Mechanism Of Granule Growth Research Articles

Investigating the Effects of Mixing Dynamics on Twin-Screw Granule Quality Attributes via the Development of a Physics-Based Process Map.

Twin-screw granulation (TSG) is an emerging continuous wet granulation technique that has not been widely applied in the industry due to a poor mechanistic understanding of the process. This study focuses on improving this mechanistic understanding by analyzing the effects of the mixing dynamics on the granule quality attributes (PSD, content uniformity, and microstructure). Mixing is an important dynamic process that simultaneously occurs along with the granulation rate mechanisms during the wet granulation process. An improved mechanistic understanding was achieved by identifying and quantifying the physically relevant intermediate parameters that affect the mixing dynamics in TSG, and then their effects on the granule attributes were analyzed by investigating their effects on the granulation rate mechanisms. The fill level, granule liquid saturation, extent of nucleation, and powder wettability were found to be the key physically relevant intermediate parameters that affect the mixing inside the twin-screw granulator. An improved geometrical model for the fill level was developed and validated against existing experimental data. Finally, a process map was developed to depict the effects of mixing on the temporal and spatial evolution of the materials inside the twin-screw granulator. This process map illustrates the mechanism of nucleation and the growth of the granules based on the fundamental material properties of the primary powders (solubility and wettability), liquid binders (viscosity), and mixing dynamics present in the system. Furthermore, it was shown that the process map can be used to predict the granule product quality based on the granule growth mechanism.

Quantitative analysis of the effects of multi-component formulation parameters on granule and tablet properties via a combined population balance and statistical predictive model

In pharmaceutical drug product manufacturing, the use of multi-component mixtures in the formulation is a common practice. However, the introduction of each material alters the powder blend properties and affects the granule growth mechanisms in a wet granulation process. In this study, we quantified the effects of varying formulation parameters on granule growth rate, expressed by the liquid amount required for granulation to reach completion, and on granule and tablet quality attributes. Process models, including population balance and statistical models, were developed to represent the granulation, milling, and tableting process, and predict relevant granule and tablet properties. Overall, prediction of granule properties had an accuracy of above 80% and the prediction of different tablet properties ranged from an R2 of 0.68 to 0.9. These models are computationally efficient and can be simulated serially to predict the performance of different multi-component formulations by using the pre-blend properties as model inputs.

A review of regime maps for granulation.

Granulation, a size enlargement technique to form agglomerates of primary particles, has proven to be effective in the production of solid dosage forms. Numerous granulation techniques can be applied, such as roll compaction, drum granulation, high shear granulation, twin-screw granulation or fluid-bed granulation. If the fundamental knowledge about the granule growth mechanism, its impacts as well as their extent and proportions on the mechanism is known, a correlation of the input variables with the granule attributes paves the way regarding a granulation process design and prediction of a systems growth behaviour if one or more affecting parameters change. The dimensionless correlation of the main controlling parameters of the process physics is able to confine an operation window within which different regime areas are defined and where the influencing parameters have different implications on the final product. A regime map is created. The usage of dimensionless numbers ensures a reduction of both the experimental workload and the number of parameters that have to be considered. Thus, a scale-independent operation window can be defined. The aim of the review is a critical discussion of proposed regime maps for different granulation processes.

Prediction of the growth kinetics and agglomeration mechanisms using a mixer torque rheometer

Although high-shear wet granulation is widely used, the knowledge of this operation is not yet fully clarified and the process design is particularly difficult.The evolution of this process depends on strength and plasticity of the wet masses, consequently the purpose of this study was to develop a rheological method able to predict the granule growth. To pursue this goal, the torque evolution over the time of three different wet powder formulations was recorded in a mixer torque rheometer (MTR3, Caleva, UK). The torque profiles were then analyzed to find a characteristic torque value that could be correlated to the strength and the deformability of the wet granules. The first selected formulation was composed of 100% (w/w) of microcrystalline cellulose (MCC100), the second consisted in a mixture 1:1 of sucrose and microcrystalline cellulose (SUCR50) and the third contained 5% (w/w) of xanthan gum and 95% (w/w) of microcrystalline cellulose (XG5).Granulation experiments (material exchange experiments and extended granulation experiments) were performed using different experimental conditions (different amount of liquid binder and impeller speed) to identify the growth mechanism of three formulations studied. Results have shown that the maximum torque peak (Tpk) developed by the wet masses over the time can be successfully used to predict the granule growth mechanisms. In particular, for formulations that developed relatively high Tpk values (>0.2Nm/g), consolidation and growth of the granules were difficult, and an induction growth mechanism could be observed (formulation XG5). If Tpk values lower than 0.2Nm/g, the deformability of the wet mass was high, and the growth regime corresponded to the steady growth (formulations MCC100 and SUCR50).In addition, experiments have shown that the higher the Tpk values, the faster the growth kinetic. In conclusion the rheological characterization of the wet masses demonstrated to be useful to predict granule growth behaviour in high shear wet granulation and the developed method could represent a valuable tool in the process design and development.

Mechanistic understanding of granule growth behavior in bi-component wet granulation processes with wettability differentials

Two case studies were studied in a high shear wet granulator using a hydrophobic API and a hydrophilic excipient An increase in granule growth was observed with an increase in percentage composition of the hydrophobic API Regime map analyses and granule characterization tests were performed confirming that in addition to wettability differences, granule deformability was a dominating factor in the type of growth mechanisms exhibited.In this study, a more physics-based approach was pursued to investigate the effect of wettability differences in bi-component granule systems on critical quality attributes such as granule size distribution (GSD) and content uniformity across size fractions. Two bi-component formulations: 1) ibuprofen-USP and microcrystalline cellulose (Case-I) and; 2) APAP and microcrystalline cellulose (Case-II), were systematically selected and only their net hydrophobicity was varied as a consequence of change in percentage composition. Both case studies resulted in a similar increase in mean granule size and GSD as a function of increased net hydrophobicity; however, they exhibited key differences in terms of content uniformity across size fractions. Case-I produced content uniform granules, while Case-II produced content non-uniform granules, with the increase in percentage composition of ibuprofen and acetaminophen respectively. This difference in component distribution was studied using growth regime maps and granule image analyses. Results showed that with the change in percentage composition (or increasing the amount of the hydrophobic material), the granule growth mechanism shifted between capillary-force-dominated layering mechanism and viscous-force-dominated aggregation mechanism. It was concluded that, uniform distribution of materials observed in Case-I granules was due to strong viscous-force-dominated aggregation mechanism; whereas, non-uniform distribution of materials observed in Case-II granules was due to much weaker capillary force dominated layering mechanism. This work seeks to improve the theoretical understanding of granule growth behavior in a bi-component wet granulation systems with components of differing wettabilities or hydrophobicities.

Use of machine learning tool to elucidate and characterize the growth mechanism of an in-situ fluid bed melt granulation

The aim of this work is to follow the agglomeration mechanism of an in situ Fluid Bed Melt Granulation (FBMG) by means of machine learning with Artificial Neural Network (ANN) modelling. Scanning Electron Microscopy (SEM) was used as a complementary tool with particle size analysis to evaluate the effect of the material properties on the quality attributes of the final granules and provide further insight into the growth mechanisms. The experiments were performed using lactose monohydrate as model filler and two grades of polyethylene glycol (PEG 2000 and 6000) as meltable binders in different contents and in different size fractions, respectively. A multilayer perceptron neural network was developed using MATLAB neural network toolbox and the evaluated quality attributes of the final granules were used as a database for the development and selection of the optimal architecture of the ANN model. The Garson equation was used to quantify the relative importance of each independent variable and thus it was established that the particle size had the highest impact on the granule properties. The distribution and immersion granule growth mechanisms were determined to occur for low and high binder particle size, respectively, as confirmed by the SEM pictures, and the response surfaces helped determine the optimal design space of the process and the optimal FBMG conditions.

流動層を用いた農薬懸濁液の直接顆粒化法における顆粒生成機構および顆粒物性の検討

流動層を用いた農薬懸濁液の直接顆粒化法における顆粒生成機構および顆粒物性の検討

An investigation on the correlation between drug dissolution properties and the growth behaviour of granules in high shear mixer

The aim of this study was to investigate the correlation between the growth behaviour and in-vitro dissolution rate of water-insoluble drugs prepared with high-shear wet granulation. Granules containing nimodipine, microcrystalline cellulose, low-substituted hydroxypropylcellulose and aqueous solution of hydroxypropylcellulose were prepared and the effects of independent process variables, including impeller speed and liquid-to-solid ratio were taken into consideration. The mean granule size, granule-size distribution (GSD), porosity and surface properties were monitored at different kneading times to identify the granule-growth mechanisms simultaneously. A computer-based method was applied to simulate the dissolution behaviour of polydisperse granules based on the GSD data. The in-vitro dissolution rate of drug was high for the early stages of granulation and sharply decreased when coalescence and consolidation of granules started, approaching a flat and low level when granules were sufficiently consolidated. The simulated dissolution results were in agreement with experimental observations and were significantly affected by the GSD, porosity and surface properties of granules during the granulation process. Moreover the GSD was directly related to the granule-growth behaviour and mechanisms. In general, it was concluded that the dissolution properties of nimodipine basically correlated with the growth behaviour of granules in a high-shear mixer. The simulation method based on GSD can be used as a convenient and rapid way to predict the dissolution properties for formulation development and granulation optimization.

Effect of operating conditions and physico–chemical properties on the wet granulation kinetics in high shear mixer

The wet granulation process is sensitive to changes in product properties and process variables. The optimal process and formulation are based on the knowledge of the granule growth mechanisms and of the effects of product properties and process variables. This paper presents the study of wet granulation of microcrystalline cellulose powder, MCC (Avicel PH101) using high-shear mixer granulator. It aims at understanding the effect of operating parameters (impeller rotational speed, liquid binder flow ate) and of physicochemical properties (viscosity, wettability) of a binder solution on solid particles surfaces, on the agglomeration kinetics. The experiments are carried out with water, aqueous solutions of sodium carboxymethylcellulose, polyvinylpyrrolidone, hydroxypropylméthylcellulose or a non ionic surfactant oxo-C 10C 6 at a critical micellar concentration. Concerning the process variables the experimental results show that an optimal interval of impeller speed operation exists ranging from 150 to 200 rpm for granule growth. Below, an uncontrollable agglomerate size and localised over-wetting occur, and above granule breakage occurs. Increasing the liquid binder flow rate reduces the extension of the non growth regime, but does not affect the granule mean size. The effect of the physicochemical properties is evaluated using a modified capillary viscous number, Ca′, that we define as the ratio between the viscous forces ( μ L U) and the work of adhesion W a = γ L(1 + cos θ). For Ca′ < 1, the viscosity of the solution does not significantly affect the granulation process. The dominant forces in the granulation process are the interfacial forces since increasing the work of adhesion enhances the growth kinetics. For Ca′ > 1.6, the viscous forces predominate and control the granule growth.

Imaging of zymogen granules in fully wet cells. Evidence for restricted mechanism of granule growth

The introduction of wet SEM imaging technology permits electron microscopy of wet samples. Samples are placed in sealed specimen capsules and are insulated from the vacuum in the SEM chamber by an impermeable, electron-transparent membrane. The complete insulation of the sample from the vacuum allows direct imaging of fully hydrated, whole-mount tissue. In the current work, we demonstrate direct inspection of thick pancreatic tissue slices (above 400 mum). In the case of scanning of the pancreatic surface, the boundaries of intracellular features are seen directly. Thus no unfolding is required to ascertain the actual particle size distribution based on the sizes of the sections. This method enabled us to investigate the true granule size distribution and confirm early studies of improved conformity to a Poisson-like distribution, suggesting that the homotypic granule growth results from a mechanism, which favors the addition of a single unit granule to mature granules.

Pharmaceutically Engineering Powders Using FHMG: The Effects of Process Parameters and Formulation Variables

Fluidized hot melt granulation (FHMG) is an innovative granulation process that has distinct advantages over techniques that are typically used in the pharmaceutical industry for powder agglomeration and mixing. The aim of this research was to investigate process and formulation parameters that affect FHMG, in a pharmaceutical context, using Lutrol ® F68 (copolymer of polyoxyethylene-polyoxypropylene) as a meltable binder with inert glass ballotini acting as a model pharmaceutical powder. Granulation process parameters investigated were: binder/bulk powder ratio, binder viscosity and granulation time. The experimental data obtained from FHMG were correlated with current granulation theory. De-fluidization occurred at >10% w/w Lutrol ® F68 binder concentration and the resultant granules were highly irregular in shape. Furthermore, the dominant mechanism of granule growth altered from layering to coalescence with increasing binder content. Moreover, a modified growth regime map successfully described experimental data.

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.

The use of Stokes deformation number as a predictive tool for material exchange behaviour of granules in the ‘equilibrium phase’ in high shear granulation

The objective of this study was three-fold; to investigate the different mechanisms of material exchange during the equilibrium phase of the granulation process and whether these mechanisms are consistent with the mechanisms described in the growth regime map, to study how material properties and process conditions affect these exchange mechanisms, and to correlate Stokes deformation number to the exchange mechanisms. Microcrystalline cellulose (MCC), α-lactose, microfine cellulose (MFC), and dextrin were granulated using water as a binding agent. Once in the equilibrium phase, 5% (w/w) of the granular mass was replaced with wet tracer granules, after which the granulation process was continued. Granules were typically of a size of approximately 1 mm in diameter. Therefore, these granules can also be called pellets. Tracer experiments show indeed solid material exchange can take place in the equilibrium phase of the high shear granulation process. Tracer material was equally dispersed throughout the whole batch for all materials tested. However, the granulation time needed to reach this homogeneous distribution varied with material and granulation conditions. Three different mechanisms of material exchange were identified: exchange by disintegration, where granules are rapidly crushed and formed to granules again; exchange by deformation, where abraded granule fragments immediately fuse with other granules; and exchange by distribution, where there is a prolonged period over which both tracer and standard granules stay intact, followed by uncontrolled growth and exchange of material. It was found that it is possible to shift between the mechanisms by changing the process conditions, e.g., changing viscosity or amount of binder liquid. These observations indicate that by choosing the appropriate process conditions improved distribution of small amounts of insoluble materials in the granules can be obtained. A relation exists between the exchange mechanisms and the growth regime map: the disintegration mechanism resembles ‘crumb behaviour’, the deformation mechanism resembles ‘steady growth’, and the distribution mechanism resembles ‘nucleation’ and ‘induction growth’. Unfortunately, Stokes deformation number cannot be used as a predictive tool when low viscosity binders like water are used, due to the importance of viscosity in the equation. However, this number is one of the variables of the growth regime map. Since the exchange mechanisms correspond to the granule growth mechanisms in the regime map, alternatively colour experiments might be used to reveal the granulation regime.

Influence of process parameters on fluidised hot-melt granulation and tablet pressing of pharmaceutical powders

This study investigates the influence of process parameters on the fluidised hot melt granulation of lactose and PEG 6000, and the subsequent tablet pressing of the granules. Granulation experiments were performed to assess the effect of granulation time and binder content of the feed on the resulting granule properties such as mass mean granule size, size distribution, granule fracture stress, and granule porosity. These data were correlated using the granule growth regime model. It was found that the dominant granule growth mechanisms in this melt granulation system were nucleation followed by steady growth (PEG 10–20% w/w). However, with binder contents greater than 20% w/w, the granulation mechanism moved to the “over-wet massing” regime in which discrete granule formation could not be obtained. The granules produced in the melt fluidised bed process were subsequently pressed into tablets using an industrial tablet press. The physical properties of the tablets: fracture stress, disintegration time and friability were assessed using industry standards. These analyses indicated that particle size and binder content of the initial granules influenced the mechanical properties of the tablets. It was noted that a decrease in initial granule size resulted in an increase in the fracture stress of the tablets formed.

The relationship between granule growth mechanism, amount of liquid binder added and properties of the wet powder mass determined using a split bed shear tester

The Peschl-split bed shear tester was utilised to study the formation of different liquid states during wet massing for granulation. Using lactose monohydrate as a model bulking agent the threshold between pendular and funicular state was found to be at about 6% (w/w) of liquid binder added to the wet mass, here a 5% colloidal solution of HPMC in water. The upper limit of the funicular state appeared to be at approximately 15% (w/w) of liquid binder. The threshold values obtained from the shear cell measurements did correlate with values obtained from dried granule characteristics such as granule density and compressive Young’s modulus determined by Dynamic Mechanical Analysis. The compressive Young’s modulus increased with an increasing density of the wet mass during the shear experiments and decreased with an increase in the angle of internal friction. The results suggest that stiffer granules were a result of densification, not the strength of liquid bridge bond formation.

Relationship between inhomogeneity phenomena and granule growth mechanisms in a high-shear mixer

A poorly understood phenomenon observed during high-shear granulation is the poor distribution of a drug in the granulate. To investigate the causes of this inhomogeneity, lactose of three different particle sizes was granulated with 0.1% micronized estradiol (5 μm) in a 10 l high-shear mixer. An aqueous solution of HPC was used as binder. Granulation with the largest lactose particles (141 μm) yielded a homogeneous granulate. However, at a prolonged process time demixing was observed. Contrary to the largest particles, granulation with the smaller lactose particles (50 and 23 μm) already leads to demixing in the first minute, although to a lesser extent. It was concluded that granulation with the largest particles resulted in breakage behavior of the granulate, thereby preventing demixing. However, once granules are strong enough (smaller particle size and prolonged process time) to survive the shear forces demixing is observed. Theoretical calculations of dynamic and static granule strength were used to explain the influence of lactose particle size and process time on breakage behavior. It was argued that once granules survive, preferential growth of the small estradiol particles in favor of the larger lactose particles causes the demixing. The extent of demixing depends on the particle size difference.

Modelling of granulation by a two-stage auto-layering mechanism in continuous industrial drums

A mechanistic model for the granulation of particulate materials with a wide size distribution in a large-scale continuous drum is presented. It takes cognizance of the effect of relevant process variables: feed size distribution, moisture content, binders such as lime, residence time distribution, feed rate, etc. The model is based on the auto-layering mechanism of granule growth and incorporates a piecewise linear model for granulation kinetics. Laboratory scale tests on a batch drum are used to provide kinetic parameters. The size-dependent residence time distribution of agglomerating mass in the continuous drum is represented by a combination of mixed and plug flow regimes operating in parallel. The model is customized for a continuous drum in an iron ore fines sintering plant. The predicted granule size distributions are in good agreement with the plant data under widely varying operating conditions. The modelling framework provides scope for modifying the individual modules for drum residence time distribution or the granulation mechanism and growth kinetics.

Liquid distribution as a means to describing the granule growth mechanism

Copper concentrate (chalcopyrite) was granulated in a rotating drum with a diameter of 0.3 m and a length of 0.2 m. Water was used as the binder and it was sprayed onto the powder bed with a nozzle. This material exhibited induction type behaviour, which was defined by Iveson and Litster [AIChE J. 44 (1998) 1510]. Induction type behaviour is characterized by the occurrence of an induction stage, during which the granules are gradually being compacted and little or no growth occurs. At the end of this induction stage, binder liquid is squeezed from the interior of the granules onto the granule surface and the granules are then surface-wet. This results in a rapid growth rate of the granules. Different types of experiments were conducted. The influence of the nozzle pressure and the distance from the nozzle to the powder bed on the growth behaviour of the granules as well as on the binder distribution was examined. The results of these experiments led to the postulation of a modified mechanism for induction type behaviour: it was found that after the binder was delivered, there were large granules containing a high amount of binder and small granules containing less binder. During the induction stage, the granules are compacted and binder liquid continuously appears at the surface of the large granules. These wet spots that are continuously being formed pick up the dry and small granules. When all the small granules have been picked up, further expulsion of binder liquid onto the granules' surface results in granules that remain surface-wet. This phenomenon marks the end of the induction stage and it coincides with the disappearance of the small granules. The hypothesis was tested by selectively removing the smaller granules during an experiment. As expected, this resulted in a shorter induction time.

A combined model for granule size distribution and cold bed permeability in the wet stage of iron ore sintering process

A combined mathematical model for granule size distribution and cold bed permeability in the iron ore sintering process is presented. The combined model is obtained by integrating the models for granulation and cold bed permeability. The granulation model is based on the two-stage granule growth mechanism and incorporates exclusion principle along with layer thickness postulates of granulation. The permeability model consists of equations for velocity of gases through the bed and the cold bed voidage. The velocity of gases is predicted using a modified Ergun equation. The bed voidage is related to the spread of the granule size distribution as well as the possible deformation of granules during charging by incorporating moisture and fines content of raw sinter feed. The model simulation of granule size distributions, cold bed voidage and velocity of gases under different operating conditions compare well with experimental data from a laboratory sintering unit. Starting from the size distribution of raw feed and its moisture content, the model predicts the granule size distribution and the cold bed voidage and permeability, without introducing any intermediate measurements. Moreover, it can be integrated with a sintering model in order to describe the complete iron ore sintering process in a quantitative fashion.

STUDY OF FLUIDIZED-BED SPRAY GRANULATION

In a batch operation fluidized-bed spray granulator, the granule growth mechanisms of sodium benzoate and sodium carboxymethy-cellulose (CMC-Na) as binder are studied. The model of maximum liquid feed rate is developed. The theoretical calculation is in reasonable agreement with the experimental data with mean deviation being 17. 7%.