Wet granulation: the effect of shear on granule properties

This paper presents a study of the wet granulation of fine cosmetic particles using a high-shear mixer granulator on a given particle and binder system. The shear effect on granule properties is highlighted. The granules formed under different impeller speeds are divided into size classes and further examined in terms of porosity, friability and binder content.

The main result of this study is that, depending on operating conditions, the granulation of a fine powder with a given binding liquid can result in the formation of granules of very different characteristics in terms of size, porosity and friability. Mechanical energy brought to the granulation system is as important as the physicochemical characteristics of the powder–binder pair.     

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.     

Steady states in granulation of pharmaceutical powders with application to scale-up

Theoretical and experimental evidence is given to show that steady states can be reached during agglomerate growth and break-up in high-shear granulation of fine powders. An earlier theoretical model [G.I. Tardos, I.M. Khan and P.R. Mort, Critical parameters and limiting conditions in binder granulation of fine powders, Powder Technology, 94, 245-258 (1997).], based on simple energy-dissipation considerations hinted at the existence of these states at the point where growth is counterbalanced by breakage. Further theoretical evidence is obtained from molecular dynamic simulations of wet and dry particles situated in a constant shear field [I. Talu, G.I. Tardos and M.I. Khan, Computer simulation of wet granulation, Powder Technology, 110, 59-75 (2000).], where the size distribution of initially identical particles, shifts in time to reach a dynamic steady state. Under the conditions of this steady state, the number of breaking agglomerates approximately equals the number of forming ones to yield a time independent final-size distribution.Experimental evidence to support the theoretical findings is obtained during the present research by measuring particle size distributions at line at crucial points during granulation of a typical pharmaceutical powder in a high-shear mixer. In order to reach a steady state, binder addition has to be slow enough and wet massing has to be long enough so that neither has an influence on the final properties of the granules. We show experimentally that if binder is spread properly and homogeneously in the powder and continuous shearing of the wet mass ensures homogeneous, equal growth of the granules, the steady state will only be a function of the total amount of fluid added provided that the shear forces in the machine are maintained constant.These findings are important in that they show that under carefully controlled conditions of binder addition and shear in the mixer, the granulation process is robust and controllable and can, in principle, be scaled up with ease once the powder ingredients and the total amount of binder are fixed.     

Wet granule breakage in a breakage only high-hear mixer: Effect of formulation properties on breakage behaviour

Wet granule breakage can occur in the granulation process, particularly in granulators with high agitation forces, such as high-shear mixers. In this paper, the granule breakage is studied in a breakage only high-shear mixer. Granule pellets made from different formulations with precisely controlled porosity and binder saturation were placed in a high-shear mixer in which the bulk medium is a non-granulating cohesive sand mixture. After subjecting the pellets to different mixing time in the granulator, the numbers of whole pellets without breakage are counted and taken as a measure of granule breakage. The experimental results showed that binder saturation, binder viscosity and surface tension as well as the primary powder size have significant influence on granule breakage behaviour. It is postulated that granule breakage is closely related to the granule yield strength, which can be calculated from a simple equation which includes both the capillary and viscous force of the liquid bridges in the granule. The Stokes deformation number calculated from the impact velocity and the granule dynamic strength gives a good prediction of whether the granule of certain formulation will break or not. The model is completely based on the physical properties of the formulations such as binder viscosity, surface tension, binder saturation, granule porosity and particle size as well as particle shape.     

Novel mechanistic description of the water granulation process for hydrophilic polymers

The purpose of this study was to investigate the mechanism behind the water granulation of the hydrophilic polymers HEC and HPMC. To gain insight into this process, properties of the polymers, e.g. molecular weight, viscosity, particle size distribution and interaction with water, were related to torque values measured during the granulation process and to the properties of the dried granules. The torque values in the high shear mixer were determined as function of the binder ratio (g added water per g dry polymer). These methods revealed differences in torque behavior between the polymers, indicating that the viscosity and gelling rate were important parameters determining the torque values. Bimodal particle size distributions for both HEC and HPMC were obtained when performing the granulation in the high shear mixer. A novel granulation mechanism is presented relating the water uptake, the viscosity and the gelling rate to the consolidation and coalescence of the granules. Furthermore, the breakage of the granules is suggested to be limited for hydrophilic granules obtained by water granulation.     

Stress measurements in high-shear granulators using calibrated “test” particles: application to scale-up

Granulation is a process by which fine powders are agglomerated into larger particles using a liquid binder. In high-shear granulation the powder–binder mix experiences intense agitation inside a mixing vessel as binder is dispersed and granules form and strengthen under the influence of shear and compacting forces in the device.

It is an implicit assumption that in a “high shear” mixer, large forces are transmitted to the powder and this results in a short and efficient granulation process. Owing to these desirable characteristics, high-shear granulation was adopted by several industries including pharmaceuticals and detergents where the process is used almost exclusively. In the work reported here, we attempt to measure shear forces in a moving powder inside a mixer-granulator. The method is based on previous numerical simulations [Powder Technology 110 (2000) 59] and experiments [Journal of Fluid Mechanism 347 (1997) 347] where we showed that at equilibrium between stresses in the mixer and the yield strength of the particles, granules attain a characteristic elongated shape. The measuring method adopted is indirect in the sense that pellets with well-defined mechanical properties were used to interrogate forces inside the granulating vessel at the point where they attain their characteristic elongated shape. We subsequently used the condition of equal shear forces in the device as a scale-up criterion so as to preserve the magnitude of stresses at both scales and thereby to expose forming granules to similar forces in both the small- and large-scale machines.

We found that shear forces in a “High-Shear” mixer-granulator with a vertical axis (Fielder) are actually not always high. The mixer has the potential to produce high shear forces but these forces are transmitted to the powder mass only if the powder is sufficiently cohesive or becomes cohesive due to binder addition. Shear forces in the granulator are strongly wet-mass-dependent and they increase rapidly as soon as a “granulation limit” is achieved, i.e., at the point where granules start to form in the shearing powder mass. We found that granulators with geometrically similar bowls can be scaled to generate comparable shear forces by decreasing the impeller rotational speed of the large machine by the factor (D/d)ⁿ, where D and d are the impeller diameters of the large and small machine, respectively, and n is a scaling index that depends on impeller geometry but not on wet mass properties. For the equipment studied in this work, the coefficient n was obtained as 0.80<n<0.85. We also propose an improved granulation process in which dry powders are pre-wetted before introduction into the main granulating device. This scheme has the potential to produce larger shear forces during wetting and binder introduction and thereby improve homogeneity and consequently final granule properties.     

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.     

Quantifying liquid coverage and powder flux in high-shear granulators

A key aspect to high-shear wet granulation is the coverage of binding fluid as it first comes into contact with the surface of a powder bed. Quantifying the parameters that determine liquid coverage with respect to powder flux could improve the ability to rationally characterize and scale wet granulation processes. In this work, the surface velocity of a powder bed was measured during wet granulation in high-shear mixers (Aeromatic-Fielder) ranging from lab (25 l) to pilot (300 l) scale. High-speed video analysis revealed that surface velocity is strongly dependent on impeller speed, mixer scale, fill level, and extent of granulation. Surface velocity results were coupled with the dimensionless spray flux concept reported by Litster et al. [Powder Technol. 114 (2001) 32] to quantify liquid coverage relative to powder flux for operating conditions commonly used to granulate pharmaceutical powder blends. Dimensionless spray flux calculations suggest that granule nucleation in high-shear mixers does not take place in the drop-controlled regime. The density of spray drops at the surface of the powder bed is sufficiently high to cause a significant amount of drop overlap, thereby hindering the formation of nuclei from individual spray drops. Dimensionless spray flux calculations predict an approximate 2.5-fold increase in liquid coverage upon scaling a standard high-shear wet granulation process from 25 to 300 l. The use of multiple spray nozzles could potentially minimize differences in liquid coverage between scales. Practical limitations of the dimensionless spray flux concept are discussed and an empirically modified version of the original spray flux equation is presented.     

Agglomeration of hydrophobic powders via solid spreading nucleation

Wet granulation of a highly hydrophobic fine powder was investigated to elucidate the granule nucleation and growth processes in systems in which distribution of granulating fluid in the granulating mass is complicated by poor wetting. A mixture containing approximately 70 wt.% (90% by volume) of a micronized poorly wetting powder was granulated in a high-shear mixer using water and the microstructure of resultant agglomerates (granules) was studied using optical and electron microscopy as well as X-ray computed tomography (XRCT). The study revealed that granules are typically spherical or elliptical in shape and range in size from 200 to 500 μm. They are strong and consist of a consolidated powder shell and an empty core. Based on the microstructure, a nucleation mechanism for such a hydrophobic system is proposed. Implications for controlling granule growth and granule properties are discussed. This study demonstrates that well-controlled nuclei formation and subsequent granule growth is achievable in a highly hydrophobic system.     

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.     

A narrow size distribution on a high shear mixer by applying a flux number approach

High shear granulation is a common technology for particle size enlargement, but generally the product properties are badly affected by the broad size distribution generated in the process. A recently published approach by Michaels et al. [J.N. Michaels, G. Wang, L. Farber, K.P. Hapgood, J.H. Chou, S. Heidel, and G.I. Tardos, 2006, One-dimensional scale-up of high-shear granulators, Paper 243c, World Congress Particle Technology 5, Orlando (FL)] employs low binder solution spray rates and long granulation times, whilst the solids are kept in roping flow, to avoid coarse formation. The present work applies this approach to a two-component binder system with a dry powder gum and water spray as activation agent. Similarities with fluidised bed granulation and coating processes are explored. The work shows that indeed narrow size distributions of fine granules can be achieved with ease. Dimensionless numbers for spray fluxes are useful to identify operating regimes and to steer optimisation efforts. Comparison of flux numbers for different systems shows that they are not useful (yet) for detailed product and process design. Further work on material-specific quantities controlling nucleation and growth, e.g. particle wetting, is recommended.     

Flow patterns in granulating systems

Particle flow patterns were investigated for wet granulation and dry powder mixing in ploughshare mixers using Positron Emission Particle Tracking (PEPT). In a 4-l mixer, calcium carbonate with mean size 45 μm was granulated using a 50 wt.% solution of glycerol and water as binding fluid, and particle movement was followed using a 600-μm calcium hydroxy-phosphate tracer particle. In a 20-l mixer, dry powder flow was studied using a 600-μm resin bead tracer particle to simulate the bulk polypropylene powder with mean size 600 μm. Important differences were seen between particle flow patterns for wet and dry systems. Particle speed relative to blade speed was lower in the wet system than in the dry system, with the ratios of average particle speed to blade tip speed for all experiments in the range 0.01–0.25. In the axial plane, the same particle motion was observed around each blade; this provides a significant advance for modelling flow in ploughshare mixers. For the future, a detailed understanding of the local velocity, acceleration and density variations around a plough blade will reveal the effects of flow patterns in granulating systems on the resultant distribution of granular product attributes such as size, density and strength.     

Development of positron emission particle tracking for studying laminar mixing in Kenics static mixer

Positron emission particle tracking (PEPT) is a flow visualisation technique that has found application in a wide range of processes. In this work, PEPT has been used to study laminar flow of a high viscosity Newtonian and non-Newtonian fluid in a Kenics static mixer (KM). Through analysis of the trajectories of many hundreds of passes of the tracer particle through the mixer, it is possible to compute the overall flow field and to visualise how the fluid twists and folds as it passes along the mixer. Eulerian velocity maps plotted for the Newtonian and non-Newtonian fluids showed that the length required for the flow to develop is shorter for the non-Newtonian fluid than the Newtonian. The stretching and folding mechanism of mixing was observed by grouping the trajectories into clusters according to whether the trajectory passes to the left or right of the blade at the transition between elements. Those trajectories making the same L–R–L decision tended to remain in the same striation through two or three elements until that striation became stretched and folded back on itself, sandwiching other layers. It is clear that the PEPT data is rich and powerful. We are hopeful that the techniques we develop for the flow and mixing in the Kenics mixer will be applicable to studying more complex laminar flows.     

Agglomeration modeling of small and large particles by a diffusion theory approach

The interaction particle‐binder during the wet granulation process plays a major role in the agglomeration of particles. This interaction has been modeled by a force balance acting on the particle where the binder's viscous force increases the strength of liquid bridge and facilitates the particle agglomeration. In this work, agglomeration kernels based on Brownian movement approach of small particles in the binder layer, the size ratio between particles (monodispersed and polydispersed), and binder's viscous forces were considered to model the wet granulation process of pharmaceutical powders in a laboratory‐scale high shear mixer. The assumptions of no‐stationary and pseudostationary behavior were suitable to describe the growth kinetics of the two stages (fast and slow) observed. A volume ratio of 150 between large and small particles produces the most effective granulation growth. The developed kernels were tested simulating experimental data obtained from a high shear mixer. © 2009 American Institute of Chemical Engineers AIChE J, 2009     

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.     

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.     

Binder addition methods and binder distribution in high shear and fluidised bed granulation

Fluidised beds and high shear mixers are both important in industrial granulation. The binder addition method (pouring, melt-in, spraying) affects the growth and properties of granules and is therefore of vital importance to the fundamental understanding of this detailed process. Non-uniformity of binder distribution is well known in high shear melt granulation, however, there is limited literature surrounding binder distribution in fluidised bed granulation. It was therefore the aim of the paper to compare the binder distribution using alternative addition methods in both high shear mixer and fluidised bed.In this work two binder addition methods, ‘wet’ and ‘dry’, in a fluidised bed and high hear mixer were used to successfully produce granules with a typical pharmaceutical size, 150-300 μm. The granules were analysed for final binder distribution in different size classes using Patent V blue dye and ultra-violet spectrometry.All binder addition methods supported previous work showing non-uniformity of binder distribution throughout the size classes. High shear mixer results show great similarity in binder content whichever binder addition method was chosen. This is likely to be due to the same mechanisms occurring due to the impeller forces in the process, mean while the fluidised bed results show little similarity. The binder distribution by mass is also investigated and shows that although most studies show a relative higher binder content in the larger size classes that actually the majority of binder can instead be found around the mean size of the batch.     

A volume-based multi-dimensional population balance approach for modelling high shear granulation

A volume-based multi-dimensional population balance model based on the approach used by Verkoeijen et al. [2002. Population balances for particulate processes—a volume approach. Chemical Engineering Science 57, 2287-2303], is further developed and applied to a wet granulation process of pharmaceutically relevant material, performed in a high shear mixer. The model is improved by a generalization that accounts for initial non-uniformly distributed liquid and air among the different particle size classes. Only the wet massing period of the granulation process has been modelled and it is experimentally found that the pores in the granules are fully saturated by liquid, i.e., no air is present in the granules during this period. Hence, an alternative model formulation is used as no model for the air in the granules is needed. Particle volume distribution, liquid saturation, liquid-to-solid ratio and porosity of the granules can all be modelled, as these properties can all be expressed as combinations of three model parameters, i.e., the volume fraction of solid material, total liquid fraction and the liquid fraction inside the granules. The model is also improved by introducing a new coalescence kernel and by increasing the number of size classes used. The simulated results are compared to measurements from a series of five designed experiments where impeller speed and water content are varied. It is found that the evolution of the volume, liquid saturation and porosity distributions could all be explained by fitting the compaction and coalescence rate constants.     

Switch from single pot to multiphase high shear wet granulation process, influence of the volume of granulation liquid in a pilot scale study

Among the high shear wet granulation equipments used in the pharmaceutical industry, two configurations are current: single pot process for which blending, granulation and drying are performed in the same apparatus and multiphase process that usually associates a mixer granulator and a fluid bed dryer. Pharmaceutical formulations are often developed with regard to a specific industrial apparatus, but production imperatives may require a switch to another type of equipment. In this work, granulation process switch was investigated at pilot scale on a first intention excipient formulation and with two drug substances chosen as model drugs on the basis of their different water solubility. Each one was tested at two concentrations, 1 and 25%. The volume of granulation liquid was first fixed at the same level whatever the granulation equipment and the formulation. In the second part of the study, the effect of the volume of granulation was highlighted. Regardless of the formulation tested, single pot granules, compared to multiphase one, had improved flow properties, compressibility and tablet cohesion but higher sticking phenomenon was observed when tableting. In the second part, the effect of an adjustment of the volume of granulation liquid for horizontal transposition between high shear granulation processes was discussed.