A new approach to high-shear mixer granulation using positron emission particle tracking

Positron emission particle tracking (PEPT) can provide quantitative information on particle motion in a mixer. For the first time, the present study clarifies the flow patterns of particles and granules during the process in which granules are formed in high-shear mixer granulation in three dimensions using PEPT. A number of different regions with size-dependent flows account for the variations in frequency and velocity of collisions between differently sized granules in the kernel when segregation occurs in the granulator. These findings offer a better understanding of the product properties and process attributes of high-shear mixer granulation, which will be of direct benefit as pharmaceutical and other products become more complex.     

Coupling granule properties and granulation rates in high-shear granulation

It is possible to link granulation rates to granule properties. The linkage is by multiple dimension population balance equations that, by means of simplifying assumptions, can be reduced to multiple one-dimensional (1-D) population balance equations (PBEs). Using simple physically based models, this paper demonstrates how multiple one-dimensional population balance equations can describe the results of high-shear granulation experiments of two different materials, calcium carbonate and lactose. Good agreement between experimental and simulated results was achieved enabling the granulation rates to be defined by two model parameters: the critical binder volume fraction and the aggregation rate constant. The modelling framework presented in this paper also provides a basis for the kinetic analysis of granulation experiments so that with further work, it is possible to determine the effect of process conditions and material properties on the model parameters.     

Development of a predictive high-shear granulation model

Within the pharmaceutical industry, high-shear granulation processes are well known for the production of drug-loaded granules. Development of such granulation processes, however, is often still more an art than a science. With the use of population balances, it is possible to link granulation rates to granule properties. Previous work demonstrated that good agreement between experimental and simulated results can be achieved [Powder Technol. 130 (2003) 162]. This enabled the granulation rates to be defined by two model parameters: the critical binder volume fraction and the aggregation rate constant. The modelling framework presented in this paper forms the basis of the kinetic analysis of granulation experiments that may lead to the development of a modelling tool that cannot only be used to simulate but also predict high-shear granulation behaviour in real-life pharmaceutical processes.     

Non-uniformity of binder distribution in high-shear granulation

Further experimental investigation based on a microscopic, or single granule, scale has been conducted to investigate the uniformity of binder composition within a given size class for high shear melt granulation. This work assesses whether there is significant non-uniformity of binder composition within size classes to warrant considering this level of detail to improving population balance modelling of high shear granulation. It is concluded that at early times in a batch granulation process there is a broad variation in binder content between individual granules and that this variation persists in granules of small size.     

Determination of coalescence kernels for high-shear granulation using DEM simulations

Discrete element method (DEM) modeling is used in parallel with a model for coalescence of deformable surface wet granules. This produces a method capable of predicting both collision rates and coalescence efficiencies for use in derivation of an overall coalescence kernel. These coalescence kernels can then be used in computationally efficient meso-scale models such as population balance equation (PBE) models. A soft-sphere DEM model using periodic boundary conditions and a unique boxing scheme was utilized to simulate particle flow inside a high-shear mixer. Analysis of the simulation results provided collision frequency, aggregation frequency, kinetic energy, coalescence efficiency and compaction rates for the granulation process. This information can be used to bridge the gap in multi-scale modeling of granulation processes between the micro-scale DEM/coalescence modeling approach and a meso-scale PBE modeling approach.     

Monitoring quality attributes for high-shear wet granulation with audible acoustic emissions

Continuing development of process analytical technology (PAT) tools is needed in the pharmaceutical industry to provide more flexible processing and achieve products of consistent quality. For high-shear wet granulation, audible acoustic emissions (AAEs) have shown potential as a PAT tool for monitoring changes in physical properties related to product quality. This article develops the relationship between AAEs and two critical quality attributes, size and density, and investigates the potential for monitoring product quality online. Condenser microphones were placed inside the air exhaust of a PMA-10 high-shear granulator to collect AAEs for a design of experiment (DOE) where particle size and density were varied by changing the grade of Avicel in the formulation. The results showed increases in particle size and density affect the observed decreases in the AAEs at granulation end-point and during over wetting. In addition, the changes in size and density could be represented by different combinations of 10 Hz frequency groups and the trends in the multivariate scores support online monitoring.     

Electrical capacitance tomography as a monitoring tool for high-shear mixing and granulation

Electrical capacitance tomography (ECT) was utilized for monitoring of high-shear mixing and high-shear granulation processes. A finite element method (FEM)-based reconstruction algorithm was utilized to take into account the specific geometrical characteristics of the experimental set-up. Two-dimensional ECT tomograms, mixing index curves and permittivity fractions were computed based on the measurements, and their suitability in the analysis of the processes was assessed. It was found that the different mixing processes and the different granulation processes could be analyzed based on these quantities.     

Simulating the early stage of high-shear granulation using a two-dimensional Monte-Carlo approach

A two-dimensional (2-D) model of a granulation process is presented in this paper. It aims to simulate an entire granulation batch without the use of an initial experimental or fictitious 2-D density function, by taking the experimental operating conditions into account. The mass of liquid and solid in the granules are the two predicted internal variables. The 2-D population balance equation is solved by a Constant Number Monte-Carlo method. This is a stochastic technique tracking the evolution of a population, whilst performing the calculations with a fixed number of particles. This is achieved by reducing or increasing the sample volume when an event results in a net production or a net decrease in the number of particles, respectively. An original multi-population approach is developed to describe the early stage of the process, where small numbers of granules are formed amongst a large number of primary particles. It consists of separating the primary particles from the granule population. A specific intensive variable is introduced to keep track of the repartition of masses. The overall density function is reconstructed a posteriori from the combination of the two populations. This approach allows the simulation to commence from the initial addition of liquid at the start of the process, rather than to start from an early granule size distribution. The early stage of the granulation process, frequently referred as nucleation, can therefore be studied numerically. Four different mechanisms are implemented. Nucleation and re-wetting describe the addition of liquid to the system. The interactions between liquid and solid phases are modelled by a layering process. An aggregation model is also included to simulate the growth of particles undergoing frequent collisions. Finally, the relevance of this new model is demonstrated by confronting the simulations to real experimental data.     

A novel nucleation apparatus for regime separated granulation

A novel nucleation apparatus is presented for the production of narrow sized nuclei from various powder and binder liquid combinations. Mono-sized binder liquid droplets are produced by a specially designed mono-disperse droplet generator. The droplet generator is positioned above a conveyor belt, transporting a powder bed through the spray zone of the droplet generator. By nucleating powder on a conveyer belt, the nucleation mechanism is completely separated from all other granulation mechanisms due to the lack of relative motion between primary particles and/or formed nuclei. Nucleation tests were performed using chalcopyrite and limestone powders with water as the binder liquid. At all operating conditions, the formed nuclei were found to originate from multiplicities of drops that merged on the powder bed surface. Investigation of the dynamics of nuclei formation showed that powder-binder liquid combinations with fast penetration dynamics result in less variation in the number of droplets from which nuclei originate. Smaller and more narrowly distributed nuclei were also achieved by increasing powder speed through the spray zone.     

On control of particle size distribution in granulation using high-shear mixers

The control of mean granule size and of size distribution is a major issue in granulation processes that utilise mechanical high-shear mixers. Fundamental mechanisms that lead to poor reproducibility are discussed. A review is made of techniques that can be applied to make the process more robust. Binders can be selected that react during the granulation process so as to reduce the binder concentration and/or increase the binder viscosity. There is potential to improve the design of the granulator to give better control of mean size and narrower size distributions. A critical review is made of the use of the mixer power/torque and mixer work for process control.     

Wet granulation in a batch high shear mixer

This study deals with the wet granulation in a high shear mixer. The experimental apparatus is a laboratory scale ”Lödige” granulator, with a maximum volume of 20 l, equipped with a chopper and a pneumatic spraying system. The main objective of the study is to point out the effect of physico-chemical properties and operating conditions on the growth mechanisms and kinetics in this type of granulation device. Two kinds of alumina with different particle size distributions (alumina SH100 and alumina SH30) were granulated using various Newtonian liquids having different surface tension, viscosity, binder concentration, density, etc. (water, aqueous solutions of polyethyleneglycol or polyvinyl alcohol). Experimental results showed that the granulation process generally proceeds through three distinct growth regimes independent of the nature of the powder, the binder liquid or the operating conditions. However, the transition between different regimes depends on the physico-chemical properties of the solids and liquids, on operating conditions and on the experimental procedure. For the alumina powder used in this study the transition occurs when a degree of liquid saturation of about 68% is reached.     

Investigation of the temporal and spatial flow features within the high-shear mixer by modal decomposition techniques

An insightful comprehension of hydrodynamics in the high-shear mixer (HSM) is crucial for its design and optimization. Therefore, the energetical and dynamical dominant features of inline HSM's velocity fields are extracted by proper orthogonal decomposition (POD) and dynamic mode decomposition (DMD), of which the sampling spaces are generated through Large-Eddy Simulation. POD results reveal that the significant flow structures located in the shear gap and the adjacent regions of rotor/stator slot inlets comprise various energy levels. The strip-shaped structures at the rotor/stator leading edges, wake and large-scale vortices within the outflow region, and circulation inside the rotor slot are also visualized. DMD results emphasize the importance of flow patterns oscillating lower than rotor teeth passage frequency and reveal that the coherent structures shift and expand as their frequencies decrease. The POD and DMD analyses provide an insightful perspective of the spatial and temporal behaviors of the flow in HSM.     

Influence of the interaction between binder and powders on melt agglomeration behavior in a high-shear mixer

The purpose of this study was to investigate the effects of the different surface properties of powders on granular agglomeration in a high-shear mixer. Polyethylene glycol 6000 (PEG 6000) was used as the melting binder. Three different powders, with mean granule sizes of 75-150 μm were used as the raw materials: calcium carbonate, calcium sulfate, and sodium carbonate. The wetting properties of the raw materials were measured with a contact angle instrument. The results indicate that the speed at which the droplets sink into the powder bed and the contact angle of binder droplets on the powder surface play important roles in determining the progress of the agglomeration process. Several types of agglomeration were found: a slurry state, heterogeneous nucleation, snowballing, and induction growth behavior. Heterogeneous dispersion leads to induction behavior and subsequent growth, but a homogeneous dispersion leads to little or no nucleation and growth of agglomerate size.     

Structure of powder flow in a planetary mixer during wet-mass granulation

Wet massing granulation, a widely used industrial process, is difficult to monitor and control and the structure of the flow is poorly understood. Flow patterns in a planetary mixer were investigated using positron emission particle tracking. Both dry and wet powders of a model pharmaceutical formulation were studied to develop understanding of the influence of moisture content on the flow structure during granulation. The flow structure was characterised using the distributions of the velocity components in different cross-sections of the mixer. Fourier analysis showed that the dry system is essentially dissipative and disordered whereas the wet system, being more inertial, shows signs of being more ordered with a periodic recirculation within the bowl. In both systems, radial and axial displacements are strongly correlated. For the dry system, within a central radial core region, the behaviour of the particle was determined by the rapid movement of the agitator, forming a single toroidal recycling cell. The radial and axial velocities of the tracer were up to two orders of magnitude lower than the tangential component. However, in the regions close to the wall, the particle was found to exhibit small movements dictated by the planetary rotation. For wet systems these two main regions were again observed. However, velocity field and velocity distribution showed the presence of two toroidal circulation loops, one above the other. In the wall region, the small movements governed by the planetary motion were again found, but with the amplitude of the displacements reduced by an order of magnitude.     

A regime map for the normal surface impact of wet and dry agglomerates

The normal surface impacts of wet and dry agglomerates are simulated in a discrete element modeling framework. While the impact behavior of dry agglomerates has been addressed previously, similar studies on wet agglomerate impact are missing. By adding a small amount of liquid to a dry agglomerate, the impact behavior changes significantly. The impact behavior of the agglomerates at different moisture contents and impact energies are analyzed through postimpact parameters and coupled to their microscopic and macroscopic properties. While increasing the impact energy breaks more interparticle bonds and intensifies damage and fragmentation, increasing the moisture content is found to provide the agglomerates with higher deformability and resistance against breakage. It is shown that the interplay of the two latter parameters together with the agglomerate structural strength creates various impact scenarios, which are classified into different regimes and addressed with a regime map. © 2018 American Institute of Chemical Engineers AIChE J, 64: 1975–1985, 2018     

Gas/liquid dispersions with a SMX static mixer in the laminar regime

A Sulzer SMX mixer was used to disperse gas into viscous, Newtonian and non-Newtonian fluids. The investigation covered the effect of the dispersed phase volume fraction, the viscosity of the continuous phase, the mixer length and the power draw. The flow regime was kept laminar in all the experiments. The dispersion of gas was carried out with gas concentrations between 1% and 7% in volume. Using the “process viscosity” concept, it was possible to collapse all the measured sizes on a single master curve by using the energy consumption in the mixer as the common variable between the experiments. Comparison was made with a Kenics mixer. The SMX mixer was found to be better adapted to the dispersion task due to its internal structure.     

A regime map for granule formation by drop impact on powder beds

“Tunneling,” “Spreading,” and “Crater Formation” are the three granule formation mechanisms known to occur when single drops impact static powder beds. To quantify the conditions under which each mechanism will occur, dimensional analysis was performed, and a new regime map was created that plots the powder bed porosity against the modified granular Bond number (Bo_g*), which is a ratio of the capillary force to the gravitational force acting on a particle. Tunneling occurred for Bo_g* > 65,000 for all values of bed porosity, whereas Spreading and Crater Formation occurred when Bo_g* < 65,000 for all values of bed porosity below the minimum fluidization porosity. The granule formation mechanism regime map provides a useful tool to design and predict wet granulation processes by predicting the granule formation mechanism, and thereby general granule shape, from a few key dimensionless groups involving formulation properties and process parameters that can be calculated a priori. © 2012 American Institute of Chemical Engineers AIChE J, 59: 96–107, 2013     

A consolidated flow regime map of upward gas fluidization

A new flow regime map, resulting from more fundamental studies on the hydrodynamics and new flow regimes, is proposed in response to more practical reclassifications of the existing regimes with the development of upward gas-solids fluidization systems. The previously reported flow regime maps and flow structures of some widely used fluidized beds are carefully examined. To better reflect the industrial applications, the fast fluidization regime is reclassified as high-density and low-density circulating fluidization regimes. A consolidated flow regime map is then proposed where the flow regimes of upward fluidization expand to include new types of fluidized beds such as circulating turbulent fluidized bed and high-density circulating fluidized bed. The proposed flow regime map consists of six flow regimes: bubbling, turbulent, circulating turbulent, high-density circulating and low-density circulating fluidization, and pneumatic transport. The transitions between the regimes are discussed with new correlations proposed for fluid catalytic cracking type particles. Analysis on the dominating phase in the different types of fluidized beds reveals the dynamic changeover from solids phase continuous in conventional low-velocity batch/“fixed” fluidization operations to gas phase continuous in high-velocity continuous/“moving” fluidization operations and provides more insights to the transitions between the flow regimes for industrial design and practice.     

Origin of profound changes in powder properties during wetting and nucleation stages of high-shear wet granulation of microcrystalline cellulose

The aim of this work was to understand the evolution of powder tabletability and flowability during wetting and nucleation stages of high-shear wet granulation (HSWG). Microcrystalline cellulose (MCC) was granulated with water using a high-shear process. Granule morphology, surface texture, size, porosity, specific surface area, tabletability, and flowability were characterized. MCC granulated with 5% water showed no change in tabletability but significantly improved flowability, corresponding to smoother surfaces and lower surface area. From 5% to 25% water, tabletability decreased by 1/4 but flowability remained unchanged. Granule shape and porosity remained unchanged while surfaces were smoothened, leading to decreased surface area. From 25% to 35% water, MCC granules became more round. There was another sharp decrease in tabletability but powder flowability remained unchanged. Forty-five percent of water led to more particle rounding and commencement of nucleation, which only slightly impacted tabletability and flowability. From 0% to 45% water, granule size decreased slightly and could not explain the significant changes in powder tabletability and flowability. Deteriorated tabletability was instead caused by surface smoothing, granule densification, and granule rounding. Enhanced powder flowability was caused mostly by surface smoothing with granule rounding as a minor contributor.     

Power-draw analysis of a coaxial mixer with Newtonian and non-Newtonian fluids in the laminar regime

The power consumption of a new coaxial mixer composed of a wall scraping arm and a series of rods and a pitched-blade turbine mounted on the same axis of revolution and operated in a contra-rotating mode has been characterized. The work is based on experimental measurements and 3D numerical simulations in the case of homogeneous Newtonian and non-Newtonian fluids in the laminar regime. Very good agreements between experimental and numerical results have been obtained. It has been shown that the Metzner-Otto concept can be extended to account for the speed ratio between the impellers, which allows to represent the power consumption results of the coaxial mixer on a single power master curve like with a single agitator mixer.