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.     

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.     

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.     

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.     

Top-spray fluid bed coating: Scale-up in terms of relative droplet size and drying force

Top-spray fluid bed coating scale-up experiments have been performed in three scales in order to test the validity of two parameters as possible scaling parameters: The drying force and the relative droplet size. The aim was to be able to reproduce the degree of agglomeration as well as the mechanical properties of the coated granules across scale. Two types of placebo enzyme granule cores were tested being non-porous glass ballotini cores (180–350 μm) and low porosity sodium sulphate cores (180–350 μm). Both types of core materials were coated with aqueous solutions of Na₂SO₄ using Dextrin as binder. Coating experiments were repeated for various drying force and relative droplet size values in three top-spray fluid bed scales being a small-scale (Type: GEA Aeromatic-Fielder Strea-1), medium-scale (Type: Niro MP-1) and large-scale (Type: GEA MP-2/3). The tendency of agglomeration was assessed in terms of particle size fractions larger than 425 μm determined by sieve analysis. Results indicated that the particle size distribution may be reproduced across scale with statistical valid precision by keeping the drying force and the relative droplet size constant across scale. It is also shown that none of the two parameters alone may be used for successful scaling. Morphology and microscope studies indicated that the coating layer is homogenous and has similar structures across scale only when both the drying force and the relative droplet size were fixed. Impact and attrition tests indicated that it is possible to produce granules with similar attrition and impact strength across scale and that the two types of mechanical properties are inversely related.     

The effect of wetting liquid droplet size on the growth of agglomerates during wet drum granulation

Results of investigation of the effect of wetting liquid droplet size on the growth of agglomerates during wet drum granulation of dolomite flour of selected grain-size composition which guaranteed geometrical similarity were discussed.

The process of granulation was carried out batch-wise in a drum granulator 0.5 m in diameter and 0.4 m long at rotational speed 0.33 s⁻¹ and constant volumetric drum filling degree =0.1. On the bed tumbling in the drum, the wetting liquid (distilled water) was supplied at a constant flow rate Q_w=12×10⁻³ m³/h. The size of wetting droplets was changed using various air flow rates through pneumatic spray nozzles in the range Q_a=1.0 to 3.0 m³/h and applying a sprinkler which supplied (drop-wise) the liquid uniformly along the entire drum length. In the whole experimental cycle, constant mean saturation degree of the feed equal to S=0.293 was used. Relationships determining the effect of wetting droplet size and particle size distribution of the raw material on the rate of agglomerate growth during drum granulation were developed.     

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.     

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.     

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.     

Electrical resistivity and thermopower of (La1−xSrx)MnO3 and (La1−xSrx)CoO3 at elevated temperatures

Electrical resistivity and Seebeck (S) measurements were performed on (La_1−xSr_x)MnO₃ (0.02x0.50) and (La_1−xSr_x)CoO₃ (0x0.15) in air up to 1073 K. (La_1−xSr_x)MnO₃ (x0.35) showed a metal-to-semiconductor transition; the transition temperature almost linearly increased from 250 to 390 K with increasing Sr content. The semiconductor phase above the transition temperature showed negative values of S. (La_1−xSr_x)CoO₃ (0x0.10) showed a semiconductor-to-metal transition at 500 K. Dominant carriers were holes for the samples of x0.02 above room temperature. LaCoO₃ showed large negative values of S below ca. 400 K, indicative of the electron conduction in the semiconductor phase.     

硝酸对溶胶-凝胶法制备AlOOH胶粒粒度的影响

为获得孔径可控的氧化铝滤膜,以异丙醇铝为原料,硝酸为胶溶剂,使用溶胶-凝胶法制备了AlOOH溶胶,并通过纳米粒度仪、Zeta电位等表征手段,研究了硝酸用量对AlOOH胶粒粒度及粒度分布的影响。结果表明,硝酸与异丙醇铝摩尔比R(n(HNO₃):n(Al(C₃H₇O₃)₃))为0.2~0.7时,随着R增大,AlOOH胶粒的平均粒径从66.69 nm(R=0.2)增大到138.80 nm(R=0.7),其粒度分布曲线的半高宽(FWHM)由144.62 nm增加到267.74 nm。AlOOH溶胶的粒度增大不是由颗粒团聚引起的,而是硝酸加入增大了异丙醇铝水解反应常数,使单位体积内能发生缩聚的中间产物增加,从而促进了AlOOH胶粒的生长。     

Breakage behaviour of enzyme granules in a repeated impact test

In many industries, handling or processing of relatively fragile particles takes place and predictions are required whether a significant proportion of the particles will be damaged. These processes have been designed and controlled solely on the basis of particle size and shape. Another parameter that needs to be introduced is particle strength. The stringent environmental laws demand improved particle mechanical quality, which has given rise to the need for a more accurate and fundamental particle strength measurement and its application in modelling and control of particulate processes. Particles need to show good resistance against static and dynamic loads.

The present paper deals with the study of breakage behaviour of different enzyme granules subjected to repeated impacts using a new instrument developed at the Delft University of Technology. The impact test involves bombarding the particles against a flat target repeatedly. The main feature of this new test is its ability to impact a large number of particles against a flat target repeatedly, and generate extremely reproducible results. Testing a large number of particles has the advantage of producing statistically correct results. The repeated impacts provide information on the breakage behaviour of the particles based on their history. In the new impact test enzyme granules can undergo very low impact velocities of the order of 5 m s⁻¹. These low impact velocities lead to attrition and chipping of the granules.

The current paper presents preliminary results on the breakage behaviour of the new impact test and its basic advantages over already existing tests. Furthermore, experiments were performed on enzyme granules, and the breakage mechanisms determined, depending on the change in size and shape of the particles.     

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     

The relationship between surface properties and binder performance in granulation

A crucial stage in the granulation of pharmaceutical products is the selection of the most appropriate formulation of drug/excipient/binder. The binder must not only wet both solid species sufficiently to form (liquid) bridges to hold them together so that granules can then proceed to grow, but also must distribute homogeneously amongst the particles in the mixture to ensure a uniform distribution of each species in the resultant granules.This paper reports a micro-scale study to elucidate the wetting behaviour of binder solutions on paracetamol crystals in order to provide a low-cost and effective selection procedure for the optimal binder solution. A previous study has determined the spreading behaviour of two commonly used binders, hydroxypropyl methylcellulose (HPMC) and polyvinylpyrrolidone (PVP), on paracetamol crystals. This study is focussed on the additional use of wetting agents, namely sodium lauryl sulphate and sodium docusate, to improve the wetting behaviour and distribution of the binders on the particles. The balance between binder adhesion (with the solid surfaces) and cohesion (for itself) in relation to granule growth is inferred from the interaction forces and the binder wetting behaviour.     

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.     

Mapping of regimes for the key processes in wet granulation: Foam vs. spray

The evaluation of foam and spray granulation mechanisms and their performances in achieving uniform liquid distribution in a high‐shear mixer‐granulator is presented. A regime map is presented to describe the granulation mechanisms for the foam and spray systems. Foam and spray granulation are shown to successfully create granules of well‐distributed moisture at the end of wet massing despite there was a deviation from the theoretical moisture content at the end of binder addition. In the wetting and nucleation regime, spray granulation involves drop penetration nucleation outside of the drop‐controlled regime, whereas foam granulation operates favorably in the mechanical dispersion regime. For foam granulation, mechanical dispersion produces more uniform granule‐size distributions below the overwetting limit. Spray granulation exhibits steady granule growth, whereas foam granulation shows induction granule growth followed by rapid granule growth. The regime map provides a basis to customize formulations and compare the different foam and spray granulation mechanisms. © 2013 American Institute of Chemical Engineers AIChE J, 59: 2328–2338, 2013     

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.     

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.     

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.     

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.