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.     

Time scale analysis for fluidized bed melt granulation III: Binder solidification rate

In series I and II of this study ( [Chua et al., 2010a] and [Chua et al., 2010b] ), we discussed the time scale of granule–granule collision, droplet–granule collision and droplet spreading in Fluidized Bed Melt Granulation (FBMG). In this third one, we consider the rate at which binder solidifies. Simple analytical solution, based on classical formulation for conduction across a semi-infinite slab, was used to obtain a generalized equation for binder solidification time. A multi-physics simulation package (Comsol) was used to predict the binder solidification time for various operating conditions usually considered in FBMG. The simulation results were validated with experimental temperature data obtained with a high speed infrared camera during solidification of ‘macroscopic’ (mm scale) droplets. For the range of microscopic droplet size and operating conditions considered for a FBMG process, the binder solidification time was found to fall approximately between 10⁻³ and 10⁻¹ s. This is the slowest compared to the other three major FBMG microscopic events discussed in this series (granule–granule collision, granule–droplet collision and droplet spreading).     

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.     

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     

Time scale analysis for fluidized bed melt granulation-II: Binder spreading rate

The spreading time of liquid binder droplet on the surface a primary particle is analyzed for Fluidized Bed Melt Granulation (FBMG). As discussed in the first paper of this series (Chua et al., in press) the droplet spreading rate has been identified as one of the important parameters affecting the probability of particles aggregation in FBMG. In this paper, the binder droplet spreading time has been estimated using Computational Fluid Dynamic modeling (CFD) based on Volume of Fluid approach (VOF). A simplified analytical solution has been developed and tested to explore its validity for predicting the spreading time. For the purpose of models validation, the droplet spreading evolution was recorded using a high speed video camera. Based on the validated model, a generalized correlative equation for binder spreading time is proposed. For the operating conditions considered here, the spreading time for Polyethylene Glycol (PEG1500) binder was found to fall within the range of 10⁻² to 10⁻⁵ s. The study also included a number of other common binders used in FBMG. The results obtained here will be further used in paper III, where the binder solidification rate is discussed.     

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.     

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.     

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.     

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.     

Progression of wet granulation in a twin screw extruder comparing two binder delivery methods

The two available wetting methods for twin screw granulation, namely foam delivery and liquid injection, were studied in detail by examining granule development along the screws as powder formulation and screw design were varied. Granulation profiles were determined by particle size analysis of samples along the screws collected using the “screw pullout” technique. Analysis of the particle size and porosity of produced granules revealed only minor differences between the two methods of wetting despite the larger dropsize of liquid injection compared to foam delivery. Excipients like microcrystalline cellulose or hydroxypropyl methyl cellulose with poor spreading properties, quantified by their specific penetration time and nucleation ratio, made the differences more apparent. The general similarities in granulation independent of wetting method implied that binder dispersion in an extruder was dominated by mechanical dispersion. Screw design (i.e., location of kneading block) had the dominant effect on the granulation process in this study. © 2014 American Institute of Chemical Engineers AIChE J, 61: 780–791, 2015     

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.     

Fabrication and characterization of eco-friendly functional wallpaper using nonmetallic minerals

The effects of amounts and particle size of nonmetallic minerals on the rheological behavior of the slurry and microstructure evolution of an eco-friendly functional wallpaper were investigated to optimize preparation parameters. Mixed binder system was used to prepare the wallpaper. Nonmetallic minerals such as TiO₂, CaCO₃, illite, pearl, and small amounts of graphite were mixed with the binder and then ball milled for 12 h. The particle size of the starting materials was controlled by the milling process, showing a significant reduction in particle size. Mixed slurries coated on base paper (substrate) were dried and pressed at 150 °C, forming seven layers. The reduced particle size increases the amounts of the nonmetallic minerals in the slurry, which causes an increase in viscosity and inhibits powder sedimentation. Despite the increase in the amounts of nonmetallic minerals, the nonmetallic minerals are homogeneously dispersed, as confirmed by microstructure and EDS mapping. The nonmetallic minerals provide the wallpaper with eco-friendly functions such as unit-infrared emission and antifungal ability, and improve the deodorization ratio and decrease the emission ratio of TVOC and HCHO compared with conventional wallpaper.     

焦粉与贫瘦煤配合制备铸造型焦的工艺研究

对以贫瘦煤和焦粉为原料、改性的焦油洗油残渣为黏结剂制备铸造型焦的工艺进行了研究,同时在实验室条件下对影响该工艺的主要因素如成型压力、配煤比、黏结剂用量及粉煤粒度等进行了探讨。结果表明,焦粉与贫瘦煤配合制备型焦的最佳工艺条件为:成型压力30 MPa、贫瘦煤质量分数75%～79%、焦粉质量分数6%～8%、黏结剂质量分数13%～15%、粉煤粒度<3 mm。按该工艺技术条件进行型焦生产,可得到优质的二级铸造型焦     

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.     

Foam and drop penetration kinetics into loosely packed powder beds

Foam granulation is a new liquid delivery method for wet granulation, where the liquid binder is delivered as an aqueous foam, rather than as an atomised spray to the powder bed. This paper reports for the first time the similarities and differences between wet granulation via foamed and sprayed binder addition methods.The kinetics of single foam and single drop (of HPC and HPMC solutions) penetrations into loosely packed powder beds (of glass ballotini and lactose powders) were studied. Specific penetration time (defined as penetration time per unit of binder mass) and nucleation ratio (defined as the ratio of nuclei granule mass to liquid binder mass) were compared between foam and drop nucleation methods. The impact of particle size and binder concentration on both parameters was also studied.The results indicate that the foamed binder addition method allows a greater mass of binder fluid to be absorbed into the particle bed and uses less liquid binder to nucleate the same number of gram of powder, which indicates improved nucleation efficiency compared to the drop addition method.     

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.     

Time scale analysis for fluidized bed melt granulation I: Granule–granule and granule–droplet collision rates

Fluidized bed spray granulators (FBMG) are widely used in the process industry for particle size growth; a desirable feature in many products, such as granulated food and medical tablets. In this paper, the first in a series of four discussing the rate of various microscopic events occurring in FBMG, theoretical analysis coupled with CFD simulations have been used to predict granule–granule and droplet–granule collision time scales. The granule–granule collision time scale was derived from principles of kinetic theory of granular flow (KTGF). For the droplet–granule collisions, two limiting models were derived; one is for the case of fast droplet velocity, where the granule velocity is considerable lower than that of the droplet (ballistic model) and another for the case where the droplet is traveling with a velocity similar to the velocity of the granules. The hydrodynamic parameters used in the solution of the above models were obtained from the CFD predictions for a typical spray fluidized bed system. The granule–granule collision rate within an identified spray zone was found to fall approximately within the range of 10⁻²–10⁻³ s, while the droplet–granule collision was found to be much faster, however, slowing rapidly (exponentially) when moving away from the spray nozzle tip. Such information, together with the time scale analysis of droplet solidification and spreading, discussed in part II and III of this study, are useful for probability analysis of the various event occurring during a granulation process, which then lead to be better qualitative and, in part IV, quantitative prediction of the aggregation rate.