Fluidized Bed Spray Granulation Research Articles

Control of segregation by non-uniform aeration in a fluidized bed spray granulator

Controlling and influencing the rate of particle growth in spray granulators is key for consistent product quality and size, while reducing energy consumption and product re-circulation. To this end, we have implemented a new control device to actively change the fluidization topology of fluidized spray granulators and to influence the local particle segregation in the areas affected by the granulation, selectively growing fine particle fractions at will. Simulations using computational fluid dynamics coupled with the discrete element method (CFD-DEM) demonstrate how the different operational modes can be switched in a short period of time, resulting in full local segregation in less than 40 s, without changing the fluidization air or inlet temperature. It is shown how a central spout preferentially drags big particles to the top of the bed, while a side aeration system, where two smaller spouts are opened at the outermost sides of the bed, creates a concentration of fines in the spraying region. This process can be repeated as long as the fluidization velocity of all particle sizes in the bed can be attained and full fluidization is underway. The spout regime could be used to clean the distributor plate of undesired big or overgrown particles, and side aeration to preferentially grow finer particles, while homogeneous aeration should be the default operation mode when no anomalies are detected.

Effect of Process Parameters, Protectants and Carrier Materials on the Survival of Yeast Cells during Fluidized Bed Granulation for Tableting.

The administration of living microorganisms is of special interest, with regard to probiotic microorganisms providing health benefits to the patient. Effective dosage forms require the preservation of microbial viability until administration. Storage stability can be improved by drying, and the tablet is an especially attractive final solid dosage form due to its ease of administration and its good patient compliance. In this study, drying of the yeast Saccharomyces cerevisiae via fluidized bed spray granulation is investigated, as the probiotic Saccharomyces boulardii is a variety of it. Fluidized bed granulation enables faster drying than lyophilization on the one hand and lower temperatures than spray drying on the other hand, which are the two predominantly used techniques for life-sustaining drying of microorganisms. Yeast cell suspensions enriched with protective additives were sprayed onto the carrier particles of common tableting excipients, namely, dicalcium phosphate (DCP), lactose (LAC) and microcrystalline cellulose (MCC). Different protectants, such as mono-, di-, oligo- and polysaccharides, but also skimmed milk powder and one alditol, were tested; as they themselves, or chemically similar molecules, are known from other drying technologies to stabilize biological structures such as cell membranes, and thus, improve survival during dehydration. With the combined use of trehalose and skimmed milk powder, survival rates were 300 times higher than without the use of protective additives. In addition to these formulation aspects, the influence of process parameters such as inlet temperature and spray rate were considered. The granulated products were characterized regarding their particle size distribution, moisture content and the viability of the yeast cells. It has been shown that thermal stress on the microorganisms is especially critical, which can be reduced, for example, by reducing the inlet temperature or increasing the spray rate; however, formulation parameters such as cell concentration also influenced survival. The results were used to specify the influencing factors on the survival of microorganisms during fluidized bed granulation and to derive their linkages. Granules based on the three different carrier materials were tableted and the survival of the microorganisms was evaluated and linked to the tablet tensile strength achieved. Using LAC enabled the highest survival of the microorganisms throughout the considered process chain.

Parallel compensator for zero dynamics stabilization in fluidized bed spray granulation

This contribution is concerned with the stabilization of continuous fluidized bed spray granulation processes with external sieve mill cycle. To keep the overall mass of particles inside the granulation chamber in well-defined bounds these processes are in general operated with a mass controller. This configuration is well-known to become unstable for certain ranges of the milling diameter. Here, the instability results in a nonlinear limit cycle of the particle size distribution. As has been shown in a previous contribution the stability problem is not inherent to the process, which is open-loop stable over a wide range of operating conditions. In fact, the root cause for the instability is the mass controller, which interacts with the unstable zero dynamics of the granulation process. To overcome this problem a parallel compensator will be designed, which allows to stabilize the process zero dynamics and thus solves the problem of control induced instabilities.

Gender-Based Eye Movement Differences in the Ilab-X Platform Using: An Eye-Tracking Study

Continuous fluidized bed spray granulation processes are known to be prone to non-linear oscillations, which requires a stabilizing controller design. In this article, a purely data-driven Koopman-based system linearization and control is proposed, which does not need any prior model knowledge and uses only systems input-output measurements. The linearization achieved by the Koopman embedding allows for linear-quadratic control design, which does not depend on the operating point. The proposed method was validated in a simulation study of a fluidized bed granulation process and was able to stabilize the particle size distribution in different operating points.

Koopman-based data-driven control for continuous fluidized bed spray granulation with screen-mill-cycle

Continuous fluidized bed spray granulation processes with external screen-mill cycle are known to be susceptible to nonlinear oscillations. As has been shown recently, mass control may induce periodical oscillation of the particle size distribution in fine grinding regimes, which requires the design of additional stabilizing control. In this contribution a data-driven control approach is investigated. It is based on the identification of the Koopman-based linear representation of the system and does not require any manual system modeling as it is based purely on input–output measurements. The resulting representation makes possible a linear–quadratic control design, that does not depend on a specific operational point. The proposed approach was successfully validated in a numerical study.

Koopman-based data-driven control for continuous fluidized bed spray granulation

Abstract Continuous fluidized bed spray granulation processes are known to be prone to non-linear oscillations, which requires a stabilizing controller design. In this article, a purely data-driven Koopman-based system linearization and control is proposed, which does not need any prior model knowledge and uses only systems input-output measurements. The linearization achieved by the Koopman embedding allows for linear-quadratic control design, which does not depend on the operating point. The proposed method was validated in a simulation study of a fluidized bed granulation process and was able to stabilize the particle size distribution in different operating points.

Control induced instabilities in fluidized bed spray granulation

This contribution is concerned with the stability problems occurring during the operation of continuous fluidized bed spray granulation processes with external sieve mill cycle. These processes are in general operated by a mass controller, which guarantees that the overall mass of particles in the granulation chamber stays in well-defined bounds. It is well-known that, depending on the milling diameter, instabilities may occur, which result in a nonlinear limit cycle of the particle size distribution. To overcome this problem two approaches have been proposed in the literature, constrain the admissible parameter space to exclude regions of instability and design additional stabilizing control loops. In the present contribution, the cause of this instability phenomenon will be studied. It will be shown that the instability is not inherent to the process, which turns out to be open-loop stable over the studied parameter range, but due to the mass controller. More specifically, it will be demonstrated that the zero dynamics of the granulation process become unstable for certain parameter ranges resulting in closed-loop unstable process behavior. To point out, that this behavior does not depend on the specific mass controller design procedure, three prototypical mass controllers of practical relevance are designed and analyzed.

Particle engineering for improved stability and handling properties of carrot concentrate powders using fluidized bed granulation and agglomeration

Carotenoid rich carrot concentrate powders were produced using spray drying, fluidized bed agglomeration and spout fluidized bed spray granulation. The powders were analyzed and compared for their microstructure, encapsulation efficiency, dissolution kinetics, flowability and oxidation stability during storage. Agglomeration and spray granulation resulted in powders with a high encapsulation efficiency (96–99%), oxidation stability and improved flowability compared to spray dried powders. Dissolution in water was fastest for agglomerated powders and significantly slowed down by lump formation in spray dried and spray granulated powders. After 168 days of storage at 35 °C, 92–93% and 86–90% of the initial carotenoids were retained in spray granulated and agglomerated powders respectively, whereas only 68–75% were retained in spray dried particles. The obtained results highlight the potential of targeted particle engineering to achieve food powders with superior functional properties and stability.

PARTEC 2019 – Overcome the Challenges in Particle and Powder Technology

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Discontinuous Galerkin solution of the convection-diffusion-reaction equations in fluidized beds

In this work, the Discontinuous Galerkin (DG) schemes were studied for the solution of convection-diffusion-reaction equations which arise from mathematical modeling of fluidized bed spray granulation process (FBSG). The discontinuous Galerkin method for space discretization is employed to treat the dominated convection behavior in the governing equations. The implicit Euler method for the temporal discretization is used. The mathematical analysis of the governing equations with a priori bounds for all the state variables is demonstrated. The investigation of experimental order of convergence is presented for test functions of degrees one and two. Finally, parallel efficiency of strong scaling is presented for the employed DG schemes.

Inferential control of product properties for fluidized bed spray granulation layering

Fluidized bed layering granulation has found application in a wide range of industrial processes, e.g. food, pharmaceutical or fertilizer manufacturing. The quality of the produced granules is a critical factor for subsequent processing steps and depends on individual particle properties like characteristic size, porosity or mechanical stability. Therefore, these properties have to be monitored closely during the process to enable accurately timed intervention by plant operators or the application of suitable feedback control algorithms. In case certain properties are not measurable due to financial or technical limitations, observer techniques can fill the gap and provide reliable estimates for these properties. In this manuscript, observer design is demonstrated and validated for a fluidized bed layering granulation process model represented by a complex set of partial and ordinary differential equations. Furthermore, an inferential integral state feedback controller is designed and applied to the complex nonlinear model.

Simulation Modeling of a Pharmaceutical Tablet Manufacturing Process via Wet Granulation

The pharmaceutical tablet manufacturing process (PTMP) via wet granulation holds a critical position in pharmaceutical industry. The interest in integrating mechanistic process modeling into the pharmaceutical development has been increased because simulation model is a prerequisite for process design, analysis, control, and optimization. So the simulation modeling for PTMP via wet granulation is very necessary and significant. This study aims at proposing a simulation modeling framework for PTMP via spray fluidized bed granulation (SFBG), which is one of the most widely used wet granulation techniques in pharmaceutical industry. For SFBG, a simulation model that simultaneously involves the influences of operating variables and material attributes on average particle size (APS) is firstly developed, and then a drying model to determine the particle moisture content is introduced to be coupled with the established model predicting APS. For PTMP, considering the important effect of porosity on tablet qualities, a model describing the changes in tablet porosity is developed based on a promoted form of the Heckel equation, and then several recognized models that are all related to porosity are introduced or constructed to calculate important tablet quality indexes. The feasibility and effectiveness of the developed simulation models are validated by performing a computational experimental study to explore the scientific understanding of process and process quality control.

Control of Multi-Chamber Continuous Fluidized Bed Spray Granulation

Abstract This paper is concerned with control of multi-chamber continuous fluidized bed spray granulation processes with external sieve-mill cycles. The process is described by a population balance equation for the particle size distribution in each chamber, resulting in a system of nonlinear partial integro-differential equations. Therefore, control design is challenging. In order to overcome these difficulties the control problem is formulated using a generalized distance measure, the discrepancy. It is shown that discrepancy based control allows to design a simple and effective nonlinear control law for multi-chamber continuous fluidized bed spray granulation processes with external sieve-mill cycles.

Adaptive discrepancy based control of continuous fluidized bed spray granulation with external sieve-mill cycle

Abstract In this contribution control design for continuous fluidized bed spray granulation with external sieve-mill cycle in the presence of uncertain mill behavior is presented. It is well-known that this specific particulate process becomes unstable in certain parameter regions. Being described by a population balance model, a nonlinear partial integro-differential equation, control design is challenging. To overcome this problem control design is studied in terms of a generalized stability theory, i.e. stability with respect to two discrepancies. The resulting discrepancy based control can be extended by additional parameter adaptation to cope with the present uncertainties.

Influence of separation properties and processing strategies on product characteristics in continuous fluidized bed spray granulation

The realization of continuous operation in fluidized bed spray granulation raises issues of process stability and product specification. It requires an appropriate process control strategy and a suitable granulator design. In previous work, a two-zone population balance (PB) model was developed and simulated product size distributions were evaluated by experiments in a Wurster granulator with external straight-duct air classification, however only regarding the process stability. The present contribution extends this population balance model with further equations for the purpose of product size control whereby the parameter setting of the former investigation serves as basis of the shown simulation study. Three process control strategies have been developed, implemented into the PB-model and investigated for diverse desired particle growth ratios and various separation sharpnesses. The simulation results show that only one of these strategies is able to provide the targeted requirements of both, process stability and product specification, but only for sufficiently good separation performance.

Analysis of the powder behavior and the residence time distribution within a production scale rotary tablet press

This study focuses on the behavior of powder particles in a rotary tablet press with special focus on the feed frame system. To obtain a better knowledge of the continuous manufacturing of tablets, the experimental setup was carried out with a production scale rotary tablet press. The behavior of the powder particles at different flow rates through the tablet press, residual moisture contents, particle sizes, and amounts of tracer was investigated. The residence time distribution was evaluated using the tracer indigo carmine, which was sprayed onto microcrystalline cellulose particle as solution with fluidized bed spray granulator to obtain a tracer blend. The residence time distribution was increased by increasing the amount of tracer blend, and a transition from a plain MCC blend to the tracer blend with regard to continuous manufacturing was shown. Furthermore, it was found that an increase in the flow rates of the powder particles through the tablet press led to a decrease of the residence time distribution (Et). The variation of the flow rate had no influence on the mechanically applied strain at high throughputs, which was confirmed by a constant number of paddle passes (Npp). At the lowest flow rate, the Npp appears to be higher than the constant Npp values at higher flow rates. The residual moisture content did not shown any significant influence on the residence time distribution. The examination of the effect of different tracer blend particle sizes led to an interesting result: It was shown that the particle size segregation only had a low influence on Et. However, a comparably higher influence of the particle size segregation on the particle distribution in the produced tablets was demonstrated. Large particles were deposited at the top of the tablet surface whereas small particles were deposited at their bottom.

Non-identifier-based adaptive control of continuous fluidized bed spray granulation

This paper is concerned with stabilizing control for continuously operated fluidized bed spray granulation with internal product classification. It is well-known that these processes may become unstable for certain operating conditions giving rise to nonlinear oscillations in the particle size distribution. In contrast to previous works, in this contribution a model-free adaptive control is proposed. It is shown that the given fluidized bed spray granulation process fulfills the required structural assumptions. The designed control schemes, universal adaptive and λ-tracking control, are tested in a noise-free scenario and including measurement noise.

Influence of process conditions on the product properties in a continuous fluidized bed spray granulation process

This work focuses on continuously operated spray granulation processes in horizontal fluidized beds highlighting the influence of process conditions on the particle properties of the resulting product granules. The drying process has a decisive influence on the kinetics of the growth rate and thus also on the properties of the particles, such as the morphological structure, particle moisture content and porosity as well as density, compression strength and the wetting behavior. This influence has been considered in this study in more detail on the basis of the model material sodium benzoate. In order to compare the produced granules at different drying conditions and spray rates of the suspension an external product classification was used to achieve a certain product granule size. The obtained experimental results show a deep influence of the thermal conditions onto granule morphology and structural properties, which is in qualitative agreement with recent experimental observations (Rieck et al., 2015; Hoffmann et al., 2015a; Schmidt et al., 2017b). The overall trend of the results reveal smoother product granules with decreasing spray rates of the suspension and increasing drying temperatures. These smoother surface morphologies lead to a more homogeneous layering which has as a consequence that the internal particle porosity is decreasing while the solids density and the compression strength of the particles are increasing at the same time. In this study the purely qualitative classification of the surface texture from previous experimental studies was extended by the topographic analysis of the product granules, giving the possibility to quantify the morphological structure by means of roughness measurements. This makes the morphological design accessible as product property and permits the utilization of models that describe the morphology according to the process conditions.

Effect of droplet size on particle-particle adhesion of colliding particles through droplet

In a fluidized bed spray granulation, a particle-particle adhesion by a liquid bridge, which shows dynamic motion due to moving particles, is the most fundamental phenomenon. Therefore, understanding of the particle-particle adhesion by such a dynamic liquid bridge is very important to elucidate mechanisms of particle agglomeration phenomenon in the wet granulation. In this study, the particle-particle adhesion phenomenon at the individual particle scale was analyzed using a direct numerical simulation. Collision of two particles mediated by binder droplets on a particle surface was simulated. In particular, the effect of droplet size under constant total liquid volume on adhesiveness of two colliding particles was investigated. In the present simulation, multiple liquid bridges were simultaneously formed, and these liquid bridges coalesced into single liquid bridge. The simulation results exhibited that the adhesiveness of particles increased with a decrease in the droplet diameter under a constant total liquid volume. In an initial stage of the particle growth in a fluidized bed spray granulation, the tendency of the calculations was consistent with experimental results. We revealed that the capillary pressure force and shapes of the liquid bridge are key factors for particle-particle adhesion at different droplet sizes under constant total liquid volume.

CFD-PBE simulation to predict particle growth in a fluidized bed melt granulation batch process

The fluidized bed spray granulation process unites the steps of solid formation and product formulation in one apparatus and is used to produce granulate products out of a liquid. According to different applications of granules, a specific product particle size distribution is required. Thus, the ability to predict the development of the particle size distribution is crucial for process design, optimization and scale-up. For this reason, population balance equations can be solved where the knowledge of particle size-dependent growth rates are the important quantities, which are difficult to obtain by experiments.Using a computational fluid dynamics multiphase model with one nozzle at its center, an advanced two-fluid model with five fluid phases is solved for short process times (~s) considering a high local and temporal resolution of the granulation process (including fluid dynamics, drop deposition and energy equations) to evaluate size-dependent growth rates, as a function of the current state of the process. By transferring particle growth rates to population balance equations, the development of particle size distribution can be finally predicted for long process times (~min).The present work applies the predictive model to an industrial melt spray granulation process in batch mode. Experimental data show that this model could be implemented successfully.