Skip to main content
Log in

Miniaturization in Pharmaceutical Extrusion Technology: Feeding as a Challenge of Downscaling

  • Research Article
  • Published:
AAPS PharmSciTech Aims and scope Submit manuscript

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.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6

Similar content being viewed by others

REFERENCES

  1. Martin C. Continuous mixing of solid dosage forms via hot-melt extrusion. Pharm Technol. 2008;32(10):76–86.

    CAS  Google Scholar 

  2. Vervaet C, Remon JP. Continuous granulation in the pharmaceutical industry. Chem Eng Sci. 2005;60:3949–57.

    Article  CAS  Google Scholar 

  3. 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.

    Article  PubMed  CAS  Google Scholar 

  4. 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.

    Article  PubMed  Google Scholar 

  5. 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.

    Article  PubMed  CAS  Google Scholar 

  6. 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.

    Article  PubMed  CAS  Google Scholar 

  7. Djuric D, Kleinebudde P. Impact of screw elements on continuous granulation with a twin-screw extruder. J Pharm Sci. 2008;97(11):4934–42.

    Article  PubMed  CAS  Google Scholar 

  8. 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.

    Article  CAS  Google Scholar 

  9. 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.

    Article  CAS  Google Scholar 

  10. 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.

    Article  PubMed  CAS  Google Scholar 

  11. Steiner R. Extruder design. Pharmaceutical extrusion technology. New York: Marcel Dekker; 2003.

    Google Scholar 

  12. Callari JJ. ‘Slower’ compounders suggest trend toward energy-efficient designs. Plast Technol. 2010;56(9):19–20.

    Google Scholar 

  13. 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.

    Article  CAS  Google Scholar 

  14. 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.

    Article  CAS  Google Scholar 

  15. 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.

    Article  CAS  Google Scholar 

  16. Martin C. Nano-scale compounding via twin screw extruders. ALEC newsletter. 2010;2010:1–6.

    Google Scholar 

  17. 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.

    Article  PubMed  CAS  Google Scholar 

  18. 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.

    Article  CAS  Google Scholar 

  19. 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.

    Article  PubMed  CAS  Google Scholar 

  20. 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.

    Article  PubMed  CAS  Google Scholar 

  21. 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.

    Article  PubMed  CAS  Google Scholar 

  22. 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.

    Article  PubMed  CAS  Google Scholar 

  23. 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.

    Article  PubMed  Google Scholar 

  24. 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.

    Article  PubMed  CAS  Google Scholar 

  25. 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.

    Article  CAS  Google Scholar 

  26. Dhumal R, Kelly A, York P, Coates P, Paradkar A. Cocrystalization and simultaneous agglomeration using hot melt extrusion. Pharmaceut Res. 2010;27:2725–33.

    Article  CAS  Google Scholar 

  27. Zlokarnik M. Scale-up in chemical engineering. Weinheim: Wiley VCH; 2006.

    Book  Google Scholar 

  28. Lindner H, Kleinebudde P. Use of powdered cellulose for the production of pellets by extrusion spheronization. J Pharm Pharmacol. 1994;46(1):2–7.

    Article  PubMed  CAS  Google Scholar 

  29. 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.

    Article  CAS  Google Scholar 

  30. 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.

    Article  CAS  Google Scholar 

  31. 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.

    Article  PubMed  CAS  Google Scholar 

  32. 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.

    Article  CAS  Google Scholar 

  33. 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.

    Article  CAS  Google Scholar 

  34. 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.

    Article  PubMed  CAS  Google Scholar 

  35. 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.

    Article  PubMed  CAS  Google Scholar 

  36. ICH. Q1A(R2) Guideline—stability testing of new drug substances and products. http://wwwichorg. 2009

  37. Schulze D. Powders and bulk solids: behavior, characterization, storage and flow. Berlin: Springer; 2008.

    Google Scholar 

  38. 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.

    Article  PubMed  CAS  Google Scholar 

  39. 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.

    Article  Google Scholar 

Download references

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.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Markus Thommes.

Rights and permissions

Reprints and permissions

About this article

Cite this article

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

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1208/s12249-011-9726-7

Key words

Navigation