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.

Thesis (M.S.)--University of North Texas, Dec., 2009. / Title from title page display. Includes bibliographical references.

Thesis (Ph. D.)--University of Texas at Austin, 2004. / Supervisor: Jack B. Swift. Vita. Includes bibliographical references. Available also from UMI company.

Thesis (Ph. D.)--Rutgers University, 2008. / "Graduate Program in Chemical and Biochemical Engineering." Includes bibliographical references (p. 158-173).

Thesis (Ph. D.)--University of Chicago, Department of Physics. / Includes bibliographical references. Also available on the Internet.

Thesis (M.Phil.)--Hong Kong University of Science and Technology, 2008. / Includes bibliographical references. Also available in electronic version.

Includes bibliographical references (p. 239-255).

Thesis (Ph. D.)--University of Queensland, 2003. / Includes bibliographical references.

Thesis (PhD)--University of Stellenbosch, 2004. / Bibliography. Also available via the Internet.

En este trabajo presentamos un nuevo algoritmo para simulación de medios granulares densos que incluye partículas estáticas en presencia de gravedad. El modelo consiste en esferas duras inelásticas, para el cual contamos con un algoritmo de simulación eficiente. Extendemos la descripción de las partículas de manera de simular sólo las relevantes a la dinámica macroscópica del sistema. Presentamos tres casos de estudio: deposiciones sobre un suelo estático, avalanchas en un plano rugoso inclinado y el flujo en un tambor rotante. Estudiamos cómo dependen los observables físicos de los parámetros del algoritmo en tres casos: la fracción de empaquetamiento de esferas iguales, el ángulo de detención para avalanchas sobre un suelo rugoso y el perfil de velocidad en un tambor rotante. Los resultados obtenenidos son prometedores y muestran que el modelo de simulación conducida por eventos es útil para simular flujos densos, siempre y cuando se disipe energía de forma adecuada. La nueva extensión permite simular sistemas de interés en un tiempo computacional mucho menor que con métodos actuales. Concluimos mostrando diferentes sistemas que pueden ser simulados con nuestro algoritmo y proponemos futuras lineas de investigación.