AAPS PharmSciTech

, Volume 19, Issue 3, pp 1061–1071 | Cite as

Fluidized Bed Hot-Melt Granulation as a Tool to Improve Curcuminoid Solubility

  • Cristiane C. C. Teixeira
  • Elias de Paiva Junior
  • Luis Alexandre Pedro de Freitas
Research Article


Curcumin is the main bioactive component of Curcuma longa L. and has recently aroused growing interest from the scientific community. Unfortunately, the medicinal properties attributed to curcuminoids are impaired by their low oral bioavailability or low solubility in aqueous solutions. Many strategies have been studied to improve curcumin solubility; however, the preparation of granules using hydrophilic materials has never been attempted. The aim of this work was to develop curcumin granules by fluidized bed hot-melt granulation using the hydrophilic carrier Gelucire® 50:13. A two-level factorial design was used to verify the influence of Gelucire® 50:13 and lactose contents found in the granules on their size, morphology, bulk and tapped densities, flow, moisture content, and water activity. The granules obtained were also evaluated by differential scanning calorimetry, thermogravimetric analysis, X-ray powder diffraction, and infrared spectrometry. The curcumin solubility and dissolution rates in water were determined by liquid chromatography. The best formulation provides an increase of curcumin solubility of 4642-fold and 3.8-fold compared to the physical mixture. The dissolution tests showed a maximum drug release from granules after 45 min of 70% at pH 1.2 and 80% at pH 5.8 and 7.4, while for non-granulated curcumin, the release was below 20% in all pH. The solid-state characterization and solubility measurement showed good stability of granules over 9 months. The results attest that the fluidized bed hot-melt granulation with hydrophilic binders is an attractive and promising alternative to obtain solid forms of curcumin with enhanced bioavailability.


curcumin hot-melt granulation solid state stability dissolution rate 


Funding Information

The financial support from FAPESP (2013/23327-5; 2015/25128-5) and CNPq (PQ-2) is gratefully acknowledged.


  1. 1.
    Cheng AL, Hsu CH, Lin JK, Hsu MM, Ho YF, Shen TS, et al. Phase I clinical trial of curcumin, a chemopreventive agent, in patients with high-risk or pre-malignant lesions. Anticancer Res. 2001;21(4B):2895–900.PubMedGoogle Scholar
  2. 2.
    Tilak JC, MB HM, Devasagayam TPA. Antioxidant availability of turmeric in relation to its medicinal and culinary uses. Phytother Res. 2004;18(10):798–804. Scholar
  3. 3.
    Srimal RC. Turmeric: a brief review of medicinal properties. Fitoterapia. 1997;68:483–93.Google Scholar
  4. 4.
    Jayaprakasha GK, Jaganmoham R, Sakariah KK. Chemistry and biological activities of C. longa. Trends Food Sci Technol. 2005;16:533–48.CrossRefGoogle Scholar
  5. 5.
    Freitas LA, Teixeira CCC, Zamarioli CM. Tumeric: therapeutical actions and toxicity. In Tumeric: nutritional properties, uses and potential benefits. New York: Nova Science Publisher, Inc.; 2015. p. 1–50.Google Scholar
  6. 6.
    Teixeira CC, Mendonca LM, Bergamaschi MM, Queiroz RH, Souza GE, Antunes LM, et al. Microparticles containing curcumin solid dispersion: stability, bioavailability and anti-inflammatory activity. AAPS PharmSciTech. 2016;
  7. 7.
    Tonnesen HH. Solubility, chemical and photochemical stability of curcumin in surfactant solutions—studies of curcumin and curcuminolds, XXVIII. Die Pharmazie. 2002;57(12):820–4.PubMedGoogle Scholar
  8. 8.
    Bambirra MLA, Junqueira RG, Gloria MB. Influence of post harvest processing conditions on yield and quality of ground turmeric (Curcuma Longa L.). Braz Arch Biol Technol. 2002;45(4):423–9.CrossRefGoogle Scholar
  9. 9.
    Tonnesen HH. Solubility and stability of curcumin in solutions containing alginate and other viscosity modifying macromolecules. Studies of curcumin and curcuminoids. XXX. Die Pharmazie. 2006;61(8):696–700.PubMedGoogle Scholar
  10. 10.
    Paradkar A, Ambike AA, Jadhav BK, Mahadik KR. Characterization of curcumin-PVP solid dispersion obtained by spray drying. Int J Pharm. 2004;271(1–2):281–6.CrossRefPubMedGoogle Scholar
  11. 11.
    Leuner C, Dressman J. Improving drug solubility for oral delivery using solid dispersions. Eur J Pharm Biopharm. 2000;50(1):47–60.CrossRefPubMedGoogle Scholar
  12. 12.
    Araújo RR, Teixeira CCC, Freitas LAP. The preparation of ternary solid dispersions of an herbal drug via spray drying of liquid feed. Dry Technol. 2010;28(3):412–21. Scholar
  13. 13.
    Naksuriya O, Okonogi S, Schiffelers RM, Hennink WE. Curcumin nanoformulations: a review of pharmaceutical properties and preclinical studies and clinical data related to cancer treatment. Biomaterials. 2014;35(10):3365–83. Scholar
  14. 14.
    Okonogi S, Puttipipatkhachorn S. Dissolution improvement of high drug-loaded solid dispersion. AAPS PharmSciTech. 2006;7(2)Google Scholar
  15. 15.
    Yuksel N, Karatas A, Ozkan Y, Savaser A, Ozkan SA, Baykara T. Enhanced bioavailability of piroxicam using Gelucire 44/14 and labrasol: in vitro and in vivo evaluation. Europe J Pharmaceut Biopharmaceut : Off J Arbeitsgemeinschaft fur Pharmazeutische Verfahrenstechnik eV. 2003;56(3):453–9.CrossRefGoogle Scholar
  16. 16.
    Vasconcelos T, Sarmento B, Costa P. Solid dispersions as strategy to improve oral bioavailability of poor water soluble drugs. Drug Discov Today. 2007;12(23/24):1068–75.CrossRefPubMedGoogle Scholar
  17. 17.
    Martins RM, Machado MO, Pereira SV, Nosari ABFL, Tacon LA, Freitas LAP. Engineering active pharmaceutical ingredients by spray drying: effects on physical properties and in vitro dissolution. Dry Technol. 2012;30:905–13.CrossRefGoogle Scholar
  18. 18.
    Corrigan OI, Holohan EM, Reilly MR. Physicochemical properties of indomethacin and related compounds co-spray dried with polyvinylpyrrolidone. Drug Dev Ind Pharm. 1985;11:677–95.CrossRefGoogle Scholar
  19. 19.
    Law SL, Lo WY, Lin FM, H CC. Dissolution and absorption of nifedipine in polyethylene glycol solid dispersion containing phosphatidylcholine. Int J Pharmarceut. 1982;84:161–6.CrossRefGoogle Scholar
  20. 20.
    Mura P, Manderiolo A, Bramanti G, Ceccarelli L. Properties of solid dispersions of naproxen in various polyethyleneglycols. Drug Dev Ind Pharm. 1986;22:909–16.CrossRefGoogle Scholar
  21. 21.
    Ozeki T, Yuasa H, Kanaya Y, Oishi K. Application of the solid dispersion method to the controlled release of medicine. VIII. Medicine release and viscosity of the hydrogel of a water-soluble polymer in a three-component solid dispersion system. Chem Pharmaceut Bull. 1995;43:660–5.CrossRefGoogle Scholar
  22. 22.
    Craig DQ. The mechanisms of drug release from solid dispersions in water-soluble polymers. Int J Pharm. 2002;231(2):131–44.CrossRefPubMedGoogle Scholar
  23. 23.
    Ford JL. The current status of solid dispersions. Pharm Acta Helv. 1986;61(3):69–88.PubMedGoogle Scholar
  24. 24.
    Achanta AS, Adusumilli PS, James KW, Rhodes CT. Hot-melt coating: water sorption behavior of excipient films. Drug Dev Ind Pharm. 2001;27(3):241–50.CrossRefPubMedGoogle Scholar
  25. 25.
    Guimaraes TF, Comelli ACC, Tacon LA, Cunha TA, Marreto RN, Freitas LAP. Fluidized bed hot melt granulation with hydrophilic materials improves enalapril maleate stability. AAPS PharmSciTech. 2016;18(4):1302–10. Scholar
  26. 26.
    Haramiishi Y, Kitazawa Y, Sakai M, Kataoka K. Study on fluidized melt-granulation. I. Examination of the factors on the glanulation. Yakugaku Zasshi: J Pharmaceut Soc Jap. 1991;111:515–23.CrossRefGoogle Scholar
  27. 27.
    Kidokoro M, Haramiishi Y, Sagasaki S, Shimizu T, Yamamoto Y. Application of fluidized hot-melt granulation (FHMG) for the preparation of granules for tableting; properties of granules and tablets prepared by FHMG. Drug Dev Ind Pharm. 2002;28(1):67–76. Scholar
  28. 28.
    Villanova JCO, Ayres E, Orefice RL. Design of prolonged release tablets using new solid acrylic excipients for direct compression. Eur J Pharm Biopharm. 2011;79:664–73.CrossRefPubMedGoogle Scholar
  29. 29.
    Nist/Sematech. e-Handbook of statistical methods. 2012 [updated 2012, April]; Available from:
  30. 30.
    Harmonisation. ICo. Guidance for industry Q1A(R2) stability testing of new drug substances and products. In: Dept. of Health and Human Services, editor. Rockville, MD : U.S. : Food and Drug Administration, Center for Drug Evaluation and Research; 2003.Google Scholar
  31. 31.
    American Pharmacopeia. USP XXX: United States pharmacopeial convention, in: United States Pharmacopeial convention, USP: Rockville, MD 2008.Google Scholar
  32. 32.
    Damian F, Blaton N, Naesens L, Balzarini J, Kinget R, Augustijns P, et al. Physicochemical characterization of solid dispersions of the antiviral agent UC-781 with polyethylene glycol 6000 and Gelucire 44/14. European journal of pharmaceutical sciences : official journal of the European Federation for Pharmaceutical Sciences. 2000;10(4):311–22.CrossRefGoogle Scholar
  33. 33.
    Haque MK, Roos YH. Crystallization and X-ray diffraction of spray-dried and freeze-dried amorphous lactose. Carbohydr Res. 2005;340(2):293–301. Scholar
  34. 34.
    Geldart D, Abdullah EC, Hassanpour A, Nwoke LC, Wouters I. Characterization of powder flowability using measurement of angle of repose. China Particuology. 2006;4(3–4):104–7.CrossRefGoogle Scholar
  35. 35.
    Serajuddin AT. Solid dispersion of poorly water-soluble drugs: early promises, subsequent problems, and recent breakthroughs. J Pharm Sci. 1999;88(10):1058–66.CrossRefPubMedGoogle Scholar
  36. 36.
    Wang W, Zhou WB. Characterization of spray-dried soy sauce powders using maltodextrins as carrier. J Food Eng. 2012;109:399–405.CrossRefGoogle Scholar
  37. 37.
    Gupta MK, Tseng YC, Goldman D, Bogner RH. Hydrogen bonding with adsorbent during storage governs drug dissolution from solid-dispersion granules. Pharm Res. 2002;19(11):1663–72.CrossRefPubMedGoogle Scholar
  38. 38.
    Chauhan B, Shimpi S, Paradkar A. Preparation and evaluation of glibenclamide-polyglycolized glycerides solid dispersions with silicon dioxide by spray drying technique. European journal of pharmaceutical sciences : official journal of the European Federation for Pharmaceutical Sciences. 2005;26(2):219–30. CrossRefGoogle Scholar
  39. 39.
    Kakkar V, Kaur IP. Evaluating potential of curcumin loaded solid lipid nanoparticles in aluminium induced behavioural, biochemical and histopathological alterations in mice brain. Food and chemical toxicology : an international journal published for the British Industrial Biological Research Association. 2011;49(11):2906–13. CrossRefGoogle Scholar

Copyright information

© American Association of Pharmaceutical Scientists 2017

Authors and Affiliations

  • Cristiane C. C. Teixeira
    • 1
  • Elias de Paiva Junior
    • 1
  • Luis Alexandre Pedro de Freitas
    • 1
  1. 1.Faculdade de Ciências Farmacêuticas de Ribeirão Preto, Instituto Nacional de Ciência e Tecnologia-INCT-Nanotecnologia FarmacêuticaUniversidade de São PauloRibeirão PretoBrazil

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