The AAPS Journal

, Volume 17, Issue 1, pp 194–205 | Cite as

Continuous Production of Fenofibrate Solid Lipid Nanoparticles by Hot-Melt Extrusion Technology: a Systematic Study Based on a Quality by Design Approach

  • Hemlata Patil
  • Xin Feng
  • Xingyou Ye
  • Soumyajit Majumdar
  • Michael A. Repka
Research Article Theme: Develop Enabling Technologies for Delivering Poorly Water Soluble Drugs: Current Status and Future Perspectives
Part of the following topical collections:
  1. Theme: Develop Enabling Technologies for Delivering Poorly Water Soluble Drugs: Current Status and Future Perspectives


This contribution describes a continuous process for the production of solid lipid nanoparticles (SLN) as drug-carrier systems via hot-melt extrusion (HME). Presently, HME technology has not been used for the manufacturing of SLN. Generally, SLN are prepared as a batch process, which is time consuming and may result in variability of end-product quality attributes. In this study, using Quality by Design (QbD) principles, we were able to achieve continuous production of SLN by combining two processes: HME technology for melt-emulsification and high-pressure homogenization (HPH) for size reduction. Fenofibrate (FBT), a poorly water-soluble model drug, was incorporated into SLN using HME-HPH methods. The developed novel platform demonstrated better process control and size reduction compared to the conventional process of hot homogenization (batch process). Varying the process parameters enabled the production of SLN below 200 nm. The dissolution profile of the FBT SLN prepared by the novel HME-HPH method was faster than that of the crude FBT and a micronized marketed FBT formulation. At the end of a 5-h in vitro dissolution study, a SLN formulation released 92–93% of drug, whereas drug release was approximately 65 and 45% for the marketed micronized formulation and crude drug, respectively. Also, pharmacokinetic study results demonstrated a statistical increase in Cmax, Tmax, and AUC0–24 h in the rate of drug absorption from SLN formulations as compared to the crude drug and marketed micronized formulation. In summary, the present study demonstrated the potential use of hot-melt extrusion technology for continuous and large-scale production of SLN.


fenofibrate high-pressure homogenizer hot-melt extrusion solid lipid nanoparticles 

Supplementary material

12248_2014_9674_MOESM1_ESM.docx (1.2 mb)
ESM 1 (DOCX 1.20 mb)


  1. 1.
    Patil A, Pokharkar V. Single step spray drying method to develop proliposomes for inhalation: a systematic study based on quality by design approach. Pulm Pharmacol Ther. 2014;27:197–207.CrossRefGoogle Scholar
  2. 2.
    Basalious EB, El-Sebaie W, El-Gazayerly O. Application of pharmaceutical QbD for enhancement of the solubility and dissolution of a class II BCS drug using polymeric surfactants and crystallization inhibitors: development of controlled-release tablets. AAPS Pharm Sci Technol. 2011;12:799–810.CrossRefGoogle Scholar
  3. 3.
    Maltesen MJ, Bjerregaard S, Hovgaard L, Havelund S, Weert M. Quality by design spray drying of insulin intended for inhalation. Eur J Pharm Biopharm. 2008;70:828–38.CrossRefPubMedGoogle Scholar
  4. 4.
    Yerlikaya F, Ozgen A, Vural I, Guven O, Karaagaoglu E, et al. Development and evaluation of paclitaxel nanoparticles using a quality-by-design approach. J Pharm Sci. 2013;102:3748–61.CrossRefPubMedGoogle Scholar
  5. 5.
    US FDA Guidance for industry: PAT—a framework for innovative pharmaceutical development, manufacturing, and quality assurance. Maryland: Silver Spring; 2004.Google Scholar
  6. 6.
    Hanafy A, Spahn-Langguth H, Vergnault G, Grenier P, Tubic Grozdanis M, et al. Pharmacokinetic evaluation of oral fenofibrate nanosuspensions and SLN in comparison to conventional suspensions of micronized drug. Adv Drug Deliv Rev. 2007;59:419–26.CrossRefPubMedGoogle Scholar
  7. 7.
    Rao GC, Kumar MS, Mathivanan N, Rao ME. Nanosuspensions as the most promising approach in nanoparticulate drug delivery systems. Pharmazie. 2004;59:5–9.PubMedGoogle Scholar
  8. 8.
    Patil H, Kulkarni V, Majumdar S, Repka MA. Continuous manufacturing of solid lipid nanoparticles by hot melt extrusion. Int J Pharm. 2014;471:153–6.CrossRefPubMedGoogle Scholar
  9. 9.
    Niu X, Wan L, Hou Z, Wang T, Sun C, et al. Mesoporous carbon as a novel drug carrier of fenofibrate for enhancement of the dissolution and oral bioavailability. Int J Pharm. 2013;452:382–9.CrossRefPubMedGoogle Scholar
  10. 10.
    Sanganwar GP, Gupta RP. Dissolution-rate enhancement of fenofibrate by adsorption onto silica using supercritical carbon dioxide. Int J Pharm. 2008;360:213–8.CrossRefPubMedGoogle Scholar
  11. 11.
    Wishart DS, Konx C, Guo AC, Shrivastava S, Hassanali M, et al. Drug bank: a comprehensive resource for in silicon drug discovery and exploration. Nucleic Acids Res. 2006;1:D668–72.CrossRefGoogle Scholar
  12. 12.
    Ming-Thau S, Ching-Min Y, Sokoloski TD. Characterization and dissolution of fenofibrate solid dispersion systems. Int J Pharm. 1994;103:137–46.CrossRefGoogle Scholar
  13. 13.
    Mehnert W, Mader K. Solid lipid nanoparticles: production, characterization and applications. Adv Drug Deliv Rev. 2001;47:165–96.CrossRefPubMedGoogle Scholar
  14. 14.
    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.CrossRefPubMedGoogle Scholar
  15. 15.
    Repka MA, Battu SK, Upadhye SB, Thumma S, Crowley MM, et al. Pharmaceutical applications of hot-melt extrusion: part II. Drug Dev Ind Pharm. 2007;33:1043–57.CrossRefPubMedGoogle Scholar
  16. 16.
    Breitenbach J. Melt extrusion: from process to drug delivery technology. Eur J Pharm Biopharm. 2002;54:107–17.CrossRefPubMedGoogle Scholar
  17. 17.
    Maniruzzaman M, Boateng JS, Snowde MJ, Douroumis D. A review of hot-melt extrusion: process technology to pharmaceutical products. ISRN Pharm. 2012;1–9.Google Scholar
  18. 18.
    Das S, Ng WK, Kanaujia P, Kim S, Tan RB. Formulation design, preparation and physicochemical characterizations of solid lipid nanoparticles containing a hydrophobic drug: effects of process variables. Colloids Surf B: Biointerfaces. 2011;88:483–9.CrossRefPubMedGoogle Scholar
  19. 19.
    Dong Y, Ng WK, Shen S, Kim S, Tan RB. Solid lipid nanoparticles: continuous and potential large-scale nanoprecipitation production in static mixers. Colloids Surf B: Biointerfaces. 2012;94:68–72.CrossRefPubMedGoogle Scholar
  20. 20.
    Raza K, Singh B, Singal P, Wadhwa S, Katare OP. Systematically optimized biocompatible isotretinoin-loaded solid lipid nanoparticles (SLNs) for topical treatment of acne. Colloids Surf B: Biointerfaces. 2013;105:67–74.CrossRefPubMedGoogle Scholar
  21. 21.
    Shah RM, Malherbe F, Eldridge D, Palombo EA, Harding IH. Physicochemical characterization of solid lipid nanoparticles (SLNs) prepared by a novel microemulsion technique. J Colloid Interface Sci. 2014;428:286–94.CrossRefPubMedGoogle Scholar
  22. 22.
    Luo Y, Chen D, Ren L, Zhao X, Qin J. Solid lipid nanoparticles for enhancing vinpocetine's oral bioavailability. J Control Release. 2006;114:53–9.CrossRefPubMedGoogle Scholar
  23. 23.
    Wang S, Chen T, Chen R, Hu Y, Chen M, et al. Emodin loaded solid lipid nanoparticles: preparation, characterization and antitumor activity studies. Int J Pharm. 2012;430:238–46.CrossRefPubMedGoogle Scholar
  24. 24.
    ICH Q 1 A (R2). Stability testing of new drug substances and products.
  25. 25.
    Hu L, Tang X, Cui F. Solid lipid nanoparticles (SLNs) to improve oral bioavailability of poorly soluble drugs. J Pharm Pharmacol. 2004;56:1527–35.CrossRefPubMedGoogle Scholar
  26. 26.
    Liu J, Hu W, Chen H, Ni Q, Xu H, et al. Isotretinoin-loaded solid lipid nanoparticles with skin targeting for topical delivery. Int J Pharm. 2007;328:191–5.CrossRefPubMedGoogle Scholar
  27. 27.
    Rahman Z, Zidan AS, Habib MJ, Khan MA. Understanding the quality of protein loaded PLGA nanoparticles variability by Plackett-Burman design. Int J Pharm. 2010;389(1–2):186–94.CrossRefPubMedCentralPubMedGoogle Scholar
  28. 28.
    Huang QP, Wang JX, Zhang ZB, Shen ZG, Chen JF, et al. Preparation of ultrafine fenofibrate powder by solidification process from emulsion. Int J Pharm. 2009;368:160–4.CrossRefPubMedGoogle Scholar
  29. 29.
    Van Drooge DJ, Hinrichs WL, Frijlink HW. Anomalous dissolution behaviour of tablets prepared from sugar glass-based solid dispersions. J Control Release. 2004;97:441–52.CrossRefPubMedGoogle Scholar
  30. 30.
    Mosharraf M, NyatrÖm C. The effect of particle size and shape on the surface specific dissolution rate of microsized practically insoluble drugs. Int J Pharm. 1995;122:35–47.CrossRefGoogle Scholar
  31. 31.
    Müller RH, Peters K. Nanosuspensions for the formulation of poorly soluble drugs: I. Preparation by a size-reduction technique. Int J Pharm. 1998;160:229–37.CrossRefGoogle Scholar
  32. 32.
    Jia Z, Lin P, Xiang Y, Wang X, Wang J, Zhang X, et al. A novel nanomatrix system consisted of colloidal silica and pH-sensitive polymethylacrylate improves the oral bioavailability of fenofibrate. Eur J Pharm Biopharm. 2011;79(1):126–34.CrossRefPubMedGoogle Scholar
  33. 33.
    Borkar N, Xia D, Holm R, Gan Y, Mullertz A, Yang M, et al. Investigating the correlation between in vivo absorption and in vitro release of fenofibrate from lipid matrix particles in biorelevant medium. Eur J Pharm Sci. 2014;51:204–10.CrossRefPubMedGoogle Scholar
  34. 34.
    Noyes AA, Whitney WR. The rate of solution of solid substances in their own solutions. J Am Chem Soc. 1897;19:930–4.CrossRefGoogle Scholar

Copyright information

© American Association of Pharmaceutical Scientists 2014

Authors and Affiliations

  • Hemlata Patil
    • 1
  • Xin Feng
    • 1
  • Xingyou Ye
    • 1
  • Soumyajit Majumdar
    • 1
  • Michael A. Repka
    • 1
    • 2
  1. 1.Department of Pharmaceutics & Drug DeliveryUniversity of MississippiUniversityUSA
  2. 2.Pii Center for Pharmaceutical Technology, School of PharmacyUniversity of MississippiUniversityUSA

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