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Ingmar Nopens - One of the best experts on this subject based on the ideXlab platform.
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Model-based analysis of a twin-screw wet granulation system for continuous solid dosage manufacturing
Computers and Chemical Engineering, 2016Co-Authors: Ashish Kumar, Séverine Thérèse F.c. Mortier, Jurgen Vercruysse, Krist V. Gernaey, Thomas De Beer, Jean Paul Remon, Chris Vervaet, Ingmar NopensAbstract: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.
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Development of a process map: A step towards a regime map for steady-state high shear wet twin screw granulation
Powder Technology, 2016Co-Authors: Ashish Kumar, Jurgen Vercruysse, Fien De Leersnyder, Jens Dhondt, Krist V. Gernaey, Valérie Vanhoorne, Thomas De Beer, Jean Paul Remon, Chris Vervaet, Ingmar NopensAbstract:Twin-screw granulation is an emerging continuous granulation technique in the pharmaceutical industry. The flexibility in process settings such as the binder addition method (wet vs. dry), screw configuration, screw speed and material throughput allows to modify the granule size and shape. However, twin-screw granulation, being a rather new granulation technique, is not yet as well understood as batch-wise high shear wet granulation. Furthermore, most of the studies performed on twin-screw granulation are limited to a certain design and scale of the twin-screw granulator. In this study, in order to improve the understanding about the granulation process and to comprehend the applicability and limits of the process variables in a scale independent manner, the regime theory was applied to one specific twin-screw granulator equipment. In this study, α-lactose monohydrate was granulated with polyvinylpyrrolidone (2.5%, w/w) as binder. The screw configuration of the 25 mm diameter co-rotating twin-screw granulator from the ConsiGma-25 unit consisted of one or two kneading zones of six kneading elements each (1 × 6 and 2 × 6, respectively), at a stagger angle of 60 °. The specific mechanical energy, which involves the combination of screw speed, material throughput and torque required to rotate the screws was correlated with the applied liquid-to-solid ratio to present process maps. The study suggested that, despite an increase in the granule size by the increasing liquid-to-solid ratio, most of the liquid contributes to formation of oversized granules. Therefore, keeping the liquid-to-solid ratio in a lower range and increasing the energy input to the system can be effectively used to lower the mean granule size. Changes in the screw geometry should also be explored to improve solid liquid mixing and breakage of oversized granules to narrow the width of the size distribution. Since, such a process map is limited to a selected formulation and equipment design, process maps based on several formulations and mechanistic mathematical modelling tools should be applied to identify the mechanisms and relevant dimensionless groups that control granule attributes, with the ultimate aim of producing a generalised regime map.
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Model-based characterisation of twin-screw granulation system for continuous solid dosage manufacturing
Computer Aided Chemical Engineering, 2015Co-Authors: Ashish Kumar, Krist V. Gernaey, Thomas De Beer, Ingmar NopensAbstract:Continuous twin-screw granulation has received increased attention as it can be embedded in a continuous manufacturing line allowing 24/7 production capacity eliminating scale-up requirements and intermediate storage. The screws have a modular structure (interchangeable transport and kneading discs) allowing greater flexibility in equipment design. However, process knowledge should be further developed both under steady state and dynamic conditions. Mechanistic models incorporating the underlying mechanisms are therefore applied. In this study, the principle constitutive mechanisms such as aggregation and breakage are included in a population balance modelling framework. Based on an experimental inflow granule size distribution and mean residence time of the granulator, predictions of the outflow granule size distribution were made. Experimental data was used for calibrating the model for individual screw modules in the twin- screw granulator. The results showed that the successive kneading blocks lead to a granulation regime-separation inside the twin-screw granulator. The first kneading block after wetting caused an increase in the aggregation rate, which was reduced after the second kneading block. The breakage rate increased successively along the length of the granulator. Such a physical separation between the granulation regimes will be promising for future design and advanced control of the continuous granulation process.
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Experimental investigation of granule size and shape dynamics in twin-screw granulation
International Journal of Pharmaceutics, 2014Co-Authors: Ashish Kumar, Giacomo Bellandi, Jurgen Vercruysse, Krist V. Gernaey, Thomas De Beer, Jean Paul Remon, Chris Vervaet, Ingmar NopensAbstract:A twin-screw granulator (TSG), a promising equipment for continuous high shear wet granulation (HSWG), achieves the desired level of mixing by a combination of the appropriate screw configuration and a suitable set of process settings (e.g. feed rate, screw speed, etc.), thus producing a certain granule size and shape distribution (GSSD). However, the primary sizing and shaping mechanism behind the resulting distribution is not well understood due to the opacity of the multiphase system in the granulator. This study experimentally characterised the GSSD dynamics along the TSG barrel length in order to understand the function of individual screw modules and process settings, as well as their interaction. Particle size analysis of granules collected at the outlet of the TSG suggested significant interaction between the process and screw configuration parameters influencing the heterogeneity in the GSSD. By characterising the samples collected along the screw length, a variable influence of the screw modules at different process conditions was observed. At low liquid-to-solid ratio (L/S), the first kneading module seemed to play a significant role in mixing, whereas the second kneading module was found to be more involved in reshaping the granules. At high L/S and high throughput, aggregation mainly took place in the second kneading module changing the GSSD. The results obtained from this study will be further used for the calibration and validation of a mechanistic model and, hence, support future development of a more detailed understanding of the HSWG process in a TSG.
Rohit Ramachandran - One of the best experts on this subject based on the ideXlab platform.
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Dynamic Flowsheet Model Development and Sensitivity Analysis of a Continuous Pharmaceutical Tablet Manufacturing Process Using the Wet Granulation Route
Processes, 2019Co-Authors: Nirupaplava Metta, Michael Ghijs, Philippe Cappuyns, Ivo Van Assche, Thomas De Beer, Ravendra Singh, Rohit Ramachandran, Elisabeth Schafer, Ashish Kumar, Marianthi G. IerapetritouAbstract:In view of growing interest and investment in continuous manufacturing, the development and utilization of mathematical model(s) of the manufacturing line is of prime importance. These models are essential for understanding the complex interplay between process-wide critical process parameters (CPPs) and critical quality attributes (CQAs) beyond the individual process operations. In this work, a flowsheet model that is an approximate representation of the ConsiGma TM -25 line for continuous tablet manufacturing, including wet granulation, is developed. The manufacturing line involves various unit operations, i.e., feeders, blenders, a twin-screw wet granulator, a fluidized bed dryer, a mill, and a tablet press. The unit operations are simulated using various modeling approaches such as data-driven models, semi-empirical models, population balance models, and mechanistic models. Intermediate feeders, blenders, and transfer lines between the units are also simulated. The continuous process is simulated using the flowsheet model thus developed and case studies are provided to demonstrate its application for dynamic simulation. Finally, the flowsheet model is used to systematically identify critical process parameters (CPPs) that affect process responses of interest using global sensitivity analysis methods. Liquid feed rate to the granulator, and air temperature and drying time in the dryer are identified as CPPs affecting the tablet properties.
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Continuous high-shear granulation: Mechanistic understanding of the influence of process parameters on critical quality attributes via elucidating the internal physical and chemical microstructure
Advanced Powder Technology, 2019Co-Authors: Wei Meng, Jakub Dvořák, Rudy Hofmeister, František Štĕpánek, Ravish Kumar, Rohit RamachandranAbstract:Over the past decade, continuous wet granulation has been emerging as a promising technology in drug product development. In this paper, the continuous high-shear mixer granulator, Lӧdige CoriMix® CM5, was investigated using a low-dose formulation with acetaminophen as the model drug. Design of experiments was deployed in conjunction with multivariate data analysis to explore the granulator design space and comprehensively understand the interrelation between process parameters and critical attributes of granules and tablets. Moreover, several complementary imaging techniques were implemented to unveil the underlying mechanisms of physical and chemical microstructure in affecting the tablet performance. The results indicated that L/S ratio and impeller speed outweighed materials feeding rate in modifying the granule and tablet properties. Increasing the degree of liquid saturation and mechanical shear input in the granulation system principally produced granules of larger size, smaller porosity, improved flowability and enhanced sphericity, which after compression generated tablets with slower disintegration process and drug release kinetics due to highly consolidated physical microstructure. Besides, in comparison to batch mixing, continuous mixing integrated with a conical mill enabled better powder de-agglomeration effect, thus accelerating the drug dissolution with increased surface area.
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HPC enabled parallel, multi-scale & mechanistic model for high shear granulation using a coupled DEM-PBM framework
Computer Aided Chemical Engineering, 2018Co-Authors: Chaitanya Sampat, Yukteshwar Baranwal, Shantenu Jha, Marianthi G. Ierapetritou, Ioannis Paraskevakos, Rohit RamachandranAbstract:A multiscale model combines the computational efficiency of a macro-scale model and the accuracy of a micro-scale model. With the current cyberinfrastructure resources available, using more computationally intensive and concurrent multiscale models are more feasible. This study proposes to use Discrete Element Method (DEM) and a Population Balance Model (PBM) in a simultaneous manner to model the granulation process of a pharmaceutical product inside a high shear granulator. The DEM provides the collision data while the PBM helps in predicting the macroscale phenomena like aggregation and breakage. The execution of each of the components is governed by a multilevel job scheduler which allocates resources. This method of using shorter bursts of each simulation led to faster simulation times as well as a more accurate model of the high shear granulator. The Quality by Design (QbD) approach is addressed using such a modelling framework and it also helps us understand the granulation process in a quantitative as well as in a mechanistic manner.
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Statistical analysis and comparison of a continuous high shear granulator with a twin screw granulator: Effect of process parameters on critical granule attributes and granulation mechanisms.
International journal of pharmaceutics, 2016Co-Authors: Wei Meng, James D. Litster, Lalith Kotamarthy, Savitha Panikar, Shankali Pradhan, Michaelis Marc, Fernando J Muzzio, Rohit RamachandranAbstract:This study is concerned with identifying the design space of two different continuous Granulators and their respective granulation mechanisms. Performance of a continuous high shear granulator and a twin screw granulator with paracetamol formulations were examined by face-centered cubic design, which focused on investigating key performance metrics, namely, granule size, porosity, flowability and particle morphology of granules as a function of essential input process parameters (liquid content, throughput and rotation speed). Liquid and residence time distribution tests were also performed to gain insights into the liquid-powder mixing and flow behavior. The results indicated that continuous high shear granulation was more sensitive to process variation and produced spherical granules with monomodal size distribution and distinct internal structure and strength variation. Twin screw granulation with such a particular screw configuration showed narrower design space and granules were featured with multimodal size distribution, irregular shape, less detectible porosity difference and tighter range of strength. Granulation mechanisms explored on the basis of nucleation and growth regime maps revealed that for most cases liquid binder was uniformly distributed with fast droplet penetration into the powder bed and that granule consolidation and coalescence mainly took place in the nucleation, steady growth and rapid growth regimes.
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Multi-dimensional mechanistic modeling of fluid bed granulation processes: An integrated approach
Advanced Powder Technology, 2013Co-Authors: Anwesha Chaudhury, Alexander Niziolek, Rohit RamachandranAbstract:This paper is concerned with the integration of a heat and mass model with a population balance model of a fluid bed granulation process. The heat/mass model helps to track the liquid and porosity changes that occur within the granulation process due to simultaneous drying in the granulator. A mechanistic kernel proposed by [22] was used to model the aggregation process, which is a function of mechanistic properties such as liquid thickness and particle size. The model takes into account various mechanisms that significantly affect the granulation outcome, such as aggregation, drying/rewetting, and consolidation. Since these rate processes evolve dynamically, the aggregation kernel is updated periodically over time and for the first time, dynamically coupled with the heat/mass model to provide a more accurate qualitative description of granulation dynamics in a fluid-bed granulator. © 2012 The Society of Powder Technology Japan. Published by Elsevier B.V. and The Society of Powder.
Ashish Kumar - One of the best experts on this subject based on the ideXlab platform.
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Dynamic Flowsheet Model Development and Sensitivity Analysis of a Continuous Pharmaceutical Tablet Manufacturing Process Using the Wet Granulation Route
Processes, 2019Co-Authors: Nirupaplava Metta, Michael Ghijs, Philippe Cappuyns, Ivo Van Assche, Thomas De Beer, Ravendra Singh, Rohit Ramachandran, Elisabeth Schafer, Ashish Kumar, Marianthi G. IerapetritouAbstract:In view of growing interest and investment in continuous manufacturing, the development and utilization of mathematical model(s) of the manufacturing line is of prime importance. These models are essential for understanding the complex interplay between process-wide critical process parameters (CPPs) and critical quality attributes (CQAs) beyond the individual process operations. In this work, a flowsheet model that is an approximate representation of the ConsiGma TM -25 line for continuous tablet manufacturing, including wet granulation, is developed. The manufacturing line involves various unit operations, i.e., feeders, blenders, a twin-screw wet granulator, a fluidized bed dryer, a mill, and a tablet press. The unit operations are simulated using various modeling approaches such as data-driven models, semi-empirical models, population balance models, and mechanistic models. Intermediate feeders, blenders, and transfer lines between the units are also simulated. The continuous process is simulated using the flowsheet model thus developed and case studies are provided to demonstrate its application for dynamic simulation. Finally, the flowsheet model is used to systematically identify critical process parameters (CPPs) that affect process responses of interest using global sensitivity analysis methods. Liquid feed rate to the granulator, and air temperature and drying time in the dryer are identified as CPPs affecting the tablet properties.
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Model-based analysis of a twin-screw wet granulation system for continuous solid dosage manufacturing
Computers and Chemical Engineering, 2016Co-Authors: Ashish Kumar, Séverine Thérèse F.c. Mortier, Jurgen Vercruysse, Krist V. Gernaey, Thomas De Beer, Jean Paul Remon, Chris Vervaet, Ingmar NopensAbstract: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.
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Development of a process map: A step towards a regime map for steady-state high shear wet twin screw granulation
Powder Technology, 2016Co-Authors: Ashish Kumar, Jurgen Vercruysse, Fien De Leersnyder, Jens Dhondt, Krist V. Gernaey, Valérie Vanhoorne, Thomas De Beer, Jean Paul Remon, Chris Vervaet, Ingmar NopensAbstract:Twin-screw granulation is an emerging continuous granulation technique in the pharmaceutical industry. The flexibility in process settings such as the binder addition method (wet vs. dry), screw configuration, screw speed and material throughput allows to modify the granule size and shape. However, twin-screw granulation, being a rather new granulation technique, is not yet as well understood as batch-wise high shear wet granulation. Furthermore, most of the studies performed on twin-screw granulation are limited to a certain design and scale of the twin-screw granulator. In this study, in order to improve the understanding about the granulation process and to comprehend the applicability and limits of the process variables in a scale independent manner, the regime theory was applied to one specific twin-screw granulator equipment. In this study, α-lactose monohydrate was granulated with polyvinylpyrrolidone (2.5%, w/w) as binder. The screw configuration of the 25 mm diameter co-rotating twin-screw granulator from the ConsiGma-25 unit consisted of one or two kneading zones of six kneading elements each (1 × 6 and 2 × 6, respectively), at a stagger angle of 60 °. The specific mechanical energy, which involves the combination of screw speed, material throughput and torque required to rotate the screws was correlated with the applied liquid-to-solid ratio to present process maps. The study suggested that, despite an increase in the granule size by the increasing liquid-to-solid ratio, most of the liquid contributes to formation of oversized granules. Therefore, keeping the liquid-to-solid ratio in a lower range and increasing the energy input to the system can be effectively used to lower the mean granule size. Changes in the screw geometry should also be explored to improve solid liquid mixing and breakage of oversized granules to narrow the width of the size distribution. Since, such a process map is limited to a selected formulation and equipment design, process maps based on several formulations and mechanistic mathematical modelling tools should be applied to identify the mechanisms and relevant dimensionless groups that control granule attributes, with the ultimate aim of producing a generalised regime map.
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Linking granulation performance with residence time and granulation liquid distributions in twin-screw granulation: An experimental investigation.
European Journal of Pharmaceutical Sciences, 2015Co-Authors: Ashish Kumar, Jurgen Vercruysse, Fien De Leersnyder, Valérie Vanhoorne, Chris Vervaet, Maija Alakarjula, Maunu Toiviainen, Mikko Juuti, Jarkko Ketolainen, Jean Paul RemonAbstract:Abstract Twin-screw granulation is a promising wet granulation technique for the continuous manufacturing of pharmaceutical solid dosage forms. A twin screw granulator displays a short residence time. Thus, the solid–liquid mixing must be achieved quickly by appropriate arrangement of transport and kneading elements in the granulator screw allowing the production of granules with a size distribution appropriate for tableting. The distribution of residence time and granulation liquid is governed by the field conditions (such as location and length of mixing zones) in the twin-screw granulator, thus contain interesting information on granulation time, mixing and resulting sub-processes such as wetting, aggregation and breakage. In this study, the impact of process (feed rate, screw speed and liquid-to-solid ratio) and equipment parameters (number of kneading discs and stagger angle) on the residence time (distribution), the granulation liquid-powder mixing and the resulting granule size distributions during twin-screw granulation were investigated. Residence time and axial mixing data was extracted from tracer maps and the solid–liquid mixing was quantified from moisture maps, obtained by monitoring the granules at the granulator outlet using near infra-red chemical imaging (NIR-CI). The granule size distribution was measured using the sieving method. An increasing screw speed dominantly reduced the mean residence time. Interaction of material throughput with the screw speed and with the number of kneading discs led to most variation in the studied responses including residence time and mixing capacity. At a high screw speed, granulation yield improved due to high axial mixing. However, increasing material throughput quickly lowers the yield due to insufficient mixing of liquid and powder. Moreover, increasing liquid-to-solid ratio resulted in more oversized granules, and the fraction of oversized granules further increased at higher throughput. Although an increasing number of kneading discs was found to be critical for achieving a uniform distribution of the granulation liquid, the granulation performance was hampered due to insufficient solid–liquid mixing capacity of the current kneading discs which is essential for wet granulation. Thus, a balance between material throughput and screw speed should be strived for in order to achieve a specific granulation time and solid–liquid mixing for high granulation yield. Additionally, more efforts are needed both in modification of the screw configuration as well as the geometry of the mixing elements to improve the mixing capacity of the twin-screw granulator. The results from the current experimental study improved the understanding regarding the interplay between granulation time and the axial and solid–liquid mixing responsible for the granulation performance in twin-screw wet granulation.
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Model-based characterisation of twin-screw granulation system for continuous solid dosage manufacturing
Computer Aided Chemical Engineering, 2015Co-Authors: Ashish Kumar, Krist V. Gernaey, Thomas De Beer, Ingmar NopensAbstract:Continuous twin-screw granulation has received increased attention as it can be embedded in a continuous manufacturing line allowing 24/7 production capacity eliminating scale-up requirements and intermediate storage. The screws have a modular structure (interchangeable transport and kneading discs) allowing greater flexibility in equipment design. However, process knowledge should be further developed both under steady state and dynamic conditions. Mechanistic models incorporating the underlying mechanisms are therefore applied. In this study, the principle constitutive mechanisms such as aggregation and breakage are included in a population balance modelling framework. Based on an experimental inflow granule size distribution and mean residence time of the granulator, predictions of the outflow granule size distribution were made. Experimental data was used for calibrating the model for individual screw modules in the twin- screw granulator. The results showed that the successive kneading blocks lead to a granulation regime-separation inside the twin-screw granulator. The first kneading block after wetting caused an increase in the aggregation rate, which was reduced after the second kneading block. The breakage rate increased successively along the length of the granulator. Such a physical separation between the granulation regimes will be promising for future design and advanced control of the continuous granulation process.
Thomas De Beer - One of the best experts on this subject based on the ideXlab platform.
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blend uniformity evaluation during continuous mixing in a twin screw granulator by in line nir using a moving f test
Analytica Chimica Acta, 2016Co-Authors: Margot Fonteyne, Rut Besseling, Wim Oostra, Ad Gerich, Jurgen Vercruysse, Fien De Leersnyder, Jean Paul Remon, Chris Vervaet, Thomas De BeerAbstract:Abstract This study focuses on the twin screw granulator of a continuous from-powder-to-tablet production line. Whereas powder dosing into the granulation unit is possible from a container of preblended material, a truly continuous process uses several feeders (each one dosing an individual ingredient) and relies on a continuous blending step prior to granulation. The aim of the current study was to investigate the in-line blending capacity of this twin screw granulator, equipped with conveying elements only. The feasibility of in-line NIR (SentroPAT, Sentronic GmbH, Dresden, Germany) spectroscopy for evaluating the blend uniformity of powders after the granulator was tested. Anhydrous theophylline was used as a tracer molecule and was blended with lactose monohydrate. Theophylline and lactose were both fed from a different feeder into the twin screw granulator barrel. Both homogeneous mixtures and mixing experiments with induced errors were investigated. The in-line spectroscopic analyses showed that the twin screw granulator is a useful tool for in-line blending in different conditions. The blend homogeneity was evaluated by means of a novel statistical method being the moving F-test method in which the variance between two blocks of collected NIR spectra is evaluated. The α- and β-error of the moving F-test are controlled by using the appropriate block size of spectra. The moving F-test method showed to be an appropriate calibration and maintenance free method for blend homogeneity evaluation during continuous mixing.
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Model-based analysis of a twin-screw wet granulation system for continuous solid dosage manufacturing
Computers and Chemical Engineering, 2016Co-Authors: Ashish Kumar, Séverine Thérèse F.c. Mortier, Jurgen Vercruysse, Krist V. Gernaey, Thomas De Beer, Jean Paul Remon, Chris Vervaet, Ingmar NopensAbstract: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.
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Development of a process map: A step towards a regime map for steady-state high shear wet twin screw granulation
Powder Technology, 2016Co-Authors: Ashish Kumar, Jurgen Vercruysse, Fien De Leersnyder, Jens Dhondt, Krist V. Gernaey, Valérie Vanhoorne, Thomas De Beer, Jean Paul Remon, Chris Vervaet, Ingmar NopensAbstract:Twin-screw granulation is an emerging continuous granulation technique in the pharmaceutical industry. The flexibility in process settings such as the binder addition method (wet vs. dry), screw configuration, screw speed and material throughput allows to modify the granule size and shape. However, twin-screw granulation, being a rather new granulation technique, is not yet as well understood as batch-wise high shear wet granulation. Furthermore, most of the studies performed on twin-screw granulation are limited to a certain design and scale of the twin-screw granulator. In this study, in order to improve the understanding about the granulation process and to comprehend the applicability and limits of the process variables in a scale independent manner, the regime theory was applied to one specific twin-screw granulator equipment. In this study, α-lactose monohydrate was granulated with polyvinylpyrrolidone (2.5%, w/w) as binder. The screw configuration of the 25 mm diameter co-rotating twin-screw granulator from the ConsiGma-25 unit consisted of one or two kneading zones of six kneading elements each (1 × 6 and 2 × 6, respectively), at a stagger angle of 60 °. The specific mechanical energy, which involves the combination of screw speed, material throughput and torque required to rotate the screws was correlated with the applied liquid-to-solid ratio to present process maps. The study suggested that, despite an increase in the granule size by the increasing liquid-to-solid ratio, most of the liquid contributes to formation of oversized granules. Therefore, keeping the liquid-to-solid ratio in a lower range and increasing the energy input to the system can be effectively used to lower the mean granule size. Changes in the screw geometry should also be explored to improve solid liquid mixing and breakage of oversized granules to narrow the width of the size distribution. Since, such a process map is limited to a selected formulation and equipment design, process maps based on several formulations and mechanistic mathematical modelling tools should be applied to identify the mechanisms and relevant dimensionless groups that control granule attributes, with the ultimate aim of producing a generalised regime map.
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Model-based characterisation of twin-screw granulation system for continuous solid dosage manufacturing
Computer Aided Chemical Engineering, 2015Co-Authors: Ashish Kumar, Krist V. Gernaey, Thomas De Beer, Ingmar NopensAbstract:Continuous twin-screw granulation has received increased attention as it can be embedded in a continuous manufacturing line allowing 24/7 production capacity eliminating scale-up requirements and intermediate storage. The screws have a modular structure (interchangeable transport and kneading discs) allowing greater flexibility in equipment design. However, process knowledge should be further developed both under steady state and dynamic conditions. Mechanistic models incorporating the underlying mechanisms are therefore applied. In this study, the principle constitutive mechanisms such as aggregation and breakage are included in a population balance modelling framework. Based on an experimental inflow granule size distribution and mean residence time of the granulator, predictions of the outflow granule size distribution were made. Experimental data was used for calibrating the model for individual screw modules in the twin- screw granulator. The results showed that the successive kneading blocks lead to a granulation regime-separation inside the twin-screw granulator. The first kneading block after wetting caused an increase in the aggregation rate, which was reduced after the second kneading block. The breakage rate increased successively along the length of the granulator. Such a physical separation between the granulation regimes will be promising for future design and advanced control of the continuous granulation process.
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Experimental investigation of granule size and shape dynamics in twin-screw granulation
International Journal of Pharmaceutics, 2014Co-Authors: Ashish Kumar, Giacomo Bellandi, Jurgen Vercruysse, Krist V. Gernaey, Thomas De Beer, Jean Paul Remon, Chris Vervaet, Ingmar NopensAbstract:A twin-screw granulator (TSG), a promising equipment for continuous high shear wet granulation (HSWG), achieves the desired level of mixing by a combination of the appropriate screw configuration and a suitable set of process settings (e.g. feed rate, screw speed, etc.), thus producing a certain granule size and shape distribution (GSSD). However, the primary sizing and shaping mechanism behind the resulting distribution is not well understood due to the opacity of the multiphase system in the granulator. This study experimentally characterised the GSSD dynamics along the TSG barrel length in order to understand the function of individual screw modules and process settings, as well as their interaction. Particle size analysis of granules collected at the outlet of the TSG suggested significant interaction between the process and screw configuration parameters influencing the heterogeneity in the GSSD. By characterising the samples collected along the screw length, a variable influence of the screw modules at different process conditions was observed. At low liquid-to-solid ratio (L/S), the first kneading module seemed to play a significant role in mixing, whereas the second kneading module was found to be more involved in reshaping the granules. At high L/S and high throughput, aggregation mainly took place in the second kneading module changing the GSSD. The results obtained from this study will be further used for the calibration and validation of a mechanistic model and, hence, support future development of a more detailed understanding of the HSWG process in a TSG.
Jean Paul Remon - One of the best experts on this subject based on the ideXlab platform.
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blend uniformity evaluation during continuous mixing in a twin screw granulator by in line nir using a moving f test
Analytica Chimica Acta, 2016Co-Authors: Margot Fonteyne, Rut Besseling, Wim Oostra, Ad Gerich, Jurgen Vercruysse, Fien De Leersnyder, Jean Paul Remon, Chris Vervaet, Thomas De BeerAbstract:Abstract This study focuses on the twin screw granulator of a continuous from-powder-to-tablet production line. Whereas powder dosing into the granulation unit is possible from a container of preblended material, a truly continuous process uses several feeders (each one dosing an individual ingredient) and relies on a continuous blending step prior to granulation. The aim of the current study was to investigate the in-line blending capacity of this twin screw granulator, equipped with conveying elements only. The feasibility of in-line NIR (SentroPAT, Sentronic GmbH, Dresden, Germany) spectroscopy for evaluating the blend uniformity of powders after the granulator was tested. Anhydrous theophylline was used as a tracer molecule and was blended with lactose monohydrate. Theophylline and lactose were both fed from a different feeder into the twin screw granulator barrel. Both homogeneous mixtures and mixing experiments with induced errors were investigated. The in-line spectroscopic analyses showed that the twin screw granulator is a useful tool for in-line blending in different conditions. The blend homogeneity was evaluated by means of a novel statistical method being the moving F-test method in which the variance between two blocks of collected NIR spectra is evaluated. The α- and β-error of the moving F-test are controlled by using the appropriate block size of spectra. The moving F-test method showed to be an appropriate calibration and maintenance free method for blend homogeneity evaluation during continuous mixing.
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Model-based analysis of a twin-screw wet granulation system for continuous solid dosage manufacturing
Computers and Chemical Engineering, 2016Co-Authors: Ashish Kumar, Séverine Thérèse F.c. Mortier, Jurgen Vercruysse, Krist V. Gernaey, Thomas De Beer, Jean Paul Remon, Chris Vervaet, Ingmar NopensAbstract: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.
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Development of a process map: A step towards a regime map for steady-state high shear wet twin screw granulation
Powder Technology, 2016Co-Authors: Ashish Kumar, Jurgen Vercruysse, Fien De Leersnyder, Jens Dhondt, Krist V. Gernaey, Valérie Vanhoorne, Thomas De Beer, Jean Paul Remon, Chris Vervaet, Ingmar NopensAbstract:Twin-screw granulation is an emerging continuous granulation technique in the pharmaceutical industry. The flexibility in process settings such as the binder addition method (wet vs. dry), screw configuration, screw speed and material throughput allows to modify the granule size and shape. However, twin-screw granulation, being a rather new granulation technique, is not yet as well understood as batch-wise high shear wet granulation. Furthermore, most of the studies performed on twin-screw granulation are limited to a certain design and scale of the twin-screw granulator. In this study, in order to improve the understanding about the granulation process and to comprehend the applicability and limits of the process variables in a scale independent manner, the regime theory was applied to one specific twin-screw granulator equipment. In this study, α-lactose monohydrate was granulated with polyvinylpyrrolidone (2.5%, w/w) as binder. The screw configuration of the 25 mm diameter co-rotating twin-screw granulator from the ConsiGma-25 unit consisted of one or two kneading zones of six kneading elements each (1 × 6 and 2 × 6, respectively), at a stagger angle of 60 °. The specific mechanical energy, which involves the combination of screw speed, material throughput and torque required to rotate the screws was correlated with the applied liquid-to-solid ratio to present process maps. The study suggested that, despite an increase in the granule size by the increasing liquid-to-solid ratio, most of the liquid contributes to formation of oversized granules. Therefore, keeping the liquid-to-solid ratio in a lower range and increasing the energy input to the system can be effectively used to lower the mean granule size. Changes in the screw geometry should also be explored to improve solid liquid mixing and breakage of oversized granules to narrow the width of the size distribution. Since, such a process map is limited to a selected formulation and equipment design, process maps based on several formulations and mechanistic mathematical modelling tools should be applied to identify the mechanisms and relevant dimensionless groups that control granule attributes, with the ultimate aim of producing a generalised regime map.
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Linking granulation performance with residence time and granulation liquid distributions in twin-screw granulation: An experimental investigation.
European Journal of Pharmaceutical Sciences, 2015Co-Authors: Ashish Kumar, Jurgen Vercruysse, Fien De Leersnyder, Valérie Vanhoorne, Chris Vervaet, Maija Alakarjula, Maunu Toiviainen, Mikko Juuti, Jarkko Ketolainen, Jean Paul RemonAbstract:Abstract Twin-screw granulation is a promising wet granulation technique for the continuous manufacturing of pharmaceutical solid dosage forms. A twin screw granulator displays a short residence time. Thus, the solid–liquid mixing must be achieved quickly by appropriate arrangement of transport and kneading elements in the granulator screw allowing the production of granules with a size distribution appropriate for tableting. The distribution of residence time and granulation liquid is governed by the field conditions (such as location and length of mixing zones) in the twin-screw granulator, thus contain interesting information on granulation time, mixing and resulting sub-processes such as wetting, aggregation and breakage. In this study, the impact of process (feed rate, screw speed and liquid-to-solid ratio) and equipment parameters (number of kneading discs and stagger angle) on the residence time (distribution), the granulation liquid-powder mixing and the resulting granule size distributions during twin-screw granulation were investigated. Residence time and axial mixing data was extracted from tracer maps and the solid–liquid mixing was quantified from moisture maps, obtained by monitoring the granules at the granulator outlet using near infra-red chemical imaging (NIR-CI). The granule size distribution was measured using the sieving method. An increasing screw speed dominantly reduced the mean residence time. Interaction of material throughput with the screw speed and with the number of kneading discs led to most variation in the studied responses including residence time and mixing capacity. At a high screw speed, granulation yield improved due to high axial mixing. However, increasing material throughput quickly lowers the yield due to insufficient mixing of liquid and powder. Moreover, increasing liquid-to-solid ratio resulted in more oversized granules, and the fraction of oversized granules further increased at higher throughput. Although an increasing number of kneading discs was found to be critical for achieving a uniform distribution of the granulation liquid, the granulation performance was hampered due to insufficient solid–liquid mixing capacity of the current kneading discs which is essential for wet granulation. Thus, a balance between material throughput and screw speed should be strived for in order to achieve a specific granulation time and solid–liquid mixing for high granulation yield. Additionally, more efforts are needed both in modification of the screw configuration as well as the geometry of the mixing elements to improve the mixing capacity of the twin-screw granulator. The results from the current experimental study improved the understanding regarding the interplay between granulation time and the axial and solid–liquid mixing responsible for the granulation performance in twin-screw wet granulation.
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Experimental investigation of granule size and shape dynamics in twin-screw granulation
International Journal of Pharmaceutics, 2014Co-Authors: Ashish Kumar, Giacomo Bellandi, Jurgen Vercruysse, Krist V. Gernaey, Thomas De Beer, Jean Paul Remon, Chris Vervaet, Ingmar NopensAbstract:A twin-screw granulator (TSG), a promising equipment for continuous high shear wet granulation (HSWG), achieves the desired level of mixing by a combination of the appropriate screw configuration and a suitable set of process settings (e.g. feed rate, screw speed, etc.), thus producing a certain granule size and shape distribution (GSSD). However, the primary sizing and shaping mechanism behind the resulting distribution is not well understood due to the opacity of the multiphase system in the granulator. This study experimentally characterised the GSSD dynamics along the TSG barrel length in order to understand the function of individual screw modules and process settings, as well as their interaction. Particle size analysis of granules collected at the outlet of the TSG suggested significant interaction between the process and screw configuration parameters influencing the heterogeneity in the GSSD. By characterising the samples collected along the screw length, a variable influence of the screw modules at different process conditions was observed. At low liquid-to-solid ratio (L/S), the first kneading module seemed to play a significant role in mixing, whereas the second kneading module was found to be more involved in reshaping the granules. At high L/S and high throughput, aggregation mainly took place in the second kneading module changing the GSSD. The results obtained from this study will be further used for the calibration and validation of a mechanistic model and, hence, support future development of a more detailed understanding of the HSWG process in a TSG.
