Thesis (M.S.)--Civil and Environmental Engineering, Georgia Institute of Technology, 2004. / Carlos Santamarina, Committee Chair ; Glenn Rix, Committee Member ; Paul W. Mayne, Committee Member. Includes bibliographical references.

Thesis (Ph. D.)--University of Chicago, Department of Physics, December 2002. / Includes bibliographical references. Also available on the Internet.

Thesis (Ph.D.)--Hong Kong University of Science and Technology, 2005. / Includes bibliographical references (leaves 197-212). Also available in electronic version.

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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.

The influence of periodic vibrations on the granular flow of materials is of great interests to scientists and engineers due to both theoretical and practical reasons. In this paper, the stability of a vertically vibrated granular layer is examined by linear stability analysis. This includes two major steps, firstly, the base state at various values of mass holdup (Mt) and energy input (Qt) is calculated and secondly, small perturbations are introduced to verify the stability of the base state by solving the resultant eigenvalue problem derived from the linearized governing equations and corresponding boundary conditions. Results from the base state solution show that, for a given pair of Mt and Qt, solid fraction tends to increase at first along the layer height and then decrease after a certain vertical position while granular temperature decreases rapidly from the bottom plate to the top surface. This may be due to the existence of inelastic collisions between particles that dissipate the energy input from the bottom. It is also found that more energy input results in a lower solid fraction and a higher granular temperature. The stability diagram is constructed by checking the stability property at different points in the Mt-Qt plane. For a fixed Mt, the base state is stable at low energy inputs, and becomes unstable if Qt is larger than a critical value Qtc1. A higher value of Mt corresponds to a larger Qtc1. There also exists a critical mass holdup (Mtc), for Mt larger than Mtc, the patterns corresponding to the instabilities are standing waves (stationary mode); otherwise the flat layer appears (layer mode). Moreover, the stationary mode turns into the layer mode when Qt is increased beyond a critical value Qtc2. These findings agree with the experimental observations of other researchers (Hsiau and Pan, 1998). The effects of restitution coefficients (ep, ew) and material properties (dp, ρp) on the stability diagram are also investigated. Together with Mt and Qt these variables can be classified into two groups, i.e. the stabilizing factors (Mt, dp, ρp) and the destabilizing factors (Qt, ep, ew). The stability of the system is enhanced with increasing stabilizing factors and decreasing destabilizing factors. / Singapore-MIT Alliance (SMA)

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