Abstract
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.
Access this chapter
Tax calculation will be finalised at checkout
Purchases are for personal use only
References
Bornhöft M, Thommes M, Kleinebudde P. Preliminary assessment of carrageenan as excipient for extrusion/spheronisation. Eur J Pharm Biopharm. 2005;59:127–31.
Mangual JO, et al. Biodegradable nanocomposite magnetite stent for implant-assisted magnetic drug targeting. J Magn Magn Mater. 2010;322(20):3094–100.
Hasa D, et al. Melt extruded helical waxy matrices as a new sustained drug delivery system. Eur J Pharm Biopharm. 2011;79(3):592–600.
Reynolds AD. A new technique for the production of spherical particles. Manufacturing Chemist & Aerosol News; June 1970. p. 40–3.
Conine JW, Hadley HR. Small solid pharmaceutical spheres. Drug & Cosmetic Industry; 1970. p. 38–41.
Young CR, Koleng JJ, McGinity JW. Production of spherical pellets by a hot-melt extrusion and spheronization process. Int J Pharm. 2002;242(1–2):87–92.
Young CR, Koleng JJ, McGinity JW. Properties of drug-containing spherical pellets produced by a hot-melt extrusion and spheronization process. J Microencapsul. 2003;20(5):613–25.
Kleinebudde P. Solid lipid extrusion. In: Repka MA, Langley N, DiNunzio J, editors. Melt extrusion. New York/Heidelberg/Dordrecht/London: Springer; 2013. p. 299–328.
Reitz C, Kleinebudde P. Spheronization of solid lipid extrudates. Powder Technol. 2009;189(2):238–44.
Krause J, Thommes M, Breitkreutz J. Immediate release pellets with lipid binders obtained by solvent-free cold extrusion. Eur J Pharm Biopharm. 2009;71(1):138–44.
Dukic-Ott A, et al. Production of pellets via extrusion-spheronisation without the incorporation of microcrystalline cellulose: a critical review. Eur J Pharm Biopharm. 2009;71(1):38–46.
Otero-Espinar FJ, Luzardo-Alvarez A, Blanco-Mendez J. Non-MCC materials as extrusion-spheronization aids in pellets production. J Drug Delivery Sci Technol. 2010;20(4):303–18.
Jain SP, Singh PP, Amin PD. Alternative extrusion-spheronization aids. Drug Dev Ind Pharm. 2010;36(11):1364–76.
Wilson Di, Rough Sl. Extrusion-spheronisation. In: Salman AD, Hounslow MJ, Seville JPK, editors. Granulation. Amsterdam: Elsevier; 2007. p. 189–217.
Trivedi NR, et al. Pharmaceutical approaches to preparing pelletized dosage forms using the extrusion-spheronization process. Crit Rev Ther Drug Carrier Syst. 2007;24(1):1–40.
Di Pretoro G, et al. Extrusion-spheronisation of highly loaded 5-ASA multiparticulate dosage forms. Int J Pharm. 2010;402(1–2):153–64.
Fielden KE, et al. Thermal studies on the interaction of water and microcrystalline cellulose. J Pharm Pharmacol. 1988;40(10):674–8.
Ek R, Newton JM. Microcrystalline cellulose as a sponge as an alternative concept to the crystallite-gel model for extrusion and spheronization. Pharm Res. 1998;15(4):509–11.
Kleinebudde P. The crystallite-gel-model for microcrystalline cellulose in wet-granulation, extrusion, and spheronization. Pharm Res. 1997;14(6):804–9.
Battista OA. Microcrystal polymer science. New York: McGraw-Hill Book Company; 1975. 18.
Kleinebudde P, Knop K. Direct pelletization of pharmaceutical pellets in fluid-bed processes. In: Salman AD, Hounslow MJ, Seville JPK, editors. Granulation. Amsterdam: Elsevier; 2007. p. 779–811.
Sarkar S, Heng PW, Liew CV. Insights into the functionality of pelletization aid in pelletization by extrusion-spheronization. Pharm Dev Technol. 2013;18(1):61–72.
Sarkar S, Ang BH, Liew CV. Influence of starting material particle size on pellet surface roughness. AAPS PharmSciTech. 2014;15(1):131–9.
Mascia S, et al. Extrusion-spheronisation of microcrystalline cellulose pastes using a non-aqueous liquid binder. Int J Pharm. 2010;389(1–2):1–9.
Dreu R, et al. Physicochemical properties of granulating liquids and their influence on microcrystalline cellulose pellets obtained by extrusion-spheronisation technology. Int J Pharm. 2005;291(1–2):99–111.
Sarkar S, Liew CV. Moistening liquid-dependent de-aggregation of microcrystalline cellulose and its impact on pellet formation by extrusion-spheronization. AAPS Pharm Sci Tech. 2014;15:753–61.
Witzleb R, et al. Influence of needle-shaped drug particles on the solid lipid extrusion process. Powder Technol. 2011;207(1–3):407–13.
Thommes M, et al. Improved bioavailability of darunavir by use of kappa-carrageenan versus microcrystalline cellulose as pelletisation aid. Eur J Pharm Biopharm. 2009;72(3):614–20.
Schroder M, Kleinebudde P. Structure of disintegrating pellets with regard to fractal geometry. Pharm Res. 1995;12(11):1694–700.
Liew CV, et al. Functionality of cross-linked polyvinylpyrrolidone as a spheronization aid: a promising alternative to microcrystalline cellulose. Pharm Res. 2005;22(8):1387–98.
Verheyen P, Steffens KJ, Kleinebudde P. Use of crospovidone as pelletization aid as alternative to microcrystalline cellulose: effects on pellet properties. Drug Dev Ind Pharm. 2009;35(11):1325–32.
Jain SP, et al. Melt-in-mouth pellets of fexofenadine hydrochloride using crospovidone as an extrusion-spheronisation aid. AAPS PharmSciTech. 2010;11(2):917–23.
Krueger C, Thommes M, Kleinebudde P. “MCC SANAQ®burst”—a new type of cellulose and its suitability to prepare fast disintegrating pellets. J Pharm Innov. 2010;5(1–2):45–57.
Krueger C, Thommes M, Kleinebudde P. Spheronisation mechanism of MCC II-based pellets. Powder Technol. 2013;238:176–87.
Rojas J, Kumar V. Evaluation of microcrystalline cellulose II (MCCII) as an alternative extrusion-spheronization aid. Pharmazie. 2012;67(7):595–7.
Krueger C, Thommes M, Kleinebudde P. Influence of MCC II fraction and storage conditions on pellet properties. Eur J Pharm Biopharm. 2013;85(3 Pt B):1039–45.
Delalonde M, et al. The rheology of wet powders: a measuring instrument, the compresso-rheometer. Int J Pharm. 1996;130(1):147–51.
Harrison PJ, Newton JM, Rowe RC. The application of capillary rheometry to the extrusion of wet powder masses. Int J Pharm. 1987;35(3):235–42.
Thoma K, Ziegler I. Investigations on the influence of the type of extruder for pelletization by extrusion-spheronization. II. Sphere characteristics. Drug Dev Ind Pharm. 1998;24(5):413–22.
Ghanam D, Kleinebudde P. Suitability of a flat die press for the manufacture of pharmaceutical pellets by extrusion/spheronization. Drug Dev Ind Pharm. 2011;37(4):456–64.
Thommes M. Systematische Untersuchungen zur Eignung von kappa-Carrageenan als Pelletierhilfsstoff in der Extrusion/ Sphäronisation. Systematic Investigations of κ-Carrageenan as novel Pelletisation Aid in Wet Extrusion/Spheronisation. Göttingen: Cuvillier; 2006.
Sakai T, Thommes M. Investigation into mixing capability and solid dispersion preparation using the DSM Xplore pharma micro extruder. J Pharm Pharmacol. 2014;66(2):218–31.
Mühlenfeld C, Thommes M. Miniaturization in pharmaceutical extrusion technology: feeding as a challenge of downscaling. AAPS PharmSciTech. 2012;13(1):94–100.
Kleinebudde P, Solvberg AJ, Lindner H. The power-consumption-controlled extruder – a tool for pellet production. J Pharm Pharmacol. 1994;46(7):542–6.
Kleinebudde P. Use of a power-consumption-controlled extruder in the development of pellet formulations. J Pharm Sci. 1995;84(10):1259–64.
Köster M, Thommes M. Inline dynamic torque measurement in twin screw extrusion process. Chem Eng J. 2010;164:371–5.
De Beer T, et al. Near infrared and Raman spectroscopy for the in-process monitoring of pharmaceutical production processes. Int J Pharm. 2011;417(1–2):32–47.
Fonteyne M, et al. Real-time assessment of critical quality attributes of a continuous granulation process. Pharm Dev Technol. 2013;18(1):85–97.
Saerens L, et al. Raman spectroscopy for the in-line polymer-drug quantification and solid state characterization during a pharmaceutical hot-melt extrusion process. Eur J Pharm Biopharm. 2011;77(1):158–63.
Saerens L, et al. In-line NIR spectroscopy for the understanding of polymer-drug interaction during pharmaceutical hot-melt extrusion. Eur J Pharm Biopharm. 2012;81(1):230–7.
Saerens L, et al. Visualization and process understanding of material behavior in the extrusion barrel during a hot-melt extrusion process using Raman spectroscopy. Anal Chem. 2013;85(11):5420–9.
Wahl PR, et al. Inline monitoring and a PAT strategy for pharmaceutical hot melt extrusion. Int J Pharm. 2013;455(1–2):159–68.
Sandler N, et al. Pellet manufacturing by extrusion-spheronization using process analytical technology. AAPS PharmSciTech. 2005;6(2):E174–83.
Crowley MM, et al. Pharmaceutical applications of hot-melt extrusion: part I. Drug Dev Ind Pharm. 2007;33(9):909–26.
Nobuo N. Method and apparatus for making spherical granules. US3277520A, 1966.
Erkoboni DF. Extrusion/spheronization. In: Ghebre Sellassie I, Martin C, editors. Pharmaceutical extrusion technology. New York: Marcel Dekker Inc; 2003. p. 277–318.
Krüger C, Thommes M. Multiple batch manufacturing of theophylline pellets using the wet-extrusion/spheronization process with kappa-carrageenan as pelletisation aid. Pharm Dev Technol. 2013;18(1):225–35.
Ghebre Sellassie I. Pellets: a general overview. In: DiNunzio J., editor. Pharmaceutical pelletization technology. New York: Marcel Dekker; 1989. p. 1–14.
Rowe RC. Spheronization: a novel pill-masking process? Pharm Int. 1985;6:119–23.
Koester M, et al. Systematic evaluations regarding interparticular mass transfer in spheronization. Int J Pharm. 2012;431(1–2):84–9.
Krüger C, Thommes M, Kleinebudde P. Spheronisation mechanism of MCC II-based pellets. Powder Technol. 2013;238:176–87.
Baert L, Remon JP. Influence of amount of granulation liquid on the drug-release rate from pellets made by extrusion spheronization. Int J Pharm. 1993;95(1–3):135–41.
Liew CV, Chua SM, Heng PWS. Elucidation of spheroid formation with and without the extrusion step. AAPS PharmSciTech. 2007;8(1):10.
Köster M, Thommes M. New insights into the pelletization mechanism by extrusion/spheronization. AAPS PharmSciTech. 2010;11(4):1549–51.
Köster M, Thommes M. Quantification of mass transfer during spheronisation. AAPS PharmSciTech. 2012;13(2):493–7.
Bialleck S, Rein H. Preparation of starch-based pellets by hot-melt extrusion. Eur J Pharm Biopharm. 2011;79(2):440–8.
Rudolf R. General overview of compounding process. In: Kohlgrüber K, editor. Corotating twin screw extruders. Munich: Carl Hanser Verlag; 2008. p. 57–89.
Martin C. Continuous mixing of solid dosage forms via hot-melt extrusion. Pharm Technol. 2008;32:76–86.
Treffer D, et al. Hot melt extrusion as a continious pharmaceutical manufacturing process. In: Repka MA, Langley N, DiNunzio JC, editors. Melt extusion. New York: Springer; 2013. p. 363–9.
Soh JLP, et al. Importance of small pores in microcrystalline cellulose for controlling water distribution during extrusion-spheronization. AAPS PharmSciTech. 2008;9(3):972–81.
Thommes M, Kleinebudde P. Comparison of different κ-Carrageenans in pelletisation by extrusion/spheronisation. 5th World meeting on Pharmaceutics, Biopharmaceutics and Pharmaceutical Technology; March 2006.
Thommes M, et al. Bioavailability of darunavir in pellets using κ-Carrageenan and MCC as pelletisation aid. AAPS annual meeting and exposition; November 2008.
Thommes M, Kleinebudde P. Use of kappa-carrageenan as alternative pelletisation aid to microcrystalline cellulose in extrusion/spheronisation. II. Influence of drug and filler type. Eur J Pharm Biopharm. 2006;63(1):68–75.
Schmidt C, Kleinebudde P. Comparison between a twin-screw extruder and a rotary ring die press. Part II: influence of process variables. Eur J Pharm Biopharm. 1998;45(2):173–9.
Bornhoft M, Thommes M, Kleinebudde P. Preliminary assessment of carrageenan as excipient for extrusion/spheronisation. Eur J Pharm Biopharm. 2005;59(1):127–31.
Michie H, Podczeck F, Newton JM. The influence of plate design on the properties of pellets produced by extrusion and spheronization. Int J Pharm. 2012;434(1–2):175–82.
Hicks DC, Freese HL. Extrusion and spheronizing equipment. In: Ghebre-Sellassie I, editor. Pharmaceutical pelletization technology. New York: Dekker; 1989. p. 71–100.
Wan LSC, Heng PWS, Liew CV. Spheronization conditions on spheroid shape and size. Int J Pharm. 1993;96(1–3):59–65.
Agrawal AM, Howard MA, Neau SH. Extruded and spheronized beads containing no microcrystalline cellulose: influence of formulation and process variables. Pharm Dev Technol. 2004;9(2):197–217.
Yoo A, Kleinebudde P. Spheronization of small extrudates containing kappa-carrageenan. J Pharm Sci. 2009;98(10):3776–87.
Corwin EI. Granular flow in a rapidly rotated system with fixed walls. Phys Rev E. 2008;77(3):031308.
Köster M, Thommes M. Analysis of particle kinematics in spheronization via particle image velocimetry. Eur J Pharm Biopharm. 2013;83(2):307–14.
Bouffard J, Bertrand F, Chaouki J. A multiscale model for the simulation of granulation in rotor-based equipment. Chem Eng Sci. 2012;81:106–17.
Bouffard J, et al. Discrete element investigation of flow patterns and segregation in a spheronizer. Comput Chem Eng. 2013;49:170–82.
Breitkreutz J, Boos J. Paediatric and geriatric drug delivery. Expert Opin Drug Deliv. 2007;4(1):37–45.
Ziegler I. Dose sipping technology – a novel dosage form for the administration of drugs. New York: Informa Healthcare; 2008.
Zimm KR, Schwartz JB, O’Connor RE. Drug release from a multiparticulate pellet system. Pharm Dev Technol. 1996;1(1):37–42.
O’Connor RE, Schwartz JB. Drug release mechanism from a microcrystalline cellulose pellet system. Pharm Res. 1993;10(3):356–61.
Fischer A, Ziegler I. Dosageform with improved release form cefuroximaxetil. PCT /EP2006/003814, 2006.
Mistry RB, Sheth NS. A review: self emulsifying drug delivery systems. Int J Pharm Pharm Sci. 2011;3(2):23–8.
Tuleu C, et al. Comparative bioavailability study in dogs of self-emulsifying formulation of progesterone presented in a pellet and liquid form compared with an aqueous suspension of progesterone. J Pharm Sci. 2004;93(6):1495–502.
Iosio T, et al. Bi-layered self-emulsifying pellets prepared by co-extrusion and spheronization: influence of formulation variables and preliminary study on the in vivo absorption. Eur J Pharm Biopharm. 2008;69(2):686–97.
Zhang Y, et al. Characterization and evaluation of self-microemulsifying sustained-release pellet formulation of puerarin for oral delivery. Int J Pharm. 2012;427(2):337–44.
Author information
Authors and Affiliations
Corresponding author
Editor information
Editors and Affiliations
Rights and permissions
Copyright information
© 2017 Controlled Release Society
About this chapter
Cite this chapter
Thommes, M., Kleinebudde, P. (2017). The Science and Practice of Extrusion-Spheronization. In: Rajabi-Siahboomi, A. (eds) Multiparticulate Drug Delivery. Advances in Delivery Science and Technology. Springer, New York, NY. https://doi.org/10.1007/978-1-4939-7012-4_3
Download citation
DOI: https://doi.org/10.1007/978-1-4939-7012-4_3
Published:
Publisher Name: Springer, New York, NY
Print ISBN: 978-1-4939-7010-0
Online ISBN: 978-1-4939-7012-4
eBook Packages: Biomedical and Life SciencesBiomedical and Life Sciences (R0)