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.     

Production of granola breakfast cereal by fluidised bed granulation

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

Multi-component granulation in a fast fluidized bed

The granulation of multi-component particles was conducted in a fast fluidized bed with an atomizing binder solution. The effects of gas velocity and binder droplet diameter on granulation rate, granule size distribution and granule composition were studied. The granulation rate and granule yield were determined by the balance between the agglomeration rate of feed particles and the disintegration rate of granules because there was no secondary granulation. With the increase in gas velocity and the reduction in binder droplet size, the agglomeration rate of feed particles decreased but the disintegration rate of granules increased, resulting in a reduced granule yield. Despite the larger fraction of small particles in the granules, the homogenous granulation of multi-component particles was achieved.     

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.     

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

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

Kinetics of fluidised bed melt granulation I: The effect of process variables

This paper is the first of a series to study the influence of operating conditions on the kinetics of fluidised bed melt granulation. First, we identify the rate processes responsible for the net growth in granule size in a top-sprayed fluidised bed granulator and propose a sequence of events based on these rate processes. The overall kinetics during the process is identified to be a combination of particle aggregation, binder solidification and granule breakage. By conducting experiments in a small-scale modified commercial fluidised bed granulator, the influence of various operating conditions (binder spray rate, bed temperature, atomising pressure, fluidising air velocity) on the granule growth behaviour was examined. The results indicate the granule growth rate to be directly dependent on the relative amount of binder sprayed into the bed, which essentially determines the speed of the aggregation process. The overall granule growth rate is observed to increase relatively with increased bed temperature for a more viscous PEG4000, while a maximum growth is seen for a lower viscosity PEG1500. A larger droplet size was also seen to have increased the overall growth rate, even though a smaller droplet seems to be able to induce a faster initial growth. The results also reveal the increase in fluidising air velocity to reduce the overall granule growth rate. The final granule size distribution was also observed to become narrower with increased bed temperature and fluidising air velocity. These observations are effectively explained using the proposed sequence of rate events.     

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].     

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

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

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.     

搅拌流化床喷雾造粒过程实验研究

在实验室规模的搅拌流化床干燥器中 ,对苯甲酸钠和聚丙烯酰胺为粘合剂的造粒过程进行了实验研究 ,分析了料液流率、过剩气体速度、雾化空气流率以及喷嘴高度对颗粒成长速率的影响 ,实验结果表明 ,苯甲酸钠明显以分层生长为主 ,聚丙烯酰胺则是团聚生长。这一结果对指导工业操作具有现实的意义     

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.     

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.     

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.     

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.     

流化床造粒影响因素及层式成长模型的研究

将流态化技术应用于粉体物料的造粒过程,在我国还是一项亟待研究开发的课题。本文对流化床造粒进行了实验研究,着重探讨了流化气速,粘合剂种类、浓度、流率,原料初始粒度,喷嘴位置等因素对颗粒成长速率及机理的影响。在此基础上,建立了粒子层式成长模型,并与实验数据进行了比较。     

流化床喷雾造粒制备MTO薄层催化剂实验研究简

根据甲醇制烯烃流化床反应一再生工艺对催化剂反应性能、球形度、耐磨强度等的要求,利用流化床喷雾造粒法制备了MTO薄层催化剂。实验研究了进料流率、分子筛组合物与粘结剂质量比、分子筛组合物浓度对薄层生长速率的影响并比较了分别以分子筛和成型催化剂为原料造粒时的薄层生长速率。实验结果表明,当分子筛组合物浓度高、进料流率大时,催化剂涂层生长速率快,表面活性成分负载量大。     

PARTICLE GROWTH IN A CONTINUOUSLY OPERATED FLUIDIZED BED GRANULATOR

Fluidized bed spray granulation offers several advantages compared to commonly used drying processes as spray drying, e.g. free flowing dust free coarse particles with a narrow particle size distribution can be produced in a single processing step. Especially for large production units a continuous operation is desirable. Unfortunately, there is still a lack of understanding concerning the mechanisms of particle formation and growth leading to difficulties in planning and operating such continuous granulators. Hence, experiments were performed to investigate the influence of process parameters on the growth process in a continuously operated fluidized bed granulator. Furthermore, a model was developed taking into consideration the particle exchange between nozzle jet and fluidized bed as well as the wetting and drying processes. The processes inside the jet are modeled in analogy to a wet scrubber. This modeling approach predicts an increase of growth rate with particle size. The prediction is in good agreement with experimental findings.     

PARTICLE GROWTH IN A CONTINUOUSLY OPERATED FLUIDIZED BED GRANULATOR

Fluidized bed spray granulation offers several advantages compared to commonly used drying processes as spray drying, e.g. free flowing dust free coarse particles with a narrow particle size distribution can be produced in a single processing step. Especially for large production units a continuous operation is desirable. Unfortunately, there is still a lack of understanding concerning the mechanisms of particle formation and growth leading to difficulties in planning and operating such continuous granulators. Hence, experiments were performed to investigate the influence of process parameters on the growth process in a continuously operated fluidized bed granulator. Furthermore, a model was developed taking into consideration the particle exchange between nozzle jet and fluidized bed as well as the wetting and drying processes. The processes inside the jet are modeled in analogy to a wet scrubber. This modeling approach predicts an increase of growth rate with particle size. The prediction is in good agreement with experimental findings.     

Granulation time in fluidized bed granulators

Size enlargement of particles in fluidized bed granulation involves mixing of particles with a binder liquid to form larger wet granules and drying them to form dry granules. Identification of the time for completion of granulation process is critical as further fluidization of dry granules is providing extra energy for their attrition. Monitoring the bed pressure drop and bed temperature of a batch fluidized bed granulator with time can provide information on the time for completion of the granulation process. Experimental observations on granulation time and size of granules in a lab-scale batch fluidized bed granulator are presented. Model based equations are developed for the estimation of granulation time and size of granules.     

Binder addition methods and binder distribution in high shear and fluidised bed granulation

Fluidised beds and high shear mixers are both important in industrial granulation. The binder addition method (pouring, melt-in, spraying) affects the growth and properties of granules and is therefore of vital importance to the fundamental understanding of this detailed process. Non-uniformity of binder distribution is well known in high shear melt granulation, however, there is limited literature surrounding binder distribution in fluidised bed granulation. It was therefore the aim of the paper to compare the binder distribution using alternative addition methods in both high shear mixer and fluidised bed.In this work two binder addition methods, ‘wet’ and ‘dry’, in a fluidised bed and high hear mixer were used to successfully produce granules with a typical pharmaceutical size, 150-300 μm. The granules were analysed for final binder distribution in different size classes using Patent V blue dye and ultra-violet spectrometry.All binder addition methods supported previous work showing non-uniformity of binder distribution throughout the size classes. High shear mixer results show great similarity in binder content whichever binder addition method was chosen. This is likely to be due to the same mechanisms occurring due to the impeller forces in the process, mean while the fluidised bed results show little similarity. The binder distribution by mass is also investigated and shows that although most studies show a relative higher binder content in the larger size classes that actually the majority of binder can instead be found around the mean size of the batch.