Non-uniformity of binder distribution in high-shear granulation

Further experimental investigation based on a microscopic, or single granule, scale has been conducted to investigate the uniformity of binder composition within a given size class for high shear melt granulation. This work assesses whether there is significant non-uniformity of binder composition within size classes to warrant considering this level of detail to improving population balance modelling of high shear granulation. It is concluded that at early times in a batch granulation process there is a broad variation in binder content between individual granules and that this variation persists in granules of small size.     

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.     

Development of a predictive high-shear granulation model

Within the pharmaceutical industry, high-shear granulation processes are well known for the production of drug-loaded granules. Development of such granulation processes, however, is often still more an art than a science. With the use of population balances, it is possible to link granulation rates to granule properties. Previous work demonstrated that good agreement between experimental and simulated results can be achieved [Powder Technol. 130 (2003) 162]. This enabled the granulation rates to be defined by two model parameters: the critical binder volume fraction and the aggregation rate constant. The modelling framework presented in this paper forms the basis of the kinetic analysis of granulation experiments that may lead to the development of a modelling tool that cannot only be used to simulate but also predict high-shear granulation behaviour in real-life pharmaceutical processes.     

The kinetics of the granulation process: Right from the early stages

In this study, experimentation and modelling were carried out to understand the granulation process. This work assesses whether there is a significant difference in the aggregation rate of the wet granulation process between the very early stages and later stages of high shear granulation. Measurements of the size distribution and binder content from the beginning of the process, just after liquid binder addition, were carried out. A population balance model based on two different kernels, the Equi Kinetic Energy (EKE) kernel and two-dimensional population balance equations with a Size Independent (SI) kernel, was applied to the high shear granulation process. It was concluded that the population balance equations with SI kernel best described the aggregation in the high shear granulation process. The value of aggregation rate constant in the early stages is smaller than aggregation kernel in the later stages.     

Binder liquid distribution during granulation process and its relationship to granule size distribution

The aim of this study is to characterize the impact of binder liquid distribution on granule properties during the wet granulation process. A new parameter, namely the binder liquid transfer coefficient, is used to characterize binder liquid distribution. The relationships between binder liquid distribution coefficient and granule size distribution are discussed. Granules are made of lactose alpha-monohydrate (97.5% w/w, d₅₀ = 31 μm) and polyvinylpyrrolidone (2.5% w/w, d₅₀ = 89 μm) and are manufactured in a Mi-Pro high shear mixer (Pro-C-epT, Belgium). Nigrosine is incorporated as a tracer in the binder liquid in order to detect its distribution in the granules during the process. The results show that the binder liquid is heterogeneously distributed at the beginning of the process whereas it tends to be evenly distributed in the powder during the process. The binder liquid transfer in granule classes obeys a first-order law and the binder liquid transfer coefficient appears to be related to operating conditions: high rotation speed, low liquid flow rate and low liquid viscosity favour the achievement of high liquid transfer coefficient. In addition, the higher the coefficient, the earlier the homogenization and the wider the granule mean diameters. Thus, granule size distribution can be controlled by the binder liquid distribution process. A binder liquid distribution mechanism is proposed, which makes it possible to discuss the influence of the operating parameters on the granule construction process.     

High shear granulation of dolomite – II: Effect of amount of binder liquid on process kinetics

This paper, the second of a series, analyzes the effect of binder amount on the kinetics of wet granulation process. Granulation experiments were conducted in batch, lab-scale high shear mixer with formulation system that was initially studied in first part of a series. First, we identify the effect of binder content on the net granulation behaviour during early stage of the process. Single entity property (its size) was accounted only within this research. The results indicate that binder content strongly promotes growth of dolomite entities. Secondly, 1-D discretized population balance equation (PBE) and Equi-Partition of Kinetic Energy (EKE) theory were used to simulate the net granulation process. Tested “coalescence-only” models provide good prediction of real dolomite granule size distributions (GSDs) during early stage of the process for each binder content value. By using modelling procedure granule growth rates were quantified. Ultimate goal of relating the coalescence rates of dolomite entities with binder amount variable is provided. This will result in a better perspective of the meso-scale of the dolomite granulation process.     

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.     

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.     

Model-based analysis of a twin-screw wet granulation system for continuous solid dosage manufacturing

Implementation of twin-screw granulation in a continuous from-powder-to-tablet manufacturing line requires process knowledge development. This is often pursued by application of mechanistic models incorporating the underlying mechanisms. In this study, granulation mechanisms considered to be dominant in the kneading element regions of the granulator i.e., aggregation and breakage, were included in a one-dimensional population balance model. The model was calibrated using the experimentally determined inflow granule size distribution, and the mean residence time was used as additional input to predict the outflow granule size distribution. After wetting, the first kneading block caused an increase in the aggregation rate which was reduced afterwards. The opposite was observed in case of the breakage rate. The successive kneading blocks lead to a granulation regime separation inside the granulator under certain process conditions. Such a physical separation between the granulation regimes is promising for future design and advanced control of the continuous granulation process.     

Rheology, granule growth and granule strength: Application to the wet granulation of lactose-MCC mixtures

This study aims at better understanding the wet granulation process of a binary mixture composed of microcrystalline cellulose (water insoluble) and lactose (water soluble). It investigates the effect of formulation (proportion of the different components in the mixture) on the granule growth kinetics, the evolution of granule morphology during granulation, the wet mass consistency and dry granule strength of the end product. Additionally the influence of mixer design has been studied by up scaling the process from the 1.9 L Mi-pro high shear mixer used as the reference scale to a 6 L Diosna P1-6 high shear mixer. The scale-up rules investigated were constant impeller tip speed and constant Froude number. Our results allowed us to draw the following conclusions:

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The increase in MCC content is found to increase the optimum binder requirement for granulation, wet mass consistency and dry granule strength.

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Granule growth takes place in three distinct stages: wetting, nucleation and growth. These stages can be identified with the help of the recorded torque values during the granulation process or by the evolution of granule size and granule morphology.

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The characterization of the starting materials by moisture sorption isotherms brings more insight to the role of each component during the granulation process.

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The increase of the granulation scale has little influence on the observed growth mechanism. However bi-modality of the granule size distribution is increased, wet mass consistency and dry granule strength are decreased with increasing scale of operation.

     

Electrical capacitance tomography as a monitoring tool for high-shear mixing and granulation

Electrical capacitance tomography (ECT) was utilized for monitoring of high-shear mixing and high-shear granulation processes. A finite element method (FEM)-based reconstruction algorithm was utilized to take into account the specific geometrical characteristics of the experimental set-up. Two-dimensional ECT tomograms, mixing index curves and permittivity fractions were computed based on the measurements, and their suitability in the analysis of the processes was assessed. It was found that the different mixing processes and the different granulation processes could be analyzed based on these quantities.     

High shear granulation of dolomite – I: Effect of shear regime on process kinetics

Wet granulation of previously unreported formulation system is presented. Dolomite powder is granulated under different shear regimes by using three-component binder formulation, water-molasses-polyvinylpyrrolidone. 1-D discretized population balance equation (PBE) and Equi-Partition of Kinetic Energy (EKE) coalescence kernel are applied to modelling granulation in a high shear mixer. Process modelling is focused to simulation of changes of the property of a group of entities, granule size distribution (GSD). The GSD predictions indicate the presence of coalescence growth as a dominant mechanism in the dolomite granulation process. Minor deviations between simulated and real GSDs signify the probability of other granulation mechanism(s) existence. A posteriori approach by integral method was used for coalescence rate constant estimation. This research highlights discrepancy in the coalescence rate of dolomite granulation process, between its early and later stages. Moreover, kinetic analysis of the high shear granulation process provides quantification of the macroscopic variable (impeller speed) influence on regarded property of a group of granules in terms of values of growth rate parameter.     

Simulating the early stage of high-shear granulation using a two-dimensional Monte-Carlo approach

A two-dimensional (2-D) model of a granulation process is presented in this paper. It aims to simulate an entire granulation batch without the use of an initial experimental or fictitious 2-D density function, by taking the experimental operating conditions into account. The mass of liquid and solid in the granules are the two predicted internal variables. The 2-D population balance equation is solved by a Constant Number Monte-Carlo method. This is a stochastic technique tracking the evolution of a population, whilst performing the calculations with a fixed number of particles. This is achieved by reducing or increasing the sample volume when an event results in a net production or a net decrease in the number of particles, respectively. An original multi-population approach is developed to describe the early stage of the process, where small numbers of granules are formed amongst a large number of primary particles. It consists of separating the primary particles from the granule population. A specific intensive variable is introduced to keep track of the repartition of masses. The overall density function is reconstructed a posteriori from the combination of the two populations. This approach allows the simulation to commence from the initial addition of liquid at the start of the process, rather than to start from an early granule size distribution. The early stage of the granulation process, frequently referred as nucleation, can therefore be studied numerically. Four different mechanisms are implemented. Nucleation and re-wetting describe the addition of liquid to the system. The interactions between liquid and solid phases are modelled by a layering process. An aggregation model is also included to simulate the growth of particles undergoing frequent collisions. Finally, the relevance of this new model is demonstrated by confronting the simulations to real experimental data.     

Population balance modelling of granulation with a physically based coalescence kernel

It was previously published by the authors that granules can either coalesce through Type I (when granules coalesce by viscous dissipation in the surface liquid layer before their surfaces touch) or Type II (when granules are slowed to a halt during rebound, after their surfaces have made contact) (AIChE J. 46 (3) (2000) 529). Based on this coalescence mechanism, a new coalescence kernel for population balance modelling of granule growth is presented. The kernel is constant such that only collisions satisfying the conditions for one of the two coalescence types are successful. One constant rate is assigned to each type of coalescence and zero is for the case of rebound. As the conditions for Types I and II coalescence are dependent on granule and binder properties, the coalescence kernel is thus physically based. Simulation results of a variety of binder and granule materials show good agreement with experimental data.     

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.     

An experimental study of the variability in the properties and quality of wet granules

For wet high-shear granulation, there can be a considerable variability in product quality in terms of the size, binder content, porosity, and appearance. Using the same equipment and feed material, it has been shown that such variability can be reduced by optimising the operating protocol. The associated narrowing of the range of mechanical properties for granules formed using an optimised procedure is exemplified by measurements of a number of parameters such as the coefficient of restitution.     

Empirical to mechanistic modelling in high shear granulation

This paper gives an overview of the different models available for granulation in high shear mixers with a focus on applicability in the pharmaceutical industry. Three examples of applications are given. The examples indicate the potential of mechanistically based models for scale-up and the importance of understanding the dynamics of the granulation process. The first two examples show how the impeller torque can be modelled and predicted in the dry and wet mixing phases of the high shear granulation process, using a solid mechanics and a hierarchical multivariate model, respectively. In the third application the particle size distribution is modelled using population balances and it is shown how different operating conditions can be included in the coalescence kernel to describe the granule growth.     

Growth kinetics and mechanism of wet granulation in a laboratory-scale high shear mixer: Effect of initial polydispersity of particle size

The effect of initial polydispersity of particle size (unimodal versus bimodal distribution) and binder characteristics on the growth kinetics and mechanism of wet granulation was studied. Wet granulation of pharmaceutical powders with initial bimodal particle size distribution (PSD) presented growth kinetics consisting of two stages: fast growth followed by slow growth. The fast stage is controlled by the amount of binder and high probability of coalescence due to the collisions of small and large particles. The second stage is characterized by slow agglomeration of powder mixtures with water content 13.6% v/w, and slow breakage of powder mixtures with water content of 9.9% and 11.7% v/w. The wet granulation of powders with initial unimodal PSD exhibited slow growth kinetics consisting of one stage, since similar particle sizes do not promote agglomeration. The experimental results were better described by a population balance equation using a coalescence kernel that favors growth rate by collision between small and large particles. In general, the probability of a successful collision increased with higher size difference between particles, smaller particle size, and higher binder content.     

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.