High-shear Granulation Research Articles

Alkali Activation–Granulation of Hazardous Fluidized Bed Combustion Fly Ashes

The increasing amount of fluidized bed combustion (FBC) ash is putting pressure on researchers to invent novel methods for utilizing the ash. The low reactivity and heavy metal content constrict the use of FBC ash in the same way as coal ash from pulverized combustion. Four FBC fly ashes from different power plants were granulated with sodium silicate solution in order to produce artificial aggregates. All aggregates matched the definition for lightweight aggregate according to the EN 13055-1 standard. The strongest aggregates were produced from fly ashes that had the highest X-ray amorphous material content and the highest amount of selectively soluble SiO2 and Al2O3. However, the same leaching problem (leaching of the anionic species) as with coal fly ashes was observed with the FBC fly ashes. The simultaneous high shear granulation and alkali activation of FBC ashes showed that artificial aggregates with satisfactory physical properties, such as density and strength, can be obtained even from low-reactive fly ashes that contain heavy metals.

Analysis of Pseudo-polymorphism Conversion of Theophylline During Wet Granulation and Drying Processes and Effect of Binder on Dehydration and Amorphization

We conducted a time-course analysis of the pseudo-polymorphism conversion (i.e., the hydration and dehydration) of the xanthine-related compound theophylline during wet granulation and drying processes, using terahertz spectroscopy. We also investigated the amorphization mechanism of theophylline hydrate during a drying process in a vacuum using terahertz, mid-infrared (mid-IR), and near-infrared (near-IR) spectroscopy. After a high-shear granulation process using a mixture of theophylline, hydroxypropyl cellulose (HPC), and water, the terahertz spectrum (which was similar to that of an anhydride) was changed to a spectrum that was quite similar to that of a monohydrate. This result suggests that (1) an anhydride was converted to a monohydrate during the wet granulation process and (2) the spectrum was changed to the original waveform after the drying process with heat. This phenomenon indicates that the theophylline monohydrate was reconverted to an anhydride during the drying process. When wet granules were dried in a vacuum, the terahertz absorption lessened and finally disappeared with the passage of time, suggesting that the theophylline monohydrate in the granules was converted to an amorphous state. During the drying process with heat, the dehydration progressed temperature dependently regardless of the presence/absence of HPC. In addition, the reconversion from a monohydrate to an anhydride was completed concurrently with the completion of dehydration. The conversion rate of theophylline from a monohydrate to an amorphous form in granules (with HPC) was faster than that without HPC. This observation suggests that HPC promotes the amorphization of theophylline.

The structural modification and rehydration behaviours of milk protein isolate powders: The effect of granule growth in the high shear granulation process

The effects of granule growth in high shear granulation on the structures and rehydration abilities of milk protein powders were investigated. In this study, milk protein isolate, as a model powder, was agglomerated in a high shear granulator. The formed granules with different sizes were used to compare the densities, granule shapes and subsequently the wettability, dispersibility and solubility. It is found that the small nuclei showed the most compacted structures. Then the primary agglomerates coalesced to create irregular secondary structures with lower density and higher porosity until the final agglomerates formed. The densely packed structures allowed the granules to be more easily wetted by water. The large granules showed quicker release of materials into water until reaching a critical size, where more mechanical energy is potentially required for further granule break down. All the agglomerated MPI granules solubilised much more slowly than the standard MPI powder.

Representing spray zone with cross flow as a well-mixed compartment in a high shear granulator

The spray zone is an important region to control nucleation of granules in a high shear granulator. In this study, a spray zone with cross flow is quantified as a well-mixed compartment in a high shear granulator. Granulation kinetics is quantitatively derived at both particle-scale and spray zone-scale. Two spatial decay rates, DGSDR (droplet-granule spatial decay rate) ζDG and DPSDR (droplet-primary particle spatial decay rate) ζDP, which are functions of volume fraction and diameter of particulate species within the powder bed, are defined to simplify the deduction. It is concluded that in cross flow, explicit analytical results show that the droplet concentration is subject to exponential decay with depth which produces a numerically infinite depth of spray zone in a real penetration process. In a well-mixed spray zone, the depth of the spray zone is 4/(ζDG+ζDP) and π2/3(ζDG+ζDP) in cuboid and cylinder shape, respectively. The first-order droplet-based collision rates of, nucleation rate B0 and rewetting rate RW0 are uncorrelated with the flow pattern and shape of the spray zone. The second-order droplet-based collision rate, nucleated granule-granule collision rate RGG, is correlated with the mixing pattern. Finally, a real formulation case of a high shear granulation process is used to estimate the size of the spray zone. The results show that the spray zone is a thin layer at the powder bed surface. We present, for the first time, the spray zone as a well-mixed compartment. The granulation kinetics of a well-mixed spray zone could be integrated into a Population Balance Model (PBM), particularly to aid development of a distributed model for product quality prediction.

Dissolution and disintegration kinetics of high-active pharmaceutical granules produced at laboratory and manufacturing scale

The effect of process scale-up from 4 to 400-L high-shear granulator on the release kinetics of the active ingredient from pharmaceutical granules has been investigated. The dissolution and disintegration rates of the granules were measured simultaneously by the combination of UV/vis spectroscopy and static light scattering. The granule batches were found to consist of sub-populations with qualitatively different dissolution behavior: “weaker” granules that disintegrated during dissolution, and “stronger” granules that retained their size and from which the active ingredient was gradually leached. The existence of these sub-populations was attributed to non-uniform distribution of normal and shear forces that prevail in granulators of different size. This hypothesis was confirmed by preparing granules at increasing values of the Froude number at the 4-L scale, and observing a transition from the break-up dissolution mode to the leaching dissolution mode with increasing granule densification. The simultaneous observation of solute concentration and particle size distribution during granules dissolution proved to be a useful tool for the understanding of dissolution mechanisms and for identifying non-uniformities of process conditions that can occur during scale-up.

Impact of impeller design on high-shear wet granulation

In recent decades, three-blade impellers have been well-established in pharmaceutical high-shear granulation. However, three-blade impellers often require high rotation speeds to initiate product circulation and to provide proper granulation performance. With high rotation speeds much energy is introduced, which is indeed favourable for granule consolidation, however it comes with undesirable thermal stressing and increased granule breakage rates. In order to improve the mixing and granulation behaviour for a more robust process, a new impeller design has been developed that works at lower rotation speeds. The impeller consists of two blades with elongated side wings. In this work, the performance of both impeller designs is intensively studied. Firstly, the mixing behaviour is experimentally investigated in a laboratory mixer (10L in volume) and at production scale (600L). The mixing homogeneity of coloured sugar pellets is examined by the digital image analysis (DIA) for several impeller rotation speeds. In a second study, discrete element method (DEM) simulations are employed to obtain shear forces and force distributions at a single-particle scale. The third study is the comparison of granulation performance using a placebo formulation in the frame of a full factorial design of experiments (DoEs). The mixing investigations show that the two-blade impeller has great potential for scale-up. The DEM simulation confirms that both impeller types investigated apply almost the same shear forces on particles. The granulation performance in the DoE is proven to be better for the two-blade impeller. Larger drive torque is measured, product temperature increases significantly less with reduced thermal stressing, and larger granules are produced. Additionally, particle growth behaviour is more robust as it depends only on the amount of liquid added and is unaffected by the impeller's rotation speed.

Microstructure and Physical Properties of Lightweight Aggregates Produced by Alkali Activation-High Shear Granulation of FBC Recovered Fuel-Biofuel Fly Ash

The fluidized-bed combustion (FBC) is an environmentally-friendly way to combust biomass and waste materials. However, as a side-product large amount of ash is created which is difficult to utilize due to its low reactivity and high heavy metal content. Instead, most of the ash ends up in landfills so novel utilization methods are needed. In this study lightweight aggregates (LWAs) were produced from recovered fuel-biofuel fly ash taken from a F boiler by granulating the fly ash with sodium silicate in a high-shear granulator. Blast furnace slag and metakaolin were studied as co-binders. Physical, chemical, and microstructural characterization was conducted for the precursors and LWAs. The crushing strength varied between 4.6 and 14.6 MPa. Addition of co-binders increased strength and produced denser structure. The loose bulk density was <1.08 g/cm3 and dry particle density was <1.77 g/cm3 for all prepared granules so they met the definition of lightweight aggregate in standard SFS-EN 13055-1. LWAs contained X-ray-amorphous material, indicating the formation of aluminosilicates and some crystalline phases, which were derived from the fly ash. This study presents a method of producing LWAs from fly ash that have physical properties comparable to LWAs manufactured by conventional methods without the need for high-temperature sintering or the usage of cement.

On continuum modelling of dense inelastic granular flows of relevance for high shear granulation

This article investigates a number of possible formulations of a continuum description for modelling dense inelastic granular flows. The revised Enskog theory (RET) for expressing the granular temperature and formulation of transport coefficients has been used within the continuum framework. The framework assumes particles as inelastic spheres and can describe a granular system at a wide range of volume fractions. The transport coefficients depend on the volume fraction through a modified expression for the radial distribution function. The proposed radial distribution function is based on previous studies on the behaviour of the shear viscosity in which an earlier divergence of the latter compared to the other transport coefficients has been demonstrated for sheared dense granular systems. Our results show that the newly developed radial distribution function maintains the ability of RET to predict the occurrence of instabilities in a homogeneous cooling granular gas. The introduced function also improves predictions for the velocity and volume fraction profiles in a Couette cell dense shear flow. Thus the proposed expression shows promising features in terms of improving predictions for volume fractions relevant in high shear granulators. We have also observed that a different expression may be needed for the densest regions.

Lightweight aggregates produced by granulation of peat-wood fly ash with alkali activator

This study presents a new method to produce lightweight aggregates (LWAs) by granulating peat-wood ash using alkali activators. Peat-wood ash was granulated with potassium silicate and sodium aluminate in a high-shear granulator to produce spherical granules. Blast furnace slag, coal fly ash and metakaolin were studied as co-binders. A suitable liquid/solid ratio, granulation growth type, microstructure, strength, and crystal structure of granules have been determined. The granulation proceeded by induction-type growth behaviour and suitable liquid/solid ratio was between 0.34 and 0.43. In the BSE images it was observed that the precursor particles were embedded in a dense alumino-silicate matrix. The X-ray diffraction analysis supported the success of the alkali activation. All co-binders increased the strength of the granules, but the blast furnace slag produced the strongest granules. The study shows that by simultaneous granulation and alkali activation it is possible to increase the utilisation of ash and produce valuable products.

Blade-granule bed stress in a cylindrical high shear granulator: Further characterisation using DEM

In high shear granulation, the rotating impeller blades impart forces on the granules which are subsequently transmitted throughout the bed through inter-granule collisions. These affect the granule growth behaviour in several ways — the granules could deform, consolidate and/or break under stress. In this paper, the blade-granule bed normal stress in a cylindrical, vertical axis high shear granulator is characterised using Discrete Element Method (DEM) simulations. The simulations are compared and validated with the measured blade-bed stress and bed surface velocities from our previous studies [1,2]. The blade-bed stresses were previously measured using a novel, custom-built telemetric impeller pressure sensor system. Following experimental validation for impeller speeds up to 350rpm, higher impeller speeds up to 700rpm or Fr=3.88 are simulated to include flow regimes that can occur in most commercial granulators. Parameter study of particle properties, impeller geometries and granulator scales is also carried out. In our previous work, a blade-bed stress equation based on the blade and granule bed inertial forces with a correction factor, B1=K11vrel to account for bed fluidisation with increasing impeller speed, was proposed and validated with a range of dry granules [1]. Here, an improved correction factor, B2=K21Frrel0.52hwD0.3θ−0.5 is introduced to account for different granulator scales, blade widths and blade angles, with a fitted constant K2.

Tablets and minitablets prepared from spray-dried SMEDDS containing naproxen

The purpose of this study was to compare different solidification techniques (i.e., adsorption technique, spray-drying process, high-shear granulation, fluid-bed granulation) for preparing solid SMEDDS powders by using solid carriers identified as appropriate and to produce a single (tablets) or multiunit (minitablets) solid dosage form based on prepared solid SMEDDS loaded with naproxen in a dissolved (6% w/w) or supersaturated (18% w/w) state. Among the solidification techniques and carriers tested, the powders produced using the spray-drying process and maltodextrin (MD) as a carrier exhibited the best self-microemulsifying properties, comparable with liquid SMEDDS. Furthermore, DoE (Design of Experiments) showed that pressure at the nozzle and pump speed (regulating feed flow rate) applied during spray drying had a major and significant influence on self-microemulsifying properties (mean droplet size and PDI) of the solid SMEDDS prepared. Furthermore, it was shown that compression of solid SMEDDS into (mini) tablets influences its self-microemulsifying properties in a negative direction. This resulted in lowering the dissolution profile of naproxen from tablets and minitablets in comparison with liquid and solid SMEDDS. However, all compressed SMEDDS formulations still had considerable influence on the dissolution profile and solubility enhancement of naproxen.

Dynamics of the dry premixing stage of a hydrophobic formulation and potential implications on the wet granulation process

Wet granulation processes typically start with a dry premixing stage in which the objective is to homogenize and prepare the powder materials for further granulation stages. This work was aimed at studying the influence of premixing conditions on the wettability of formulations that contain hydrophobic components and the potential implications on early granulation stages.A binary lactose-based formulation was chosen as the model system and magnesium stearate (MgSt) as the hydrophobic ingredient. The formulations were processed in a laboratory-scale high shear granulator according to a factorial experimental design to evaluate the effect of MgSt concentrations and applied premixing shear strains on the hydrophobicity of the formulation. The experimental design included five concentrations of MgSt (from 0% to 3% w/w) and three levels of applied shear strain ranging from 450 to 1800 blade passes (bp). A modified Washburn method was implemented to determine the hydrophobicity of blend samples after the premixing and hyperspectral images, collected with a NIR Chemical Imaging (NIR-CI), were used to assess the spatial dispersion of MgSt.Statistical results demonstrated that both studied factors increase the hydrophobicity of the formulation and suggest that the magnitude of this effect depends on the mixing mechanism of the hydrophobic ingredient. The findings can be of interest in the formulation and process design to modify the wettability of hydrophobic blends before granulation.

Continuum modeling of multi-regime particle flows in high-shear mixing

This article compares and evaluates different approaches for continuum modeling in high shear mixers covering the full range of the solid volume fraction. High shear mixing is considered as the first stage in industrial high shear granulation processes. The study is focused on and compared with experimental data for a MiPro mixer. Different granular flow regimes are located in different regions of the system and suitable models are applied for each region. Accordingly, the dilute regions are modeled with the standard kinetic theory of granular flow (KTGF) model. The dense regions are modeled using a framework developed by Jop et al. [1] which treats dense flows with pseudo-plastic rheology. The transitional region from dilute to dense is either modeled with KTGF or by using modifications to the transport coefficients that describe the solid phase stresses as proposed by Bocquet et al. [2] (the viscosity divergence model). The results using the latter model show significant improvement compared to similar studies in the past. A very good agreement between simulation and experiments is achieved. It should be noted that the proposed modeling frameworks are formulated for the full range of volume fractions and can be applied to various particulate flows. To sum up, this research provides a better description of multi-regime granular flows, particularly the transitional behavior in the intermediate range of volume fractions.

The effects of improper mixing and preferential wetting of active and excipient ingredients on content uniformity in high shear wet granulation

This work focuses on the content non-homogeneity in granules across size classes in a high shear wet granulation process as a result of powder segregation during dry mixing coupled with preferential wettability of one of the ingredients with the binder fluid.A two component API-excipient system comprised of acetaminophen (APAP) and microcrystalline cellulose PH-101 (MCC) is investigated in a high shear granulation environment for content uniformity of the granules with respect to APAP. It was found that the fine granules were super potent while the coarse granules were starved of the APAP. This was attributed to a dual cause of powder segregation during dry mixing and superior wettability of the MCC compared to APAP. Post the dry mixing stage, the top layer of the powder bed is found to be sub-potent due to percolation of the smaller APAP particles to the bottom of the bed as they find spaces between the larger MCC particles. Thus, a drop of the binder fluid which falls on the bed is likely to be surrounded by MCC particles, which give them a higher chance of being incorporated in the nucleus. Moreover, MCC being the superior wetting of the two ingredients, also preferentially attaches itself to the growing granules. The granules are thus starved of the APAP leading to disparity in content across size classes.Lastly, the effect of content non-uniformity was categorically quantified on the rate of active release. It was observed that content non-uniformity results in a lack of predictability and consequently control, on the rate of release of the active ingredient from the granules. This work highlights the need for qualitative understanding and quantitative analysis of factors that contribute to the occurrence of granule content non-uniformity, if one is to enable inherently robust pharmaceutical product design.

Comparison of a continuous ring layer wet granulation process with batch high shear and fluidized bed granulation processes

The traditional batch wet granulation processes encounter several challenges, such as problems in the scale-up step, batch-to-batch variability together with the multivariate and difficult to control nature of the process. A continuous wet granulation technique could be a possible solution for the scale-up problem, offering adjustable production volumes with the same equipment. In this study, a continuous ring layer wet granulation process (factors: shaft speed and binder flow rate) was compared with two batch granulation processes: high shear (factors: impeller speed and chopper speed) and fluidized bed (factors: inlet air temperature during granulation and binder flow rate) with formulations consisting of paracetamol, microcrystalline cellulose and polyvinylpyrrolidone. A quantitative PLS model was formed to assess the effects of the process parameters on the granule properties (the mean granule size and flowability). In the case of the continuous ring layer granulation process, the mean granule size increased linearly with increasing shaft speed and binder flow rate, and the granules resembled morphologically more the granules produced by the high shear granulation than by the fluidized bed granulation. It is notable that the continuous ring layer granulation process was easier to control than the fluidized bed and high shear granulation processes due to the linear responses towards changes in operation conditions. Both types of tablets, compressed either from the granules produced by the continuous ring layer granulation or by the high shear granulation, achieved an immediate drug release. In summary, the continuous ring layer granulation process was demonstrated to represent a promising tool for the production of pharmaceutical granules.

A multi-compartment population balance model for high shear granulation

This work extends the granulation model published by Braumann et al. (2007) to include multiple compartments in order to account for mixture heterogeneity encountered in powder mixing processes. A stochastic weighted algorithm is adapted to solve the granulation model which includes simultaneous coalescence and breakage. Then, a new numerical method to solve stochastic reactor networks is devised. The numerical behaviour of the adapted stochastic weighted algorithm is compared against the existing direct simulation algorithm. Lastly, the performance of the new compartmental model is then investigated by comparing the predicted particle size distribution against an experimentally measured size distribution. It is found that the adapted stochastic weighted algorithm exhibits superior performance compared to the direct simulation algorithm and the multi-compartment model produces results with better agreement with the experimental results compared to the original single-compartment model.

Characterisation of lactose powder and granules for multivariate wet granulation modelling

Granulation and size enlargement of particulate materials is a complex process with broad application in industry. For better understanding of the governing mechanisms, we aim to develop a multivariate population balance model to describe granulation. For meaningful model design we require physical characteristics of real materials undergoing granulation. In this work, α-lactose monohydrate powder was investigated as a representative substance due to its broad use in the pharmaceutical industry for tablets. Powder and granules resulting from a high-shear granulation process are characterized with respect to size, shape, porosity and strength using various analytical methods. Particle size distributions are obtained by static image analysis, laser scattering and sieving. Granule porosities are determined using μCT and mercury intrusion porosimetry. Lactose granules show absolute porosities increasing from 30% to 40% along the size classes. The μCT derived visual information of larger granules shows internal pore structures with denser cores and porous shell parts. AFM, SEM and μCT are used for surface characterisation, yielding a maximum value for model particle roughness up to 0.7μm. The strength of the product granules measured via uniaxial compression testing follows a logarithmic decrease with size from 1.2 to 0.2MPa. The multivariate data set was then used for model performance analysis and parameter fitting. The size and porosity prediction performance of the computer model could be improved using the newly available data. The rate of coagulation was found to be the most dominant simulation parameter. Comparison with the experiment revealed limitations, for example in PSD shape predictions.

Compartment based population balance modeling of a high shear wet granulation process using data analytics

Population balance models (PBMs) are used extensively to model various particulate processes such as granulation. A high shear granulation process is often assumed to be well mixed and is represented using a single compartment PBM. However, the inhomogeneities existent within the granulator are not effectively addressed using the single PBM representation for the process. Thus, a multi-compartment model is needed to account for the inhomogeneities within the granulator. In this study, the multiple compartments are identified from data mining methods (e.g. clustering) and their average values are thereby obtained. Using regression analysis, a general expression is obtained for the size of the compartments and the average values for different operating conditions. These expressions are then used within a multi-compartment PBM formulation to describe the process dynamics. Validation for the regression expressions also showed good agreement against the varying operating conditions. Also, the multi-compartment model is able to account for mechanical dispersion behaviors that is typically associated with a high-shear process. This study shows that the assumption of a single compartment for a high-shear granulator is often inadequate and the multi-compartment based approach can offer a better physical representation of the process.

Role of Main Physical Properties in Granule Yield of &lt;i&gt;Andrographis &lt;/i&gt;Extract Mixtures in the High Shear Granulation

The purpose of this study was to establish a relationship between the physical properties of powder and its behavior during high shear granulation. Andrographis extract was utilized as a model drug and microcrystalline cellulose (MCC) and soluble starch were selected as excipients. The extract was mixed with different excipient with the ratio 1:0.5, 1:1, 1:2 by weigh, respectively. The granules were prepared by using high shear granulation. The result of HSG was evaluated by monitoring such responses as granule yield, the ratio of Lumps and Fine. The effect of physical properties on granulation behavior was analyzed through stepwise regression. The results showed that angle of repose, moisture content, pore volume, and density were the main factors linked to the granulation. The main physical properties of extract powder were the important factors for high shear granulation, and statistical analysis identified the trends that interpreted in light of physical models of high shear granulation.

Mechanistic Basis for the Role of Binary Mixtures Flowability and Related Factors in the Processability and Performance of High Shear and Extrusion Granulation

The purpose of this study was to establish a relationship between the raw material properties and granulation behavior in extrusion wet granulation (WEG) and high shear wet granulation (HSWG). moisture content (MC), Carr index (CI), angle of repose (AOR), and mean size distribution (MSD) of binary mixtures were examined. The effect of these variables on the processibility and performance of the granulations was evaluated by monitoring such response along with granule growth. The prominent involved findings were that moisture content and Carr index had significant impacts on granule growth, followed by particle size, while angle of repose showed a minimal correlation. These results were physically interpreted by the previous wet granulation theories. The granule growth was linked to the properties of primary mixture. And in the process of high shear and extrusion granulation process, flowability showed an important effect on critical attributes of final product. Understanding the impact of primary properties of raw materials will be useful in mapping a new material to predict its performance in these two different granulation methods.