Behaviour of soft granules under compression: Effect of reactive and non-reactive nature of the binder on granule properties

Granulation is a process where primary powder particles are made to adhere to form multi-particle entities called granules and this is achieved by using a binder. The binders can be broadly classified into two categories viz. reactive (reacts with base powder) and non-reactive (does not react with the base powder). The effect of various parameters related to binder liquid (binder viscosity, addition rate, distribution over the bed etc.) on the mechanism of granulation and physical/mechanical properties of granules is well studied. However, comparison of physical and mechanical properties of granules made via reactive and non-reactive binder using the same base primary particles has not been reported. In this paper, granulation of sodium carbonate primary particles under reactive and non reactive conditions was studied. The mechanical properties of sodium carbonate granules were characterized using single granule compression measurements. The average single granule apparent strength of reactive granules was higher compared to non-reactive granules. It was observed that granules formed using non reactive binder were brittle and showed multiple breakages. However granules made using reactive binder showed single breakage followed by significant plastic flow. In addition, bulk granule compression measurements were also carried out. Known models of Heckel, Kawakita and Ludde, and Adams et al. (developed mainly for pharmaceutical and metal powders) were used to predict mechanical properties of soft detergent granules. The bulk granule compression measurements also showed that reactive granules have higher strength compared to non-reactive granules. However, the absolute values of granule strength obtained from the empirical models were lower than the granule strength obtained from single granule compression measurements.     

The effect of granule microstructure on dissolution rate

The relationship between the microstructure of granules and their dissolution rate has been investigated. Granules consisting of mannitol primary particles and PVP aqueous binder have been prepared by top-spray fluid-bed granulation, and granules consisting of sucrose primary particles and PEG binder by in-situ melt fluid-bed granulation. Granule microstructure has been systematically varied by manipulating the primary particle size distribution and the binder content in each case. In both cases granule porosity was found to be a decreasing function of binder content and a minimum of porosity as function of the fine/coarse primary particle mixing ratio has been observed, in line with theoretical expectations. Granule microstructures have been analysed using X-ray computed micro-tomography and compared with three-dimensional “virtual granules” generated by a computer simulation of the agglomeration process. The dissolution rate of granules has then been measured. While porosity was found to have a strong effect on the dissolution rate of mannitol granules, the dissolution rate was found to be practically independent of porosity in the case of sucrose granules. The formulation-microstructure and microstructure-dissolution correlations established in course of this work are in line with previous computer simulation results and form part of a computer-aided granule design methodology.     

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.     

Binder liquid distribution during granulation process and its relationship to granule size distribution

The aim of this study is to characterize the impact of binder liquid distribution on granule properties during the wet granulation process. A new parameter, namely the binder liquid transfer coefficient, is used to characterize binder liquid distribution. The relationships between binder liquid distribution coefficient and granule size distribution are discussed. Granules are made of lactose alpha-monohydrate (97.5% w/w, d₅₀ = 31 μm) and polyvinylpyrrolidone (2.5% w/w, d₅₀ = 89 μm) and are manufactured in a Mi-Pro high shear mixer (Pro-C-epT, Belgium). Nigrosine is incorporated as a tracer in the binder liquid in order to detect its distribution in the granules during the process. The results show that the binder liquid is heterogeneously distributed at the beginning of the process whereas it tends to be evenly distributed in the powder during the process. The binder liquid transfer in granule classes obeys a first-order law and the binder liquid transfer coefficient appears to be related to operating conditions: high rotation speed, low liquid flow rate and low liquid viscosity favour the achievement of high liquid transfer coefficient. In addition, the higher the coefficient, the earlier the homogenization and the wider the granule mean diameters. Thus, granule size distribution can be controlled by the binder liquid distribution process. A binder liquid distribution mechanism is proposed, which makes it possible to discuss the influence of the operating parameters on the granule construction process.     

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.     

Foam granulation: Liquid penetration or mechanical dispersion?

There have been significant advances in the understanding of wet granulation processes. Foam granulation is the latest development and an emerging area of interest for pharmaceutical manufacturing.Single foam penetration experiments were carried out on static powder beds, followed by short-nucleation experiments (where nuclei are formed by a nucleation-only mechanism) and full foam granulation experiments (where nucleation, growth and breakage are occurring simultaneously). All experiments were performed with lactose monohydrate powder using a 5 L high shear mixer–granulator. The foam penetration/dispersion behaviour was examined and the granule size distributions were investigated as a function of foam quality (83–97% FQ), impeller speed (105–515 rpm) and wet massing period (0–4 min).Nucleation in foam granulation is postulated to undergo either “foam drainage” or “mechanical dispersion” controlled mechanisms. For “foam drainage” mechanism, the foam penetrates the powder bed to form coarse and broad granule size distributions. For “mechanical dispersion” mechanism, the wetting and nucleation conditions are governed by the powder mixing conditions and similar granule size distributions are produced. Regardless of the mechanism, the initial wetting and nucleation behaviour controls the initial nuclei size distribution, and this initial distribution is retained in the final granule size distribution. This work demonstrated the critical importance of the nucleation and binder distribution in determining the granule size distributions for foam granulation process.     

Effect of process parameters on the melt granulation of pharmaceutical powders

Co-melt granulation of lactose and PEG was investigated in a fluidised bed granulator. The effect of process parameters such as binder content and binder viscosity were correlated to granulation time and particle size distribution. The experimental data indicated that after initial nucleation the granulation mechanism was dependent upon binder content and binder viscosity. When the binder content was increased above 18% (w/w) de-fluidisation of the bed occurred and granulation moved to the slurry regime. As the process involved the melt granulation of relatively high molecular weight (6-20 k) and thus high viscosity PEG (500-19000 mPa s), it was found that binder viscosity had a significant affect on the granule growth mechanism. Granulation with a binder viscosity of 500 mPa s resulted in granule growth by coalescence, however, an increase in binder viscosity resulted in less coalescence and a lower granule growth rate. Furthermore, the granulation data were characterised by Stokes number analysis.     

Challenges in granulation technology

Research on granulation processes has concentrated on the use of mechanical mixers. Understanding of the mechanisms by which granules are formed interact with each other and change in size has increased greatly. We now appreciate why products frequently have a bimodal distribution, wide size range and non-uniform binder content. The effects of changing binder viscosity and size of the constituent particles are also partially understood. However, much remains to be done. Three areas of research are suggested that may repay intensive investigation. The first challenge is to improve knowledge of the strength of wet assemblies. This is fundamental to granule deformation and coalescence processes and yet is not well understood. Another challenge is to develop better models for granule coalescence. Although there have been significant advances on understanding of the processes of granule adhesion and coalescence, more needs to be done. The third challenge is to learn how to design mixers that inherently give a better control of granule size. This requires an understanding of the motion of material within granulators and how the granulator interacts with the material being granulated.     

Multi-component granulation in a fast fluidized bed

The granulation of multi-component particles was conducted in a fast fluidized bed with an atomizing binder solution. The effects of gas velocity and binder droplet diameter on granulation rate, granule size distribution and granule composition were studied. The granulation rate and granule yield were determined by the balance between the agglomeration rate of feed particles and the disintegration rate of granules because there was no secondary granulation. With the increase in gas velocity and the reduction in binder droplet size, the agglomeration rate of feed particles decreased but the disintegration rate of granules increased, resulting in a reduced granule yield. Despite the larger fraction of small particles in the granules, the homogenous granulation of multi-component particles was achieved.     

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.     

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.     

Effect of scale of operation on granule strength in high shear granulators

Results of a study on the influence of operation scale and impeller speed of high shear mixer granulators on the strength of granlues are reported in this paper. Calcium carbonate particles have been granulated in four scales of a geometrically similar high shear granulator (Cyclomix) with 1, 5, 50 and 250 L capacities. For the smallest scale, the effect of a small deviation from geometric similarity was also investigated. An aqueous solution of polyethylene glycol was used as the binder. Three scaling rules of constant tip speed, constant shear stress and constant Froude number have been used to determine the impeller speed for the different scales of the granulators. The granules produced in these experiments have been dried and tested for strength using side crushing test method. The data have then been analysed and compared. Operation of granulators according to the constant tip speed rule produces granules with a similar strength for all four scales, followed by a similar trend for the constant shear stress rule, albeit to the less extent. The constant Froude number rule produces a heterogeneous strength distribution and is not a suitable criterion for scaling-up of high shear granulators. The distribution of granule strength has been fitted to the normal, log-normal and Weibull distributions. Weibull distribution fits the data well for the constant tip speed operations.     

Formation of hollow granules from liquid marbles: Small scale experiments

Research into formation of hollow granules from liquid marbles is an emerging field in hydrophobic granulation. A liquid marble is formed by a network of self-assembled hydrophobic powder around a droplet, and this paper investigates the conditions required for forming hollow granules from a liquid marble precursor.Single drops of fluid were produced using a syringe and placed onto loosely packed powder beds of hydrophobic powders. Liquid marbles formed from several powder/liquid combinations were dried at several conditions to investigate the drying conditions required for formation of a stable hollow granule.The formation of stable hollow granules was found to depend on drying temperature and binder concentration. For HPMC and PVP binder, formation of hollow granule is proportional to binder viscosity and for HPC binder, this relationship is constant. Different combinations of powder and binder at both drying temperatures - 60 °C and 100 °C - had mixed success rates in forming hollow granules, but generally the success rate was improved by using higher drying temperatures, smaller particles or higher viscosity binder fluids.     

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.     

Rheology, granule growth and granule strength: Application to the wet granulation of lactose-MCC mixtures

This study aims at better understanding the wet granulation process of a binary mixture composed of microcrystalline cellulose (water insoluble) and lactose (water soluble). It investigates the effect of formulation (proportion of the different components in the mixture) on the granule growth kinetics, the evolution of granule morphology during granulation, the wet mass consistency and dry granule strength of the end product. Additionally the influence of mixer design has been studied by up scaling the process from the 1.9 L Mi-pro high shear mixer used as the reference scale to a 6 L Diosna P1-6 high shear mixer. The scale-up rules investigated were constant impeller tip speed and constant Froude number. Our results allowed us to draw the following conclusions:

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The increase in MCC content is found to increase the optimum binder requirement for granulation, wet mass consistency and dry granule strength.

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Granule growth takes place in three distinct stages: wetting, nucleation and growth. These stages can be identified with the help of the recorded torque values during the granulation process or by the evolution of granule size and granule morphology.

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The characterization of the starting materials by moisture sorption isotherms brings more insight to the role of each component during the granulation process.

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The increase of the granulation scale has little influence on the observed growth mechanism. However bi-modality of the granule size distribution is increased, wet mass consistency and dry granule strength are decreased with increasing scale of operation.

     

Hot melt granulation of coarse pharmaceutical powders in a spouted bed

The hot melt granulation of a coarse pharmaceutical powder in a top spray spouted bed is described. The substrate was lactose-polyvinylpyrrolidone particles containing or not acetaminophen as a drug model. Polyethylene glycol (MW, 4000) used as binder was atomized onto the bed by a two-fluid spray nozzle. The granulation experiments followed a 2³ factorial design with triplicates at the center point and were carried out by varying the spray nozzle vertical position, the atomizing air flow rate and the binder feed rate. Granules were evaluated by their pharmacotechnical properties like size distribution, bulk and tapped densities, Carr index, Hausner ratio and tableting characteristics. Analysis of variance showed that granule sizes were affected by the PEG feed rate and atomizing air pressure at the significance levels of 1.0 and 5.0%, respectively, but spray nozzle distance to the substrate bed was not significant. The spray conditions also affected granule flow and consolidation properties, measured by the Carr index and Hausner ratio. Measured densities, Carr indexes and Hausner ratios proved that granules flowability and consolidation properties are adequate for pharmaceutical processing and tableting. Tablets prepared with acetaminophen-containing granules showed good properties and adequate release profiles in in vitro dissolution tests. The results indicate the suitability of spouted beds for the hot melt granulation of pharmaceutical coarse powders.     

Influence of Slurry Parameters on the Characteristics of Spray-Dried Granules

A systematic study has been performed to determine how the characteristics of granules prepared by spray drying aqueous alumina slurries are influenced by processing parameters: binder type (PEG Compound 20M or PEG-8000), solids loading (30 or 40 vol%), ammonium polyacrylate deflocculant level (0.35-1.00 wt%), and spray-dryer type. Correlations between slurry rheology and granule characteristics have been made, and a model for granule formation is presented. The packing density of the primary particles within the granules is lower for slurries with higher yield stress and is dependent on the slurry solids loading. Granules prepared using 0.35 wt% deflocculant (0.14 mg/m²), which correspond to high slurry yield stress, are of solid morphology, whereas higher deflocculant levels result in hollow granules that contain a single large open pore or crater. The degree to which particles are able to rearrange during drying influences the final granule density and is determined by the strength of the floc structure, as indicated by the slurry yield stress. When the yield stress is low, a crater may form from the inward collapse of the surface of a forming granule when the particle packing density in a droplet continues to increase after the droplet size becomes fixed by the formation of a rigid shell, leaving an internal void with internal pressure lower than that of the surrounding atmosphere.     

Computer simulation of granule microstructure formation

The diagenesis (porous microstructure evolution) of granules formed by a layering growth mechanism in a wet granulation process has been modelled. The model includes the packing of primary particles with a given size and shape distribution, and the deposition, spreading, and solidification of binder droplets within the growing granule. The dependence of granule porosity on the binder/solids ratio, primary particle size and morphology, and the rates of binder spreading and solidification has been investigated. The results are presented in the form of structure maps relating volume-averaged microstructure parameters with dimensionless groups including the ratio of droplet spreading and solidification times and the mean time between particle collisions. These graphs can guide the selection of process operating conditions or formulation ingredient properties required to obtain a particular granule microstructure.     

Composition limits in granulation with active component in the binder

The process of reactive granulation is considered. Sodium carbonate primary particles react with dodecyl‐benzenesulfonic acid droplets to form granules where the active component is an anionic surfactant formed by the reaction. The effect of primary particle size on the maximum binder/solids ratio was systematically investigated and found to be directly proportional to the specific surface area of the primary particles regardless of how this surface area was achieved—whether by monodisperse powders or bimodal powder mixtures. The effect of binder viscosity on the maximum binder capacity has shown a nontrivial behavior: while the maximum binder content increased with increasing binder viscosity for fine primary particles, the opposite trend was observed in the case of coarse primary particles. This behavior was explained by detailed studies of primary particle wetting and binder penetration into particle beds, as well as by microtomography analysis of the internal granule structure. © 2014 American Institute of Chemical Engineers AIChE J, 61: 395–406, 2015