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.     

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.     

The effect of powder size on induction behaviour and binder distribution during high shear melt agglomeration of calcium carbonate

Growth mechanisms in high shear mixer granulation were observed over a wide range of particle size and liquid-to-solid (L/S) ratio. The materials used were calcium carbonate (CaCO₃; size fractions in the range 1.5 to 85 μm) with a binder of polyethylene glycol 6000 (PEG 6k). The binder, solid at room temperature, was added by the “melt-in” method. A 10 L vertical-axis granulator was used, with a chopper and a four-bladed impeller.

The mean granule size and granule size distribution were measured at regular intervals during the agglomeration process by careful sampling and sieving. The uniformity of binder distribution among the granules was also measured.

The growth behaviours of each grade of primary particles were classified and compared. An induction type mechanism was observed with an initial period of slow growth in mean particle size that lasted 2 to 3 min (the induction period). This was followed by a short rapid growth phase lasting 1 to 2 min. The final stage was a plateau of more or less zero growth. Interestingly, the end of the induction period and the onset of rapid growth corresponded to a change in the granule size distribution from bimodal to monomodal and a similar change in the distribution of binder. Induction period growth rate tended to be lower for granules of finer particles, but these grew more rapidly during the rapid growth stage and produced larger granules than the coarser primary particles.

The liquid-to-solid (L/S) ratio had a significant effect on the growth rate during the rapid growth stage but a minor effect on the granule size distribution and binder distribution. Primary particle size had a significant effect on the final average size of granules, the growth rate during the rapid growth stage and the distribution of granule size and binder.     

Foam granulation: Binder dispersion and nucleation in mixer-granulators

Traditional wet granulation method involves spraying of liquid binder onto a moving powder bed to granulate the powder particles in the granulator. A new alternative method of wet granulation has been developed where foam delivery of binder is used to granulate the powder particles.This study investigated binder distribution in wet granulation and focused on the nucleation stage, where nuclei are formed during the initial binder distribution. Nucleation experiments were used to study the formation of nuclei by the foam and spray delivery methods in a high shear mixer-granulator. The distribution of foams on a dynamic powder bed were also investigated by filming small portion of foams as they penetrated into moving powder beds under different powder flow conditions in a high shear mixer-granulator.Nucleation experiments in this study show that foam delivery tends to create a narrower nuclei size distribution during the early stage of wet granulation process compared to spray delivery at the same processing conditions, demonstrating the potential of foam granulation in achieving improved binder distribution. For foam delivery, the nuclei formation is influenced by the foam properties and powder flow conditions in the granulator. The experiments show that the narrowest nuclei size distribution is obtained by granulating with high-quality foam and intensive powder mixing conditions. Coarser nuclei are formed when low-quality foam is dispersed in a less intensively agitated powder. The interactions of foam quality and the powder flow pattern are discussed and two distinct wetting and nucleation mechanisms are proposed: (1) under bumping flow, a low-quality foam tends to induce localised wetting and nucleation. The wetting and nucleation is “foam drainage” controlled. (2) Under roping flow, foam will be dispersed by the motion of the agitated powder. The wetting and nucleation is “mechanical dispersion” controlled.     

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.     

Breakage of drop nucleated granules in a breakage only high shear mixer

Wet granule breakage is a significant mechanism, particularly in high shear mixer granulation. This paper presents a study of the wet breakage mechanism using a Breakage Only Granulator. Granules with varying powder and liquid binder properties were created using single drop nucleation. These granules were inserted in a Breakage Only Granulator, a high shear mixer granulator with non-granulating cohesive sand as the bulk medium. Two different impellers were used at impeller speeds of 500 and 750 rpm. An 11° beveled edge impeller was used to create both impact and shear in the granulator, and a flat plate impeller was used to minimize impact and maximize shear in the granulator. The fraction of granules which broke during the granulation process was used as a measure of granule breakage within the granulator. These results were compared with Stokes deformation numbers calculated using mean dynamic peak flow stresses measured in unconfined uni-axial compression tests. Results for the beveled edge impeller blade show increasing breakage with increasing Stokes deformation number. Significant breakage was observed at high Stokes deformation number. Increasing impeller speed increased the magnitude of breakage. The Stokes deformations number appears to be a reasonable predictor for granule breakage within the granulator. Results for the flat plate impeller show very little breakage at 500 rpm, and significant breakage for only one formulation at 750 rpm. This suggests that either impact is dominant over shear for breakage within the granulator, or that the two impeller designs give substantially different collision velocities in the granulator. The impeller speed, type and shape have a profound effect on granule breakage in high shear mixer granulators.     

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.     

High shear wet granulation modelling—a mechanistic approach using population balances

A population balance approach based on splitting the coalescence kernel into two factors, the first describing the collision frequency of particles and the second describing the collision efficiency, is applied to modelling wet granulation in a high shear mixer. Four different expressions for the collision frequency are compared and discussed. The kernels are the size independent kernel, the shear kernel proposed by Smoluchowski [M. Smoluchowski, “Versuch einer matematischen Theorie der Koagulationskinetic kolloider Lösungen”, Z. Physik. Chem. 92, (1917) 129–168.] and the two kernels proposed by Hounslow [M.J. Hounslow, “The population balance as a tool for understanding particle rate processes”, Kona (1998) 179–193.], i.e. the EKE kernel and the less used kernel based on equipartition of fluctuating translational momentum (ETM kernel). Microcrystalline cellulose (mcc) is granulated under different process conditions and it is found that the ETM kernel best describes the granulation at higher impeller speeds, whereas the EKE kernel gives better agreement at lower impeller speeds. The collision efficiency is assumed to be a function of the liquid saturation. By using this assumption, it was possible to detect similar trends for the remaining part of the collision efficiency regardless of process conditions.     

Effects of process parameters on granules properties produced in a high shear granulator

Results of a study on the influence of process parameters such as impeller speed, granulation time and binder viscosity on granule strength and properties are reported. A high shear granulator (Cyclomix manufactured by Hosokawa Micron B.V., The Netherlands) has been used to produce granules. Calcium carbonate (Durcal) was used as feed powder and aqueous polyethylene glycol (PEG) as the binder. The dried granules have been analysed for their strength, density and size distribution. The results show that increasing the granulation time has a great affect on granules strength, until an optimum time has been reached. The underlying cause is an increase in granule density. Granules are consolidated more at higher impeller speeds. Moreover, the granule size distribution seems not to be affected significantly by an increase in impeller speed. Granules produced with high binder viscosity have a considerably lower strength, wide strength distribution due to poor dispersion of binder on the powder bed. Binder addition methods have showed no considerable effect on granule strength or on granule size distribution.     

High shear granulation of dolomite – I: Effect of shear regime on process kinetics

Wet granulation of previously unreported formulation system is presented. Dolomite powder is granulated under different shear regimes by using three-component binder formulation, water-molasses-polyvinylpyrrolidone. 1-D discretized population balance equation (PBE) and Equi-Partition of Kinetic Energy (EKE) coalescence kernel are applied to modelling granulation in a high shear mixer. Process modelling is focused to simulation of changes of the property of a group of entities, granule size distribution (GSD). The GSD predictions indicate the presence of coalescence growth as a dominant mechanism in the dolomite granulation process. Minor deviations between simulated and real GSDs signify the probability of other granulation mechanism(s) existence. A posteriori approach by integral method was used for coalescence rate constant estimation. This research highlights discrepancy in the coalescence rate of dolomite granulation process, between its early and later stages. Moreover, kinetic analysis of the high shear granulation process provides quantification of the macroscopic variable (impeller speed) influence on regarded property of a group of granules in terms of values of growth rate parameter.     

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.     

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.     

Modification of faujasites to generate novel hosts for “ship-in-a-bottle” complexes

Zeolites X, Y, and DAY have been modified by a post-synthetical dealumination procedure to generate mesopores that are completely surrounded by micropores. In these novel host materials several bulky transition metal salen complexes have been occluded via the “ship-in-a-bottle” synthesis approach. Both the host materials and the “ship-in-a-bottle” catalysts have been characterized by FTIR spectroscopy and nitrogen adsorption. Additionally, the “ship-in-a-bottle” catalysts have been characterized by thermogravimetric analysis and ICP-AES spectroscopy. The catalysts have been tested in the stereoselective epoxidation of R-(+)-limonene and (−)--pinene with molecular oxygen as oxidant. The best results so far — 100% conversion, 96% selectivity and 91% de — were achieved with the immobilized (R,R)-(N,N′)-bis(3,5-di-tert-butylsalicylidene)-1,2-diphenylethylene-1,2-diaminocobalt complex in the epoxidation of (−)--pinene.     

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     

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.     

Single drop behaviour in a high shear granulator

The wet granulation process starts when a liquid drop makes contact with the powder bed. In a powder bed, drops are subjected to centripetal and gravitational forces. These forces may affect the size and shape of the drop as it is incorporated into the bed. The majority of experiments studying droplet behaviour have been performed on static bed surfaces. This paper seeks to demonstrate droplet behaviour during the initial contact stage with a dynamic powder bed representative of that occurring during high shear granulation. Particle image velocimetry (PIV) is used to determine droplet and powder bed surface velocities. Due to inclination of powder bed part of drop de-accelerate slowly moved downward while other parts remain attached to powder bed this result in their deformation and breakage. Amount of deformation of drop and span of area where it occurred was increased as drop was added farther from the outer edge of the mixer. This paper shows that the binder drop may deform or break in high shear granulator depending on its initial impact position. This will affect size distribution and other properties of nuclei.     

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.     

CHARACTERISTICS OF MICROMETER AND SUBMICROMETER SIZE O/W EMULSIONS PRODUCED BY RAMOND SUPERMIXER®

A novel motionless mixer named the Ramond Supermixer® (RSM®) was employed to produce O/W emulsions composed of micrometer and submicrometer-size droplets. Liquid paraffin as dispersed phase, aqueous sucrose solution as continuous phase, and anionic sodium dodecyl sulfate as emulsifying agent were used as the model emulsification system. Pressure drop, droplet size distribution, Sauter mean diameter (d₃₂), and geometric standard deviation of the droplet size distribution (σ_g) were investigated under the various combinations of process variables; superficial liquid velocity, number of mixing units, number of passages through RSM®, dispersed phase viscosity (η_d), continuous phase viscosity (η_c), and dispersed phase volume fraction. Different modes of droplet size variations with process variables were obtained, with respect to micrometer- and submicrometer-size ranges, and theoretical explanations are forwarded. For the micrometer-size range, maximum droplet diameter (d_max) was proportional to d₃₂. For the submicrometer-size range, d_max varied with d₃₂ in the range of 1.53-2.19-fold, and a correlation is proposed with K (=η_d/η_c); d₃₂ and σ_g were well correlated with the process variables. Furthermore, a semi-empirical mechanistic model was developed for the formation of droplets obtained under inertial sub-range to interpret the effect of process variables.     

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.     

Theory of “Cohesive” vs “Adhesive” Separation in an Adhering System

It is shown that there is limited validitity to the doctrine that true interfacial separation, in an adhering system, is highly improbable. An analysis employing the Griffith-Irwin crack theory yields these results: The important parameters are, difference in elastic moduli, ΔE; differences in g, the energy dissipation per unit crack extension; thickness, Δ₁ or δ₂, of the region where dissipation occurs; and the presence or absence of strong interfacial bonds. If the forces across the interface are appreciably weaker than the cohesive forces in either phase, there is a strong minimum in g at the interface. For flaws of equal size, an interfacial flaw will be the site of initiation of failure. If strong interfacial bonds are present, then if Δg and ΔE have the same sign, failure is most probable, deep within one phase. If Δg and ΔE have opposite signs, failure may be initiated, and may propagate, at a distance δ from the interface, in the phase with lower g. This may be mistaken for weak-boundary layer failure.