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Fibrillated Cellulose via High Pressure Homogenization: Analysis and Application for Orodispersible Films

AAPS PharmSciTech volume 21, Article number: 33 (2020) Cite this article

Abstract

Powdered cellulose (PC) and microcrystalline cellulose (MCC) are common excipients in pharmaceuticals. Recent investigations imply that particle size is the most critical parameter for the different performance in many processes. High-pressure homogenization (HPH) was used to reduce fiber size of both grades. The effect of the homogenization parameters on suspension viscosity, particle size, and mechanical properties of casted films was investigated. PC suspensions showed higher apparent viscosities and yield stresses under the same process conditions than MCC. SLS reduced shear viscosity and thixotropic behavior of both cellulose grades probably due to increased electrostatic repulsion. Homogenization reduced cellulose particle sizes, but re-agglomeration was too strong to analyze the particle size correctly. MCC films showed a tensile strength of up to 16.0 MPa and PC films up to 4.1 MPa. PC films disintegrated within 30 s whereas MCC films did not. Mixtures of MCC and PC led to more stable films than PC alone, but these films did not disintegrate anymore. Diclofenac sodium was incorporated in therapeutic dose with drug load of 47% into orodispersible PC films. The content uniformity of these films fulfilled requirements of Ph.Eur and the films disintegrated in 12 s. In summary, PC and MCC showed comparable results after HPH and most differences could be explained by the smaller particle size of MCC suspensions. These results confirm the hypothesis that mainly the fiber size during processing is responsible for the existing differences of MCC and PC in pharmaceutical process, e.g., wet-extrusion/spheronization.

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References

  1. Kamel S, Ali N, Jahangir K, Shah SM, El-Gendy AA. Pharmaceutical significance of cellulose: a review. Express Polym Lett. 2008;2(11):758–78.

    CAS  Google Scholar 

  2. Klemm D, Heublein B, Fink HP, Bohn A. Cellulose: fascinating biopolymer and sustainable raw material. Angew Chem Int Ed Engl. 2005;44(22):3358–93.

    CAS  PubMed  Google Scholar 

  3. Qua EH, Hornsby PR, Sharma HSS, Lyons G. Preparation and characterisation of cellulose nanofibres. J Mater Sci. 2011;46(18):6029–45.

    CAS  Google Scholar 

  4. Klemm D, Kramer F, Moritz S, Lindstrom T, Ankerfors M, Gray D, et al. Nanocelluloses: a new family of nature-based materials. Angew Chem Int Ed Engl. 2011;50(24):5438–66.

    CAS  PubMed  Google Scholar 

  5. Battista OA. Hydrolysis and crystallization of cellulose. Ind Eng Chem. 1950;42(3):502–7.

    CAS  Google Scholar 

  6. Battista OA, Smith PA. Microcrystalline Cellulose - Oldest Polymer Finds New Industrial Uses. Ind Eng Chem. 1962;54(9):20.

    CAS  Google Scholar 

  7. Reynolds AD. A New Technique for Production of Spherical Particles. Manuf Chemist. 1970;41(6):40.

    Google Scholar 

  8. Newton JM. Extrusion and extruders. In: Swarbrick J, editor. Encyclopedia of pharmaceutical technology. 3. 3rd ed. Boca Raton: Taylor & Francis; 2007. p. 1712–28.

    Google Scholar 

  9. Fielden KE, Newton JM, O'Brien P, Rowe RC. Thermal studies on the interaction of water and microcrystalline cellulose. J Pharm Pharmacol. 1988;40(10):674–8.

    CAS  PubMed  Google Scholar 

  10. 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):509–12.

    CAS  PubMed  Google Scholar 

  11. Tomer G, Newton JM. Water movement evaluation during extrusion of wet powder masses by collecting extrudate fractions. Int J Pharm. 1999;182(1):71–7.

    CAS  PubMed  Google Scholar 

  12. Rough SL, Bridgwater J, Wilson DI. Effects of liquid phase migration on extrusion of microcrystalline cellulose pastes. Int J Pharm. 2000;204(1–2):117–26.

    CAS  PubMed  Google Scholar 

  13. Luukkonen P, Newton JM, Podczeck F, Yliruusi J. Use of a capillary rheometer to evaluate the rheological properties of microcrystalline cellulose and silicified microcrystalline cellulose wet masses. Int J Pharm. 2001;216(1–2):147–57.

    CAS  PubMed  Google Scholar 

  14. Luukkonen P, Maloney T, Rantanen J, Paulapuro H, Yliruusi J. Microcrystalline cellulose-water interaction--a novel approach using thermoporosimetry. Pharm Res. 2001;18(11):1562–9.

    CAS  PubMed  Google Scholar 

  15. Fechner PM, Wartewig S, Futing M, Heilmann A, Neubert RH, Kleinebudde P. Properties of microcrystalline cellulose and powder cellulose after extrusion/spheronization as studied by fourier transform Raman spectroscopy and environmental scanning electron microscopy. AAPS PharmSci. 2003;5(4):E31.

    PubMed  Google Scholar 

  16. Kleinebudde P. The crystallite-gel-model for microcrystalline cellulose in wet-granulation, extrusion, and spheronization. Pharm Res. 1997;14(6):804–9.

    CAS  PubMed  Google Scholar 

  17. Suzuki T, Kikuchi H, Yamamura S, Terada K, Yamamoto K. The change in characteristics of microcrystalline cellulose during wet granulation using a high-shear mixer. J Pharm Pharmacol. 2001;53(5):609–16.

    CAS  PubMed  Google Scholar 

  18. 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.

    CAS  PubMed  Google Scholar 

  19. Sarkar S, Liew CV. Moistening liquid-dependent de-aggregation of microcrystalline cellulose and its impact on pellet formation by extrusion-spheronization. AAPS PharmSciTech. 2014;15(3):753–61.

    CAS  PubMed  PubMed Central  Google Scholar 

  20. Lenhart V, Quodbach J, Kleinebudde P. Mechanistic understanding regarding the functionality of microcrystalline cellulose and powdered cellulose as pelletization aids in wet-extrusion/ spheronization. Cellulose. 2019. https://doi.org/10.1007/s10570-019-02895-y

  21. Kolakovic R, Peltonen L, Laukkanen A, Hirvonen J, Laaksonen T. Nanofibrillar cellulose films for controlled drug delivery. Eur J Pharm Biopharm. 2012;82(2):308–15.

    CAS  PubMed  Google Scholar 

  22. Kolakovic R, Peltonen L, Laaksonen T, Putkisto K, Laukkanen A, Hirvonen J. Spray-dried cellulose nanofibers as novel tablet excipient. AAPS PharmSciTech. 2011;12(4):1366–73.

    CAS  PubMed  PubMed Central  Google Scholar 

  23. Xu X, Liu F, Jiang L, Zhu JY, Haagenson D, Wiesenborn DP. Cellulose nanocrystals vs. cellulose nanofibrils: a comparative study on their microstructures and effects as polymer reinforcing agents. ACS Appl Mater Interfaces. 2013;5(8):2999–3009.

    CAS  PubMed  Google Scholar 

  24. Moberg T, Sahlin K, Yao K, Geng SY, Westman G, Zhou Q, et al. Rheological properties of nanocellulose suspensions: effects of fibril/particle dimensions and surface characteristics. Cellulose. 2017;24(6):2499–510.

    CAS  Google Scholar 

  25. DIN EN ISO 527-1:2012, Plastics - Determination of tensile properties - Part 1: General principles (ISO 527-1:2012). 2012.

  26. Preis M, Woertz C, Kleinebudde P, Breitkreutz J. Oromucosal film preparations: classification and characterization methods. Expert Opin Drug Deliv. 2013;10(9):1303–17.

    CAS  PubMed  PubMed Central  Google Scholar 

  27. Jonoobi M, Oladi R, Davoudpour Y, Oksman K, Dufresne A, Hamzeh Y, et al. Different preparation methods and properties of nanostructured cellulose from various natural resources and residues: a review. Cellulose. 2015;22(2):935–69.

    CAS  Google Scholar 

  28. Turbak AF, Snyder FW, Sandberg KR, editors. Microfibrillated cellulose, a new cellulose product: properties, uses, and commercial potential. J Appl Polym Sci Appl Polym Symp;(United States). Shelton: ITT Rayonier Inc.; 1983.

    Google Scholar 

  29. Taheri H, Samyn P. Effect of homogenization (microfluidization) process parameters in mechanical production of micro- and nanofibrillated cellulose on its rheological and morphological properties. Cellulose. 2016;23(2):1221–38.

    CAS  Google Scholar 

  30. Floury J, Desrumaux A, Lardières J. Effect of high-pressure homogenization on droplet size distributions and rheological properties of model oil-in-water emulsions. Innovative Food Sci Emerg Technol. 2000;1(2):127–34.

    CAS  Google Scholar 

  31. Qian C, McClements DJ. Formation of nanoemulsions stabilized by model food-grade emulsifiers using high-pressure homogenization: factors affecting particle size. Food Hydrocoll. 2011;25(5):1000–8.

    CAS  Google Scholar 

  32. Lee SY, Chun SJ, Kang IA, Park JY. Preparation of cellulose nanofibrils by high-pressure homogenizer and cellulose-based composite films. J Ind Eng Chem. 2009;15(1):50–5.

    Google Scholar 

  33. Lamprecht A, Ubrich N, Hombreiro Perez M, Lehr C, Hoffman M, Maincent P. Influences of process parameters on nanoparticle preparation performed by a double emulsion pressure homogenization technique. Int J Pharm. 2000;196(2):177–82.

    CAS  PubMed  Google Scholar 

  34. Paakko M, Ankerfors M, Kosonen H, Nykanen A, Ahola S, Osterberg M, et al. Enzymatic hydrolysis combined with mechanical shearing and high-pressure homogenization for nanoscale cellulose fibrils and strong gels. Biomacromolecules. 2007;8(6):1934–41.

    CAS  PubMed  Google Scholar 

  35. Li J, Wei X, Wang Q, Chen J, Chang G, Kong L, et al. Homogeneous isolation of nanocellulose from sugarcane bagasse by high pressure homogenization. Carbohydr Polym. 2012;90(4):1609–13.

    CAS  PubMed  Google Scholar 

  36. Quennouz N, Hashmi SM, Choi HS, Kim JW, Osuji CO. Rheology of cellulose nanofibrils in the presence of surfactants. Soft Matter. 2016;12(1):157–64.

    CAS  PubMed  Google Scholar 

  37. Iotti M, Gregersen OW, Moe S, Lenes M. Rheological studies of Microfibrillar cellulose water dispersions. J Polym Environ. 2011;19(1):137–45.

    CAS  Google Scholar 

  38. Saarikoski E, Saarinen T, Salmela J, Seppala J. Flocculated flow of microfibrillated cellulose water suspensions: an imaging approach for characterisation of rheological behaviour. Cellulose. 2012;19(3):647–59.

    CAS  Google Scholar 

  39. Kleinebudde P, Jumaa M, El Saleh F. Influence of the degree of polymerization on the behavior of cellulose during homogenization and extrusion/spheronization. AAPS PharmSci. 2000;2(3):E21.

    CAS  PubMed  Google Scholar 

  40. Hu Z, Cranston ED, Ng R, Pelton R. Tuning cellulose nanocrystal gelation with polysaccharides and surfactants. Langmuir. 2014;30(10):2684–92.

    CAS  PubMed  Google Scholar 

  41. Fall AB, Lindstrom SB, Sundman O, Odberg L, Wagberg L. Colloidal stability of aqueous nanofibrillated cellulose dispersions. Langmuir. 2011;27(18):11332–8.

    CAS  PubMed  Google Scholar 

  42. Syverud K, Stenius P. Strength and barrier properties of MFC films. Cellulose. 2008;16(1):75–85.

    Google Scholar 

  43. Kleinebudde P. Shrinking and swelling properties of pellets containing microcrystalline cellulose and low substituted hydroxypropylcellulose: II Swelling properties. Int J Pharm. 1994;109(3):221–7.

    CAS  Google Scholar 

  44. Millili GP, Wigent RJ, Schwartz JB. Autohesion in pharmaceutical solids. Drug Dev Ind Pharm. 1990;16(16):2383–407.

    CAS  Google Scholar 

  45. Pietsch W, Hoffman E, Rumpf H. Tensile Strength of Moist Agglomerates. End Eng Chem Prod Res Dev. 1969;8(1):58.

    CAS  Google Scholar 

  46. Pietsch W, Rumpf H. Haftkraft, Kapillardruck, Flüssigkeitsvolumen und Grenzwinkel einer Flüssigkeitsbrücke zwischen zwei Kugeln. Chem-Ing-Tech. 1967;39(15):885–93.

    CAS  Google Scholar 

  47. Benitez AJ, Torres-Rendon J, Poutanen M, Walther A. Humidity and multiscale structure govern mechanical properties and deformation modes in films of native cellulose nanofibrils. Biomacromolecules. 2013;14(12):4497–506.

    CAS  PubMed  Google Scholar 

  48. Hoffmann EM, Breitenbach A, Breitkreutz J. Advances in orodispersible films for drug delivery. Expert Opin Drug Deliv. 2011;8(3):299–316.

    CAS  PubMed  PubMed Central  Google Scholar 

  49. Stelte W, Sanadi AR. Preparation and characterization of cellulose nanofibers from two commercial hardwood and softwood pulps. Ind Eng Chem Res. 2009;48(24):11211–9.

    CAS  Google Scholar 

  50. Daly R, Harrington TS, Martin GD, Hutchings IM. Inkjet printing for pharmaceutics - a review of research and manufacturing. Int J Pharm. 2015;494(2):554–67.

    CAS  PubMed  Google Scholar 

  51. Thabet Y, Sibanc R, Breitkreutz J. Printing pharmaceuticals by inkjet technology: proof of concept for stand-alone and continuous in-line printing on orodispersible films. J Manuf Process. 2018;35:205–15.

    Google Scholar 

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Acknowledgments

The authors would like to thank JRS Pharma GmbH for supplying the powdered cellulose and microcrystalline cellulose used in this study. The authors would also like to thank Anna-Lena Beiersmann and Julia Stock for the execution of several experiments.

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Affiliations

  1. Institute of Pharmaceutics and Biopharmaceutics, Heinrich Heine University Düsseldorf, Universitätsstraße 1, 40225, Dusseldorf, Germany

    Vincent Lenhart, Julian Quodbach & Peter Kleinebudde

  2. Department of Pharmacy, Upsala University, Husargatan 3, 751 23, Uppsala, Sweden

    Julian Quodbach

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  1. Vincent Lenhart
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Correspondence to Peter Kleinebudde.

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Lenhart, V., Quodbach, J. & Kleinebudde, P. Fibrillated Cellulose via High Pressure Homogenization: Analysis and Application for Orodispersible Films. AAPS PharmSciTech 21, 33 (2020). https://doi.org/10.1208/s12249-019-1593-7

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  • DOI: https://doi.org/10.1208/s12249-019-1593-7

KEY WORDS

  • microfibrillated cellulose
  • nanofibrillated cellulose
  • microcrystalline cellulose
  • powdered cellulose
  • orodispersible films