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.     

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.     

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.     

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.     

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.     

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.     

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.     

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.     

Effect of internal binder on microstructure in compacts made from granules

This paper focuses on the influence of granule characteristics on the microstructure of the compact. Alumina granules were prepared with a poly-acryl acid (PAA) or a poly-vinyl alcohol (PVA) as binders by a spray-drying method. Observation with a liquid immersion method shows a significant difference in the binder distribution. Very uniform and non-uniform distributions were noted for the PAA and PVA binders, respectively. PVA binder segregated at surface and subsurface of the granules. The compression strength and deformation behavior were examined on a single granule with a micro-compression testing machine. The granule with the PAA binder has a low yield stress. In the forming process, the relative density of the compact body started to increase at low pressure. Homogeneous internal structures were noted in the green compact at all pressures examined. The granule with PVA binder showed higher yield stress. The internal structure of the compact was inhomogeneous, and large interstices were often observed between granules in the green compact also.     

Quantitative proof of liquid penetration-involved granule formation in a high shear mixer

Previous work of the authors [K. van den Dries, H. Vromans, Qualitative proof of liquid penetration-involved nucleation in a high shear mixer, Eur. J. Pharm. Sci. 58 (2004), 551–559.] revealed that the granule formation in a high shear mixer depends on a balance between the rate of liquid penetration and binder dispersion. Three distinct nucleation mechanisms could be qualified; (I) granule formation by liquid penetration followed by granule breakage or (II) absence of granule breakage and (III) complete dispersion of the binder liquid. The aim of this study was to quantify the mechanisms of granule formation. A substandard amount (1.5% w/w) of binder liquid was added to a lactose mixture, while the mixer was operating. The powder mixture was frozen with liquid nitrogen after 15 s and analysed by sieving. The results show that, despite the minimal liquid amount, granules are formed under most conditions. It is argued granules are being formed by a liquid penetration process. These freshly formed granules are broken down at low viscosity (< 1 Pa s) and remain intact at higher viscosity (> 1 Pa s). Only at extreme conditions (viscosity > 30 Pa s) hardly any granules are formed. In this case penetration of the liquid becomes practically impossible and the binder is completely dispersed. A model based on the processes of liquid penetration, binder dispersion and granule breakage, confirms the observed nucleation behaviour. It is conclusively shown that an increase in viscosity results in a transition from nucleation mechanism I→II→III.     

Particle growth mechanisms in fluidised bed granulation—II: Comparison of experimental data with growth models

Growth data from batch granulation experiments have been fitted to simple geometrical models. Layered granule growth approximates to concentric coating of core particles with binder, although the actual mechanism of growth is different. In the case of agglomeration, a relationship is established betwee mean granule size and binder content.     

Kinetics of fluidised bed melt granulation I: The effect of process variables

This paper is the first of a series to study the influence of operating conditions on the kinetics of fluidised bed melt granulation. First, we identify the rate processes responsible for the net growth in granule size in a top-sprayed fluidised bed granulator and propose a sequence of events based on these rate processes. The overall kinetics during the process is identified to be a combination of particle aggregation, binder solidification and granule breakage. By conducting experiments in a small-scale modified commercial fluidised bed granulator, the influence of various operating conditions (binder spray rate, bed temperature, atomising pressure, fluidising air velocity) on the granule growth behaviour was examined. The results indicate the granule growth rate to be directly dependent on the relative amount of binder sprayed into the bed, which essentially determines the speed of the aggregation process. The overall granule growth rate is observed to increase relatively with increased bed temperature for a more viscous PEG4000, while a maximum growth is seen for a lower viscosity PEG1500. A larger droplet size was also seen to have increased the overall growth rate, even though a smaller droplet seems to be able to induce a faster initial growth. The results also reveal the increase in fluidising air velocity to reduce the overall granule growth rate. The final granule size distribution was also observed to become narrower with increased bed temperature and fluidising air velocity. These observations are effectively explained using the proposed sequence of rate events.     

粘结剂对喷雾造粒ZrO2(Y2O3)粉末特性的影响

采用喷雾造粒工艺对及ZrO2(Y2O3)粉体进行造粒，研究喷雾造粒过程中粘结剂含量对粉料流动性、填充性、造粒团聚体强度的影响，并对坯体成形过程中团聚体的破碎行为进行了分析。结果表明：喷雾造粒过程中粘结剂含量较高时，造粒团聚体粒子具有良好的填充性，但粒子强度高，在成形过程中不易破碎，将阻碍致密化烧结。     

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.     

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.     

Population balance modelling of granulation with a physically based coalescence kernel

It was previously published by the authors that granules can either coalesce through Type I (when granules coalesce by viscous dissipation in the surface liquid layer before their surfaces touch) or Type II (when granules are slowed to a halt during rebound, after their surfaces have made contact) (AIChE J. 46 (3) (2000) 529). Based on this coalescence mechanism, a new coalescence kernel for population balance modelling of granule growth is presented. The kernel is constant such that only collisions satisfying the conditions for one of the two coalescence types are successful. One constant rate is assigned to each type of coalescence and zero is for the case of rebound. As the conditions for Types I and II coalescence are dependent on granule and binder properties, the coalescence kernel is thus physically based. Simulation results of a variety of binder and granule materials show good agreement with experimental data.     

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.     

喷雾造粒因素对粉体颗粒形成的影响

通过研究BaTiO3浆料的造粒干燥过程,雾化条件、固含量、粘结剂的比例对PTC粉体是形成致密颗粒还是空心颗粒或絮状颗粒起决定性作用,实验证实,高固体物含量、适量的粘结剂和较高泵压是形成实心颗粒、松装密度大的粉体的重要条件,并从理论上给出了初步分析结果。     

High shear granulation of dolomite – II: Effect of amount of binder liquid on process kinetics

This paper, the second of a series, analyzes the effect of binder amount on the kinetics of wet granulation process. Granulation experiments were conducted in batch, lab-scale high shear mixer with formulation system that was initially studied in first part of a series. First, we identify the effect of binder content on the net granulation behaviour during early stage of the process. Single entity property (its size) was accounted only within this research. The results indicate that binder content strongly promotes growth of dolomite entities. Secondly, 1-D discretized population balance equation (PBE) and Equi-Partition of Kinetic Energy (EKE) theory were used to simulate the net granulation process. Tested “coalescence-only” models provide good prediction of real dolomite granule size distributions (GSDs) during early stage of the process for each binder content value. By using modelling procedure granule growth rates were quantified. Ultimate goal of relating the coalescence rates of dolomite entities with binder amount variable is provided. This will result in a better perspective of the meso-scale of the dolomite granulation process.     

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.