controlled release dosage forms.

Liposomes are used as biocompatible carriers of drugs, peptides, proteins, plasmic DNA, antisense oligonucleotides or ribozymes, for pharmaceutical, cosmetic, and biochemical purposes. They are considered as effective drug delivery systems due to their colloidal size, easily controllable surface and membrane properties, large carrying capacity of drugs and biocompatibility. / This study was concerned with the stability of liposomes, their interaction at solid-liquid interfaces and their release of hydrophilic drug compounds. Either conventional liposomes containing lecithin and cholesterol, and Stealth® liposomes containing polyethylene glycol (PEG) 5000-lipids or PEG2000-lipids were investigated. Steric hindrance introduced by PEG chains proved to be influential in controlling liposome stability, interaction and drug release processes. Electrostatic forces were shown to be essential to the mechanisms and kinetics of liposome adsorption and colloidal stability, but not influential for the release of guanosine, used as a model hydrophilic drug. / Findings from this research improve the understanding of liposome interaction during drug delivery, give insight into the actions of liposomes in the body and may form the basis for improved liposome formulation. In addition, this research has developed a more comprehensive understanding of the role of PEG in controlling the colloidal stability, interfacial interactions of liposomes and drug transport kinetics across the lipid bilayers of liposomes. / Thesis (PhDAppliedScience)--University of South Australia, 2005.

For controlled drug delivery applications, an ideal carrier system should release its drug payload only at the site where the therapeutic activity is required. One elegant strategy for site-selective release of drugs is to utilize the acidic sites in the body, for example, tumor sites and intracellular endocytic compartments. The objective of this thesis is to develop a series of new acid-cleavable polymeric nanoparticles for pH-triggered delivery oftherapeutics. Four new acid-cleavable benzaldehyde acetal crosslinkers have been designed and synthesized. They were then used in the generation of acid-labile polymeric nanoparticle drug carrier systems via various synthetic strategies and drug loading approaches for the delivery of therapeutics with different nature: (l) the coreshell poly(butyl acrylate)-g-poly(polyethylene glycol acrylate) nanoparticles, synthesized via the reversible addition-fragmentation chain transfer (RAFT)-mediated dispersion polymerization, were used for the delivery of hydrophobic drugs; (2) the core-crosslinked poly(hydroxyethyl acrylate)-b-poly(butyl acrylate) copolymer micelles, synthesized via the RAFT-mediated chain-extension polymerization, were used for the delivery of an antitumor drug, doxorubicin; (3) the poly(hydroxyethyl methacrylate) microgel particles, synthesized via the inverse-emulsion polymerization, were used for the delivery of biomacromolecular drugs. The designed physiochemical features such as the size, surface chemistry, cytotoxicity and the pH-triggered drug release properties of the developed carrier systems have been assessed. The synthesized systems offered release of the drug payload at slightly acidic conditions. The structural integrity of the polymeric carriers remained intact in the physiological, neutral pH conditions. The results support the potential value of the developed systems to be used for acidic-site delivery of therapeutics e.g. tumor sites and intracellular compartments. The content of this thesis has been published as three peer-reviewed international journal articles.

Thesis (M.S.)--University of Akron, Dept. of Chemical Engineering, 2007. / "December, 2007." Title from electronic thesis title page (viewed 02/25/2008) Advisor, Stephanie T. Lopina; Faculty readers, Bi-min Newby, Helen Qammar; Department Chair, Lu-Kwang Ju; Dean of the College, George K. Haritos; Dean of the Graduate School, George R. Newkome. Includes bibliographical references.

Thesis (Ph.D.)--Drexel University, 2008. / Includes abstract and vita. Includes bibliographical references (leaves 251).

Thesis (Ph.D.)--Drexel University, 2008. / Includes abstract and vita. Includes bibliographical references (leaves 165-168).