Modelling nucleation in wet granulation

Nucleation is the first stage in any granulation process where binder liquid first comes into contact with the powder. This paper investigates the nucleation process where binder liquid is added to a fine powder with a spray nozzle. The dimensionless spray flux approach of Hapgood et al. (Powder Technol. 141 (2004) 20) is extended to account for nonuniform spray patterns and allow for overlap of nuclei granules rather than spray drops. A dimensionless nuclei distribution function which describes the effects of the design and operating parameters of the nucleation process (binder spray characteristics, the nucleation area ratio between droplets and nuclei and the powder bed velocity) on the fractional surface area coverage of nuclei on a moving powder bed is developed. From this starting point, a Monte Carlo nucleation model that simulates full nuclei size distributions as a function of the design and operating parameters that were implemented in the dimensionless nuclei distribution function is developed. The nucleation model was then used to investigate the effects of the design and operating parameters on the formed nuclei size distributions and to correlate these effects to changes of the dimensionless nuclei distribution function. Model simulations also showed that it is possible to predict nuclei size distributions beyond the drop controlled nucleation regime in Hapgood's nucleation regime map. Qualitative comparison of model simulations and experimental nucleation data showed similar shapes of the nuclei size distributions. In its current form, the nucleation model can replace the nucleation term in one-dimensional population balance models describing wet granulation processes. Implementation of more sophisticated nucleation kinetics can make the model applicable to multi-dimensional population balance models.     

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.     

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.     

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.     

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.     

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.     

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.     

Wet granule breakage in a breakage only high-hear mixer: Effect of formulation properties on breakage behaviour

Wet granule breakage can occur in the granulation process, particularly in granulators with high agitation forces, such as high-shear mixers. In this paper, the granule breakage is studied in a breakage only high-shear mixer. Granule pellets made from different formulations with precisely controlled porosity and binder saturation were placed in a high-shear mixer in which the bulk medium is a non-granulating cohesive sand mixture. After subjecting the pellets to different mixing time in the granulator, the numbers of whole pellets without breakage are counted and taken as a measure of granule breakage. The experimental results showed that binder saturation, binder viscosity and surface tension as well as the primary powder size have significant influence on granule breakage behaviour. It is postulated that granule breakage is closely related to the granule yield strength, which can be calculated from a simple equation which includes both the capillary and viscous force of the liquid bridges in the granule. The Stokes deformation number calculated from the impact velocity and the granule dynamic strength gives a good prediction of whether the granule of certain formulation will break or not. The model is completely based on the physical properties of the formulations such as binder viscosity, surface tension, binder saturation, granule porosity and particle size as well as particle shape.     

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.     

Measurement of the velocity field and frictional properties of wet masses in a high shear mixer

In order to develop predictive process models and to enhance process understanding in high shear granulation, there is an ongoing search for non-intrusive methods for measuring the wet mass velocities in the mixer. In this study, a high speed CCD camera is used in combination with software for particle image velocimetry (PIV) calculations to obtain information about the wet mass velocities. The focus has been on obtaining good spatial and angular resolution for the velocities along the glass bowl wall. In a Jenike shear cell, both internal and wall frictional properties have been measured and together with velocity data, this information is used for prediction of the impeller torque. It has been shown that the near wall velocities are strongly dependent on the coefficient of wall friction, which decreases during liquid addition. The decrease in the coefficient of wall friction results in increased wet mass velocities close to the bowl wall. It is also found that the wet mass velocity has a strong angular dependence, resulting in a high frequency pulsing bed behaviour which cannot be detected by visual inspection. The predictive impeller torque model developed by Knight et al. [2001. Prediction of impeller torque in high shear powder mixers. Chemical Engineering Science 56, 4457-4471] has been generalized to account for cohesive materials and with frictional and velocity data, the level of the impeller torque is well predicted. However, the model is based on crude assumptions regarding the velocity distribution and hence, it cannot capture the dynamics in the measured torque curve satisfactorily.     

制冷剂瞬态喷雾冷却表面传热特性

喷雾冷却在工业工程中应用广泛,其表面相变传热过程非常复杂,需要开展深入研究揭示其机理与规律。以R134a、R407C及R404A制冷剂为工质开展瞬态喷雾冷却表面相变传热特性实验研究,提出了表征冷却表面内部导热阻力与喷雾表面对流传热阻力之比的喷雾Biot数,以及表征瞬态喷雾冷却最大热通量及其出现时刻的量纲1 Reynolds数Re_l和Fourier数Fo_l。将Jakob数Ja与Re_l及液滴Weber数We关联,提出了最大热通量及其出现时刻的通用量纲1关联式。发现不同制冷剂的瞬态喷雾冷却过程具有相似性,得到了热通量随时间变化的量纲1关联式。利用上述关联式对喷雾表面瞬态温度进行模拟,结果与实验结果吻合较好,证明了关联式的准确性。     

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     

Wet granulation: the effect of shear on granule properties

This paper presents a study of the wet granulation of fine cosmetic particles using a high-shear mixer granulator on a given particle and binder system. The shear effect on granule properties is highlighted. The granules formed under different impeller speeds are divided into size classes and further examined in terms of porosity, friability and binder content.

The main result of this study is that, depending on operating conditions, the granulation of a fine powder with a given binding liquid can result in the formation of granules of very different characteristics in terms of size, porosity and friability. Mechanical energy brought to the granulation system is as important as the physicochemical characteristics of the powder–binder pair.     

Fluidized bed spray granulation: Investigation of the coating process on a single sphere

The coating and granulation of solid particles in a fluidized bed is a process which converts pumpable and atomizable liquids (solutions, slurries, melts) into granular solids in one step by means of drying. The solution to be processed is sprayed onto a fluidized bed. Particle growth can take place either via surface layering or agglomeration. In the case of surface layering the atomized droplets deposit a thin layer of liquid onto the seed particles. The solvent is then evaporated by the hot fluidizing, leaving behind the dissolved material on the surface. Although fluidized bed spray granulation and film coating have been applied in industry for several years, there is still a lack of understanding of the physical fundamentals and the mechanisms by which spherical granules are formed. Hence a new method was developed which allows the direct observation of the subsequent particle-forming mechanisms such as droplet deposition, spreading, wetting and drying. The authors present a laboratory scale apparatus in which a single freely suspended particle can be coated under well defined and constant coating and drying conditions. With this device, particle-growth-rate and the development of particle morphology were measured and investigated under various experimental conditions.     

牛初乳粉低温造粒的实验研究

为考察料液流量、料液浓度和料液种类等影响牛初乳颗粒生长速率的因素,得到牛初乳颗粒的生长规律及工艺参数,为流态化低温造粒装置的研制提供依据,以牛初乳粉为原料,采用低温流态化喷雾造粒技术制取了牛初乳颗粒。结果表明,低温造粒能够保护产品质量不变,保持物质原有的色、香、味及营养。     

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.     

Origin of profound changes in powder properties during wetting and nucleation stages of high-shear wet granulation of microcrystalline cellulose

The aim of this work was to understand the evolution of powder tabletability and flowability during wetting and nucleation stages of high-shear wet granulation (HSWG). Microcrystalline cellulose (MCC) was granulated with water using a high-shear process. Granule morphology, surface texture, size, porosity, specific surface area, tabletability, and flowability were characterized. MCC granulated with 5% water showed no change in tabletability but significantly improved flowability, corresponding to smoother surfaces and lower surface area. From 5% to 25% water, tabletability decreased by 1/4 but flowability remained unchanged. Granule shape and porosity remained unchanged while surfaces were smoothened, leading to decreased surface area. From 25% to 35% water, MCC granules became more round. There was another sharp decrease in tabletability but powder flowability remained unchanged. Forty-five percent of water led to more particle rounding and commencement of nucleation, which only slightly impacted tabletability and flowability. From 0% to 45% water, granule size decreased slightly and could not explain the significant changes in powder tabletability and flowability. Deteriorated tabletability was instead caused by surface smoothing, granule densification, and granule rounding. Enhanced powder flowability was caused mostly by surface smoothing with granule rounding as a minor contributor.     

Wet granulation in a batch high shear mixer

This study deals with the wet granulation in a high shear mixer. The experimental apparatus is a laboratory scale ”Lödige” granulator, with a maximum volume of 20 l, equipped with a chopper and a pneumatic spraying system. The main objective of the study is to point out the effect of physico-chemical properties and operating conditions on the growth mechanisms and kinetics in this type of granulation device. Two kinds of alumina with different particle size distributions (alumina SH100 and alumina SH30) were granulated using various Newtonian liquids having different surface tension, viscosity, binder concentration, density, etc. (water, aqueous solutions of polyethyleneglycol or polyvinyl alcohol). Experimental results showed that the granulation process generally proceeds through three distinct growth regimes independent of the nature of the powder, the binder liquid or the operating conditions. However, the transition between different regimes depends on the physico-chemical properties of the solids and liquids, on operating conditions and on the experimental procedure. For the alumina powder used in this study the transition occurs when a degree of liquid saturation of about 68% is reached.     

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.     

Flow patterns in granulating systems

Particle flow patterns were investigated for wet granulation and dry powder mixing in ploughshare mixers using Positron Emission Particle Tracking (PEPT). In a 4-l mixer, calcium carbonate with mean size 45 μm was granulated using a 50 wt.% solution of glycerol and water as binding fluid, and particle movement was followed using a 600-μm calcium hydroxy-phosphate tracer particle. In a 20-l mixer, dry powder flow was studied using a 600-μm resin bead tracer particle to simulate the bulk polypropylene powder with mean size 600 μm. Important differences were seen between particle flow patterns for wet and dry systems. Particle speed relative to blade speed was lower in the wet system than in the dry system, with the ratios of average particle speed to blade tip speed for all experiments in the range 0.01–0.25. In the axial plane, the same particle motion was observed around each blade; this provides a significant advance for modelling flow in ploughshare mixers. For the future, a detailed understanding of the local velocity, acceleration and density variations around a plough blade will reveal the effects of flow patterns in granulating systems on the resultant distribution of granular product attributes such as size, density and strength.