Liquid distribution in wet granulation: dimensionless spray flux

This study investigates binder distribution in wet granulation and focuses on the nucleation zone, which is the area where the liquid binder and powder surface come into contact and form the initial nuclei. An equipment independent parameter, dimensionless spray flux Ψ_a, is defined to characterise the most important process parameters in the nucleation process: solution flowrate, powder flux, and binder drop size.Ex-granulator experiments are used to study the relationship between dimensionless spray flux, process variables and the coverage of binder fluid on the powder surface. Lactose monohydrate powder on a variable speed riffler passed under a flat spray once only. Water and 7% HPC solution at two spray pressures were used as binders. Experiments with red dye and image analysis demonstrate that changes in dimensionless spray flux correlate with a measurable difference in powder surface coverage. Nucleation experiments show that spray flux controls the size and shape of the nuclei size distribution. At low Ψ_a, the system operates in the drop controlled regime, where one drop forms one nucleus and the nuclei size distribution is narrow. At higher Ψ_a, the powder surface cakes creating a broader size distribution. For controlled nucleation with the narrowest possible size distribution, it is recommended that the dimensionless spray flux be less than 0.1 to be in the drop-controlled regime.     

Foam granulation: Binder dispersion and nucleation in mixer-granulators

Traditional wet granulation method involves spraying of liquid binder onto a moving powder bed to granulate the powder particles in the granulator. A new alternative method of wet granulation has been developed where foam delivery of binder is used to granulate the powder particles.This study investigated binder distribution in wet granulation and focused on the nucleation stage, where nuclei are formed during the initial binder distribution. Nucleation experiments were used to study the formation of nuclei by the foam and spray delivery methods in a high shear mixer-granulator. The distribution of foams on a dynamic powder bed were also investigated by filming small portion of foams as they penetrated into moving powder beds under different powder flow conditions in a high shear mixer-granulator.Nucleation experiments in this study show that foam delivery tends to create a narrower nuclei size distribution during the early stage of wet granulation process compared to spray delivery at the same processing conditions, demonstrating the potential of foam granulation in achieving improved binder distribution. For foam delivery, the nuclei formation is influenced by the foam properties and powder flow conditions in the granulator. The experiments show that the narrowest nuclei size distribution is obtained by granulating with high-quality foam and intensive powder mixing conditions. Coarser nuclei are formed when low-quality foam is dispersed in a less intensively agitated powder. The interactions of foam quality and the powder flow pattern are discussed and two distinct wetting and nucleation mechanisms are proposed: (1) under bumping flow, a low-quality foam tends to induce localised wetting and nucleation. The wetting and nucleation is “foam drainage” controlled. (2) Under roping flow, foam will be dispersed by the motion of the agitated powder. The wetting and nucleation is “mechanical dispersion” controlled.     

Quantifying liquid coverage and powder flux in high-shear granulators

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

Drop penetration time in heterogeneous powder beds

Wet granulation is a technique in which enlarged particles or ‘granules’ are produced from the coalescence of fine particles, with the intention of improving the powder properties. High shear granulators are often used to carry out the granulation process where the powder mass is agitated in a vessel by mechanical means while liquid is sprayed from above onto the powder bed surface. When the binder droplets impact the powder surface, the drop penetration time of the droplet into the powder is important for uniform binder dispersion and the prediction of the formation of granule nuclei from the nucleation map, which depends on the dimensionless spray flux. Previous studies on the drop penetration time were carried out on predominantly hydrophilic powder beds. Although this gives a good prediction of the nucleation behaviour in granulation, it does not reflect the condition where hydrophobic drugs are used in the formulation without surfactants. This paper aims to look at the effects of powder bed hydrophobicity on the drop penetration time.Single drop nucleation experiments using a syringe and a small powder bed were carried out on varying ratios of salicylic acid and lactose powders to study the kinetic of drop penetration. As expected, the drop penetration time increased as the proportion of hydrophobic component increased in the powder mixture. However, long drop penetration times were observed for low degrees of drug loading, showing that hydrophobicity strongly influences the drop penetration time. The wettability of the powder mixture also has a pronounced affect on the granule properties in which the hydrophobicity of the powder mixture is proportional to the granule strength and inversely proportional to the granule size. These findings have important implications in terms of the design of the granulation process where conditions of minimum spray flux or efficient mechanical forces are recommended to produce a more uniform granulation batch.     

Foam and drop penetration kinetics into loosely packed powder beds

Foam granulation is a new liquid delivery method for wet granulation, where the liquid binder is delivered as an aqueous foam, rather than as an atomised spray to the powder bed. This paper reports for the first time the similarities and differences between wet granulation via foamed and sprayed binder addition methods.The kinetics of single foam and single drop (of HPC and HPMC solutions) penetrations into loosely packed powder beds (of glass ballotini and lactose powders) were studied. Specific penetration time (defined as penetration time per unit of binder mass) and nucleation ratio (defined as the ratio of nuclei granule mass to liquid binder mass) were compared between foam and drop nucleation methods. The impact of particle size and binder concentration on both parameters was also studied.The results indicate that the foamed binder addition method allows a greater mass of binder fluid to be absorbed into the particle bed and uses less liquid binder to nucleate the same number of gram of powder, which indicates improved nucleation efficiency compared to the drop addition method.     

A novel nucleation apparatus for regime separated granulation

A novel nucleation apparatus is presented for the production of narrow sized nuclei from various powder and binder liquid combinations. Mono-sized binder liquid droplets are produced by a specially designed mono-disperse droplet generator. The droplet generator is positioned above a conveyor belt, transporting a powder bed through the spray zone of the droplet generator. By nucleating powder on a conveyer belt, the nucleation mechanism is completely separated from all other granulation mechanisms due to the lack of relative motion between primary particles and/or formed nuclei. Nucleation tests were performed using chalcopyrite and limestone powders with water as the binder liquid. At all operating conditions, the formed nuclei were found to originate from multiplicities of drops that merged on the powder bed surface. Investigation of the dynamics of nuclei formation showed that powder-binder liquid combinations with fast penetration dynamics result in less variation in the number of droplets from which nuclei originate. Smaller and more narrowly distributed nuclei were also achieved by increasing powder speed through the spray zone.     

A narrow size distribution on a high shear mixer by applying a flux number approach

High shear granulation is a common technology for particle size enlargement, but generally the product properties are badly affected by the broad size distribution generated in the process. A recently published approach by Michaels et al. [J.N. Michaels, G. Wang, L. Farber, K.P. Hapgood, J.H. Chou, S. Heidel, and G.I. Tardos, 2006, One-dimensional scale-up of high-shear granulators, Paper 243c, World Congress Particle Technology 5, Orlando (FL)] employs low binder solution spray rates and long granulation times, whilst the solids are kept in roping flow, to avoid coarse formation. The present work applies this approach to a two-component binder system with a dry powder gum and water spray as activation agent. Similarities with fluidised bed granulation and coating processes are explored. The work shows that indeed narrow size distributions of fine granules can be achieved with ease. Dimensionless numbers for spray fluxes are useful to identify operating regimes and to steer optimisation efforts. Comparison of flux numbers for different systems shows that they are not useful (yet) for detailed product and process design. Further work on material-specific quantities controlling nucleation and growth, e.g. particle wetting, is recommended.     

Foam granulation: Liquid penetration or mechanical dispersion?

There have been significant advances in the understanding of wet granulation processes. Foam granulation is the latest development and an emerging area of interest for pharmaceutical manufacturing.Single foam penetration experiments were carried out on static powder beds, followed by short-nucleation experiments (where nuclei are formed by a nucleation-only mechanism) and full foam granulation experiments (where nucleation, growth and breakage are occurring simultaneously). All experiments were performed with lactose monohydrate powder using a 5 L high shear mixer–granulator. The foam penetration/dispersion behaviour was examined and the granule size distributions were investigated as a function of foam quality (83–97% FQ), impeller speed (105–515 rpm) and wet massing period (0–4 min).Nucleation in foam granulation is postulated to undergo either “foam drainage” or “mechanical dispersion” controlled mechanisms. For “foam drainage” mechanism, the foam penetrates the powder bed to form coarse and broad granule size distributions. For “mechanical dispersion” mechanism, the wetting and nucleation conditions are governed by the powder mixing conditions and similar granule size distributions are produced. Regardless of the mechanism, the initial wetting and nucleation behaviour controls the initial nuclei size distribution, and this initial distribution is retained in the final granule size distribution. This work demonstrated the critical importance of the nucleation and binder distribution in determining the granule size distributions for foam granulation process.     

Influence of liquid binder dispersion on agglomeration in an intensive mixer

In industrial scale mixer granulation, liquid binder is usually sprayed onto the agitated powder bed by means of a nozzle in order to enhance the agglomeration process. The early stage of this process, where granule nuclei are formed and grow, is not well understood. As it is desirable to model the agglomeration state right from the beginning of the process for the purposes of control and modeling, this nucleation step is therefore an important field of interest.To investigate the influence of binder droplet size on the nucleation stage of the agglomeration process, experiments were carried out with lactose and water in an intensive mixer. Water was sprayed in to the mixer with different nozzles to vary the size of the produced droplets. As a comparison, water was also directly poured into the turning mixer. Samples of the produced granules were taken at specific time intervals and analysed for size and water content. As the experiments were focused on examining short granulation times, the first samples were taken after only half of the water was added.Particle size distribution and liquid distribution in the wet granule samples were analyzed. It was found, that the droplet size of the binder liquid has great influence on agglomerate size and binder distribution at short mixing times, with increasing time, the mechanical stresses acting in the mixer becomes more and more dominating in the process. Preliminary comparisons are also carried out with single drop penetration tests in an attempt to correlate drop size to penetration time and also to produced granule size.In conclusion this paper studies the effect of different drop size conditions and subsequent spray flux on the behaviour of the nucleation and the early stages of the agglomeration process. The context of these findings for agglomeration in an intensive mixer is examined.     

Rewetting effects and droplet motion on partially wetted powder surfaces

In high shear mixer granulation, the powder is agitated in a vessel while liquid is sprayed onto the powder. Formation of “nuclei” can be predicted using a nucleation regime map. However, this approach assumes that only dry powder enters the spray zone. Industrial granulation processes commonly add 20–50 wt % fluid, and the partially wetted powder recirculates many times through the spray zone. The effect of partially wetted powder re‐entering the spray zone is not currently known. To investigate, droplets were added to a powder bed at controlled separation distances and time intervals. A strong correlation between drop penetration time and droplet motion on the powder bed surface was observed. For fast penetrating systems, nucleation was only slightly affected by the presence of the previous droplet. However, systems with long penetration times showed lateral droplet motion due to Laplace pressure differences. Implications for the nucleation regime map are discussed. © 2009 American Institute of Chemical Engineers AIChE J, 2009     

Mapping of regimes for the key processes in wet granulation: Foam vs. spray

The evaluation of foam and spray granulation mechanisms and their performances in achieving uniform liquid distribution in a high‐shear mixer‐granulator is presented. A regime map is presented to describe the granulation mechanisms for the foam and spray systems. Foam and spray granulation are shown to successfully create granules of well‐distributed moisture at the end of wet massing despite there was a deviation from the theoretical moisture content at the end of binder addition. In the wetting and nucleation regime, spray granulation involves drop penetration nucleation outside of the drop‐controlled regime, whereas foam granulation operates favorably in the mechanical dispersion regime. For foam granulation, mechanical dispersion produces more uniform granule‐size distributions below the overwetting limit. Spray granulation exhibits steady granule growth, whereas foam granulation shows induction granule growth followed by rapid granule growth. The regime map provides a basis to customize formulations and compare the different foam and spray granulation mechanisms. © 2013 American Institute of Chemical Engineers AIChE J, 59: 2328–2338, 2013     

A new technique to determine rate constants for growth and agglomeration with size- and time-dependent nuclei formation

Fluidized bed spray agglomeration is a particle size enlargement process where particles stick together with the help of spraying binder. High impact forces between particles lead to attrition. Attrition may be modeled as poly-disperse nucleation. Furthermore, particulate event like over-spray leads to the formation of particles in a wide range of volume. A new technique for the determination of agglomeration, growth and nucleation parameters is presented in this work. The model is based on a previous approach which takes mono disperse nuclei formation in the smallest class into account. Frequently in crystallization processes, nucleation is assumed to be mono-disperse. The technique presented here incorporates nuclei formation in a certain range of volume. It is quite general and applicable to consider size- and time-dependent nuclei formation. For two particular cases of growth and agglomeration including size-dependent nuclei formation, simulation data was generated by continuous feeding of nuclei in a certain range to demonstrate the capability of parameter extraction of the model. Further, the new technique is applied to extract rate constants from experimental data measured during fluidized bed spray agglomeration. This technique is also useful for the prediction of bimodal behavior of particle size distributions (PSD).     

Effect of process parameters on the melt granulation of pharmaceutical powders

Co-melt granulation of lactose and PEG was investigated in a fluidised bed granulator. The effect of process parameters such as binder content and binder viscosity were correlated to granulation time and particle size distribution. The experimental data indicated that after initial nucleation the granulation mechanism was dependent upon binder content and binder viscosity. When the binder content was increased above 18% (w/w) de-fluidisation of the bed occurred and granulation moved to the slurry regime. As the process involved the melt granulation of relatively high molecular weight (6-20 k) and thus high viscosity PEG (500-19000 mPa s), it was found that binder viscosity had a significant affect on the granule growth mechanism. Granulation with a binder viscosity of 500 mPa s resulted in granule growth by coalescence, however, an increase in binder viscosity resulted in less coalescence and a lower granule growth rate. Furthermore, the granulation data were characterised by Stokes number analysis.     

Nucleation and growth in fluidised hot melt granulation

Fluidised hot melt granulation (FHMG) is a novel technology for granulation process in pharmaceutical industry, which has distinct advantages over other commercial techniques. The aim of this research was to investigate granulation and the effect of process parameters that may affect FHMG process. In this work, ballotini beads were used as the model particles and Lutrol® F 68 Poloxamer 188 was used as meltable solid binder. In order to determine the granulation and nucleation mechanism in this co-melt FHMG system, several parameters were investigated, such as binder content, particle size of binder and particle size and hydrophobicity of ballotini. These parameters were correlated to granule size distribution, mean granule size and granule shape. Furthermore, these experimental investigations were designed so that the coalescence model could be applied to the co-melt FHMG system. The analysis indicated that the non-inertial regime extends over a relatively short time period of < 60s, however this accounts for the majority of the particle size increase in the entire process. A decrease in the extent of granulation was induced by increasing the hydrophobicity of the ballotini, which was ascribed to a decrease in capillary pressure of the system.     

A basic population balance model for fluid bed spray granulation

A basic population balance approach is developed for a granulation process in a fluid bed spray granulator. The particle size distribution predicted by the model is confirmed by plant data. Hence this model is considered to be useful to describe and optimize an industrial process. The model depends on a limited number of parameters (most of these factors can be measured or are known): the spray volume flux, the nucleation fraction (the fraction of the spray volume flux which leads to new particles formed), the nucleation particle diameter, the product withdrawal threshold diameter, and the product withdrawal rate. Analysis of the model reveals a steady-state constraint; a steady state does not exist if the nucleation fraction is too large. For cases where the steady state does exist, the steady-state particle size distribution is solved analytically. A numerical implementation of the model is used to illustrate the transient evolution of the process. The steady-state solution appears to be stable for a constant nucleation fraction. However, if the nucleation fraction depends on the bed height the steady state can be unstable. Such a situation may occur if the spray inlet is near the height of the bed surface. Instead of convergence towards a steady state, the transient solution displays ongoing oscillatory behavior with an oscillation period of a number of hours. A linear stability analysis is performed to confirm the findings on the stability of the steady state.     

Kinetics and mechanisms of growth in batch and continuous fluidized bed granulation

Aspects of the development of a model for prediction of product size distributions from fluidized bed granulation by agglomeration are described. Experimental work includes small scale continuous and batch granulation and analysis of the distribution of sprayed binder. A simple method of measuring one of the parameters in the numerical model is presented.     

Hot melt granulation of coarse pharmaceutical powders in a spouted bed

The hot melt granulation of a coarse pharmaceutical powder in a top spray spouted bed is described. The substrate was lactose-polyvinylpyrrolidone particles containing or not acetaminophen as a drug model. Polyethylene glycol (MW, 4000) used as binder was atomized onto the bed by a two-fluid spray nozzle. The granulation experiments followed a 2³ factorial design with triplicates at the center point and were carried out by varying the spray nozzle vertical position, the atomizing air flow rate and the binder feed rate. Granules were evaluated by their pharmacotechnical properties like size distribution, bulk and tapped densities, Carr index, Hausner ratio and tableting characteristics. Analysis of variance showed that granule sizes were affected by the PEG feed rate and atomizing air pressure at the significance levels of 1.0 and 5.0%, respectively, but spray nozzle distance to the substrate bed was not significant. The spray conditions also affected granule flow and consolidation properties, measured by the Carr index and Hausner ratio. Measured densities, Carr indexes and Hausner ratios proved that granules flowability and consolidation properties are adequate for pharmaceutical processing and tableting. Tablets prepared with acetaminophen-containing granules showed good properties and adequate release profiles in in vitro dissolution tests. The results indicate the suitability of spouted beds for the hot melt granulation of pharmaceutical coarse powders.     

Single drop behaviour in a high shear granulator

The wet granulation process starts when a liquid drop makes contact with the powder bed. In a powder bed, drops are subjected to centripetal and gravitational forces. These forces may affect the size and shape of the drop as it is incorporated into the bed. The majority of experiments studying droplet behaviour have been performed on static bed surfaces. This paper seeks to demonstrate droplet behaviour during the initial contact stage with a dynamic powder bed representative of that occurring during high shear granulation. Particle image velocimetry (PIV) is used to determine droplet and powder bed surface velocities. Due to inclination of powder bed part of drop de-accelerate slowly moved downward while other parts remain attached to powder bed this result in their deformation and breakage. Amount of deformation of drop and span of area where it occurred was increased as drop was added farther from the outer edge of the mixer. This paper shows that the binder drop may deform or break in high shear granulator depending on its initial impact position. This will affect size distribution and other properties of nuclei.     

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].     

Steady states in granulation of pharmaceutical powders with application to scale-up

Theoretical and experimental evidence is given to show that steady states can be reached during agglomerate growth and break-up in high-shear granulation of fine powders. An earlier theoretical model [G.I. Tardos, I.M. Khan and P.R. Mort, Critical parameters and limiting conditions in binder granulation of fine powders, Powder Technology, 94, 245-258 (1997).], based on simple energy-dissipation considerations hinted at the existence of these states at the point where growth is counterbalanced by breakage. Further theoretical evidence is obtained from molecular dynamic simulations of wet and dry particles situated in a constant shear field [I. Talu, G.I. Tardos and M.I. Khan, Computer simulation of wet granulation, Powder Technology, 110, 59-75 (2000).], where the size distribution of initially identical particles, shifts in time to reach a dynamic steady state. Under the conditions of this steady state, the number of breaking agglomerates approximately equals the number of forming ones to yield a time independent final-size distribution.Experimental evidence to support the theoretical findings is obtained during the present research by measuring particle size distributions at line at crucial points during granulation of a typical pharmaceutical powder in a high-shear mixer. In order to reach a steady state, binder addition has to be slow enough and wet massing has to be long enough so that neither has an influence on the final properties of the granules. We show experimentally that if binder is spread properly and homogeneously in the powder and continuous shearing of the wet mass ensures homogeneous, equal growth of the granules, the steady state will only be a function of the total amount of fluid added provided that the shear forces in the machine are maintained constant.These findings are important in that they show that under carefully controlled conditions of binder addition and shear in the mixer, the granulation process is robust and controllable and can, in principle, be scaled up with ease once the powder ingredients and the total amount of binder are fixed.