A combined experimental and computational study of wet granulation in a Wurster fluid bed granulator

A methodology combining theoretical and experimental techniques for analyzing the growth of granules in a fluidized bed granulator was developed. The methodology combines several key features of this complicated process: (i) population balancing (PB) of growth of different granules; (ii) hydrodynamic modeling of the gas-solid mixture flow using Computational Flow Dynamics (CFD); (iii) modeling of contact mechanics and granule formation; (iv) the Stokes number analysis for calculation of successful collisions; (v) well-controlled experimental study of the wet granulation. First, a detailed CFD model of the gas-solid flow and agglomeration (Model CFD-PB) within the Wurster type granulator was developed. Second, a simplified PB model of agglomeration in a homogeneous system (Model H-PB) was developed. The quadrature method of moments (QMOM) was used for solution of PB equations in both models. The kinetic theory of granular flow (KTGF) was employed in both models for calculation of the number of collisions between solid particles of different classes. Success factors, based on the Stokes number analysis, were calculated using results of extensive mesoscale simulations of the formation of realistic three-dimensional virtual granules. Comparison of simulation results of CFD-PB vs. H-PB models allowed evaluation of the KTGF kernel functionality to be used in H-PB model. Next, fluid bed granulation experiments were conducted for typical pharmaceutical excipients (microcrystalline cellulose, mannitol and dicalcium phosphate) with 15% HPC binder solution in a pilot plant Wurster granulator. The observed granule growth was a function of the surface roughness of excipients. Finally, the H-PB model was fitted to the experimental data. The only adjustable parameter of the H-PB model was an effective agglomeration rate constant, which we expect to be mostly related to the binder wetness on the surface of colliding granules.     

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.     

Mechanisms in high-viscosity immersion-granulation

An atypical high-shear granulation process is investigated in which a fine inert powder is bound with a highly viscous surfactant paste. The mechanism comprises adsorption of powder particles onto paste fragments, breakage of powder-coated paste granules, micro-mixing of the granules with incorporation of the powder, granule growth via coalescence, and finally granule consolidation. These stages are supported by micrographic and granule size distribution data. The agglomeration process features two main mechanisms, namely binder distribution followed by granule consolidation and coalescence, the transition between which is shown to be dependent upon the operating parameters.A number of time-dependent consistency regimes can be identified and quantitatively described using bulk tapping compaction tests. Of particular interest is the trend in Hausner ratio, which provides information on the inter-granular friction and cohesivity. Various pseudo-steady state tapping parameters are used to track the agglomeration process, the results of which are consistent with the Iveson et al. (2001a, Powder Technology 117, 83-97) steady state agglomeration regime maps. The effects of paste/powder composition, paste rheology and mixing speed upon the agglomeration rate can be explained physically in terms of adsorption, viscous and mechanical energy dissipation mechanisms. In summary, the work introduces a preliminary analysis of an immersion-granulation mechanism in which a number of key features are identified.     

Influence of liquid binder dispersion on agglomeration in an intensive mixer

In industrial scale mixer granulation, liquid binder is usually sprayed onto the agitated powder bed by means of a nozzle in order to enhance the agglomeration process. The early stage of this process, where granule nuclei are formed and grow, is not well understood. As it is desirable to model the agglomeration state right from the beginning of the process for the purposes of control and modeling, this nucleation step is therefore an important field of interest.To investigate the influence of binder droplet size on the nucleation stage of the agglomeration process, experiments were carried out with lactose and water in an intensive mixer. Water was sprayed in to the mixer with different nozzles to vary the size of the produced droplets. As a comparison, water was also directly poured into the turning mixer. Samples of the produced granules were taken at specific time intervals and analysed for size and water content. As the experiments were focused on examining short granulation times, the first samples were taken after only half of the water was added.Particle size distribution and liquid distribution in the wet granule samples were analyzed. It was found, that the droplet size of the binder liquid has great influence on agglomerate size and binder distribution at short mixing times, with increasing time, the mechanical stresses acting in the mixer becomes more and more dominating in the process. Preliminary comparisons are also carried out with single drop penetration tests in an attempt to correlate drop size to penetration time and also to produced granule size.In conclusion this paper studies the effect of different drop size conditions and subsequent spray flux on the behaviour of the nucleation and the early stages of the agglomeration process. The context of these findings for agglomeration in an intensive mixer is examined.     

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.     

On the small composite granules formed in a continuous rotating conical vessel containing grinding media: effect of the methods of feeding powder on the size and structure of binary composite granules

To investigate the effect of the methods of feeding SiC and CaCO₃ powders on the size and structure of binary composite granules made of the powders, experiments were performed by a simultaneous operation of granulation, grinding and separation in a continuous rotating conical vessel using two kinds of methods for feeding the binary powder. The structure of a composite granule was characterized by comparing the granule size with the size of the SiC-agglomerates contained in the granule.

It was found that (i) by feeding dry SiC with CaCO₃ powders, it was difficult to obtain composite granules smaller than 0.3 mm in size, and that (ii) by feeding SiC-powder with binder in a slurry state, it was possible to make composite granules of larger than at least 0.13 mm, though the structure of composite granules depended on the concentration of SiC-powder in the slurry.     

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.     

The effect of primary particle surface energy on agglomeration rate in fluidised bed wet granulation

The effect of primary particle surface wettability by a binder solution on the rate of agglomeration in a fluid-bed top-spray granulation process was investigated. A model system consisting of hydrophilic and hydrophobic spherical primary particles with a narrow size distribution, and an aqueous solution of hydroxy propyl-cellulose (HPC) as binder, was used. The surface energy of the primary particles was measured by inverse gas chromatography (IGC) and their wettability was characterised by static and dynamic contact angle. Granulation was carried out in a desktop fluid-bed granulator and the resulting granule size distribution and granule microstructure were analysed. The hydrophobic particles gave a wider granule size distribution (larger maximum granule size) than hydrophilic ones under otherwise identical conditions, and the granules were notably rounder and more compact. However, the fraction of un-granulated fines was also higher in the case of hydrophobic primary particles. SEM analysis of granule microstructure revealed that the hydrophilic particles were coated by the binder solution, which left a smaller amount of binder available to form bonds at particle contacts. On the other hand, all of the binder was found to form solid bridges in the case of hydrophobic primary particles. A population balance model was used to explain the observed granulation behaviour.     

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.     

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.     

Growth kinetics and mechanism of wet granulation in a laboratory-scale high shear mixer: Effect of initial polydispersity of particle size

The effect of initial polydispersity of particle size (unimodal versus bimodal distribution) and binder characteristics on the growth kinetics and mechanism of wet granulation was studied. Wet granulation of pharmaceutical powders with initial bimodal particle size distribution (PSD) presented growth kinetics consisting of two stages: fast growth followed by slow growth. The fast stage is controlled by the amount of binder and high probability of coalescence due to the collisions of small and large particles. The second stage is characterized by slow agglomeration of powder mixtures with water content 13.6% v/w, and slow breakage of powder mixtures with water content of 9.9% and 11.7% v/w. The wet granulation of powders with initial unimodal PSD exhibited slow growth kinetics consisting of one stage, since similar particle sizes do not promote agglomeration. The experimental results were better described by a population balance equation using a coalescence kernel that favors growth rate by collision between small and large particles. In general, the probability of a successful collision increased with higher size difference between particles, smaller particle size, and higher binder content.     

Theory of Spherical Agglomeration. II. Layering/Crushing Process in a Rotating Conical Drum

Abstract

A theoretical study is made of the so-called layering/crushing agglomeration process in a rotating conical drum under steady-state continuous flow conditions. A particular application is the separation of bitumen from the solid particles in oil sands, where the nonwetting liquid is a bitumen-solvent mixture and the wetting liquid is water. It may be assumed that the water is completely imbibed by the agglomerating granules (particles), so that the system consists of granules suspended in the nonwetting liquid. In the layering/crushing process, the granules are divided into two nonoverlapping size distributions, the small crushed granules and the large granules on which the layering takes place. The agglomeration process therefore becomes a complicated example of three-phase flow. The three phases are the continuous nonwetting liquid and the two granular phases. The steady-state mass balance equations for the two groups of granules in the rotating conical drum can be integrated approximately. The mean velocity of the layered (large) granules parallel to the axis of the cone is directed from apex to     

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     

Spherical agglomeration in a conical drum

The spherical agglomeration process is a means of size enlargement in which agitated particles, suspended in a liquid, are bonded together by a second liquid, which will wet the solid surfaces and be immiscible with the suspending medium. A process is described in which agglomeration takes place in a cone shaped vessel, rotating horizontally about its symmetric axis. The cone configuration of the agglomerator imparts a longitudinal impulse to the charge, which is most effective on the largest particles. This causes a size classification within the cone, with the largest agglomerates congregating at the base. The result is the continuous production of uniformly sized, highly spherical pellets. The factors affecting agglomerate growth and size are outlined and discussed.     

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.     

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.     

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 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.     

Modelling and validation of granulation with heterogeneous binder dispersion and chemical reaction

In this paper a multidimensional model for binder granulation is presented. The particles undergo different transformations such as coalescence, compaction, and breakage. Further chemical reaction in the granules is taken into account in order to incorporate binder solidification which is observed to be a significant transformation in many industrial applications. The equations of the model framework are solved numerically with a direct simulation Monte Carlo (DSMC) algorithm. In addition to the comparison between experiment and simulation, the model framework also enables the study of critical parameters in binder granulation such as reaction rate (solidification of binder) and size of the added binder droplets, which demonstrates its promising potential.     

Electrical Agglomeration of Aerosol Particles in an Alternating Electric Field

A laboratory scale test system has been designed and constructed to study the electrical agglomeration of charged aerosol particles as a method to increase the fine particle collection efficiency of electrostatic precipitators. The system consists of test aerosol generator, aerosol charger, agglomerator chambers, and aerosol measurement equipment. Air atomizing nozzles and the TSI six-jet atomizer have been used as the test particle generators. The test particles have been charged by a corona discharge. Two types of agglomerator chambers have been investigated. In one agglomerator the gas flows between two parallel plates, across which the alternating high voltage is applied. The other agglomerator is a quadrupole structure with cylindrical electrodes positioned between the grounded plates. Particle concentration and size distribution measurements have been carried out downstream of the agglomerator with agglomerator voltage on and off. Particle concentrations and size distributions have been measured with differential mobility analyzer (DMA) and a Berner low pressure impactor. These measurements show that agglomeration causes about a 4%-8% decrease in the fine particle concentration when the total mass concentration is between 1 and 2 g/m³. There was no difference between the results measured with the parallel plate and the quadrupole agglomerator.