Fluidized Bed Granulation Research Articles

Valorization of anaerobic digestion liquid residue through the production of organic fertilizer by fluidized bed granulation

In this work the feasibility of developing a solid fertilizer by fluidized bed granulation, using digestate (liquid residue from anaerobic digestion) as binder and different minerals as seeds is analysed. Full characterization of the selected mineral particles and the liquid digestate was performed. Particularly, phosphorous and potassium content was assayed before and after granulation. Friability and breakage strength of product granules were tested as well. Also, the process operating conditions (bed temperature, fluidization air temperature and flowrate, digestate temperature and flowrate, etc.) that enable stable operation and the production of completely coated granules were successfully established for lab- and pilot-scale granulation units.

Recovery of copper salts by fluidized-bed homogeneous granulation process: High selectivity on malachite crystallization

Anthropogenic copper content in water is of health and environmental concern. Copper recovery from polluted effluents may become a possible dual solution for copper scarcity and copper pollution. In this work we study the possible removal and recovery of copper by fluidized-bed homogeneous crystallization (FBHC) from metallurgy industry effluents. This emergent technology may allow recovering high pure copper salts as granules for their ulterior reuse in different applications. Operational parameters of FBHC were optimized allowing up to 92% of copper recovery. The characterization of the spheroidal crystals obtained allowed identifying malachite as the unique crystal phase.

Development and Evaluation of Poorly Water-Soluble Celecoxib as Solid Dispersions Containing Nonionic Surfactants Using Fluidized-Bed Granulation.

The purpose of this study is to develop a solid dispersion system with improved dissolution, absorption, and patient compliance of poorly water-soluble celecoxib (CXB). Instead of sodium lauryl sulfate (SLS), an anionic surfactant used in the marketed product (Celebrex®), solubilization was performed using non-ionic surfactants with low toxicity. Cremophor RH40 (Cre-RH) was selected as the optimal solubilizer. Granules and tablets containing CXB and Cre-RH were prepared via fluid-bed and tableting processes, respectively. The morphology, crystallinity, flowability, dissolution, and pharmacokinetics for CXB-solid dispersion granules (SDGs) and the hardness and friability for CXB-solid dispersion tablets (SDTs) were evaluated. The solubility of CXB was found to be increased by about 717-fold when using Cre-RH. The dissolution of granules containing Cre-RH was found to be increased greatly compared with CXB API and Celebrex® (66.9% versus 2.3% and 37.2% at 120 min). The improvement of the dissolution was confirmed to be the same as that of granules in tablets. The CXB formulation resulted in 4.6- and 4.9-fold higher AUCinf and Cmax of CXB compared with those of an oral dose of CXB powder in rats. In short, these data suggest that the solid dispersion based on Cre-RH—a non-toxic solubilizer, non-ionic surfactant— may be an effective formulation for CXB to enhance its oral bioavailability and safety.

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.

Fluidized Bed Granulation Parameters Effect on Urea Granule Physical Properties

The aim of this study is to determine the effect of different airflow patterns and process conditions on the physical properties of granules produced using fluidized bed granulation technique. It was observed that spiral airflow was the most important factor to produce granules with required size and density under similar process conditions if compared with normal airflow. From ANOVA, binder spray pressure and bag shake duration showed the strongest influence on hardness of granules on both types of airflow patterns. Optimization studies for spiral and normal airflow proved that granules with desired density and hardness can be produced at middle level of wind velocity and binder spray pressure together with high level bag shake duration. For spiral airflow, the optimum value for wind velocity, binder spray pressure and bag shake duration was 28 m/s, 0.31 MPa and 60 s respectively; for normal airflow, it was 25 m/s, 0.20 MPa and 15 s respectively.

Enhanced recovery of aluminum from wastewater using a fluidized bed homogeneously dispersed granular reactor

The recovery of aluminum from wastewater is one of the main environmental issues that need to be addressed in the aluminum finishing industry. A new technique of converting a soft slurry into hard granules using the homogeneous granulation process in the fluidized-bed reactor (FBR) can respond to this problem. It is a better method of remediation than producing a slurry containing 70% water. This study deals with the recovery of aluminum from aqueous solutions using Fluidized-bed homogeneous granulation process (FBHGP) without seeds. The hydraulic operating conditions were optimized using Box-Behnken Design (BBD) to attain the optimum aluminum removal (AR%) and granulation ratio (GR%). Optimum values of AR% = 98.8% and GR% = 96.9% were attained at the following conditions: influent aluminum concentration, 334.1 mg L−1; precipitant pH, 10.4; molar ratio (MR) of precipitant to metal [OH−]in/[Al3+]in, 2.5. The characteristics of the granules were comparable with those of orthorhombic structure of aluminum oxide (Al2.66O4). FBHGP was proven to be effective as dictated by the reaction mechanism in the recovery of aluminum from aluminum-rich aqueous solutions.

A large-scale experimental comparison of batch and continuous technologies in pharmaceutical tablet manufacturing using ethenzamide

This paper compares batch and continuous technologies in terms of product quality and process performance in pharmaceutical tablet manufacturing using ethenzamide as the active pharmaceutical ingredient. Batch and continuous processes using wet granulation were investigated by performing experiments on the scale of 5 and up to 100 kg/lot, using the same raw materials. Three technologies were tested and compared: (i) batch technology using fluidized bed granulation, (ii) batch technology using high shear granulation, (iii) continuous technology using high shear granulation. In the full-scale experiment, in all three technologies including continuous technology, the quality of the tablets fulfilled the target values regarding hardness, active pharmaceutical ingredient content, and dissolution. The granules produced by different technologies, however, presented varying attributes regarding granule size distribution, loose bulk density, or scanning electron microscope images. The process performance, more specifically the yield, was slightly better for batch technologies than for the continuous technology, mainly due to losses in the start-up operation. Notably, this study has shown that continuous technology, which is generally believed to not entail scale-up procedures, could in fact, require parameter adjustment for prolonged operation. The results provided suggestions for improvements to implement large-scale continuous technologies in the pharmaceutical industry.

Statistical modelling of an ammonium nitrate fluidised bed granulator for inference measurement

Abstract Fluidised bed granulation is a widely used wet granulation technique. The operation of a fluidised bed granulator (FBG) as well as the quality of the product is strongly influenced by multiple process variables and disturbances. Controlling this process is difficult due to long lag times between sample analysis. Inference sensors are therefore an effective control solution for this complex process. A continuous industrial FBG was used to develop multiple linear regression (MLR) models that included two-way interaction effects. Elementary artificial neural network (ANN) models were developed to qualitatively assess the MLR models. The influences of the fluidizing air, the spray liquid and the seed particle size on the product quality were investigated and modelled. The spray liquid was found to have the largest correlation with the quality variables. Both modelling techniques produced accurate models, however undertraining of some ANN models resulted in a larger deviation between the model and validation data.

In Situ Cocrystallization of Dapsone and Caffeine during Fluidized Bed Granulation Processing.

Different pharmaceutical manufacturing processes have been demonstrated to represent feasible platforms for the production of pharmaceutical cocrystals. However, new methods are needed for the manufacture of cocrystals on a large scale. In this work, the suitability of the use of a fluidized bed system for granulation and concomitant cocrystallization was investigated. Dapsone (DAP) and caffeine (CAF) have been shown to form a stable cocrystal by simple solvent evaporation. DAP is the active pharmaceutical ingredient (API) and CAF is the coformer. In the present study, DAP-CAF cocrystals were produced through liquid-assisted milling and the product obtained was used as a cocrystal reference. The granulation of DAP and CAF was carried out using four different experimental conditions. The solid-state properties of the constituents of the granules were characterised by differential scanning calorimetry (DSC) and x-ray powder diffraction (PXRD) analysis while the granule size distribution and morphology were investigated using laser diffraction and scanning electron microscopy (SEM), respectively. DAP-CAF cocrystal granules were successfully produced during fluidized bed granulation. The formation of cocrystals was possible only when the DAP and CAF were dissolved in the liquid phase and sprayed over the fluidized solid particles. Furthermore, the presence of polymers in solution interferes with the cocrystallization, resulting in the amorphization of the DAP and CAF. Cocrystallization via fluidized bed granulation represents a useful tool and a feasible alternative technique for the large scale manufacture of pharmaceutical cocrystals for solid dosage forms.

Design, Optimization and Evaluation of Lurasidone Hydrochloride Nanocrystals as Fast Disintegrating Tablets

Formulation of poorly water-soluble drugs for oral drug delivery has always been a difficult task for formulation scientists. Lurasidone hydrochloride is one such agent which is used to control bipolar depre-ssion. The objective of this study was to formulate and optimize lurasi-done nanosuspension, further formulating optimized nanosuspensions as fast disintegrating tablets for improved patient compliance. In the present study, lurasidone nanosuspension was prepared by nanomilling technique. Optimized nanosuspension has mean particle diameter of 248.9 nm, polydispersity index of 0.127 and zeta potential of 18.1 mV. The lyophilized optimized nanocrystals, optimize nanosuspension as granulating fluid and as top spraying dispersion for granulation in fluid bed granulator being used to formulate fast disintegrating tablets with suitable super disintegrant. Croscarmellose sodium was found to be best superdisintegrant compared to sodium starch glycolate and crospovidone, as its acts by both mechanism swelling and wicking. Its swells 4-8 folds in less than 10 s. Many folds increase in the rate of drug release observed compare to micronized lurasidone and marketed product. There was no change in crystalline nature after nanomilling as characterized by XRD and FTIR, and it was found to be chemically stable with high drug content. The developed fast disintegrating tablets would be an alternative better formulation than its conventional formulation to address its bioavailability issue and for improved patient compliance. However, this should be further confirmed by appropriate in vivo studies.

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.

CFD-DEM Simulation of the Fluidized-bed Granulation of Food Powders

In this study, the granulation behavior of food powders was simulated by taking into account the changes in the rheological properties and water content of the powders. Several food powders were studied and classified into self-agglomerating or non-agglomerating powders depending on the presence of a glass transition temperature. Cricket powder, which is incapable of self-agglomeration, was mixed with dextrin powder to enable the granulation process. Cricket + dextrin powder was used as a simulation model, and the glass transition temperature of dextrin and a newly derived evaporation model were adopted in our simulation studies. Similar tendencies were observed in both the experimental and simulation results. Our granulation model can describe all of the following: nucleation, granulation based on the powder properties and changes in particle water content due to evaporation; these behaviors have not been modeled in this way previously.

Novel, lean and environment-friendly granulation method: Green fluidized bed granulation (GFBG)

The Green fluidized bed granulation (GFBG) technology is based on the moisture activated dry granulation (MADG) technique and consists only of a mixing and a spraying process using a fluidized bed granulator, requiring no heating process. This provides a less energy-consuming and environment-friendly granulation method compared to current fluidized bed granulation (FBG) and high-shear granulation (HSG) methods. The aim of this study is to compare and evaluate the manufacturability, and granule and tablet properties among GFBG, MADG, FBG and HSG.The GFBG process time took less than 20 min for producing final blends at a 700 g scale, which was comparable to MADG. This process time was significantly shorter than that of FBG and HSG. GFBG not only had the shortest process time but also reduced the number of manufacturing machines compared to FBG and HSG.The Hausner ratio (HR) of granules from GFBG (1.30) indicated a good flowability, and no problems were observed in the tablet mass variability during compression.Tablets produced using GFBG achieved sufficient tensile strength (>1.5 MPa) even at a low compression force and demonstrated the fastest disintegration time compared to the other manufacturing methods. Tablet disintegration is related to wettability and porosity, therefore the tablet wettability (initial and capillary wetting) and tablet porosity were investigated. As a result, the capillary wetting of the tablets produced using GFBG was 3.6 times higher than the tablets produced using FBG, which might have affected the fast disintegration of the tablets produced using GFBG.

Moisture Monitoring in Fluid-Bed Granulation by Multi-Resonance Microwave Sensor: Applicability on Crystal-Water Containing Donepezil Granules.

Multi-resonance microwave sensors have recently been introduced for moisture monitoring of pharmaceutical particulates up to > 20% residual moisture. The extended measuring range compared to previous systems as well as the microwave moisture values independent of other physical attributes make them promising process analytical technology (PAT) tools for various pharmaceutical production processes. However, so far, research focused on measurements on raw materials or drug-free model granulates and has neither evaluated the applicability for materials with crystal water containing excipients nor for active ingredients. In this study, possible influence of crystal water was evaluated using lactose monohydrate and donepezil hydrochloride, an active pharmaceutical ingredient (API) against dementia. The study clearly showed that the contained hydrate does not cause interferences and is not monitored by the applied frequencies. Material-related limits measuring lactose monohydrate were only observed above typical granulation moistures and could be explained using raw resonance curves. Furthermore, the inclusion of donepezil hydrochloride into the monitored formulations and varied process parameters demonstrated the versatility of the microwave resonance sensor system. Inlet air temperature, spraying rate, and air flow were varied according to a 23 full factorial experimental design. A predictive model (R2= 0.9699, RMSEC = 0.33%) could be established using samples produced with different process parameter settings adjusted according to the corner points of the full factorial design and validated on the center point granulation processes (RMSEV = 0.38%). Thereby, performance on actual formulations and conditions faced during process development could be thoroughly assessed, and hence, another key requirement for applicability in formulation development could be met.

Evaluation of in-line particle measurement with an SFT-probe as monitoring tool for process automation using a new time-based buffer approach

The Process Analytical Technology (PAT) initiative published by the Food and Drug administration (FDA) describes PAT systems as important tools to optimize pharmaceutical processes in order to ensure the final product quality. Real-time particle size measurements provide a promising approach for process automation of fluid bed granulation processes. This work focuses on the introduction and evaluation of a new time-based buffer approach for in-line spatial filtering technique (SFT) in order to provide a minimum time delay of the real-time measurement. Comparing the new buffer system to the conventionally used number-based approach, a reduced influence of the particle rate and a constant response time was found. A performance qualification of the Parsum probe IPP 80 using this buffer approach according to the ICH guideline Q2 was performed to investigate whether common variations of process parameters influence the real-time particle size measurement. Focussing on the main requirements for process control, hereby a good precision and specificity as well as an adequate robustness was found. Summarized, this study identified the time-based buffer system as more suitable buffer system for process automation.

Effect of different binders on reconstitution behaviors and physical, structural, and morphological properties of fluidized bed agglomerated yoghurt powder

Fluidized bed agglomeration is a widely used technique in the production of instant food powders. In this process, primary particles are agglomerated to give a granule-shaped product with improved instant characteristics compared to the original primary particles. Instant products are easy to use by the consumers and hence are favored over the unagglomerated particles. Depending on the type of binder used and process conditions, agglomerates exhibit different shapes, structures and instant properties. In this study, spray-dried yoghurt powders were agglomerated in a top sprayed fluid bed granulator. The influence of different binders (distilled water, ionic, and sugar-based solutions) on agglomeration growth mechanism, particle morphology, and chemical bonds were investigated. The results showed that sugar-based binders caused large particle size and porosity compared to water binders (p < 0.05). Hydrophilic sugars also improved wettability. b* value of powders enhanced with sugar binders. Protein and stretching vibration of N–H groups were affected by acidity of water and resulted in an improvement of powder solubility. Circularity of particles decreased with the usage of hydrophilic sugar solutions while elongation increased.

Two-compartment modeling and dynamics of top-sprayed fluidized bed granulator

• Compartmental approach is used to model and simulate a top sprayed fluidized bed granulator. • The dynamic behavior is analysed by varying the process conditions and parameters. • Finite volume scheme is modified to solve the proposed mathematical model. • New analytical solutions are derived for the verification of model. • Constant volume Monte Carlo is developed for the proposed model and used for the validation. A top Spray Fluidized Bed Granulator (SFBG) is being modeled and analyzed with the help of population balance equation (PBE) and analytical as well as numerical results. The mathematical model for SFBG is derived using the concept of compartment modeling. The granulator is divided into two compartments, a wet compartment in which aggregation is the dominant process, and a dry compartment that is dominated by breakage. A new discretization is given to solve the model which is based on the idea of conserving the important properties of the system. The numerical results of the moments derived by the new discretization are validated against the developed exact results for different combinations of the aggregation and breakage kernels. The model is also tested for physical tractable kernel and the numerical results are authenticated with the results of constant volume Monte Carlo. The two-compartment model is shown to behave dynamically in a distinctly different manner to the simpler one-compartment model. The most critical parameter is the exchange flow between the compartments. When the characteristic time for this flow is low relative to the rates of aggregation and breakage, the effect of breakage is amplified disproportionally relative to breakage, and whereas the single-compartment granulator always reaches steady state between the rates of aggregation and breakage, the two-compartment model may, under some conditions, lead to continuously decreasing size under the dominance of breakage.

Conversion of PLGA nanoparticle suspensions into solid dosage forms via fluid bed granulation and tableting

Incorporating poorly soluble drugs into polymeric nanoparticles is a widely investigated approach to improve their biopharmaceutical performance. Poly(DL-lactide-co-glycolide) (PLGA) nanoparticle formulations have previously been tested and recommended as drug carriers for peroral administration of poorly soluble porphyrin derivatives intended for photodynamical therapy. Based on those PLGA formulations the present study investigates conventional techniques like fluid bed granulation and tableting for conversion of such polymeric nanoparticle suspensions into solid dosage forms. Analytical methods like asymmetrical flow field-flow fractionation (AF4) and photon correlation spectroscopy (PCS) were used to assess changes of the nanoparticle properties during processing and the recovery after redispersion of the solid dosage forms. Preliminary experiments were conducted to demonstrate the feasibility of the granulation and tableting strategy. Afterwards, design of experiments (DoE) was used to determine formulation and process parameters with critical influence on several properties of the solid forms, in particular the recovery of nanoparticles during dissolution testing.Fluid bed granulation with aqueous PLGA nanoparticle suspensions and soluble carriers was shown to be a simple and high yield process for drying of the nanoparticles. The nanoparticle concentration of the granulation suspension and the ratio of the spraying rate and the atomization air pressure were critical for the physicochemical characteristics of the granules like density and particle size distribution (PSD) as well as for the redispersibility to nanoparticle suspensions of original properties. The granules were compressed to tablets without impairing the nanoparticle diameter and the recovery when an adequate level of filler and low compression forces were used.

The effect of different feed frame components on the powder behavior and the residence time distribution with regard to the continuous manufacturing of tablets

The present study focused on the effect of different feed frame components on the residence time distribution of a three-chamber feed frame system (Fill-O-Matic). A production-scale rotary tablet press was used to simulate the industrial manufacture of tablets. The powder residence time distribution was used to characterize the powder behavior in the Fill-O-Matic. Therefore, two powder blends based on microcrystalline cellulose, one of them serving as a plain powder blend (MCC blend) and the other blend (tracer blend) spray colored with an indigo carmine solution by a fluid bed granulator, were used. With these powder blends, the effect of the reduction of the Fill-O-Matic volume with a perspex disc on the residence time distribution was compared with the standard configuration of the Fill-O-Matic. Furthermore, the filling wheel design with regard to the rod shape and different gap size configurations between the feed frame and the die disc were investigated. Interestingly, the reduction of the feed frame volume led to a remarkable decrease of the mean residence time and the mean centered variance. Moreover, the results of the filling wheel design showed that the rod shape of the filling wheels had a high influence on the intermixing of the powder particles in the filling chamber, whereas the corresponding tablet weights and their relative standard deviation were not affected. The gap size between the feed frame and the die disc had low influence on the residence time distribution but an effect on the tablet weights and their standard deviation.

Novel population balance model for granule aggregation and breakage in fluidized bed granulation and drying

A novel population balance model for the fluidized bed granulation and drying process was developed taking into consideration moisture content for determining the coalescence and breakage probabilities. Experimental data of pharmaceutical powders manufactured at production scale was used to determine the coalescence and breakage rate constant. It was found that the calculated mean volume diameter and frequency distribution showed good agreement with the experimental ones observed during the coalescence growth and the breakage stages.