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.     

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.     

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.     

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.     

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.     

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     

Advanced 3D and 4D microstructure study of single granule formation for pharmaceutical powders using synchrotron x-ray imaging

Monitoring the microstructure of the granule in the wet granulation process could play a decisive role in obtaining high-quality granules. Due to the complex, fast and opaque nature of wet granulation, it cannot be captured by conventional methods. In this study, synchrotron x-ray imaging was employed for the first time to investigate the internal real-time pore evolution during the granule formation process, based on the single droplet impact method. It was found that granules from coarser and more homogenous powders experienced a higher rate of pore evolution during nucleation with a more uniform pore distribution. Dynamic wetting studies showed the granule formation mechanisms, the crater mechanism was found for most binary mixtures with 50 wt. % excipients. According to the physical tests, the granules with lower porosity and finer pores exhibited higher hardness and a slower dissolution rate.     

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.     

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.     

Distribution and accessibility of binder in wet granules

The effect of primary particle morphology on the spatial distribution of binder in wet granules was investigated by numerical simulations. The shape factors of four commonly used pharmaceutical excipients - mannitol, lactose, microcrystalline cellulose, and calcium phosphate - were evaluated by digital image analysis and used for three-dimensional computer reconstruction of virtual particle populations. The formation of wet agglomerates was simulated by close random packing of primary particles and then finding the equilibrium distribution of a liquid binder in the pore space within the close packed structures, using the Volume of Fluid (VOF) method. The spatial distribution of binder in the computer-generated wet agglomerates was then analysed and the dependence of the fractional surface coverage by liquid on the overall binder/solids ratio was systematically obtained for different values of primary particle surface roughness. The obtained dependence was used to explain experimentally observed differences in the granulation kinetics of the four pharmaceutical excipients under otherwise identical conditions.     

Particle growth mechanisms in fluidised bed granulation—I: The effect of process variables

Two types of product granule have been identified in an experimental study of batch fluidised bed granulation; agglomerates which consist of two or more, and usually several, initial particles; and layered granules, which consist of single primary particles with dried feed material adhering to the surface. Increasing the excess fluidising gas velocity, in the range U-U_mf = 0.15-0.525 m s^?1, resulted in decreased particle growth rates and, depending upon the binder material, a change in product morphology from agglomerates to layered granules. Similar changes resulted from increasing the mean size of the starting material. Thus, a mechanism of particle growth is proposed in which the strength of inter-particle bridges and the extent of fluid drag and inertial forces on particles determine the equilibrium granule form and size. However, if the initial particles are porous this mechanism may break down since liquid may enter intra-particle pores and be unavailable for the initial formation of liquid bonds.     

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.     

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.     

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.     

Controlling the morphology of ceramic and composite powders obtained via spray drying – A review

Spray drying is one of the most convenient methods for drying suspensions (slurries) and for granulation of materials. Spray dried powders have good flowability, narrow size distribution and controllable morphology. Morphology of powder particles (also called granules or microspheres) strongly affects the use and handling of powders. This review discusses the latest research on parameters that affect morphology and size of granules obtained by spray drying: atomization parameters, properties of sprayed slurry, mass transfer etc. The formation of hollow and dense granules is extensively reviewed. Granule size is affected by droplet size, slurry concentration and initial particle size. Morphology mostly depends on size distribution of initial ceramic particles, agglomeration tendency in the slurry and mechanical strength of the shell of a granule during the drying process compared to capillary force of the suspension liquid. Polymer additives (e.g. binders and lubricants) change the properties of granule shell and the evaporation of moisture; thus, polymer additives significantly affect morphology.     

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.     

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.     

Origin of profound changes in powder properties during wetting and nucleation stages of high-shear wet granulation of microcrystalline cellulose

The aim of this work was to understand the evolution of powder tabletability and flowability during wetting and nucleation stages of high-shear wet granulation (HSWG). Microcrystalline cellulose (MCC) was granulated with water using a high-shear process. Granule morphology, surface texture, size, porosity, specific surface area, tabletability, and flowability were characterized. MCC granulated with 5% water showed no change in tabletability but significantly improved flowability, corresponding to smoother surfaces and lower surface area. From 5% to 25% water, tabletability decreased by 1/4 but flowability remained unchanged. Granule shape and porosity remained unchanged while surfaces were smoothened, leading to decreased surface area. From 25% to 35% water, MCC granules became more round. There was another sharp decrease in tabletability but powder flowability remained unchanged. Forty-five percent of water led to more particle rounding and commencement of nucleation, which only slightly impacted tabletability and flowability. From 0% to 45% water, granule size decreased slightly and could not explain the significant changes in powder tabletability and flowability. Deteriorated tabletability was instead caused by surface smoothing, granule densification, and granule rounding. Enhanced powder flowability was caused mostly by surface smoothing with granule rounding as a minor contributor.     

Nucleation and growth in fluidised hot melt granulation

Fluidised hot melt granulation (FHMG) is a novel technology for granulation process in pharmaceutical industry, which has distinct advantages over other commercial techniques. The aim of this research was to investigate granulation and the effect of process parameters that may affect FHMG process. In this work, ballotini beads were used as the model particles and Lutrol® F 68 Poloxamer 188 was used as meltable solid binder. In order to determine the granulation and nucleation mechanism in this co-melt FHMG system, several parameters were investigated, such as binder content, particle size of binder and particle size and hydrophobicity of ballotini. These parameters were correlated to granule size distribution, mean granule size and granule shape. Furthermore, these experimental investigations were designed so that the coalescence model could be applied to the co-melt FHMG system. The analysis indicated that the non-inertial regime extends over a relatively short time period of < 60s, however this accounts for the majority of the particle size increase in the entire process. A decrease in the extent of granulation was induced by increasing the hydrophobicity of the ballotini, which was ascribed to a decrease in capillary pressure of the system.     

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.