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The purpose of the research was to introduce a procedure to derive a powder compression parameter (EM A) representing particle yield stress using an effective medium equation and to compare the EM A parameter with the Heckel compression parameter (1/K). 16 pharmaceutical powders, including drugs and excipients, were compressed in a materials testing instrument and powder compression profiles were derived using the EM and Heckel equations. The compression profiles thus obtained could be sub-divided into regions among which one region was approximately linear and from this region, the compression parameters EM A and 1/K were calculated. A linear relationship between the EM A parameter and the 1/K parameter was obtained with a strong correlation. The slope of the plot was close to 1 (0.84) and the intercept of the plot was small in comparison to the range of parameter values obtained. The relationship between the theoretical EM A parameter and the 1/K parameter supports the interpretation of the empirical Heckel parameter as being a measure of yield stress. It is concluded that the combination of Heckel and EM equations represents a suitable procedure to derive a value of particle plasticity from powder compression data.

Triaxial compression of plastically deforming particles was studied with the finite element method in order to identify the mechanisms that underlie the particle response under confined conditions. In addition to the established elastoplastic behaviour at small and intermediate strains, the coalescence of plastic zones centred at contacts resulted in a reduced stiffness, whereas a significantly increased stiffness was seen once the material displaced by plastic deformation filled the ambient void space, signifying the onset of a stage dominated by elastic volume reduction. Moreover, an analytical model for multiple simultaneous contacts was formulated, assuming that the deformed particle shape could be approximated by a truncated sphere and that the behaviour of each individual contact could be described in terms of a hardness. The thus obtained model exhibited a promising agreement with the numerical results.

The effect of degree of compression on the evolution of tablet microstructure and bond probability during compression of granular solids has been studied. Microcrystalline cellulose pellets of low (about 11%) and of high (about 32%) porosity were used. Tablets were compacted at 50, 100 and 150 MPa applied pressures and the degree of compression and the tensile strength of the tablets determined. The tablets were subjected to mercury intrusion measurements and from the pore size distributions, a void diameter and the porosities of the voids and the intra-granular pores were calculated. The pore size distributions of the tablets had peaks associated with the voids and the intra-granular pores. The void and intra-granular porosities of the tablets were dependent on the original pellet porosity while the total tablet porosity was independent. The separation distance between pellets was generally lower for tablets formed from high porosity pellets and the void size related linearly to the degree of compression. Tensile strength of tablets was higher for tablets of high porosity pellets and a scaled tablet tensile strength related linearly to the degree of compression above a percolation threshold. In conclusion, the degree of compression controlled the separation distance and the probability of forming bonds between pellets in the tablet.

Granule shear behaviour was investigated experimentally and numerically to evaluate the reliability of the numerical model. Additionally, parameters affecting the ensuing flow regimes - elastic quasi-static and inertial non-collisional - were highlighted. Furthermore, the influence of using the Lees-Edwards periodic boundary conditions or the standard boundary conditions was studied. Experiments were performed with microcrystalline cellulose granules of three size distributions using the FT4 powder rheometer. The numerical parameters, particle size, effective density, and particle stiffness were selected to match the experimental conditions. Experimentally, an unexpected particle size effect was evident where the resistance to shear increased with particle size. Numerically, combining rolling friction. and increased shear rate enabled a transition from the inertial non-collisional to the elastic quasi-static regime at a reduced sliding friction coefficient. Presumably, this is an effect of increased particle overlap creating stronger contacts and facilitating force chain formation. Both boundary conditions provided comparable results provided a correction of system size was made, where larger systems were required for the standard boundary conditions. A satisfactory qualitative agreement between the experimentally and numerically determined yield loci emphasised the predictive capacity of the DEM. Rolling friction was in addition concluded to be an essential model parameter for obtaining an improved quantitative agreement.

Proteolytic degradation and release of microgel-bound peptides was investigated for trypsin, poly(acrylic acid-co-acrylamide) microgels (70-90 mu m in diameter), and oppositely charged polylysine, using a method combination of confocal microscopy and micromanipulator-assisted light microscopy. Results show that trypsin-induced release of polylysine increased with increasing trypsin concentration, decreasing microgel charge density and decreasing peptide molecular weight. While the microgel offered good protection against enzymatic degradation at high microgel charge density, it was also observed that the cationic peptide enabled trypsin to bind throughout the peptide-loaded microgels, even when it did not bind to the peptide-void ones. With the exception of highly charged microgels, proteolytic degradation throughout the peptide-loaded microgel resulted in the generation of short and non-adsorbing peptide stretches, giving rise to the concentration and peptide length dependence observed. A simple random scission model was able to qualitatively capture these experimental findings. collectively, the results demonstrate that microgel charge density, peptide molecular weight, and enzyme concentration greatly influence degradation/release of microgel-bound peptides and need to be considered in the use of microgels, e.g., as carriers for protein and peptide drugs.

The purpose of the research was to introduce a procedure to derive a powder compression parameter (EM A) representing particle yield stress using an effective medium equation and to compare the EM A parameter with the Heckel compression parameter (1/K). 16 pharmaceutical powders, including drugs and excipients, were compressed in a materials testing instrument and powder compression profiles were derived using the EM and Heckel equations. The compression profiles thus obtained could be sub-divided into regions among which one region was approximately linear and from this region, the compression parameters EM A and 1/K were calculated. A linear relationship between the EM A parameter and the 1/K parameter was obtained with a strong correlation. The slope of the plot was close to 1 (0.84) and the intercept of the plot was small in comparison to the range of parameter values obtained. The relationship between the theoretical EM A parameter and the 1/K parameter supports the interpretation of the empirical Heckel parameter as being a measure of yield stress. It is concluded that the combination of Heckel and EM equations represents a suitable procedure to derive a value of particle plasticity from powder compression data.

Triaxial compression of plastically deforming particles was studied with the finite element method in order to identify the mechanisms that underlie the particle response under confined conditions. In addition to the established elastoplastic behaviour at small and intermediate strains, the coalescence of plastic zones centred at contacts resulted in a reduced stiffness, whereas a significantly increased stiffness was seen once the material displaced by plastic deformation filled the ambient void space, signifying the onset of a stage dominated by elastic volume reduction. Moreover, an analytical model for multiple simultaneous contacts was formulated, assuming that the deformed particle shape could be approximated by a truncated sphere and that the behaviour of each individual contact could be described in terms of a hardness. The thus obtained model exhibited a promising agreement with the numerical results.

The effect of degree of compression on the evolution of tablet microstructure and bond probability during compression of granular solids has been studied. Microcrystalline cellulose pellets of low (about 11%) and of high (about 32%) porosity were used. Tablets were compacted at 50, 100 and 150 MPa applied pressures and the degree of compression and the tensile strength of the tablets determined. The tablets were subjected to mercury intrusion measurements and from the pore size distributions, a void diameter and the porosities of the voids and the intra-granular pores were calculated. The pore size distributions of the tablets had peaks associated with the voids and the intra-granular pores. The void and intra-granular porosities of the tablets were dependent on the original pellet porosity while the total tablet porosity was independent. The separation distance between pellets was generally lower for tablets formed from high porosity pellets and the void size related linearly to the degree of compression. Tensile strength of tablets was higher for tablets of high porosity pellets and a scaled tablet tensile strength related linearly to the degree of compression above a percolation threshold. In conclusion, the degree of compression controlled the separation distance and the probability of forming bonds between pellets in the tablet.

Granule shear behaviour was investigated experimentally and numerically to evaluate the reliability of the numerical model. Additionally, parameters affecting the ensuing flow regimes - elastic quasi-static and inertial non-collisional - were highlighted. Furthermore, the influence of using the Lees-Edwards periodic boundary conditions or the standard boundary conditions was studied. Experiments were performed with microcrystalline cellulose granules of three size distributions using the FT4 powder rheometer. The numerical parameters, particle size, effective density, and particle stiffness were selected to match the experimental conditions. Experimentally, an unexpected particle size effect was evident where the resistance to shear increased with particle size. Numerically, combining rolling friction. and increased shear rate enabled a transition from the inertial non-collisional to the elastic quasi-static regime at a reduced sliding friction coefficient. Presumably, this is an effect of increased particle overlap creating stronger contacts and facilitating force chain formation. Both boundary conditions provided comparable results provided a correction of system size was made, where larger systems were required for the standard boundary conditions. A satisfactory qualitative agreement between the experimentally and numerically determined yield loci emphasised the predictive capacity of the DEM. Rolling friction was in addition concluded to be an essential model parameter for obtaining an improved quantitative agreement.

The purpose of the research was to introduce a procedure to derive a powder compression parameter (EM A) representing particle yield stress using an effective medium equation and to compare the EM A parameter with the Heckel compression parameter (1/K). 16 pharmaceutical powders, including drugs and excipients, were compressed in a materials testing instrument and powder compression profiles were derived using the EM and Heckel equations. The compression profiles thus obtained could be sub-divided into regions among which one region was approximately linear and from this region, the compression parameters EM A and 1/K were calculated. A linear relationship between the EM A parameter and the 1/K parameter was obtained with a strong correlation. The slope of the plot was close to 1 (0.84) and the intercept of the plot was small in comparison to the range of parameter values obtained. The relationship between the theoretical EM A parameter and the 1/K parameter supports the interpretation of the empirical Heckel parameter as being a measure of yield stress. It is concluded that the combination of Heckel and EM equations represents a suitable procedure to derive a value of particle plasticity from powder compression data.

Triaxial compression of plastically deforming particles was studied with the finite element method in order to identify the mechanisms that underlie the particle response under confined conditions. In addition to the established elastoplastic behaviour at small and intermediate strains, the coalescence of plastic zones centred at contacts resulted in a reduced stiffness, whereas a significantly increased stiffness was seen once the material displaced by plastic deformation filled the ambient void space, signifying the onset of a stage dominated by elastic volume reduction. Moreover, an analytical model for multiple simultaneous contacts was formulated, assuming that the deformed particle shape could be approximated by a truncated sphere and that the behaviour of each individual contact could be described in terms of a hardness. The thus obtained model exhibited a promising agreement with the numerical results.

The effect of degree of compression on the evolution of tablet microstructure and bond probability during compression of granular solids has been studied. Microcrystalline cellulose pellets of low (about 11%) and of high (about 32%) porosity were used. Tablets were compacted at 50, 100 and 150 MPa applied pressures and the degree of compression and the tensile strength of the tablets determined. The tablets were subjected to mercury intrusion measurements and from the pore size distributions, a void diameter and the porosities of the voids and the intra-granular pores were calculated. The pore size distributions of the tablets had peaks associated with the voids and the intra-granular pores. The void and intra-granular porosities of the tablets were dependent on the original pellet porosity while the total tablet porosity was independent. The separation distance between pellets was generally lower for tablets formed from high porosity pellets and the void size related linearly to the degree of compression. Tensile strength of tablets was higher for tablets of high porosity pellets and a scaled tablet tensile strength related linearly to the degree of compression above a percolation threshold. In conclusion, the degree of compression controlled the separation distance and the probability of forming bonds between pellets in the tablet.

Granule shear behaviour was investigated experimentally and numerically to evaluate the reliability of the numerical model. Additionally, parameters affecting the ensuing flow regimes - elastic quasi-static and inertial non-collisional - were highlighted. Furthermore, the influence of using the Lees-Edwards periodic boundary conditions or the standard boundary conditions was studied. Experiments were performed with microcrystalline cellulose granules of three size distributions using the FT4 powder rheometer. The numerical parameters, particle size, effective density, and particle stiffness were selected to match the experimental conditions. Experimentally, an unexpected particle size effect was evident where the resistance to shear increased with particle size. Numerically, combining rolling friction. and increased shear rate enabled a transition from the inertial non-collisional to the elastic quasi-static regime at a reduced sliding friction coefficient. Presumably, this is an effect of increased particle overlap creating stronger contacts and facilitating force chain formation. Both boundary conditions provided comparable results provided a correction of system size was made, where larger systems were required for the standard boundary conditions. A satisfactory qualitative agreement between the experimentally and numerically determined yield loci emphasised the predictive capacity of the DEM. Rolling friction was in addition concluded to be an essential model parameter for obtaining an improved quantitative agreement.

The purpose of the research was to introduce a procedure to derive a powder compression parameter (EM A) representing particle yield stress using an effective medium equation and to compare the EM A parameter with the Heckel compression parameter (1/K). 16 pharmaceutical powders, including drugs and excipients, were compressed in a materials testing instrument and powder compression profiles were derived using the EM and Heckel equations. The compression profiles thus obtained could be sub-divided into regions among which one region was approximately linear and from this region, the compression parameters EM A and 1/K were calculated. A linear relationship between the EM A parameter and the 1/K parameter was obtained with a strong correlation. The slope of the plot was close to 1 (0.84) and the intercept of the plot was small in comparison to the range of parameter values obtained. The relationship between the theoretical EM A parameter and the 1/K parameter supports the interpretation of the empirical Heckel parameter as being a measure of yield stress. It is concluded that the combination of Heckel and EM equations represents a suitable procedure to derive a value of particle plasticity from powder compression data.

The effect of degree of compression on the evolution of tablet microstructure and bond probability during compression of granular solids has been studied. Microcrystalline cellulose pellets of low (about 11%) and of high (about 32%) porosity were used. Tablets were compacted at 50, 100 and 150 MPa applied pressures and the degree of compression and the tensile strength of the tablets determined. The tablets were subjected to mercury intrusion measurements and from the pore size distributions, a void diameter and the porosities of the voids and the intra-granular pores were calculated. The pore size distributions of the tablets had peaks associated with the voids and the intra-granular pores. The void and intra-granular porosities of the tablets were dependent on the original pellet porosity while the total tablet porosity was independent. The separation distance between pellets was generally lower for tablets formed from high porosity pellets and the void size related linearly to the degree of compression. Tensile strength of tablets was higher for tablets of high porosity pellets and a scaled tablet tensile strength related linearly to the degree of compression above a percolation threshold. In conclusion, the degree of compression controlled the separation distance and the probability of forming bonds between pellets in the tablet.

Triaxial compression of plastically deforming particles was studied with the finite element method in order to identify the mechanisms that underlie the particle response under confined conditions. In addition to the established elastoplastic behaviour at small and intermediate strains, the coalescence of plastic zones centred at contacts resulted in a reduced stiffness, whereas a significantly increased stiffness was seen once the material displaced by plastic deformation filled the ambient void space, signifying the onset of a stage dominated by elastic volume reduction. Moreover, an analytical model for multiple simultaneous contacts was formulated, assuming that the deformed particle shape could be approximated by a truncated sphere and that the behaviour of each individual contact could be described in terms of a hardness. The thus obtained model exhibited a promising agreement with the numerical results.

Granule shear behaviour was investigated experimentally and numerically to evaluate the reliability of the numerical model. Additionally, parameters affecting the ensuing flow regimes - elastic quasi-static and inertial non-collisional - were highlighted. Furthermore, the influence of using the Lees-Edwards periodic boundary conditions or the standard boundary conditions was studied. Experiments were performed with microcrystalline cellulose granules of three size distributions using the FT4 powder rheometer. The numerical parameters, particle size, effective density, and particle stiffness were selected to match the experimental conditions. Experimentally, an unexpected particle size effect was evident where the resistance to shear increased with particle size. Numerically, combining rolling friction. and increased shear rate enabled a transition from the inertial non-collisional to the elastic quasi-static regime at a reduced sliding friction coefficient. Presumably, this is an effect of increased particle overlap creating stronger contacts and facilitating force chain formation. Both boundary conditions provided comparable results provided a correction of system size was made, where larger systems were required for the standard boundary conditions. A satisfactory qualitative agreement between the experimentally and numerically determined yield loci emphasised the predictive capacity of the DEM. Rolling friction was in addition concluded to be an essential model parameter for obtaining an improved quantitative agreement.

The purpose of the research was to introduce a procedure to derive a powder compression parameter (EM A) representing particle yield stress using an effective medium equation and to compare the EM A parameter with the Heckel compression parameter (1/K). 16 pharmaceutical powders, including drugs and excipients, were compressed in a materials testing instrument and powder compression profiles were derived using the EM and Heckel equations. The compression profiles thus obtained could be sub-divided into regions among which one region was approximately linear and from this region, the compression parameters EM A and 1/K were calculated. A linear relationship between the EM A parameter and the 1/K parameter was obtained with a strong correlation. The slope of the plot was close to 1 (0.84) and the intercept of the plot was small in comparison to the range of parameter values obtained. The relationship between the theoretical EM A parameter and the 1/K parameter supports the interpretation of the empirical Heckel parameter as being a measure of yield stress. It is concluded that the combination of Heckel and EM equations represents a suitable procedure to derive a value of particle plasticity from powder compression data.

Triaxial compression of plastically deforming particles was studied with the finite element method in order to identify the mechanisms that underlie the particle response under confined conditions. In addition to the established elastoplastic behaviour at small and intermediate strains, the coalescence of plastic zones centred at contacts resulted in a reduced stiffness, whereas a significantly increased stiffness was seen once the material displaced by plastic deformation filled the ambient void space, signifying the onset of a stage dominated by elastic volume reduction. Moreover, an analytical model for multiple simultaneous contacts was formulated, assuming that the deformed particle shape could be approximated by a truncated sphere and that the behaviour of each individual contact could be described in terms of a hardness. The thus obtained model exhibited a promising agreement with the numerical results.

Granule shear behaviour was investigated experimentally and numerically to evaluate the reliability of the numerical model. Additionally, parameters affecting the ensuing flow regimes - elastic quasi-static and inertial non-collisional - were highlighted. Furthermore, the influence of using the Lees-Edwards periodic boundary conditions or the standard boundary conditions was studied. Experiments were performed with microcrystalline cellulose granules of three size distributions using the FT4 powder rheometer. The numerical parameters, particle size, effective density, and particle stiffness were selected to match the experimental conditions. Experimentally, an unexpected particle size effect was evident where the resistance to shear increased with particle size. Numerically, combining rolling friction. and increased shear rate enabled a transition from the inertial non-collisional to the elastic quasi-static regime at a reduced sliding friction coefficient. Presumably, this is an effect of increased particle overlap creating stronger contacts and facilitating force chain formation. Both boundary conditions provided comparable results provided a correction of system size was made, where larger systems were required for the standard boundary conditions. A satisfactory qualitative agreement between the experimentally and numerically determined yield loci emphasised the predictive capacity of the DEM. Rolling friction was in addition concluded to be an essential model parameter for obtaining an improved quantitative agreement.

The effect of degree of compression on the evolution of tablet microstructure and bond probability during compression of granular solids has been studied. Microcrystalline cellulose pellets of low (about 11%) and of high (about 32%) porosity were used. Tablets were compacted at 50, 100 and 150 MPa applied pressures and the degree of compression and the tensile strength of the tablets determined. The tablets were subjected to mercury intrusion measurements and from the pore size distributions, a void diameter and the porosities of the voids and the intra-granular pores were calculated. The pore size distributions of the tablets had peaks associated with the voids and the intra-granular pores. The void and intra-granular porosities of the tablets were dependent on the original pellet porosity while the total tablet porosity was independent. The separation distance between pellets was generally lower for tablets formed from high porosity pellets and the void size related linearly to the degree of compression. Tensile strength of tablets was higher for tablets of high porosity pellets and a scaled tablet tensile strength related linearly to the degree of compression above a percolation threshold. In conclusion, the degree of compression controlled the separation distance and the probability of forming bonds between pellets in the tablet.

Tablet production involves compression of free flowing powder in an enclosed cavity of defined geometry. The complexity of the powder bed system necessitates that a way be found to better understand what occurs during compression. One such approach is by means of compaction equations, of which, the Heckel and Kawakita equations are the best known. This work attempts to experimentally evaluate the applicability of the effective medium (EM) equation introduced by Frenning et al. (2009) to powder systems. Two powder types (sodium chloride and lactose monohydrate), each consisting of three size fractions (<40, 125-212 and 212-300 mu m) were characterised and compressed to a pressure of 500 MPa. These powders were chosen because of their differing mechanical properties. An invariance which is inherent in the EM equation is exposed by varying the starting points of compression, and can yield insights into compression mechanisms. Such invariant regions were observed once plastic particle deformation started to dominate the compression behaviour, and enabled the determination of the point where particle rearrangement stops.

Tablet production involves compression of free flowing powder in an enclosed cavity of defined geometry. The complexity of the powder bed system necessitates that a way be found to better understand what occurs during compression. One such approach is by means of compaction equations, of which, the Heckel and Kawakita equations are the best known. This work attempts to experimentally evaluate the applicability of the effective medium (EM) equation introduced by Frenning et al. (2009) to powder systems. Two powder types (sodium chloride and lactose monohydrate), each consisting of three size fractions (<40, 125-212 and 212-300 mu m) were characterised and compressed to a pressure of 500 MPa. These powders were chosen because of their differing mechanical properties. An invariance which is inherent in the EM equation is exposed by varying the starting points of compression, and can yield insights into compression mechanisms. Such invariant regions were observed once plastic particle deformation started to dominate the compression behaviour, and enabled the determination of the point where particle rearrangement stops.

Tablet production involves compression of free flowing powder in an enclosed cavity of defined geometry. The complexity of the powder bed system necessitates that a way be found to better understand what occurs during compression. One such approach is by means of compaction equations, of which, the Heckel and Kawakita equations are the best known. This work attempts to experimentally evaluate the applicability of the effective medium (EM) equation introduced by Frenning et al. (2009) to powder systems. Two powder types (sodium chloride and lactose monohydrate), each consisting of three size fractions (<40, 125-212 and 212-300 mu m) were characterised and compressed to a pressure of 500 MPa. These powders were chosen because of their differing mechanical properties. An invariance which is inherent in the EM equation is exposed by varying the starting points of compression, and can yield insights into compression mechanisms. Such invariant regions were observed once plastic particle deformation started to dominate the compression behaviour, and enabled the determination of the point where particle rearrangement stops.

Tablet production involves compression of free flowing powder in an enclosed cavity of defined geometry. The complexity of the powder bed system necessitates that a way be found to better understand what occurs during compression. One such approach is by means of compaction equations, of which, the Heckel and Kawakita equations are the best known. This work attempts to experimentally evaluate the applicability of the effective medium (EM) equation introduced by Frenning et al. (2009) to powder systems. Two powder types (sodium chloride and lactose monohydrate), each consisting of three size fractions (<40, 125-212 and 212-300 mu m) were characterised and compressed to a pressure of 500 MPa. These powders were chosen because of their differing mechanical properties. An invariance which is inherent in the EM equation is exposed by varying the starting points of compression, and can yield insights into compression mechanisms. Such invariant regions were observed once plastic particle deformation started to dominate the compression behaviour, and enabled the determination of the point where particle rearrangement stops.

Tablet production involves compression of free flowing powder in an enclosed cavity of defined geometry. The complexity of the powder bed system necessitates that a way be found to better understand what occurs during compression. One such approach is by means of compaction equations, of which, the Heckel and Kawakita equations are the best known. This work attempts to experimentally evaluate the applicability of the effective medium (EM) equation introduced by Frenning et al. (2009) to powder systems. Two powder types (sodium chloride and lactose monohydrate), each consisting of three size fractions (<40, 125-212 and 212-300 mu m) were characterised and compressed to a pressure of 500 MPa. These powders were chosen because of their differing mechanical properties. An invariance which is inherent in the EM equation is exposed by varying the starting points of compression, and can yield insights into compression mechanisms. Such invariant regions were observed once plastic particle deformation started to dominate the compression behaviour, and enabled the determination of the point where particle rearrangement stops.

Flowability - as measured by hopper discharge rate, angle of repose and Carr's index (CI) - of surface modified microcrystalline cellulose granules was investigated experimentally. Three-dimensional simulations of the granule flow were performed, using the discrete element method (DEM), including either sliding and rolling friction or sliding friction and cohesion in the model. Granule surface modification with polymer coating and lubrication was found to have a significant effect on the sliding friction coefficient. This effect was also reflected in the ensuing flow behaviour, as quantified by the experimental discharge rate and angle of repose, whereas the results for the Cl were inconclusive. The numerical results demonstrated that granular flow was qualitatively different for non-cohesive and cohesive granules, occurring in the form of individual particles for the former and in larger clusters for the latter. Rolling friction and cohesion nevertheless affected the simulated discharge rate in a similar manner, producing results comparable to those observed experimentally and calculated with the Beverloo equation. The numerical results for the cohesive granules demonstrated that cohesion alone was sufficient to produce stable heaps. However, the agreement with experimental data was satisfactory only for the non-cohesive granules, demonstrating the importance of rolling friction.

We employ the carbon paper technique with the aim of investigating the effect of spherical-agglomerate (pellet) strength on force distributions, through confined compression of approximately 1 mm sized pellets formed from microcrystalline cellulose and polyethylene glycol. The carbon paper technique relies on the transference of imprints from compressed pellets onto white photo quality paper, which are digitised and processed via image processing software. The investigated pellets can both deform plastically and develop localised cracks in response to an applied stress, while remaining largely intact during confined compression. Our results indicate that such crack formation - henceforth referred to as fracture - has a decisive influence on force distributions. Previous work on non-fracturing systems has found that the distribution of normalized forces tends to narrow with increasing particle deformation. No narrowing is observed after the point of fracture in this study and the width of the distributions - as quantified by the standard deviation of non-normalized forces - is found to increase with the difference between non-normalized mean force and fracture force. Additional corroborative results show that spatial force-force correlations typically exhibit a marked change once the fracture force is exceeded.

The purpose of this review is to provide a comprehensive overview of mathematical procedures that can be used to describe the release of drugs from inert matrix systems. The review focuses on general principles rather than particular applications. The inherent multiscale nature of the drug-release process is pointed out and multiscale modelling is exemplified for inert porous matrices. Although effects of stagnant layers and finite volumes of release media are briefly discussed, the systematic analysis is restricted to systems under sink conditions. When the initial drug loading exceeds the drug solubility in the matrix, Higuchi-type moving-boundary descriptions continue to be highly valuable for obtaining approximate analytical solutions, especially when coupled with integral balance methods. Continuous-field descriptions have decisive advantages when numerical solutions are sought. This is because the mathematical formulation reduces to a diffusion equation with a nonlinear source term, valid over the entire matrix domain. Solutions can thus be effortlessly determined for arbitrary geometries using standard numerical packages.

We apply a theory to the constrained swelling of gel particles, explicitly accounting for the propagation of elastic forces through the particle. This approach, together with conventional thermodynamics of gel swelling, allows modelling of the equilibrium state of gels with properties that are spatially inhomogeneous. In our case we consider both a discrete inhomogeneity in the form of assigning different water solubilities to the core and shell domains of the particle, and a continuous inhomogeneity in allowing the density of chemical cross-links to vary gradually through the network. The model is used to understand the behaviour of temperature-sensitive poly(N-isopropyl acrylamide) core/poly(N-isopropyl methacrylamide) shell microgels investigated in an earlier experimental study. How the swelling of the core and shell is affected by the presence of each other at different temperatures is investigated and explained from a mechanical and thermodynamic perspective.

Flowability - as measured by hopper discharge rate, angle of repose and Carr's index (CI) - of surface modified microcrystalline cellulose granules was investigated experimentally. Three-dimensional simulations of the granule flow were performed, using the discrete element method (DEM), including either sliding and rolling friction or sliding friction and cohesion in the model. Granule surface modification with polymer coating and lubrication was found to have a significant effect on the sliding friction coefficient. This effect was also reflected in the ensuing flow behaviour, as quantified by the experimental discharge rate and angle of repose, whereas the results for the Cl were inconclusive. The numerical results demonstrated that granular flow was qualitatively different for non-cohesive and cohesive granules, occurring in the form of individual particles for the former and in larger clusters for the latter. Rolling friction and cohesion nevertheless affected the simulated discharge rate in a similar manner, producing results comparable to those observed experimentally and calculated with the Beverloo equation. The numerical results for the cohesive granules demonstrated that cohesion alone was sufficient to produce stable heaps. However, the agreement with experimental data was satisfactory only for the non-cohesive granules, demonstrating the importance of rolling friction.

We employ the carbon paper technique with the aim of investigating the effect of spherical-agglomerate (pellet) strength on force distributions, through confined compression of approximately 1 mm sized pellets formed from microcrystalline cellulose and polyethylene glycol. The carbon paper technique relies on the transference of imprints from compressed pellets onto white photo quality paper, which are digitised and processed via image processing software. The investigated pellets can both deform plastically and develop localised cracks in response to an applied stress, while remaining largely intact during confined compression. Our results indicate that such crack formation - henceforth referred to as fracture - has a decisive influence on force distributions. Previous work on non-fracturing systems has found that the distribution of normalized forces tends to narrow with increasing particle deformation. No narrowing is observed after the point of fracture in this study and the width of the distributions - as quantified by the standard deviation of non-normalized forces - is found to increase with the difference between non-normalized mean force and fracture force. Additional corroborative results show that spatial force-force correlations typically exhibit a marked change once the fracture force is exceeded.

The purpose of this review is to provide a comprehensive overview of mathematical procedures that can be used to describe the release of drugs from inert matrix systems. The review focuses on general principles rather than particular applications. The inherent multiscale nature of the drug-release process is pointed out and multiscale modelling is exemplified for inert porous matrices. Although effects of stagnant layers and finite volumes of release media are briefly discussed, the systematic analysis is restricted to systems under sink conditions. When the initial drug loading exceeds the drug solubility in the matrix, Higuchi-type moving-boundary descriptions continue to be highly valuable for obtaining approximate analytical solutions, especially when coupled with integral balance methods. Continuous-field descriptions have decisive advantages when numerical solutions are sought. This is because the mathematical formulation reduces to a diffusion equation with a nonlinear source term, valid over the entire matrix domain. Solutions can thus be effortlessly determined for arbitrary geometries using standard numerical packages.

We employ the carbon paper technique with the aim of investigating the effect of spherical-agglomerate (pellet) strength on force distributions, through confined compression of approximately 1 mm sized pellets formed from microcrystalline cellulose and polyethylene glycol. The carbon paper technique relies on the transference of imprints from compressed pellets onto white photo quality paper, which are digitised and processed via image processing software. The investigated pellets can both deform plastically and develop localised cracks in response to an applied stress, while remaining largely intact during confined compression. Our results indicate that such crack formation - henceforth referred to as fracture - has a decisive influence on force distributions. Previous work on non-fracturing systems has found that the distribution of normalized forces tends to narrow with increasing particle deformation. No narrowing is observed after the point of fracture in this study and the width of the distributions - as quantified by the standard deviation of non-normalized forces - is found to increase with the difference between non-normalized mean force and fracture force. Additional corroborative results show that spatial force-force correlations typically exhibit a marked change once the fracture force is exceeded.

Flowability - as measured by hopper discharge rate, angle of repose and Carr's index (CI) - of surface modified microcrystalline cellulose granules was investigated experimentally. Three-dimensional simulations of the granule flow were performed, using the discrete element method (DEM), including either sliding and rolling friction or sliding friction and cohesion in the model. Granule surface modification with polymer coating and lubrication was found to have a significant effect on the sliding friction coefficient. This effect was also reflected in the ensuing flow behaviour, as quantified by the experimental discharge rate and angle of repose, whereas the results for the Cl were inconclusive. The numerical results demonstrated that granular flow was qualitatively different for non-cohesive and cohesive granules, occurring in the form of individual particles for the former and in larger clusters for the latter. Rolling friction and cohesion nevertheless affected the simulated discharge rate in a similar manner, producing results comparable to those observed experimentally and calculated with the Beverloo equation. The numerical results for the cohesive granules demonstrated that cohesion alone was sufficient to produce stable heaps. However, the agreement with experimental data was satisfactory only for the non-cohesive granules, demonstrating the importance of rolling friction.

We employ the carbon paper technique with the aim of investigating the effect of spherical-agglomerate (pellet) strength on force distributions, through confined compression of approximately 1 mm sized pellets formed from microcrystalline cellulose and polyethylene glycol. The carbon paper technique relies on the transference of imprints from compressed pellets onto white photo quality paper, which are digitised and processed via image processing software. The investigated pellets can both deform plastically and develop localised cracks in response to an applied stress, while remaining largely intact during confined compression. Our results indicate that such crack formation - henceforth referred to as fracture - has a decisive influence on force distributions. Previous work on non-fracturing systems has found that the distribution of normalized forces tends to narrow with increasing particle deformation. No narrowing is observed after the point of fracture in this study and the width of the distributions - as quantified by the standard deviation of non-normalized forces - is found to increase with the difference between non-normalized mean force and fracture force. Additional corroborative results show that spatial force-force correlations typically exhibit a marked change once the fracture force is exceeded.

Flowability - as measured by hopper discharge rate, angle of repose and Carr's index (CI) - of surface modified microcrystalline cellulose granules was investigated experimentally. Three-dimensional simulations of the granule flow were performed, using the discrete element method (DEM), including either sliding and rolling friction or sliding friction and cohesion in the model. Granule surface modification with polymer coating and lubrication was found to have a significant effect on the sliding friction coefficient. This effect was also reflected in the ensuing flow behaviour, as quantified by the experimental discharge rate and angle of repose, whereas the results for the Cl were inconclusive. The numerical results demonstrated that granular flow was qualitatively different for non-cohesive and cohesive granules, occurring in the form of individual particles for the former and in larger clusters for the latter. Rolling friction and cohesion nevertheless affected the simulated discharge rate in a similar manner, producing results comparable to those observed experimentally and calculated with the Beverloo equation. The numerical results for the cohesive granules demonstrated that cohesion alone was sufficient to produce stable heaps. However, the agreement with experimental data was satisfactory only for the non-cohesive granules, demonstrating the importance of rolling friction.

The purpose of this review is to provide a comprehensive overview of mathematical procedures that can be used to describe the release of drugs from inert matrix systems. The review focuses on general principles rather than particular applications. The inherent multiscale nature of the drug-release process is pointed out and multiscale modelling is exemplified for inert porous matrices. Although effects of stagnant layers and finite volumes of release media are briefly discussed, the systematic analysis is restricted to systems under sink conditions. When the initial drug loading exceeds the drug solubility in the matrix, Higuchi-type moving-boundary descriptions continue to be highly valuable for obtaining approximate analytical solutions, especially when coupled with integral balance methods. Continuous-field descriptions have decisive advantages when numerical solutions are sought. This is because the mathematical formulation reduces to a diffusion equation with a nonlinear source term, valid over the entire matrix domain. Solutions can thus be effortlessly determined for arbitrary geometries using standard numerical packages.

The purpose of this review is to provide a comprehensive overview of mathematical procedures that can be used to describe the release of drugs from inert matrix systems. The review focuses on general principles rather than particular applications. The inherent multiscale nature of the drug-release process is pointed out and multiscale modelling is exemplified for inert porous matrices. Although effects of stagnant layers and finite volumes of release media are briefly discussed, the systematic analysis is restricted to systems under sink conditions. When the initial drug loading exceeds the drug solubility in the matrix, Higuchi-type moving-boundary descriptions continue to be highly valuable for obtaining approximate analytical solutions, especially when coupled with integral balance methods. Continuous-field descriptions have decisive advantages when numerical solutions are sought. This is because the mathematical formulation reduces to a diffusion equation with a nonlinear source term, valid over the entire matrix domain. Solutions can thus be effortlessly determined for arbitrary geometries using standard numerical packages.

Flowability - as measured by hopper discharge rate, angle of repose and Carr's index (CI) - of surface modified microcrystalline cellulose granules was investigated experimentally. Three-dimensional simulations of the granule flow were performed, using the discrete element method (DEM), including either sliding and rolling friction or sliding friction and cohesion in the model. Granule surface modification with polymer coating and lubrication was found to have a significant effect on the sliding friction coefficient. This effect was also reflected in the ensuing flow behaviour, as quantified by the experimental discharge rate and angle of repose, whereas the results for the Cl were inconclusive. The numerical results demonstrated that granular flow was qualitatively different for non-cohesive and cohesive granules, occurring in the form of individual particles for the former and in larger clusters for the latter. Rolling friction and cohesion nevertheless affected the simulated discharge rate in a similar manner, producing results comparable to those observed experimentally and calculated with the Beverloo equation. The numerical results for the cohesive granules demonstrated that cohesion alone was sufficient to produce stable heaps. However, the agreement with experimental data was satisfactory only for the non-cohesive granules, demonstrating the importance of rolling friction.

We employ the carbon paper technique with the aim of investigating the effect of spherical-agglomerate (pellet) strength on force distributions, through confined compression of approximately 1 mm sized pellets formed from microcrystalline cellulose and polyethylene glycol. The carbon paper technique relies on the transference of imprints from compressed pellets onto white photo quality paper, which are digitised and processed via image processing software. The investigated pellets can both deform plastically and develop localised cracks in response to an applied stress, while remaining largely intact during confined compression. Our results indicate that such crack formation - henceforth referred to as fracture - has a decisive influence on force distributions. Previous work on non-fracturing systems has found that the distribution of normalized forces tends to narrow with increasing particle deformation. No narrowing is observed after the point of fracture in this study and the width of the distributions - as quantified by the standard deviation of non-normalized forces - is found to increase with the difference between non-normalized mean force and fracture force. Additional corroborative results show that spatial force-force correlations typically exhibit a marked change once the fracture force is exceeded.

The purpose of this review is to provide a comprehensive overview of mathematical procedures that can be used to describe the release of drugs from inert matrix systems. The review focuses on general principles rather than particular applications. The inherent multiscale nature of the drug-release process is pointed out and multiscale modelling is exemplified for inert porous matrices. Although effects of stagnant layers and finite volumes of release media are briefly discussed, the systematic analysis is restricted to systems under sink conditions. When the initial drug loading exceeds the drug solubility in the matrix, Higuchi-type moving-boundary descriptions continue to be highly valuable for obtaining approximate analytical solutions, especially when coupled with integral balance methods. Continuous-field descriptions have decisive advantages when numerical solutions are sought. This is because the mathematical formulation reduces to a diffusion equation with a nonlinear source term, valid over the entire matrix domain. Solutions can thus be effortlessly determined for arbitrary geometries using standard numerical packages.

We employ the carbon paper technique to aid the understanding of in die force and spatial distributions, upon compression of approximately I mm sized spherical agglomerates (pellets) of microcrystalline cellulose (MCC). The aim in this study was to test for the effect of lubricant film on force and spatial distributions. Pellets of MCC were formed via granulation and extrusion/spheronisation. Investigation of pellet bed compression was performed on a materials tester. Prior to compression studies the pellets were characterised for bulk density. size and deformability. Two pellet types were investigated; MCC and MCC lubricated with magnesium stearate. The carbon paper technique relies upon carbon paper as the medium for transferring imprints from compressed pellets onto photo quality paper. The digitised images of these imprints form the basis of analysis through the use of image processing software. Using the carbon paper technique within the range of 10-30 MPa indicates that lubrication does not have a significant effect on the distribution of forces between spherical agglomerates during uniaxial compression. Spatial analysis of the imprints revealed that the lubricated pellets exhibited a higher packing order than the unlubricated ones at low applied pressures (10 and 20 MPa), a difference that could not be observed at 30 MPa. Hence interparticle friction and/or cohesion appear to influence the initial particle rearrangement, whereas confinement is suggested to dominate at higher pressures.

Compression of three-dimensional beds comprising 1000 plastically deforming initially spherical granules is investigated by using the combined finite/discrete element (FE/DE) method. The material model is formulated within the framework of multiplicative plasticity, and utilizes a density-dependent elliptic yield surface that allows porous particles to both deform and to densify plastically, whereas only volume-preserving plastic deformation is possible for nonporous ones. Granules with different characteristics (yield stress and initial porosity) are studied, and the relationship between the single-granule properties and the global compression behaviour of the granule bed is investigated. It is demonstrated that the FE/DE method may shed light on the deformation and densification behaviour of individual granules, since the size and shape of each granule are continually determined as an integral part of the solution procedure, and that the method thus provides a comprehensive picture of the processes occurring during confined compression of granular materials. (C) 2010 Elsevier Ltd. All rights reserved.

We employ the carbon paper technique to aid the understanding of in die force and spatial distributions, upon compression of approximately I mm sized spherical agglomerates (pellets) of microcrystalline cellulose (MCC). The aim in this study was to test for the effect of lubricant film on force and spatial distributions. Pellets of MCC were formed via granulation and extrusion/spheronisation. Investigation of pellet bed compression was performed on a materials tester. Prior to compression studies the pellets were characterised for bulk density. size and deformability. Two pellet types were investigated; MCC and MCC lubricated with magnesium stearate. The carbon paper technique relies upon carbon paper as the medium for transferring imprints from compressed pellets onto photo quality paper. The digitised images of these imprints form the basis of analysis through the use of image processing software. Using the carbon paper technique within the range of 10-30 MPa indicates that lubrication does not have a significant effect on the distribution of forces between spherical agglomerates during uniaxial compression. Spatial analysis of the imprints revealed that the lubricated pellets exhibited a higher packing order than the unlubricated ones at low applied pressures (10 and 20 MPa), a difference that could not be observed at 30 MPa. Hence interparticle friction and/or cohesion appear to influence the initial particle rearrangement, whereas confinement is suggested to dominate at higher pressures.

Compression of three-dimensional beds comprising 1000 plastically deforming initially spherical granules is investigated by using the combined finite/discrete element (FE/DE) method. The material model is formulated within the framework of multiplicative plasticity, and utilizes a density-dependent elliptic yield surface that allows porous particles to both deform and to densify plastically, whereas only volume-preserving plastic deformation is possible for nonporous ones. Granules with different characteristics (yield stress and initial porosity) are studied, and the relationship between the single-granule properties and the global compression behaviour of the granule bed is investigated. It is demonstrated that the FE/DE method may shed light on the deformation and densification behaviour of individual granules, since the size and shape of each granule are continually determined as an integral part of the solution procedure, and that the method thus provides a comprehensive picture of the processes occurring during confined compression of granular materials. (C) 2010 Elsevier Ltd. All rights reserved.

We employ the carbon paper technique to aid the understanding of in die force and spatial distributions, upon compression of approximately I mm sized spherical agglomerates (pellets) of microcrystalline cellulose (MCC). The aim in this study was to test for the effect of lubricant film on force and spatial distributions. Pellets of MCC were formed via granulation and extrusion/spheronisation. Investigation of pellet bed compression was performed on a materials tester. Prior to compression studies the pellets were characterised for bulk density. size and deformability. Two pellet types were investigated; MCC and MCC lubricated with magnesium stearate. The carbon paper technique relies upon carbon paper as the medium for transferring imprints from compressed pellets onto photo quality paper. The digitised images of these imprints form the basis of analysis through the use of image processing software. Using the carbon paper technique within the range of 10-30 MPa indicates that lubrication does not have a significant effect on the distribution of forces between spherical agglomerates during uniaxial compression. Spatial analysis of the imprints revealed that the lubricated pellets exhibited a higher packing order than the unlubricated ones at low applied pressures (10 and 20 MPa), a difference that could not be observed at 30 MPa. Hence interparticle friction and/or cohesion appear to influence the initial particle rearrangement, whereas confinement is suggested to dominate at higher pressures.

Compression of three-dimensional beds comprising 1000 plastically deforming initially spherical granules is investigated by using the combined finite/discrete element (FE/DE) method. The material model is formulated within the framework of multiplicative plasticity, and utilizes a density-dependent elliptic yield surface that allows porous particles to both deform and to densify plastically, whereas only volume-preserving plastic deformation is possible for nonporous ones. Granules with different characteristics (yield stress and initial porosity) are studied, and the relationship between the single-granule properties and the global compression behaviour of the granule bed is investigated. It is demonstrated that the FE/DE method may shed light on the deformation and densification behaviour of individual granules, since the size and shape of each granule are continually determined as an integral part of the solution procedure, and that the method thus provides a comprehensive picture of the processes occurring during confined compression of granular materials. (C) 2010 Elsevier Ltd. All rights reserved.

We employ the carbon paper technique to aid the understanding of in die force and spatial distributions, upon compression of approximately I mm sized spherical agglomerates (pellets) of microcrystalline cellulose (MCC). The aim in this study was to test for the effect of lubricant film on force and spatial distributions. Pellets of MCC were formed via granulation and extrusion/spheronisation. Investigation of pellet bed compression was performed on a materials tester. Prior to compression studies the pellets were characterised for bulk density. size and deformability. Two pellet types were investigated; MCC and MCC lubricated with magnesium stearate. The carbon paper technique relies upon carbon paper as the medium for transferring imprints from compressed pellets onto photo quality paper. The digitised images of these imprints form the basis of analysis through the use of image processing software. Using the carbon paper technique within the range of 10-30 MPa indicates that lubrication does not have a significant effect on the distribution of forces between spherical agglomerates during uniaxial compression. Spatial analysis of the imprints revealed that the lubricated pellets exhibited a higher packing order than the unlubricated ones at low applied pressures (10 and 20 MPa), a difference that could not be observed at 30 MPa. Hence interparticle friction and/or cohesion appear to influence the initial particle rearrangement, whereas confinement is suggested to dominate at higher pressures.

Compression of three-dimensional beds comprising 1000 plastically deforming initially spherical granules is investigated by using the combined finite/discrete element (FE/DE) method. The material model is formulated within the framework of multiplicative plasticity, and utilizes a density-dependent elliptic yield surface that allows porous particles to both deform and to densify plastically, whereas only volume-preserving plastic deformation is possible for nonporous ones. Granules with different characteristics (yield stress and initial porosity) are studied, and the relationship between the single-granule properties and the global compression behaviour of the granule bed is investigated. It is demonstrated that the FE/DE method may shed light on the deformation and densification behaviour of individual granules, since the size and shape of each granule are continually determined as an integral part of the solution procedure, and that the method thus provides a comprehensive picture of the processes occurring during confined compression of granular materials. (C) 2010 Elsevier Ltd. All rights reserved.