High Shear Mixer Granulator Research Articles

Granular flow fields in vertical high shear mixer granulators

AbstractThis study aims to elucidate some basic features of the granular flow field in a conical frustum‐shaped vertical high shear mixer granulator by using the Positron Emission Particle Tracking technique. The tested range of particle size (d50 = 23, 43, and 60 μm) and shape as quantified by the angle of internal friction (26° and 38°) have a negligible effect on the granular flow field in the mixer granulator. Density of particle imposes great influence on the flow field where reducing density from 2600 to 700 kg m−3 increase the tangential velocity by 1.95 time. Decreasing fill level from 3.5 to 0.9 kg increases the tangential velocity by a factor of 1.19. No obvious discrepancy in the solids motion is seen between machines of 1 and 5 L capacity and both machines have similar mixing and dispersion with constant tip speed criterion. © 2007 American Institute of Chemical Engineers AIChE J, 2008

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.

Effect of scale of operation on granule strength in high shear granulators

Results of a study on the influence of operation scale and impeller speed of high shear mixer granulators on the strength of granlues are reported in this paper. Calcium carbonate particles have been granulated in four scales of a geometrically similar high shear granulator (Cyclomix) with 1, 5, 50 and 250 L capacities. For the smallest scale, the effect of a small deviation from geometric similarity was also investigated. An aqueous solution of polyethylene glycol was used as the binder. Three scaling rules of constant tip speed, constant shear stress and constant Froude number have been used to determine the impeller speed for the different scales of the granulators. The granules produced in these experiments have been dried and tested for strength using side crushing test method. The data have then been analysed and compared. Operation of granulators according to the constant tip speed rule produces granules with a similar strength for all four scales, followed by a similar trend for the constant shear stress rule, albeit to the less extent. The constant Froude number rule produces a heterogeneous strength distribution and is not a suitable criterion for scaling-up of high shear granulators. The distribution of granule strength has been fitted to the normal, log-normal and Weibull distributions. Weibull distribution fits the data well for the constant tip speed operations.

High shear mixing granulation of ibuprofen and β-cyclodextrin: Effects of process variables on ibuprofen dissolution

The aims of the study were to evaluate the effect of high shear mixer (HSM) granulation process parameters and scale-up on wet mass consistency and granulation characteristics. A mixer torque rheometer (MTR) was employed to evaluate the granulating solvents used (water, isopropanol, and 1:1 vol/vol mixture of both) based on the wet mass consistency. Gral 25 and mini-HSM were used for the granulation. The MTR study showed that the water significantly enhanced the beta-cyclodextrin (beta CD) binding tendency and the strength of liquid bridges formed between the particles, whereas the isopropanol/water mixture yielded more suitable agglomerates. Mini-HSM granulation with the isopropanol/water mixture (1:1 vol/vol) showed a reduction in the extent of torque value rise by increasing the impeller speed as a result of more breakdown of agglomerates than coalescence. In contrast, increasing the impeller speed of the Gral 25 resulted in higher torque readings, larger granule size, and consequently, slower dissolution. This was due to a remarkable rise in temperature during Gral granulation that reduced the isopropanol/water ratio in the granulating solvent as a result of evaporation and consequently increased the beta CD binding strength. In general, the HSM granulation retarded ibuprofen dissolution compared with the physical mixture because of densification and agglomeration. However, a successful HSM granulation scale-up was not achieved due to the difference in the solvent mixture's effect from 1 scale to the other.

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 (CaCO 3; 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.

Solids motion of calcium carbonate particles in a high shear mixer granulator: A comparison between dry and wet conditions

An experimental study has been carried out on the solids motion in a conical frustum-shaped vertical high shear mixer granulator by using the positron emission particle tracking (PEPT) technique. The mixer granulator has a vertical shaft, to which four sets of impellers are attached at different elevations. The shaft is operated at 3.9 Hz, 4.9 Hz and 5.8 Hz, which corresponded to the top impeller tip speed of 2.8, 3.5 and 4.1 m/s. The motion of calcium carbonate particles with and without a liquid binder is evaluated. Particles are observed to circulate in both the horizontal and vertical directions. The macroscopic solids circulation in the vertical direction reduces after adding the binder. There is a dominant solids motion in the tangential direction under both the dry and wet conditions with the maximum tangential velocity of 2.2 to 12.6 times that of the maximum axial and radial velocities. No obvious change is observed in the average axial and radial velocities when the impeller speed is changed under both dry and wet conditions, while the ratio of the maximum tangential velocity to the tip speed decreases with increasing impeller speed, suggesting a velocity-dependent behaviour. The three velocity components decrease in the magnitude after adding the binder at all tested agitation speeds except for the tangential velocity at a shaft speed of 3.9 Hz. The main difference between the dry and wet operations is that the decrease of tangential velocity in the near-wall zone under the dry condition is not observed under the wet condition.

Modeling of agglomerate behavior under shear deformation: effect of velocity field of a high shear mixer granulator on the structure of agglomerates

Abstract -High shear mixer granulators are typically found in pharmaceutical and detergent industries, and are capable of reducing processing time and producing agglomerates with high strength and density. Generally, several granulation scaling-up stages are involved before reaching the production level. This is conducted to exert better understanding, control and optimization at the smaller scales before proceeding to the larger scales in terms of geometric, kinematic and/or dynamic similarities. During granulation scaling-up stages, the mechanics of particle interactions and the prevailing level of compressive stresses and strains within the granulator are affected by the variation in hydrodynamics of the granulator as a result of different scales. This in turn affects the final structure of the agglomerates. In this paper we analyze the effect of velocity field of two different scales of high shear mixer granulator (1 and 5 l) on the structure of the evolved agglomerates. The study is based on computer simulation using the discrete element method (DEM). A single agglomerate is generated using DEM computer code and is placed in a bed of primary particles. A velocity field is then superimposed on the surrounding particles. This velocity field corresponds to that obtained experimentally from a separate study using Positron Emission Particle Tracking analysis on 1- and 5-l granulators which were scaled up based on the condition of constant shear stress. The results show that when the velocity profile of the 1-l granulator is used the agglomerate becomes more elongated and it has a smaller packing fraction. Therefore the agglomerate would be weaker.

Influence of Metronidazole Particle Properties on Granules Prepared in a High-Shear Mixer-Granulator

ABSTRACTMetronidazole is a good example of high-dose drug substance with poor granulating and tableting properties. Tablets are generally produced by liquid granulation; however, the technological process failure is quite frequent. In order to verify how the metronidazole particle characteristics can influence granule properties, three metronidazole batches differing for crystal habit, mean particle size, BET surface area and wettability were selected, primarily designed according to their different elongation ratio: needle-shaped, stick-shaped, and isodimensional. In the presence of lactose monohydrate and pregelatinized maize starch, respectively as diluent and binder, they were included in a formula for wet granulation in a high-shear mixer-granulator. In order to render the process comparable as far as possible, all parameters and experimental conditions were maintained constant. Four granule batches were obtained: granules from placebo (G-placebo), granules from needle-shaped crystals (G-needle-shaped), granules from stick-shaped crystals (G-stick-shaped), and granules from isodimensional crystals (G-isodimensional). Different granule properties were considered, in particular concerning porosity, friability, loss on drying (LOD), and flowability. In order to study their tabletability and compressibility, the different granules obtained were then compressed in a rotary press. The best tabletability was obtained with the isodimensional batch, while the poorest was exhibited by the stick-shaped one. Differences in tabletability are in good accordance with compressibility results: to a better tabletability corresponds an important granule ability to undergo a volume reduction as a result of an applied pressure. In particular, it was proposed that the greatest compressibility of the G-isodimensional must be related to the greatest granule porosity percentage.

Solids motion in a conical frustum-shaped high shear mixer granulator

An experimental study has been carried out on the solids motion in a conical frustum-shaped vertical high shear mixer granulator by using the positron emission particle tracking (PEPT) technique. The mixer granulator has a vertical shaft attached to which are 4 sets of impellers at different elevations. The shaft is operated at 3, 6 and 12 Hz, which correspond to the top impeller tip speed of 2.1, 4.1 and 8.3 m/s. Particles are observed to circulate in both the horizontal and vertical directions. The period of horizontal circulation is short and is in the order of seconds, whereas that of the vertical circulation takes tens of seconds and often consists of lots of higher frequency fluctuations. There is a dominant solids motion in the tangential direction at all impeller speeds with the maximum tangential velocity 2.2–5.3 times that of the maximum axial and radial velocities. The maximum values of the three velocity components increase with increasing impeller speed, but the ratios of the maximum velocity to the tip speed decreases with increasing impeller speed, suggesting a rate-dependent behaviour. The particle flow pattern shows the presence of swirling flows at a position depending on the impeller speed. The results also suggest the existence of an optimal impeller speed that gives the best macroscopic mixing characterised by the vertical solids circulation.

Wet granulation in a batch high shear mixer

This study deals with the wet granulation in a high shear mixer. The experimental apparatus is a laboratory scale ”Lödige” granulator, with a maximum volume of 20 l, equipped with a chopper and a pneumatic spraying system. The main objective of the study is to point out the effect of physico-chemical properties and operating conditions on the growth mechanisms and kinetics in this type of granulation device. Two kinds of alumina with different particle size distributions (alumina SH100 and alumina SH30) were granulated using various Newtonian liquids having different surface tension, viscosity, binder concentration, density, etc. (water, aqueous solutions of polyethyleneglycol or polyvinyl alcohol). Experimental results showed that the granulation process generally proceeds through three distinct growth regimes independent of the nature of the powder, the binder liquid or the operating conditions. However, the transition between different regimes depends on the physico-chemical properties of the solids and liquids, on operating conditions and on the experimental procedure. For the alumina powder used in this study the transition occurs when a degree of liquid saturation of about 68% is reached.

Empirical to mechanistic modelling in high shear granulation

This paper gives an overview of the different models available for granulation in high shear mixers with a focus on applicability in the pharmaceutical industry. Three examples of applications are given. The examples indicate the potential of mechanistically based models for scale-up and the importance of understanding the dynamics of the granulation process. The first two examples show how the impeller torque can be modelled and predicted in the dry and wet mixing phases of the high shear granulation process, using a solid mechanics and a hierarchical multivariate model, respectively. In the third application the particle size distribution is modelled using population balances and it is shown how different operating conditions can be included in the coalescence kernel to describe the granule growth.

Scale-Up of High Shear Granulation Based on Agitation Power

Scale-up of wet granulation in a vertical high shear mixer was conducted. Pharmaceutical excipient mixtures composed of lactose, cornstarch and micro-crystalline cellulose, and hydroxypropylecellulose as a binder were mixed together and then granulated with purified water under various operating conditions and vessel scales. Torque of agitator shaft was continuously measured and then agitation power per unit vessel volume was calculated. The agitation power per unit vessel volume showed a good correlation with physical properties of obtained granules, such as mass median diameter, strength and compressibility. This implied that the scale-up characteristics could be well analyzed by means of the agitation power per unit vessel volume. In addition, the effects of agitator tip speed and Froude number on the agitation power per unit vessel volume were investigated. The results showed that the agitation power per unit vessel volume was well characterized by the tip speed rather than the Froude number. This meant that the granule growth mainly progressed by the shear stress from the agitator blade. Dynamic characteristics of high shear granulation were also discussed here.

Scale-Up of High Shear Granulation Based on the Internal Stress Measurement

Scale-up of wet granulation in a vertical high shear mixer was conducted. Pharmaceutical excipient powders composed of lactose, cornstarch and micro-crystallinecellulose, and hydroxypropylcellulose as a binder were mixed together and then granulated with purified water under various operating conditions and vessel scales. A novel internal stress measurement system was developed and stress of normal and tangential directions that granules received from the agitator blade during the granulation was continuously measured. The results indicated that granules received stress mainly from the tangential direction, which also showed the largest value near at the vessel wall. The effects of the agitator tip speed and the centrifugal acceleration on the measured stress was investigated. It was found that the tip speed of the agitator blade could be the main factor for the granule growth. The physical properties such as strength, size distribution and compressibility of granules prepared by changing the operating conditions and the vessel scales were evaluated and the scale-up characteristics of high shear granulation were investigated experimentally. The results showed that these physical properties had linear correlations with the tip speed. It was finally concluded that the scale-up of high shear granulation could be well conducted by means of the tip speed of the agitator blade.

Self-emulsifying pellets prepared by wet granulation in high-shear mixer: influence of formulation variables and preliminary study on the in vitro absorption

A method of producing self-emulsifying pellets by wet granulation of powder mixture composed of microcrystalline cellulose, lactose and nimesulide as model drug with a mixture containing mono- and di-glycerides, polisorbate 80 and water, in a 10-l high shear mixer has been investigated. The effects of the formulation variables on pellets characteristics were evaluated by mixtures experimental design and by a polynomial model, in order to describe the phenomenon, to verify eventual interactions among components of the mixture and to investigate the feasibility of scaling-up. After determination of size distribution, the pellets were characterised by scanning electron microscopy, dissolution and disintegration tests, and by in vitro absorption test Such an approach, applied to the development of a self-emulsifying system for nimesulide as poorly water-soluble model drug, resulted in different formulations with improved drug solubility and permeability characteristics. The data demonstrate that pellets composed of oil to surfactant ratio of 1:4 (w/w) presented improvement in performance in permeation experiments.

Quantifying liquid coverage and powder flux in high-shear granulators

A key aspect to high-shear wet granulation is the coverage of binding fluid as it first comes into contact with the surface of a powder bed. Quantifying the parameters that determine liquid coverage with respect to powder flux could improve the ability to rationally characterize and scale wet granulation processes. In this work, the surface velocity of a powder bed was measured during wet granulation in high-shear mixers (Aeromatic-Fielder) ranging from lab (25 l) to pilot (300 l) scale. High-speed video analysis revealed that surface velocity is strongly dependent on impeller speed, mixer scale, fill level, and extent of granulation. Surface velocity results were coupled with the dimensionless spray flux concept reported by Litster et al. [Powder Technol. 114 (2001) 32] to quantify liquid coverage relative to powder flux for operating conditions commonly used to granulate pharmaceutical powder blends. Dimensionless spray flux calculations suggest that granule nucleation in high-shear mixers does not take place in the drop-controlled regime. The density of spray drops at the surface of the powder bed is sufficiently high to cause a significant amount of drop overlap, thereby hindering the formation of nuclei from individual spray drops. Dimensionless spray flux calculations predict an approximate 2.5-fold increase in liquid coverage upon scaling a standard high-shear wet granulation process from 25 to 300 l. The use of multiple spray nozzles could potentially minimize differences in liquid coverage between scales. Practical limitations of the dimensionless spray flux concept are discussed and an empirically modified version of the original spray flux equation is presented.

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.

Growth regime map for liquid-bound granules: further development and experimental validation

An attempt was made to quantify the boundaries and validate the granule growth regime map for liquid-bound granules recently proposed by Iveson and Litster (AIChE J. 44 (1998) 1510). This regime map postulates that the type of granule growth behaviour is a function of only two dimensionless groups: the amount of granule deformation during collision (characterised by a Stokes deformation number, St def) and the maximum granule pore saturation, s max. The results of experiments performed with a range of materials (glass ballotini, iron ore fines, copper chalcopyrite powder and a sodium sulphate and cellulose mixture) using both drum and high shear mixer granulators were examined. The drum granulation results gave good agreement with the proposed regime map. The boundary between crumb and steady growth occurs at St def of order 0.1 and the boundary between steady and induction growth occurs at St def of order 0.001. The nucleation only boundary occurs at pore saturations that increase from 70% to 80% with decreasing St def. However, the high shear mixer results all had St def numbers which were too large. This is most likely to be because the chopper tip-speed is an over-estimate of the average impact velocity granules experience and possibly also due to the dynamic yield strength of the materials being significantly greater than the yield strengths measured at low strain rates. Hence, the map is only a useful tool for comparing the granulation behaviour of different materials in the same device. Until we have a better understanding of the flow patterns and impact velocities in granulators, it cannot be used to compare different types of equipment. Theoretical considerations also revealed that several of the regime boundaries are also functions of additional parameters not explicitly contained on the map, such as binder viscosity.

撹はん型造粒機における双峰型造粒特性の数学的表現

Features of agglomeration with various binder contents were investigated using a high-shear mixer granulator. The bimodal size distribution of product was successfully expressed by a weighted sum of two log-normal distributions. The two peaks were seemingly caused by different agglomeration mechanisms, i. e., the layering of particles which is a prevailing mechanism at low binder content, and the secondary agglomeration of agglomerates which becomes dominant with increasing binder content.

Applicability of a scale-up methodology for wet granulation processes in Collette Gral high shear mixer-granulators

This study investigates the extension of a scale-up methodology based on dimensionless power relationships, to a series of vertical mixer-granulators in which the bowl is removable, i.e. both impeller and chopper blades are mounted on top-driven vertical shafts positioned through the lid. Granulation runs were carried out in several bowl sizes belonging to the series of Collette Gral mixer–granulators, ranging from 8 to 600 l capacities. It was shown that under certain conditions a common scale-up master curve could be drawn from the data gathered for each bowl, thus permitting the use of such a curve for the determination of mixer–granulator power consumption at a defined granulation end-point. The results also helped to clarify the concept of similitude, both geometrical and dynamic, which is implied in the methodology. The importance of wall slippage (as promoted by the insertion of a PTFE lining into the bowls) and batch size are illustrated.

Agglomeration behaviour of powders in a Lödige mixer granulator

Abstract The agglomeration of a powder mixture which is commonly used to make granules containing enzyme was examined in a high shear mixer granulator of the Lodige type. The validity and extension of current granulation theory for practical high shear granulation was investigated. The effects of process variables such as the amount of binder liquid, choppe impact, binder viscosity and temperature on the granulation were in agreement with the theory. The onset of the different granulation mechanisms (nucleation, compaction, coalescence, and crushing and layering) was demonstrated.