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Peter Kleinebudde - One of the best experts on this subject based on the ideXlab platform.
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mechanistic understanding regarding the functionality of microcrystalline cellulose and powdered cellulose as pelletization aids in wet extrusion Spheronization
Cellulose, 2020Co-Authors: Vincent Lenhart, Julian Quodbach, Peter KleinebuddeAbstract:Powdered cellulose (PC) and microcrystalline cellulose (MCC) show considerable different behavior during wet-extrusion and Spheronization. While MCC is an appropriate pelletization aid, PC is not suitable. The differences were explained by either the “molecular-sponge” or the “crystallite-gel” hypothesis. To elucidate the differences in functionality, the effect of several polar solvents on liquid–solid interaction with PC and MCC was investigated. In addition, PC was homogenized via high pressure homogenization to reduce particle size without affecting the degree of polymerization. Mixer torque rheometry (MTR), laser diffraction and texture analysis were used to characterize the behavior of PC and MCC in wet pastes, suspensions and pellets. PC and MCC interacted differently with solvents like dimethyl sulfoxide, dimethylformamide and several glycols during MTR experiments. While PC mainly swells in appropriate solvents, MCC showed a particle size reduction, partly into colloidal dimensions. Solvents that induced liberation of colloidal fibers, also enabled a wet-extrusion/Spheronization process. The quantity of colloidal cellulose only had minor effect on the resulting pellet quality. Also, the properties of the used solvent had only minor impact on the pellet size, shape and mechanical stability. PC contained small amounts of colloidal fibers after high pressure homogenization. With this pre-treated PC, wet-extrusion/Spheronization process was also possible although the pellet quality is inferior to MCC pellets. Colloidal cellulose fibers have a major impact on the behavior of wet mass and on the feasibility for pellet production via wet-extrusion/Spheronization. These insights provide new evidence for the “crystallite-gel” model.
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The Science and Practice of Extrusion-Spheronization
Advances in Delivery Science and Technology, 2017Co-Authors: Markus Thommes, Peter KleinebuddeAbstract:Extrusion-Spheronization is one of the important techniques for pellet production. In most cases, the extruded-spheronized pellets are then coated with a functional coating. Extrusion-Spheronization is a robust process and allows high drug loading of the pellets. The mean particle size is mainly determined by the die diameter, and its distribution is usually controlled to obtain a narrow particle size distribution. A pelletization aid is required to allow extrusion and Spheronization of drugs, and microcrystalline cellulose (MCC) is the standard pelletization aid used in the industry. Different models have been used to explain the functionality of MCC. However, in certain cases MCC may not be suitable for this application, for example, in the case of drugs with low solubility, it may lead to slower drug release. In these cases, alternative pelletization aids like carrageenan or crospovidone have been studied. In recent years, the scale-down for early formulation development was in focus, and therefore, small-scale extruders and spheronizers have been developed. In case of twin-screw extruders, the feeding systems are of high importance with respect to constant product quality. The extrusion process control and application of process analytical technologies (PAT) have made significant progress. In addition, in recent years the Spheronization process is better understood.
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production of pellets via extrusion spheronisation without the incorporation of microcrystalline cellulose a critical review
European Journal of Pharmaceutics and Biopharmaceutics, 2009Co-Authors: Aleksandra Dukicott, Markus Thommes, Peter Kleinebudde, Jean Paul Remon, Chris VervaetAbstract:Abstract Microcrystalline cellulose (MCC) is the golden standard to manufacture spherical particles (pellets) via extrusion–spheronisation since wetted microcrystalline cellulose has the proper rheological properties, cohesiveness and plasticity to yield strong and spherical particles. However, microcrystalline cellulose is not universally applicable due to a number of limitations: prolonged drug release of poorly soluble drugs, chemical incompatibility with specific drugs, drug adsorption onto MCC fibers. Hence, several products have been evaluated to explore their application as extrusion–spheronisation aid, aiming to avoid the disadvantages of MCC and to provide a broad application platform for extrusion–spheronisation: powdered cellulose, starch, chitosan, kappa-carrageenan, pectinic acid, hydroxypropylmethyl cellulose, hydroxyethyl cellulose, polyethylene oxide, cross-linked polyvinylpyrrolidone, glycerol monostearate. To determine the true potential of the proposed alternatives for MCC this review critically discusses the properties of the different materials and the quality of the resulting pellets in relation to the properties required for an ideal extrusion–spheronisation aid.
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Spheronization of Small Extrudates Containing κ-Carrageenan
Journal of pharmaceutical sciences, 2009Co-Authors: Angelina Yoo, Peter KleinebuddeAbstract:Spheronization of extrudates of around 500 µm diameter needs improvement of the Schlueter spheronizer conditions with regard to moisture content of the extrudates. The extrudates were obtained by a twin-screw extruder and contained κ-carrageenan as pelletization aid. The influences of Spheronization speed, residence time, temperature of the spheronizer wall and loading on the responses aspect ratio, pellet size and yield, were studied with a central composite circumscribed design. The Schlueter spheronizer was compared with a Nica spheronizer. Further, additional spheronizer process variables such as temperature of the spheronizer wall and inlet air pressure were also investigated. The results were evaluated in a full factorial (mixed) design. The micropellets in general showed a pellet size between 500 and 700 µm. A twisted-rope movement during the Spheronization process was not observed and adhesion to the spheronizer wall resulted in suboptimal micropellets. However, at suitable moisture content, less loading in the spheronizer, higher Spheronization speed and longer residence time micropellets with an aspect ratio below 1.1 were obtained. In addition the adhesion to the spheronizer wall was reduced. Spheronizer wall temperature and inlet air pressure were negligible variables. Significant differences between the two spheronizers could not be established. © 2008 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci 98:3776–3787, 2009
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Spheronization of solid lipid extrudates
Powder Technology, 2009Co-Authors: Claudia Reitz, Peter KleinebuddeAbstract:The objective of this study was the examination and development of a solvent-free Spheronization process as a manufacturing tool for sustained release matrix spheres. Extrudates prepared from a binary lipid mixture with different amounts of Dynasan 114® and Witocan 42/44® and theophylline as model drug were processed in systematic Spheronization experiments by varying pellet formulation and spheronizer-jacket temperature. The rounding procedure of the pellets was investigated by analyzing spot samples after different processing times. The obtained pellets were characterized according to their shape, size distribution, porosity and drug release properties. Round lipid pellets with a mean aspect ratio below 1.1 and a narrow particle size distribution with median equivalent diameters around 1.5 mm could be obtained. The pellets showed sustained drug release properties and porosities below 1%. The Spheronization process was shown to be strongly temperature- and formulation dependent. The material temperature during the process was influenced by the adjusted jacket temperature and friction- and shear forces between the rounded particles; control of material temperature seems to pose the challenge in the investigated process.
Guy Couarraze - One of the best experts on this subject based on the ideXlab platform.
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Extruder scale-up assessment in the process of extrusion-Spheronization: comparison of radial and axial systems by a design of experiments approach
Drug Development and Industrial Pharmacy, 2013Co-Authors: Amelie Desire, Bruno Paillard, Joel Bougaret, Michel Baron, Guy CouarrazeAbstract:Scaling-up the extrusion-Spheronization process involves the separate scale-up of each of the five process steps: dry mixing, granulation, extrusion, Spheronization, and drying. The aim of the study was to compare two screw extrusion systems regarding their suitability for scaling-up. Two drug substances of high-and low-solubility in water were retained at different concentrations as formulation variables. Different Spheronization times were tested. The productivity of the process was followed up using the extrusion rate and yield. Pellets were characterized by their size and shape, and by their structural and mechanical properties. A response surface design of experiments was built to evaluate the influence of the different variables and their interactions on each response, and to select the type of extrusion which provides the best results in terms of product quality, the one which shows less influence on the product after scale-up (''scalability'') and when the formula used changes (''robustness''), and the one which allows the possibility to adjust pellet properties with Spheronization variables (''flexibility''). Axial system showed the best characteristics in terms of product quality at lab and industrial scales, the best robustness at industrial scale, and the best scalability, by comparison with radial system. Axial system thus appeared as the easiest scaled-up system. Compared to lab scale, the conclusions observed at industrial scale were the same in terms of product quality, but different for robustness and flexibility, which confirmed the importance to test the systems at industrial scale before acquiring the equipment.
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extruder scale up assessment in the process of extrusion Spheronization comparison of radial and axial systems by a design of experiments approach
Drug Development and Industrial Pharmacy, 2013Co-Authors: Amelie Desire, Bruno Paillard, Joel Bougaret, Michel Baron, Guy CouarrazeAbstract:Scaling-up the extrusion–Spheronization process involves the separate scale-up of each of the five process steps: dry mixing, granulation, extrusion, Spheronization, and drying. The aim of the study was to compare two screw extrusion systems regarding their suitability for scaling-up. Two drug substances of high- and low-solubility in water were retained at different concentrations as formulation variables. Different Spheronization times were tested. The productivity of the process was followed up using the extrusion rate and yield. Pellets were characterized by their size and shape, and by their structural and mechanical properties. A response surface design of experiments was built to evaluate the influence of the different variables and their interactions on each response, and to select the type of extrusion which provides the best results in terms of product quality, the one which shows less influence on the product after scale-up (“scalability”) and when the formula used changes (“robustness”), and t...
Jörg Breitkreutz - One of the best experts on this subject based on the ideXlab platform.
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Spheronization of solid lipid extrudates: Elucidation of spheroid formation mechanism
European Journal of Pharmaceutics and Biopharmaceutics, 2018Co-Authors: Gustavo Freire Petrovick, Jörg BreitkreutzAbstract:Abstract To explain the rounding mechanism of extrudates by Spheronization method, two main concepts are found in literature: one proposed by Rowe (1985) and one proposed by Baert et al. (1993). These concepts are based on wet extrusion-Spheronization method using microcrystalline cellulose as mains excipient. However, there are no concepts for the Spheronization mechanism of extrudates based on solid lipids as Spheronization aid. Therefore, the aim of this study is to systematically investigate the mechanism of pellet formation of lipid based extrudates by lipid Spheronization method. Different lipid based extrudate formulations were spheronized and particle size distribution and shape of the pellets, at each minute of the process, were characterized. Additionally, visual investigations of the morphological alterations were performed by optical and scanning electron microscopy. Two main material temperature phases were identified as presenting important influence on the pellet formation during the process: (1) a “brittle phase”, where the extrudates are broken into smaller particles and (2) a “plastic phase”, where the material starts to partially melt, allowing the particles to deform. By the same token, different morphological stages, from cylindrical rods to sphere-shaped passing through a dumbbell-shaped particle, were observed and showed to be highly dependent on temperature and process time. Moreover, a new particle shape, defined as “two-spheres”, was recognized and a sequential material overlapping (covering) phenomenon was identified. This particular dislocation of material, from the edges to the central region of the particles (increasing their mean diameter), was recognized at longer process times and led to the formation of a smooth surface and the final spherical shape. At the end, a new concept of pellet formation from lipid extrudates is presented considering the observed changes in the morphology and particle size of the pellets during the Spheronization process.
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Spheronization of solid lipid extrudates: A novel approach on controlling critical process parameters.
European journal of pharmaceutics and biopharmaceutics : official journal of Arbeitsgemeinschaft fur Pharmazeutische Verfahrenstechnik e.V, 2015Co-Authors: Gustavo Freire Petrovick, Markus Thommes, Miriam Pein, Jörg BreitkreutzAbstract:Solid lipids are non-toxic excipients, which are known to potentially enhance delivery and bioavailability of poorly water-soluble drugs and moreover to mask unpleasant tasting drugs. Multiple unit matrix dosage forms based on solid lipids, such as lipid pellets, can be obtained by solvent-free cold extrusion and Spheronization. This method presents advantages in the processing of sensitive substances, such as low process temperatures, the absence of solvents and a drying step. However, the material temperature during the Spheronization showed to be critical so far. The process leads to increased material temperatures, causing particle agglomeration and discontinuity of the Spheronization. In the present study, extrudates of 0.5mm in diameter containing metformin hydrochloride, and either semisynthetic hard fat (Witocan® 42/44) or different ternary mixtures based on hard fat, glyceryl trimyristate, and glyceryl distearate, were spheronized. By applying common process parameters, particle agglomeration or material stickiness on equipment walls was observed in preliminary experiments after 2-6min, depending on the lipid composition. Therefore, an innovative instrumental setup to control the Spheronization process was developed utilizing an infrared light source, which was positioned over the particle bed. The new approach enabled a Spheronization process that reached the desired Spheronization temperature after 2-3min and neither particle agglomeration nor material adherence occurred even after longer process times. The different formulations, even those based on high amount of solid lipids, were successfully spheronized over 15min, resulting in small diameter lipid pellets with smooth surface and aspect ratios below 1.3.
Markus Thommes - One of the best experts on this subject based on the ideXlab platform.
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Scale-up of the rounding process in pelletization by extrusion-Spheronization
Pharmaceutical development and technology, 2019Co-Authors: Maria Evers, Dominik Weis, Sergiy Antonyuk, Markus ThommesAbstract:AbstractPreviously described scaling models for the Spheronization process of wet extrudates are incomplete, often concluding with an adjustment of the plate speed according to the spheronizer diam...
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DEM simulation of the mixing behavior in a Spheronization process
Chemical Engineering Science, 2018Co-Authors: Dominik Weis, Markus Thommes, Maria Evers, Sergiy AntonyukAbstract:Abstract Spherical pellets for pharmaceutical applications are widely produced by an extrusion-Spheronization process. To achieve an equal, spherical pellet shape with a Spheronization process, it is crucial that all pellets are exposed to similar stress conditions. However, in a spheronizer the pellets close to the friction plate are subjected to much higher stresses than pellets at the top of the torus, resulting in a strongly inhomogeneous stress distribution within the particle bed. Therefore, the product quality depends in particular on the mixing process in the spheronizer. In this study, the mixing behavior in a Spheronization process is analyzed using DEM simulations. The real geometry and realistic process parameters of a lab scale spheronizer were investigated. To determine the mechanical properties of the wet pellets for the contact model, various single particle experiments were conducted with MCC-based pellets produced by extrusion-Spheronization. The spatial mixing was characterized in different ways. Besides the determination of the degree of mixing based on statistical analysis, the Fokker-Planck equation was utilized. In this way the spatial distribution of the degree of mixing over the time was obtained. By using the poloidal distribution of the transport and dispersion coefficients of the Fokker-Planck equation the course of the degree of mixing in the different zones of the spheronizer was clarified.
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The Science and Practice of Extrusion-Spheronization
Advances in Delivery Science and Technology, 2017Co-Authors: Markus Thommes, Peter KleinebuddeAbstract:Extrusion-Spheronization is one of the important techniques for pellet production. In most cases, the extruded-spheronized pellets are then coated with a functional coating. Extrusion-Spheronization is a robust process and allows high drug loading of the pellets. The mean particle size is mainly determined by the die diameter, and its distribution is usually controlled to obtain a narrow particle size distribution. A pelletization aid is required to allow extrusion and Spheronization of drugs, and microcrystalline cellulose (MCC) is the standard pelletization aid used in the industry. Different models have been used to explain the functionality of MCC. However, in certain cases MCC may not be suitable for this application, for example, in the case of drugs with low solubility, it may lead to slower drug release. In these cases, alternative pelletization aids like carrageenan or crospovidone have been studied. In recent years, the scale-down for early formulation development was in focus, and therefore, small-scale extruders and spheronizers have been developed. In case of twin-screw extruders, the feeding systems are of high importance with respect to constant product quality. The extrusion process control and application of process analytical technologies (PAT) have made significant progress. In addition, in recent years the Spheronization process is better understood.
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Spheronization of solid lipid extrudates: A novel approach on controlling critical process parameters.
European journal of pharmaceutics and biopharmaceutics : official journal of Arbeitsgemeinschaft fur Pharmazeutische Verfahrenstechnik e.V, 2015Co-Authors: Gustavo Freire Petrovick, Markus Thommes, Miriam Pein, Jörg BreitkreutzAbstract:Solid lipids are non-toxic excipients, which are known to potentially enhance delivery and bioavailability of poorly water-soluble drugs and moreover to mask unpleasant tasting drugs. Multiple unit matrix dosage forms based on solid lipids, such as lipid pellets, can be obtained by solvent-free cold extrusion and Spheronization. This method presents advantages in the processing of sensitive substances, such as low process temperatures, the absence of solvents and a drying step. However, the material temperature during the Spheronization showed to be critical so far. The process leads to increased material temperatures, causing particle agglomeration and discontinuity of the Spheronization. In the present study, extrudates of 0.5mm in diameter containing metformin hydrochloride, and either semisynthetic hard fat (Witocan® 42/44) or different ternary mixtures based on hard fat, glyceryl trimyristate, and glyceryl distearate, were spheronized. By applying common process parameters, particle agglomeration or material stickiness on equipment walls was observed in preliminary experiments after 2-6min, depending on the lipid composition. Therefore, an innovative instrumental setup to control the Spheronization process was developed utilizing an infrared light source, which was positioned over the particle bed. The new approach enabled a Spheronization process that reached the desired Spheronization temperature after 2-3min and neither particle agglomeration nor material adherence occurred even after longer process times. The different formulations, even those based on high amount of solid lipids, were successfully spheronized over 15min, resulting in small diameter lipid pellets with smooth surface and aspect ratios below 1.3.
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Spheronization process particle kinematics determined by discrete element simulations and particle image velocimentry measurements
International Journal of Pharmaceutics, 2014Co-Authors: Martin Koester, Edwin R Garcia, Markus ThommesAbstract:Abstract Spheronization is an important pharmaceutical manufacturing technique to produce spherical agglomerates of 0.5–2 mm diameter. These pellets have a narrow size distribution and a spherical shape. During the Spheronization process, the extruded cylindrical strands break in short cylinders and evolve from a cylindrical to a spherical state by deformation and attrition/agglomeration mechanisms. Using the discrete element method, an integrated modeling-experimental framework is presented, that captures the particle motion during the Spheronization process. Simulations were directly compared and validated against particle image velocimetry (PIV) experiments with monodisperse spherical and dry γ-Al 2 O 3 particles. Result demonstrate a characteristic torus like flow pattern, with particle velocities about three times slower than the rotation speed of the friction plate. Five characteristic zones controlling the Spheronization process are identified: Zone I, where particles undergo shear forces that favors attrition and contributes material to the agglomeration process; Zone II, where the static wall contributes to the mass exchange between particles; Zone III, where gravitational forces combined with particle motion induce particles to collide with the moving plate and re-enter Zone I; Zone IV, where a subpopulation of particles are ejected into the air when in contact with the friction plate structure; and Zone V where the low poloidal velocity favors a stagnant particle population and is entirely controlled by the batch size. These new insights in to the particle motion are leading to deeper process understanding, e.g., the effect of load and rotation speed to the pellet formation kinetics. This could be beneficial for the optimization of a manufacturing process as well as for the development of new formulations.
Amelie Desire - One of the best experts on this subject based on the ideXlab platform.
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Extruder scale-up assessment in the process of extrusion-Spheronization: comparison of radial and axial systems by a design of experiments approach
Drug Development and Industrial Pharmacy, 2013Co-Authors: Amelie Desire, Bruno Paillard, Joel Bougaret, Michel Baron, Guy CouarrazeAbstract:Scaling-up the extrusion-Spheronization process involves the separate scale-up of each of the five process steps: dry mixing, granulation, extrusion, Spheronization, and drying. The aim of the study was to compare two screw extrusion systems regarding their suitability for scaling-up. Two drug substances of high-and low-solubility in water were retained at different concentrations as formulation variables. Different Spheronization times were tested. The productivity of the process was followed up using the extrusion rate and yield. Pellets were characterized by their size and shape, and by their structural and mechanical properties. A response surface design of experiments was built to evaluate the influence of the different variables and their interactions on each response, and to select the type of extrusion which provides the best results in terms of product quality, the one which shows less influence on the product after scale-up (''scalability'') and when the formula used changes (''robustness''), and the one which allows the possibility to adjust pellet properties with Spheronization variables (''flexibility''). Axial system showed the best characteristics in terms of product quality at lab and industrial scales, the best robustness at industrial scale, and the best scalability, by comparison with radial system. Axial system thus appeared as the easiest scaled-up system. Compared to lab scale, the conclusions observed at industrial scale were the same in terms of product quality, but different for robustness and flexibility, which confirmed the importance to test the systems at industrial scale before acquiring the equipment.
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extruder scale up assessment in the process of extrusion Spheronization comparison of radial and axial systems by a design of experiments approach
Drug Development and Industrial Pharmacy, 2013Co-Authors: Amelie Desire, Bruno Paillard, Joel Bougaret, Michel Baron, Guy CouarrazeAbstract:Scaling-up the extrusion–Spheronization process involves the separate scale-up of each of the five process steps: dry mixing, granulation, extrusion, Spheronization, and drying. The aim of the study was to compare two screw extrusion systems regarding their suitability for scaling-up. Two drug substances of high- and low-solubility in water were retained at different concentrations as formulation variables. Different Spheronization times were tested. The productivity of the process was followed up using the extrusion rate and yield. Pellets were characterized by their size and shape, and by their structural and mechanical properties. A response surface design of experiments was built to evaluate the influence of the different variables and their interactions on each response, and to select the type of extrusion which provides the best results in terms of product quality, the one which shows less influence on the product after scale-up (“scalability”) and when the formula used changes (“robustness”), and t...
