Pharmaceutical Research

, Volume 32, Issue 8, pp 2775–2786 | Cite as

The Development of Direct Extrusion-Injection Moulded Zein Matrices as Novel Oral Controlled Drug Delivery Systems

  • Jacob Bouman
  • Peter Belton
  • Paul Venema
  • Erik van der Linden
  • Renko de Vries
  • Sheng QiEmail author
Research Paper



To evaluate the potential of zein as a sole excipient for controlled release formulations prepared by hot melt extrusion.


Physical mixtures of zein, water and crystalline paracetamol were hot melt extruded (HME) at 80°C and injection moulded (IM) into caplet forms. HME-IM Caplets were characterised using differential scanning calorimetry, ATR-FTIR spectroscopy, scanning electron microscopy and powder X-ray diffraction. Hydration and drug release kinetics of the caplets were investigated and fitted to a diffusion model.


For the formulations with lower drug loadings, the drug was found to be in the non-crystalline state, while for the ones with higher drug loadings paracetamol is mostly crystalline. Release was found to be largely independent of drug loading but strongly dependent upon device dimensions, and predominately governed by a Fickian diffusion mechanism, while the hydration kinetics shows the features of Case II diffusion.


In this study a prototype controlled release caplet formulation using zein as the sole excipient was successfully prepared using direct HME-IM processing. The results demonstrated the unique advantage of the hot melt extruded zein formulations on the tuneability of drug release rate by alternating the device dimensions.


controlled release diffusion mechanism dissolution kinetics modelling hot melt extrusion-injection moulding Zein 



Attenuated Total Reflection Fourier Transform Infrared Spectroscopy


Differential Scanning Calorimetry


Hot melt extrusion


Hot melt extrusion-injection moulding


Injection moulding


Powder X-ray diffraction


Relative humidity


Scanning electron microscopy


Glass transition temperature



This work is part of the Industrial Partnership Programme (IPP) Bio(-Related)Materials of the Stichting voor Fundamenteel Onderzoek der Materie (FOM), which is financially supported by the Nederlandse Organisatie voor Wetenschappelijk Onderzoek (NWO). The IPP BRM is co-financed by the Top Institute Food and Nutrition and the Dutch Polymer Institute.

Supplementary material

11095_2015_1663_MOESM1_ESM.docx (64 kb)
ESM (DOCX 64.0 kb)


  1. 1.
    Uhrich KE, Cannizzaro SM, Langer RS, Shakesheff KM. Polymeric systems for controlled drug release. Chem Rev. 1999;99:3181–98.PubMedCrossRefGoogle Scholar
  2. 2.
    Grund S, Bauer M, Fischer D. Polymers in drug delivery-state of the art and future trends. Adv Eng Mater. 2011;13:B61–87.CrossRefGoogle Scholar
  3. 3.
    Liu X, Sun Q, Wang H, Zhang L, Wang JY. Microspheres of corn protein, zein, for an ivermectin drug delivery system. Biomaterials. 2005;26:109–15.PubMedCrossRefGoogle Scholar
  4. 4.
    Wang H-J, Lin Z-X, Liu X-M, Sheng S-Y, Wang J-Y. Heparin-loaded zein microsphere film and hemocompatibility. J Control Release. 2005;105:120–31.PubMedCrossRefGoogle Scholar
  5. 5.
    Georget DMR, Barker SA, Belton PS. A study on maize proteins as a potential new tablet excipient. Eur J Pharm Biopharm. 2008;69:718–26.PubMedCrossRefGoogle Scholar
  6. 6.
    Lawton JW. Zein: a history of processing and use. Cereal Chem. 2002;79:1–18.CrossRefGoogle Scholar
  7. 7.
    Wang Q, Yin L, Padua G. Effect of hydrophilic and lipophilic compounds on zein microstructures. Food Biophysics. 2008;3:174–81.CrossRefGoogle Scholar
  8. 8.
    Belton PS, Delgadillo I, Halford NG, Shewry PR. Kafirin structure and functionality. J Cereal Sci. 2006;44:272–86.CrossRefGoogle Scholar
  9. 9.
    Selling GW. The effect of extrusion processing on zein. Polym Degrad Stab. 2010;95:2241–9.CrossRefGoogle Scholar
  10. 10.
    Paliwal R, Palakurthi S. Zein in controlled drug delivery and tissue engineering. J Control Release. 2014;189:108–22.PubMedCrossRefGoogle Scholar
  11. 11.
    Takagi K, Teshima R, Okunuki H, Sawada JI. Comparative study of in vitro digestibility of food proteins and effect of preheating on the digestion. Biol Pharm Bull. 2003;26:969–73.PubMedCrossRefGoogle Scholar
  12. 12.
    Zhang M, Reitmeier CA, Hammond EG, Myers DJ. Production of textile fibers from zein and a soy protein-zein blend. Cereal Chem. 1997;74:594–8.CrossRefGoogle Scholar
  13. 13.
    Selling GW, Woods KK, Biswas A, Willett JL. Reactive extrusion of zein with glyoxal. J Appl Polym Sci. 2009;113:1828–35.CrossRefGoogle Scholar
  14. 14.
    Eith L, Stepto RFT, Tomka I, Wittwer F. The injection-moulded capsule. Drug Dev Ind Pharm. 1986;12:2113–26.CrossRefGoogle Scholar
  15. 15.
    Deng JS, Meisters M, Li L, Setesak J, Claycomb L, Tian Y, et al. The development of an injection-molding process for a polyanhydride implant containing gentamicin sulfate. PDA J Pharm Sci Technol. 2002;56:65–77.PubMedGoogle Scholar
  16. 16.
    Gilpinand RK, Zhou W. Studies of the thermal degradation of acetaminophen using a conventional HPLC approach and electrospray ionization-mass spectrometry. J Chromatogr Sci. 2004;42:15–20.CrossRefGoogle Scholar
  17. 17.
    Forato LA, Bicudo TDC, Colnago LA. Conformation of α zeins in solid state by Fourier transform IR. Biopolymers - Biospectroscopy Sect. 2003;72:421–6.CrossRefGoogle Scholar
  18. 18.
    Georgetand DMR, Belton PS. Effects of temperature and water content on the secondary structure of wheat gluten studied by FTIR spectroscopy. Biomacromolecules. 2006;7:469–75.CrossRefGoogle Scholar
  19. 19.
    Fang JY, Chen JP, Leu YL, Wang HY. Characterization and evaluation of silk protein hydrogels for drug delivery. Chem Pharm Bull. 2006;54:156–62.PubMedCrossRefGoogle Scholar
  20. 20.
    Ahlneckand C, Zografi G. The molecular basis of moisture effects on the physical and chemical stability of drugs in the solid state. Int J Pharm. 1990;62:87–95.CrossRefGoogle Scholar
  21. 21.
    Peterson ML, Morissette SL, McNulty C, Goldsweig A, Shaw P, LeQuesne M, et al. Iterative high-throughput polymorphism studies on acetaminophen and an experimentally derived structure for form III. J Am Chem Soc. 2002;124:10958–9.PubMedCrossRefGoogle Scholar
  22. 22.
    Rossi A, Savioli A, Bini M, Capsoni D, Massarotti V, Bettini R, et al. Solid-state characterization of paracetamol metastable polymorphs formed in binary mixtures with hydroxypropylmethylcellulose. Thermochim Acta. 2003;406:55–67.CrossRefGoogle Scholar
  23. 23.
    Gopalakrishnan TR. Polymorphism of acetaminophen under nanoconfinement, Naturwissenschaftliche Fakultät II, Martin-Luther-Universität Halle-Wittenberg, Halle, 2010.Google Scholar
  24. 24.
    Gillgren T, Barker SA, Belton PS, Georget DMR, Stading M. Plasticization of zein: a thermomechanical, FTIR, and dielectric study. Biomacromolecules. 2009;10:1135–9.PubMedCrossRefGoogle Scholar
  25. 25.
    Qi S, Avalle P, Saklatvala R, Craig DQM. An investigation into the effects of thermal history on the crystallisation behaviour of amorphous paracetamol. Eur J Pharm Biopharm. 2008;69:364–71.PubMedCrossRefGoogle Scholar
  26. 26.
    Peterlin A. Diffusion in a network with discontinuous swelling. J Polym Sci B Polym Lett. 1965;3:1083–7.CrossRefGoogle Scholar
  27. 27.
    Thomasand NL, Windle AH. A theory of case II diffusion. Polymer. 1982;23:529–42.CrossRefGoogle Scholar
  28. 28.
    Gallyamov MO. Sharp diffusion front in diffusion problem with change of state. Eur Phys J E Soft Matter. 2013;36(8):92.PubMedCrossRefGoogle Scholar
  29. 29.
    Yong YH, Yamaguchi S, Gu YS, Mori T, Matsumura Y. Effects of enzymatic deamidation by protein-glutaminase on structure and functional properties of α-zein. J Agric Food Chem. 2004;52:7094–100.PubMedCrossRefGoogle Scholar
  30. 30.
    Peppas NA, Sahlin JJ. A simple equation for the description of solute release. III coupling of diffusion and relaxation. Int J Pharm. 1989;57:169–72.CrossRefGoogle Scholar
  31. 31.
    Ritgerand PL, Peppas NA. A simple equation for description of solute release I. Fickian and non-fickian release from non-swellable devices in the form of slabs, spheres, cylinders or discs. J Control Release. 1987;5:23–36.CrossRefGoogle Scholar
  32. 32.
    Alfrey T, Gurnee EF, Lloyd WG. Diffusion in glassy polymers. J Polym Sci C Polym Symp. 1966;12:249–61.CrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2015

Authors and Affiliations

  • Jacob Bouman
    • 1
    • 2
    • 3
  • Peter Belton
    • 4
  • Paul Venema
    • 2
  • Erik van der Linden
    • 2
  • Renko de Vries
    • 1
    • 5
  • Sheng Qi
    • 3
    Email author
  1. 1.Laboratory of Physical Chemistry and Colloid ScienceWageningen UniversityWageningenThe Netherlands
  2. 2.Laboratory of Physical Chemistry and Physics of FoodsWageningen UniversityWageningenThe Netherlands
  3. 3.School of PharmacyUniversity of East AngliaNorwichUK
  4. 4.School of ChemistryUniversity of East AngliaNorwichUK
  5. 5.Department of Biomedical EngineeringUniversity of Groningen and University Medical Centre GroningenGroningenThe Netherlands

Personalised recommendations