Binder Spray Rate Research Articles

Influence of multi-factor interactions on particle growth during top-spray fluidized bed agglomeration

Considering the strong dependence of agglomerate characteristics on various operating parameters, this study employs the control variable methodology (CVM) and response surface methodology (RSM) to investigate the influence of multi-factor interactions on particle growth during top-spray fluidized bed agglomeration. First, CVM is conducted to assess the effects of individual operating parameters on the agglomerate properties, such as mean particle size, relative width, and sphericity. Then, the interactive relationship between these input variables and the quality attributes of the process is investigated using RSM. The results show that the mean particle size increases with the increase of binder viscosity and spray rate, while it decreases with the increase of fluidization gas velocity and inlet gas temperature. The relative width of the particle size distribution increases with the spray rate, binder viscosity, and fluidization gas velocity, and hardly changes with the inlet gas temperature. The mean particle size is more sensitive to the binder spray rate at a lower level of fluidization gas velocity or a higher level of inlet gas temperature. The fluidization gas velocity corresponding to the maximum D50 changes when the binder viscosity and binder spray rate are at different levels.

The role of adding nanoparticles and surfactant to the enzyme liquid binder in fluidized bed granulation process

The influence of enzyme liquid binder properties on wet granulation process was evaluated at both micro- and macro-scales. The micro-scale phenomena, including binder droplet spreading on and penetration into the powder bed, as well as liquid bridge shape and force, were analyzed by introducing SiO2 nanoparticles and SDS surfactant into the liquid binder containing a protease enzyme and 1 wt% of NaCMC. Moreover, the simultaneous effect of formulation variables, including NPs and SDS concentrations, and process conditions, such as binder spray rate and air temperature, was investigated using design of experiments. The average size and the span were considered as the responses. Nanofluid binder without SDS exhibited lower spreading and penetration times and a stronger bridge force. All formulation and process factors significantly influenced granule size distribution. Notably, increasing nanoparticle concentration and binder flow rate, while decreasing SDS concentration and air temperature, resulted in larger granules and a narrower size distribution.

Process Behavior and Product Quality in Fertilizer Manufacturing Using Continuous Hopper Transfer Pan Granulation—Experimental Investigations

Fertilizers are commonly used to improve the soil quality in both conventional and organic agriculture. One such fertilizer is dolomite for which soil application in granulated form is advantageous. These granules are commonly produced from ground dolomite powder in continuous pan transfer granulators. During production, the granulator’s operation parameters affect the granules’ properties and thereby also the overall performance of the fertilizer. To ensure product granules of certain specifications and an efficient overall production, process control and intensification approaches based on mathematical models can be applied. However, the latter require high-quality quantitative experimental data describing the effects of process operation parameters on the granule properties. Therefore, in this article, such data is presented for a lab-scale experimental setup. Investigations were carried out into how variations in binder spray rate, binder composition, feed powder flow rate, pan inclination angle, and angular velocity affect particle size distribution, mechanical stability, and humidity. Furthermore, in contrast to existing work samples from both, pan granules and product granules are analyzed. The influence of operation parameter variations on the differences between both, also known as trajectory separation, is described quantitatively. The results obtained indicate an increase in the average particle size with increasing binder flow rate to feed rate and increasing binder concentration and the inclination angle of the pan. Compressive strength varied significantly depending on the operating parameters. Significant differences in properties were observed for the product and the intermediate (pan) samples. In fact, for some operation parameters, e.g., binder feed rate, the magnitude of the separation effect strongly depends on the specific value of the operation parameter. The presented concise data will enable future mathematical modeling of the pan granulation process, e.g., using the framework of population balance equations.

Effect of Biodegradable Binder Properties and Operating Conditions on Growth of Urea Particles in a Fluidized Bed Granulator.

Granulation is an important step during the production of urea granules. Most of the commercial binders used for granulation are toxic and non-biodegradable. In this study, a fully biodegradable and cost-effective starch-based binder is used for urea granulation in a fluidized bed granulator. The effect of binder properties such as viscosity, surface tension, contact angle, penetration time, and liquid bridge bonding force on granulation performance is studied. In addition, the effect of fluidized bed process parameters such as fluidizing air inlet velocity, air temperature, weight of primary urea particles, binder spray rate, and binder concentration is also evaluated using response surface methodology. Based on the results, binder with higher concentration demonstrates higher viscosity and higher penetration time that potentially enhance the granulation performance. The viscous Stokes number for binder with higher concentration is lower than critical Stokes number that increases coalescence rate. Higher viscosity and lower restitution coefficient of urea particles result in elastic losses and subsequent successful coalescence. Statistical analysis indicate that air velocity, air temperature, and weight of primary urea particles have major effects on granulation performance. Higher air velocity increases probability of collision, whereby lower temperature prevents binder to be dried up prior to collision. Findings of this study can be useful for process scale-up and industrial application.

Fluidised bed granulation of two APIs: QbD approach and development of a NIR in-line monitoring method

The study focused on the fluid-bed granulation process of a product with two active pharmaceutical ingredients, intended for coated tablets preparation and further transfer to industrial scale. The work aimed to prove that an accurate control of the critical granulation parameters can level the input material variability and offer a user-friendly process control strategy. Moreover, an in-line Near-Infrared monitoring method was developed, which offered a real time overview of the moisture level along the granulation process, thus a reliable supervision and control process analytical technology (PAT) tool. The experimental design's results showed that the use of apparently interchangeable active pharmaceutical ingredients (APIs) and filler sorts that comply with pharmacopoeial specifications, lead to different end-product critical attributes. By adapting critical granulation parameters (i.e. binder spray rate and atomising pressure) as a function of material characteristics, led to granules with average sizes comprised in a narrow range of 280–320 µm and low non-granulated fraction of under 5%. Therefore, the accurate control of process parameters according to the formulation particularities achieved the maintenance of product within the design space and removed material related variability. To complete the Quality by design (QbD) strategy, despite its limited spectral domain, the microNIR spectrometer was successfully used as a robust PAT monitoring tool that offered a real time overview of the moisture level and allowed the supervision and control of the granulation process.

CFD–DEM–PBM coupled model development and validation of a 3D top-spray fluidized bed wet granulation process

In pharmaceutical manufacturing, fluidized bed granulation is one of the common processing options available to achieve better flowability of powders through size enlargement of primary particles. In fact over the last 50 years, various fluidized bed operations including freezing, drying, impregnation, coating, etc. have become a common place in the chemical processing industry due to the high level of contacts between fluids and solids attainable in a fluid bed system. These complex interactions between the fluid and particles also mean that simulating fluidized beds are still a challenging endeavor. Generally, Computational Fluid Dynamics (CFD) packages are employed to model the pressure drops in fluids; however, the presence of high concentration of solids and the complexity of granulation behavior require more advanced particle models than are available with CFD software. As a result, coupled frameworks that utilize the strength of particulate simulations such as Discrete Element Method (DEM) and bulk granulation modeling such as Population Balance Model (PBM) in conjunction with CFD information are the next steps to developing practical fluid bed granulation models.This paper aims to provide a comprehensive description of the development and validation of a coupled CFD–DEM–PBM framework for a fluidized bed wet granulation operation. A two-way coupled CFD–DEM model is developed for a 3-dimensional, lab-scale, top spray fluid bed granulator to study the effects of process parameters such as inlet air flow rate and inlet air temperature on the particle flow dynamics and the residence time in the spray zone. A one-way transfer of data from CFD–DEM to PBM is then applied to relate the effects of particle-fluid interactions to granulation behavior occurring within the fluidized bed system. Mechanistic rate expressions were developed in the PBM to create links between CFD–DEM results and PBM rate kernels which can express the effect of critical process parameters (CPPs) such as air flow rate, inlet air temperature, binder spray rate, etc. to experimentally measured critical quality attributes (CQAs) including granule size distribution and liquid content values. From comparison with experimental results, the framework presented shows good accuracy at capturing the dynamics of the system. The presented framework demonstrates a practical process model development methodology by efficiently coupling multi-phase simulation techniques which can be used for effective process design, development and scale-up purposes.

Application of near-infrared spectroscopy combined with design of experiments for process development of the pulsed spray fluid bed granulation process

The boundaries of a target product quality profile of certain failure modes can be exploited to construct the operation window, a process design space (PDS), for the granulation process. The purpose of this study is to implement process design and development for the pulsed spray fluid bed granulation (PSFBG) on a laboratory-scale granulator. This work consists of three parts: (1) implementation of Process Analytical Technology (PAT) combined with multivariate data analysis to monitor the formulation characteristics including moisture content, particle size and granule yield; (2) adoption of a new design of experiments (DoE) method Definitive Screening Design (DSD), with the well-established PAT monitoring tools, to investigate the process response to the intended changes in the critical process parameters (CPPs); and finally, (3) the definition of a PDS for the PSFBG, within which the acceptable performance of the process is guaranteed. The effects of the process parameters (i.e., the inlet air temperature, inlet air relative humidity, binder spray rate, atomization pressure, pulse cycle and pulse width) on granule size were evaluated. Two different failure modes were identified based on the measured target product quality (granule size) profile: risk of bed collapse due to over-wetting and low granulating efficiency. Using the constructed PDS for desired granulation, the expected final granule attributes can be obtained through properly controlling the process trajectory by adjusting the process parameters.

Application of definitive screening design to quantify the effects of process parameters on key granule characteristics and optimize operating parameters in pulsed-spray fluid-bed granulation

The pulsed-spray fluid-bed granulation (PSFBG) process was investigated and optimized using definitive screening design, a recently proposed new class of three-level design of experiment method. Such a design enabled quadratic models to be established that described the effect of six input process parameters – inlet air temperature, inlet air humidity, binder spray rate, atomization pressure, pulse period, and pulse width – on the granule quality in a PSFBG process. Mathematical models of the mean particle size, relative size distribution width, production yield, and porosity were developed to quantify the relationships between the influencing factors and critical quality attributes. On the basis of constraints on the desired granule properties, a design space for PSFBG was determined and ranges of the operating parameters were defined. An acceptable degree of prediction was confirmed by validation experiments, demonstrating the reliability and effectiveness of using definitive screening design to study the PSFBG process. This method can accelerate screening and optimization of this process within a large multidimensional design space.

Population balance modelling and multi-stage optimal control of a pulsed spray fluidized bed granulation

In this work, one-dimensional population balance models (PBMs) have been developed to model a pulsed top-spray fluidized bed granulation. The developed PBMs have linked the key binder solution spray operating factors of the binder spray rate, atomizing air pressure and pulsed frequency of spray with the granule properties to predict granule growth behaviour in the pulsed spray fluidized bed granulation process at different operating conditions with accuracy. A multi-stage open optimal control strategy based on the developed PBMs was proposed to reduce the model mismatch, in which through adjusting the trajectory of the evolution of the granule size distribution at predefined sample intervals, to determine the optimal operating variables related to the binder spray including the spray rate of binding liquid, atomizing air pressure and pulsed frequency of spray. The effectiveness of the proposed modelling and multi-stage open optimal control strategies has been validated by experimental and simulation tests.

A priori prediction of aggregation efficiency and rate constant for fluidized bed melt granulation

This paper presents a predictive aggregation rate model for spray fluidized bed melt granulation. The aggregation rate constant was derived from probability analysis of particle–droplet contact combined with time scale analysis of droplet solidification and granule–granule collision rates. The latter was obtained using the principles of kinetic theory of granular flow (KTGF). The predicted aggregation rate constants were validated by comparison with reported experimental data for a range of binder spray rate, binder droplet size and operating granulator temperature. The developed model is particularly useful for predicting particle size distributions and growth using population balance equations (PBEs).

Using the Box–Behnken experimental design to optimise operating parameters in pulsed spray fluidised bed granulation

In this work, the influence factors of pulsed frequency, binder spray rate and atomisation pressure of a top-spray fluidised bed granulation process were studied using the Box-Behnken experimental design method. Different mathematical models were developed to predict the mean size of granules, yield, relative width of granule distribution, Hausner ratio and final granule moisture content. The study has supported the theory that the granule size can be controlled through the liquid feed pulsing. However, care has to be taken when the pulsed frequency is chosen for controlling the granule size due to the nonlinear quadratic relation in the regression model. The design space of the ranges of operating parameters has been determined based on constraints of the mean size of granules and granule yield. High degree of prediction obtained from validation experiments has shown the reliability and effectiveness of using the Box-Behnken experimental design method to study a fluidised bed granulation process.

Comparison of quality parameters of granola produced by wet granulation with commercially available product

This study involves comparing key quality parameters (size, textural) of commercially available breakfast cereal granola with product produced by high shear and fluidised bed granulation processes. Impeller rotational speed was found to be the single most important process parameter which influences granola physical and textural properties in the production of high shear granola. In a fluidised bed granulation process nozzle air pressure and binder spray rate were both found to affect aggregate quality attributes. Overall, the high shear granulation process led to larger, denser, less porous and stronger (less likely to break) aggregates compared with the fluidised bed process.Commercial granola samples were compared with the granola produced in this study and showed a large variation in terms of size and textural properties across the brands investigated. Depending in the type of granola required (for example, to be sold as a stand alone breakfast cereal or as accompaniment to yogurt) different manufacturing processes and process parameters may be recommended. The insights gained from this work can aid in developing processes for the production of granola or similar products to match with consumer and manufacture expectations and requirements.

Production of granola breakfast cereal by fluidised bed granulation

In the fluidised bed granulation process the effect of nozzle air pressure and binder spray rate on key aggregate quality attributes were studied. The experimental results show that a decrease in nozzle air pressure leads to larger mean granule size. The combination of lowest nozzle air pressure and lowest binder spray rate results in granules with the highest levels of hardness and crispness. The combination of low nozzle air pressure and low binder spray rate results in the least distribution span. Granola hardness was affected by nozzle air pressure. Nozzle air pressure and binder spray rate did not have significant effect on crispness.

Comparison between two types of Artificial Neural Networks used for validation of pharmaceutical processes

Two types of Artificial Neural Networks (ANNs), a Multi-Layer Perceptron (MLP) and a Generalized Regression Neural Network (GRNN), have been used for the validation of a fluid bed granulation process. The training capacity and the accuracy of these two types of networks were compared. The variations of the ratio of binder solution to feed material, product bed temperature, atomizing air pressure, binder spray rate, air velocity and batch size were taken as input variables for training the MLP and GRNN. The properties of size, size distribution, flow rate, angle of repose and Hausner's ratio of granules produced, were measured and used as output variables. Qualitatively, the two networks gave comparable results, as both pointed out the importance of the binder spray rate and the atomizing air pressure to the granulation process. However, the averaged absolute error of the MLP was higher than the averaged absolute error of the GRNN. Furthermore, the correlation coefficients between the experimentally determined and the calculated output values, the corresponding prediction accuracy for the different granule properties as well as the overall prediction accuracy using GRNN were better than using MLP. In conclusion, the comparison of two different networks (MLP, a so-called feed-forward back-propagation network and GRNN, a so-called Bayesian Neural Network) showed the higher capacity of the latter for validation of such granulation processes.

Air-dictated bottom spray process: impact of fluid dynamics on granule growth and morphology

Background: Growing interest in the use of the less-explored bottom spray technique for fluidized bed granulation provided impetus for this study. Aim: The impact of fluid dynamics (air accelerator insert diameter; partition gap) and wetting (binder spray rate) on granule properties were investigated. Method: In this 33 full factorial study, the results were fitted to a quadratic model using response surface methodology. The air velocity at the spray granulation zone for the investigated conditions was measured using a pitot tube. Results: Air accelerator insert diameter correlated to measured air velocity at the spray granulation zone and was found to not only dictate growth but also influence granule morphology. The partition gap was found to play important roles in regulating particle movement into the spray granulation zone and optimizing process yields, whereas binder spray rate significantly affected granule morphology but not granule size. Conclusions: Unlike conventional fluidized bed granulation, ease of modulation of fluid dynamics and insensitivity of the bottom spray process to wetting allow flexible control of granule size, shape, and flow. Its good drying ability also indicated potential use in granulating moisture-sensitive materials.

Optimization and scale-up of a fluid bed tangential spray rotogranulation process

The production of pellets in the pharmaceutical industry generally involves multi-step processing: (1) mixing, (2) wet granulation, (3) spheronization and (4) drying. While extrusion-spheronization processes have been popular because of their simplicity, fluid-bed rotogranulation (FBRG) is now being considered as an alternative, since it offers the advantages of combining the different steps into one processing unit, thus reducing processing time and material handling. This work aimed at the development of a FBRG process for the production of pellets in a 4.5-l Glatt GCPG1 tangential spray rotoprocessor and its optimization using factorial design. The factors considered were: (1) rotor disc velocity, (2) gap air pressure, (3) air flow rate, (4) binder spray rate and (5) atomization pressure. The pellets were characterized for their physical properties by measuring size distribution, roundness and flow properties. The results indicated that: pellet mean particle size is negatively affected by air flow rate and rotor plate speed, while binder spray rate has a positive effect on size; pellet flow properties are enhanced by operating with increased air flow rate and worsened with increased binder spray rate. Multiple regression analysis enabled the identification of an optimal operating window for production of acceptable pellets. Scale-up of these operating conditions was tested in a 30-l Glatt GPCG15 FBRG.

Kinetics of fluidized bed melt granulation—II: Modelling the net rate of growth

Previous work [Tan, H.S., Goldschmidt, M.J.V., Boerefijn, R., Hounslow, M.J., Salman, A.D., Kuipers, J.A.M. (2004a). Building population balance for fluidized bed granulation: lessons from kinetic theory of granular flow. Powder Technology, 142, 103–109] shows that we can derive an aggregation kernel (equi-partition of kinetic energy (EKE)) on the basis of the kinetic theory of granular flow and use it effectively to describe the net granule growth in fluidized bed melt granulation (FBMG). In this paper, we incorporate the EKE kernel into a population balance model to extract the effective aggregation rate constant that accounts for the net granule growth for the series of FBMG experiments shown in Tan, et al. [(2004b). Kinetics of fluidized bed melt granulation I: effect of process variables, Chemical Engineering Science, to be submitted]. These extracted rate constants are subsequently expressed as a function of different operating condition. The results consistently show that the aggregation rate constant increases in direct proportion with binder spray rate, from where we conclude that the rate of granule formation is directly dependent on the amount of binder available for aggregation per unit time. The aggregation rate constant was also observed to increase with higher bed temperature when a higher viscosity binder was used, but showed a maximum value for a less viscous binder as a function of temperature. The aggregation rate was also seen to be faster when granulating using a larger droplet size and at a lower fluidizing air velocity. The observations in the rate constant plot can be effectively explained by the physical parameters in the EKE model and the sequence of rate events proposed in Tan, et al. [(2004b). Kinetics of fluidized bed melt granulation I: effect of process variables, Chemical Engineering Science, to be submitted].

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.

Optimal control and operation of drum granulation processes

Process optimisation and optimal control of batch and continuous drum granulation processes are studied in this paper. The main focus of the current research has been: (i) construction of optimisation and control relevant, population balance models through the incorporation of moisture content, drum rotation rate and bed depth into the coalescence kernels; (ii) investigation of optimal operational conditions using constrained optimisation techniques; (iii) development of optimal control algorithms based on discretized population balance equations; and (iv) comprehensive simulation studies on optimal control of both batch and continuous granulation processes. The objective of steady state optimisation is to minimise the recycle rate with minimum cost for continuous processes. It has been identified that the drum rotation-rate, bed depth (material charge), and moisture content of solids are practical decision (design) parameters for system optimisation. The objective for the optimal control of batch granulation processes is to maximize the mass of product-sized particles with minimum time and binder consumption. The objective for the optimal control of the continuous process is to drive the process from one steady state to another in a minimum time with minimum binder consumption, which is also known as the state-driving problem. It has been known for some time that the binder spray-rate is the most effective control (manipulative) variable. Although other possible manipulative variables, such as feed flow-rate and additional powder flow-rate have been investigated in the complete research project, only the single input problem with the binder spray rate as the manipulative variable is addressed in the paper to demonstrate the methodology. It can be shown from simulation results that the proposed models are suitable for control and optimisation studies, and the optimisation algorithms connected with either steady state or dynamic models are successful for the determination of optimal operational conditions and dynamic trajectories with good convergence properties.

Kinetics of fluidised bed melt granulation V: Simultaneous modelling of aggregation and breakage

The main purpose of this paper is to quantify the aggregation and breakage rates in fluidised bed melt granulation (FBMG) and to subsequently relate them to various experimental conditions. The earlier paper of this series (2004d, Powder Technology 143–144, 65–83) illustrated a sequence of development and verification work on a breakage model for FBMG, based on the population balance modelling work on tracer experimental studies. A new error-weighted integral technique was also developed, which allows simultaneous extraction of the aggregation and breakage selection rate constant, as well as the attrition constant that reveals the relative amount of attrition during FBMG. Further research is conducted here, as the similar modelling strategy is employed to extract the aggregation and breakage kinetics at different operating conditions. A series of plots revealing the influence of operating conditions (binder spray rates, bed temperature, droplet size and fluidising air flow rate) on these extracted constants are therefore established. The aggregation rate constant plots reveal that the particle aggregation rate is dependent on the amount of binder available per unit time, and hence scales directly with the binder spray rate. The aggregation rate is also observed to increase with increased bed temperature when a higher viscosity binder is used, but reveals a maximum aggregation rate for a less viscous binder. The aggregation rate also increases with larger droplet size and lower fluidising air velocity. The breakage selection rate and attrition constant plot both reveal no direct dependence on binder spray rate, due to the separation in time scale over which the granule breakage occurs. The breakage rate and the extent of granule attrition is also found to decrease with increased bed temperature and increased fluidising air velocity. Due to scatter in the data, it is not possible to deduce any sensible trend on the influence of droplet size on its relative breakage rate and attrition.