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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)

published_or_final_version / Civil Engineering / Doctoral / Doctor of Philosophy

The Discrete Element Method (DEM) has been applied to numerical modelling of the bulk compression of low modulus particulates. An existing DE code for modelling the contact mechanics of high modulus particles using a linear elastic contact law was modified to incorporate non-linear viscoelastic contact, real containing walls and particle deformation. The new model was validated against experimental data from the literature and physical experiments using synthetic spherical particles, apple and rapeseed. It was then used to predict particle deformation, optimum padding thickness in a handling line and bulk compression parameters during oilseed expression. The application of DEM has previously been limited to systems of hard particles of high compressive and shear modulii with relatively low failure strain. Material interactions have therefore commonly been modelled using linear contact law. For high modulus particles, particle shape change resulting from deformation is a not a significant factor. Most agricultural particulates however deform substantially before failure and their interaction is better represented with non-linear hysteretic viscoelastic contact relationship. Deformation of geometrically shaped particles in DEM is usually treated as "virtual" deformation, which means that particles are allowed to overlap rather than deform due to contact force. Change to particle shape has not previously been possible other than in the case of particles modelled as 2-D polygons or where each particle is also modelled concurrently with an FE mesh. In this work a new approach has been developed which incorporates a non-linear deformation dependent contact damping relationship and a shape change while maintaining sufficient geometrical symmetry to allow the problem to be handled by the same DE algorithms as used for true spheres. The method was validated with available experimental results on impact behaviour of rubber and the variations with different damping coefficients were simulated for a selected fruit. A fruit handling process dependent on the impact process was then simulated to obtain data required in the design of a fruit processing line. Changes in shape of spherical synthetic rubber particles and rapeseeds under compression were predicted and validated with physical experiments. Images were taken and analysed using image processing techniques with 1: 1 scaling. The method on shape change entails a number of simplifying assumptions such as uniform stress distribution and homogeneous material properties and uniform material distribution when deformed, which are not observed in real agricultural materials and will tend to overestimate the true contact area between particles. In reality for fruits and vegetables, material redistribution is a complex process involving a combination of compaction and movement. However with the new method a better approximation of bed voidage (which standard DEM approaches underestimate) and stress were obtained in the compression of a synthetic material. This is a significant improvement on existing methods particularly with respect to stress distribution within a bulk particulate system comprising deforming elements where the size and orientation of contact surface between particles has a strong influence on the bulk modulus. The new model was used for prediction of mechanical oil expression in four oilseed beds. Similar patterns in the variation of the characteristic parameters were obtained as observed in existing experimental data. The data could not be matched exactly as the quantity and arrangement of seeds in the initial seedbeds were not the same as those used in the experimental work. However the DE model gave approximate oil point data for seedbeds with the same physical properties and initial conditions as in the experiment. This suggests that the new model may be a useful tool in the study of mechanical seed-oil expression and other agricultural particulate compression processes.

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

Dissertation (Ph.D.)--Auburn University, 2009. / Abstract. Vita. Includes bibliographic references (p.147-151).

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