Abstract
In recent years, extrusion technology has shifted the focus of pharmaceutical research due to versatile applications like pelletization, bioavailability improvement or manipulation of solid-state properties of drugs, continuous granulation, and the development of novel solid dosage forms. Meanwhile, a major effort has been devoted to the miniaturization of equipment in pharmaceutical extrusion technology, particularly with regard to the requirements of the development of new chemical entities and formulations. In the present study, a lab-scale twin-screw extruder was investigated in order to determine the limitations imposed by the feeding systems. The wet extrusion process was considered as challenging because both a powder and a liquid feeder have to be considered. Initially, the accuracy and uniformity of the powder and liquid feeder were tested independently of the extrusion process. After modification of the powder feeder, both feeders were investigated in conjunction with extrusion. Based on this, an optimization of the liquid feeder was required and completed. Both feeder modifications reduced the variability of the moisture content in the extrudates 10-fold. This led to a reliable small-scale extrusion process.
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REFERENCES
Martin C. Continuous mixing of solid dosage forms via hot-melt extrusion. Pharm Technol. 2008;32(10):76–86.
Vervaet C, Remon JP. Continuous granulation in the pharmaceutical industry. Chem Eng Sci. 2005;60:3949–57.
Dukic-Ott A, Thommes M, Remon JP, Kleinebudde P, Vervaet C. Production of pellets via extrusion–spheronisation without the incorporation of microcrystalline cellulose: a critical review. Eur J Pharm Biopharm. 2009;71(1):38–46.
Sandler N, Rantanen J, Heinämäki J, Römer M, Marvola M, Yliruusi J. Pellet manufacturing by extrusion–spheronization using process analytical technology. AAPS PharmSciTech. 2005;6(2):E174–83.
Crowley MM, Zhang F, Repka MA, Thumma S, Upadhye SB, Battu SK, et al. Pharmaceutical applications of hot-melt extrusion: part I. Drug Dev Ind Pharm. 2007;33(9):909–26.
Kinoshita M, Baba K, Nagayasu A, Yamabe K, Shimooka T, Takeichi Y, et al. Improvement of solubility and oral bioavailability of a poorly water-soluble drug, TAS-301, by its melt-adsorption on a porous calcium silicate. J Pharm Sci. 2002;91(2):362–70.
Djuric D, Kleinebudde P. Impact of screw elements on continuous granulation with a twin-screw extruder. J Pharm Sci. 2008;97(11):4934–42.
Lindberg NO, Tufvesson C, Holm P, Olbjer L. Extrusion of an effervescent granulation with a twin screw extruder, Baker Perkins MPF 50 D. Influence on intragranular porosity and liquid saturation. Drug Dev Ind Pharm. 1988;14(13):1791–8.
Lindberg NO, Myrenas M, Tufvesson C, Olbjer L. Extrusion of an effervescent granulation with a twin screw extruder, Baker Perkins MPF 50D. Determination of mean residence time. Drug Dev Ind Pharm. 1988;14(5):649–55.
Wening K, Breitkreutz J. Novel delivery device for monolithical solid oral dosage forms for personalized medicine. Int J Pharm. 2010;395(1–2):174–81.
Steiner R. Extruder design. Pharmaceutical extrusion technology. New York: Marcel Dekker; 2003.
Callari JJ. ‘Slower’ compounders suggest trend toward energy-efficient designs. Plast Technol. 2010;56(9):19–20.
Jonoobi M, Harun J, Mathew AP, Oksman K. Mechanical properties of cellulose nanofiber (CNF) reinforced polylactic acid (PLA) prepared by twin screw extrusion. Compos Sci Technol. 2010;70(12):1742–7. doi:10.1016/j.compscitech.2010.07.005.
Damadzadeh B, Jabari H, Skrifvars M, Airola K, Moritz N, Vallittu P. Effect of ceramic filler content on the mechanical and thermal behaviour of poly-l-lactic acid and poly-l-lactic-co-glycolic acid composites for medical applications. J Mater Sci Material Med. 2010;21(9):2523–31.
Mangual JO, Li S, Ploehn HJ, Ebner AD, Ritter JA. Biodegradable nanocomposite magnetite stent for implant-assisted magnetic drug targeting. J Magn Magn Mater. 2010;322(20):3094–100. doi:10.1016/j.jmmm.2010.05.036.
Martin C. Nano-scale compounding via twin screw extruders. ALEC newsletter. 2010;2010:1–6.
Verreck G, Decorte A, Heymans K, Adriaensen J, Liu D, Tomasko D, et al. Hot stage extrusion of p-amino salicylic acid with EC using CO2 as a temporary plasticizer. Int J Pharm. 2006;327(1–2):45–50. doi:10.1016/j.ijpharm.2006.07.024.
Chiou BS, Wood D, Yee E, Imam SH, Glenn GM, Orts WJ. Extruded starch–nanoclay nanocomposites: effects of glycerol and nanoclay concentration. Polym Eng Sci. 2007;47(11):1898–904.
Ozkan S, Kalyon DM, Yu X, McKelvey CA, Lowinger M. Multifunctional protein-encapsulated polycaprolactone scaffolds: fabrication and in vitro assessment for tissue engineering. Biomaterials. 2009;30(26):4336–47.
Erisken C, Kalyon DM, Wang H. Functionally graded electrospun polycaprolactone and β-tricalcium phosphate nanocomposites for tissue engineering applications. Biomaterials. 2008;29(30):4065–73.
Quinten T, Beer TD, Vervaet C, Remon JP. Evaluation of injection moulding as a pharmaceutical technology to produce matrix tablets. Eur J Pharm Biopharm. 2009;71(1):145–54.
Schilling SU, Shah NH, Waseem Malick A, McGinity JW. Properties of melt extruded enteric matrix pellets. Eur J Pharm Biopharm. 2010;74(2):352–61. doi:10.1016/j.ejpb.2009.09.008.
Özgüney I, Shuwisitkul D, Bodmeier R. Development and characterization of extended release Kollidon® SR mini-matrices prepared by hot-melt extrusion. Eur J Pharm Biopharm. 2009;73(1):140–5. doi:10.1016/j.ejpb.2009.04.006.
Almeida A, Possemiers S, Boone MN, De Beer T, Quinten T, Van Hoorebeke L, et al. Ethylene vinyl acetate as matrix for oral sustained release dosage forms produced via hot-melt extrusion. Eur J Pharm Biopharm. 2011;77(2):297–305. doi:10.1016/j.ejpb.2010.12.004.
Truss RW, Yeow TK. Effect of exfoliation and dispersion on the yield behavior of melt-compounded polyethylene–montmorillonite nanocomposites. J Appl Polym Sci. 2006;100(4):3044–9.
Dhumal R, Kelly A, York P, Coates P, Paradkar A. Cocrystalization and simultaneous agglomeration using hot melt extrusion. Pharmaceut Res. 2010;27:2725–33.
Zlokarnik M. Scale-up in chemical engineering. Weinheim: Wiley VCH; 2006.
Lindner H, Kleinebudde P. Use of powdered cellulose for the production of pellets by extrusion spheronization. J Pharm Pharmacol. 1994;46(1):2–7.
Fielden KE, Newton JM, Rowe RC. The influence of moisture content on spheronization of extrudate processed by a ram extruder. Int J Pharm. 1993;97(1–3):79–92.
Schmidt C, Lindner H, Kleinebudde P. Comparison between a twin-screw extruder and a rotary ring die press. Part I. Influence of formulation variables. Eur J Pharm Biopharm. 1997;44(2):169–76.
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.
Baert L, Remon JP. Influence of amount of granulation liquid on the drug release rate from pellets made by extrusion spheronisation. Int J Pharm. 1993;95(1–3):135–41.
Bataille B, Ligarski K, Jacob M, Thomas C, Duru C. Study of the influence of spheronization and drying conditions on the physico-mechanical properties of neutral spheroids containing Avicel pH 101 and lactose. Drug Dev Ind Pharm. 1993;19(6):653–71.
Knight PE, Podczeck F, Newton JM. The rheological properties of modified microcrystalline cellulose containing high levels of model drugs. J Pharm Sci. 2009;98(6):2160–9.
MacRitchie KA, Newton JM, Rowe RC. The evaluation of the rheological properties of lactose/microcrystalline cellulose and water mixtures by controlled stress rheometry and the relationship to the production of spherical pellets by extrusion/spheronization. Eur J Pharm Sci. 2002;17(1–2):43–50.
ICH. Q1A(R2) Guideline—stability testing of new drug substances and products. http://wwwichorg. 2009
Schulze D. Powders and bulk solids: behavior, characterization, storage and flow. Berlin: Springer; 2008.
Brittain HG, Lewen G, Newman AW, Fiorelli K, Bogdanowich S. Changes in material properties accompanying the national formulary (NF) identity test for microcrystalline cellulose. Pharm Res. 1993;10(1):61–7.
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.
ACKNOWLEDGEMENTS
We gratefully acknowledge Meggle (Wasserburg, Germany) and Pharmatrans SANAQ (Basel, Switzerland) for donating materials, the financial support of Leistritz Extrusion Technology, and the assistance of Elizabeth Ely (EIES, Lafayette IN, USA) in preparing the manuscript.
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Muehlenfeld, C., Thommes, M. Miniaturization in Pharmaceutical Extrusion Technology: Feeding as a Challenge of Downscaling. AAPS PharmSciTech 13, 94–100 (2012). https://doi.org/10.1208/s12249-011-9726-7
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DOI: https://doi.org/10.1208/s12249-011-9726-7