International journal of pharmaceutics, Jan 21, 2018
This work demonstrates the use of multi-scale simulations coupled with experiments to build a qua... more This work demonstrates the use of multi-scale simulations coupled with experiments to build a quantitative prediction tool for the performance of adhesive mixtures in a dry powder inhaler (DPI). Using discrete element model (DEM), the behaviour of fine-carrier particle assemblies upon different mechanisms encountered during dose entrainment and dispersion can be described at the individual particle level. Combining these results with computational fluid dynamics (CFD) simulations, the complete dosing event from a DPI can be captured and key performance measures can be extracted. A concept of apparent surface energy, ASE, was introduced to overcome challenges associated with the complex particle properties, e.g. irregular particle shapes and surface roughness. This approach correctly predicts trends observed experimentally regarding API adhesivity, flow rate and device geometry. By incorporating the effects of drug load, critical adhesion and surface energy distributions to the simul...
The conventional, geometrically lumped description of the physical processes inside a high shear ... more The conventional, geometrically lumped description of the physical processes inside a high shear granulator is not reliable for process design and scale‐up. In this study, a compartmental Population Balance Model (PBM) with spatial dependence is developed and validated in two lab‐scale high shear granulation processes using a 1.9L MiPro granulator and 4L DIOSNA granulator. The compartmental structure is built using a heuristic approach based on computational fluid dynamics (CFD) analysis, which includes the overall flow pattern, velocity and solids concentration. The constant volume Monte Carlo approach is implemented to solve the multi‐compartment population balance equations. Different spatial dependent mechanisms are included in the compartmental PBM to describe granule growth. It is concluded that for both cases (low and high liquid content), the adjustment of parameters (e.g. layering, coalescence and breakage rate) can provide a quantitative prediction of the granulation proce...
Understanding the dynamics and kinetics of mixing mechanisms, i.e. random mixing, de-agglomeratio... more Understanding the dynamics and kinetics of mixing mechanisms, i.e. random mixing, de-agglomeration, adhesion, and redistribution, is critical in order to achieve a structure of interest in adhesive particle mixing. In this work, the redistribution of fines between carrier particles, one of the key mechanisms in establishing a homogeneous mixture, was investigated. Coloured carriers (tracers) and image analysis utilizing CIELCH colour space are used as a tool to assess the dynamics of such a mechanism via the evolution of the colour of blends. It is found that, in a high shear mixer, redistribution quickly reaches a pseudo-steady state within a time scale that is of the same order of magnitude as that of random mixing. Considering all the governing mechanisms necessary to achieve an adhesive mixture, it is concluded that the de-agglomeration of fine-particle agglomerates is the rate-limiting step. This work also demonstrates that the redistribution of fines is influenced by the structure of fines on carrier surfaces resulting from processing conditions. This finding supports the fact that beside material properties, blending conditions, e.g. mixing speed and time, are crucial as regards the structure of adhesive mixtures for inhalation. (C) 2016 Elsevier B.V. All rights reserved.
ABSTRACT In this study, discrete element method (DEM) simulations are used to examine the breakag... more ABSTRACT In this study, discrete element method (DEM) simulations are used to examine the breakage and capturing behaviour of loose fine-particle agglomerates on impact with a target particle. The model system is an agglomerate composed of 5 mu m fine particles and a 200 gm target particle. The cohesion between fine particles was modelled using the Johnson, Kendall and Roberts (JKR) theory. In contrast to the breakage of hard agglomerates which break in large fragments, as commonly investigated, loose agglomerates break in finer fragments. Impact velocity was found to be a significant parameter not only for the adhesion strength but also for the structure of the particles captured on the target. The capture ratio of the agglomerate as well as the thickness of the particle layer covering the target decreases with increasing impact velocity. High impact velocity results in finer fragments attached to the target with greater tensile strength due to the re-structuring mechanism that occurs during impact. Accordingly, impact velocity is one of the critical parameters governing the structure resulting after collision. However, the effect of material properties, e.g. surface energy, material hardness and plasticity, on adhesion behaviour should be investigated to obtain a full picture of the breakage-adhesion regime map.
ABSTRACT Particle mixing is one of the key operations in pharmaceutical processing. In this work,... more ABSTRACT Particle mixing is one of the key operations in pharmaceutical processing. In this work, an Eulerian-Eulerian multiphase framework has been employed to model and simulate particulate flow and mixing behaviour in the blending of dry powders for inhalation. The kinetic theory of granular flow and the frictional stress model are used to close the transport equations of dense particulate flow in a high shear mixer. The transient mixing dynamics, including start-up, within the mixer are captured by adding a scalar transport equation as a tracer. The solid velocity profile at the wall is experimentally determined by using a high speed camera and particle image velocimetry (PIV) evaluation. The evolution of a tracer movement is experimentally tracked using an imaging technique that is processed in the Matlab image toolbox to obtain the local particle concentration. The model can capture the main features in granular flow motion, e.g. bed height and the dominating flow direction. The mixing mechanism is found to be a combination of azimuthal, axial and radial mixing at the same order of magnitude. Rapid mixing is captured in the simulation and is in agreement with experimental data. Even though the continuum-based model can predict well some flow features and the transient mixing time, there is a need for further development of the continuum description of dense particulate flows.
European journal of pharmaceutical sciences : official journal of the European Federation for Pharmaceutical Sciences, Jan 7, 2015
This study exploits the mechanisms governing blending of adhesive mixtures, i.e. random mixing, d... more This study exploits the mechanisms governing blending of adhesive mixtures, i.e. random mixing, de-agglomeration and adhesion, and their relative importance to achieve mixing homogeneity. To this end, blending of micronized particles (fines) with carrier particles was carried out using a high shear mixer. Dry particle sizing using laser diffraction coupled with a strong powder dispersion unit was employed to measure the fines content in samples collected during mixing, and hence to assess blend homogeneity. The method was also employed to evaluate the relative strength of the agglomerates present in the fines. Particle sizing using a non-destructive imaging technique was used to monitor changes in particle size during blending. It could be shown that the de-agglomeration of the fine-particle agglomerates is the slowest mechanism and hence the rate-limiting step as regards achieving a homogeneous adhesive mixture. Consequently, a longer mixing time is needed for blending of larger ag...
International journal of pharmaceutics, Jan 21, 2018
This work demonstrates the use of multi-scale simulations coupled with experiments to build a qua... more This work demonstrates the use of multi-scale simulations coupled with experiments to build a quantitative prediction tool for the performance of adhesive mixtures in a dry powder inhaler (DPI). Using discrete element model (DEM), the behaviour of fine-carrier particle assemblies upon different mechanisms encountered during dose entrainment and dispersion can be described at the individual particle level. Combining these results with computational fluid dynamics (CFD) simulations, the complete dosing event from a DPI can be captured and key performance measures can be extracted. A concept of apparent surface energy, ASE, was introduced to overcome challenges associated with the complex particle properties, e.g. irregular particle shapes and surface roughness. This approach correctly predicts trends observed experimentally regarding API adhesivity, flow rate and device geometry. By incorporating the effects of drug load, critical adhesion and surface energy distributions to the simul...
The conventional, geometrically lumped description of the physical processes inside a high shear ... more The conventional, geometrically lumped description of the physical processes inside a high shear granulator is not reliable for process design and scale‐up. In this study, a compartmental Population Balance Model (PBM) with spatial dependence is developed and validated in two lab‐scale high shear granulation processes using a 1.9L MiPro granulator and 4L DIOSNA granulator. The compartmental structure is built using a heuristic approach based on computational fluid dynamics (CFD) analysis, which includes the overall flow pattern, velocity and solids concentration. The constant volume Monte Carlo approach is implemented to solve the multi‐compartment population balance equations. Different spatial dependent mechanisms are included in the compartmental PBM to describe granule growth. It is concluded that for both cases (low and high liquid content), the adjustment of parameters (e.g. layering, coalescence and breakage rate) can provide a quantitative prediction of the granulation proce...
Understanding the dynamics and kinetics of mixing mechanisms, i.e. random mixing, de-agglomeratio... more Understanding the dynamics and kinetics of mixing mechanisms, i.e. random mixing, de-agglomeration, adhesion, and redistribution, is critical in order to achieve a structure of interest in adhesive particle mixing. In this work, the redistribution of fines between carrier particles, one of the key mechanisms in establishing a homogeneous mixture, was investigated. Coloured carriers (tracers) and image analysis utilizing CIELCH colour space are used as a tool to assess the dynamics of such a mechanism via the evolution of the colour of blends. It is found that, in a high shear mixer, redistribution quickly reaches a pseudo-steady state within a time scale that is of the same order of magnitude as that of random mixing. Considering all the governing mechanisms necessary to achieve an adhesive mixture, it is concluded that the de-agglomeration of fine-particle agglomerates is the rate-limiting step. This work also demonstrates that the redistribution of fines is influenced by the structure of fines on carrier surfaces resulting from processing conditions. This finding supports the fact that beside material properties, blending conditions, e.g. mixing speed and time, are crucial as regards the structure of adhesive mixtures for inhalation. (C) 2016 Elsevier B.V. All rights reserved.
ABSTRACT In this study, discrete element method (DEM) simulations are used to examine the breakag... more ABSTRACT In this study, discrete element method (DEM) simulations are used to examine the breakage and capturing behaviour of loose fine-particle agglomerates on impact with a target particle. The model system is an agglomerate composed of 5 mu m fine particles and a 200 gm target particle. The cohesion between fine particles was modelled using the Johnson, Kendall and Roberts (JKR) theory. In contrast to the breakage of hard agglomerates which break in large fragments, as commonly investigated, loose agglomerates break in finer fragments. Impact velocity was found to be a significant parameter not only for the adhesion strength but also for the structure of the particles captured on the target. The capture ratio of the agglomerate as well as the thickness of the particle layer covering the target decreases with increasing impact velocity. High impact velocity results in finer fragments attached to the target with greater tensile strength due to the re-structuring mechanism that occurs during impact. Accordingly, impact velocity is one of the critical parameters governing the structure resulting after collision. However, the effect of material properties, e.g. surface energy, material hardness and plasticity, on adhesion behaviour should be investigated to obtain a full picture of the breakage-adhesion regime map.
ABSTRACT Particle mixing is one of the key operations in pharmaceutical processing. In this work,... more ABSTRACT Particle mixing is one of the key operations in pharmaceutical processing. In this work, an Eulerian-Eulerian multiphase framework has been employed to model and simulate particulate flow and mixing behaviour in the blending of dry powders for inhalation. The kinetic theory of granular flow and the frictional stress model are used to close the transport equations of dense particulate flow in a high shear mixer. The transient mixing dynamics, including start-up, within the mixer are captured by adding a scalar transport equation as a tracer. The solid velocity profile at the wall is experimentally determined by using a high speed camera and particle image velocimetry (PIV) evaluation. The evolution of a tracer movement is experimentally tracked using an imaging technique that is processed in the Matlab image toolbox to obtain the local particle concentration. The model can capture the main features in granular flow motion, e.g. bed height and the dominating flow direction. The mixing mechanism is found to be a combination of azimuthal, axial and radial mixing at the same order of magnitude. Rapid mixing is captured in the simulation and is in agreement with experimental data. Even though the continuum-based model can predict well some flow features and the transient mixing time, there is a need for further development of the continuum description of dense particulate flows.
European journal of pharmaceutical sciences : official journal of the European Federation for Pharmaceutical Sciences, Jan 7, 2015
This study exploits the mechanisms governing blending of adhesive mixtures, i.e. random mixing, d... more This study exploits the mechanisms governing blending of adhesive mixtures, i.e. random mixing, de-agglomeration and adhesion, and their relative importance to achieve mixing homogeneity. To this end, blending of micronized particles (fines) with carrier particles was carried out using a high shear mixer. Dry particle sizing using laser diffraction coupled with a strong powder dispersion unit was employed to measure the fines content in samples collected during mixing, and hence to assess blend homogeneity. The method was also employed to evaluate the relative strength of the agglomerates present in the fines. Particle sizing using a non-destructive imaging technique was used to monitor changes in particle size during blending. It could be shown that the de-agglomeration of the fine-particle agglomerates is the slowest mechanism and hence the rate-limiting step as regards achieving a homogeneous adhesive mixture. Consequently, a longer mixing time is needed for blending of larger ag...
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Papers by Ingela Bjorn