Design and Evaluation of Non-steroidal Anti-inflammatory Drug Intercalated into Layered Zinc Hydroxide as a Drug Delivery System

  • Hafezeh NabipourEmail author


Non-steroidal anti-inflammatory drugs are a broad class of agents with analgesic and anti-inflammatory properties. Despite their frequent current uses, they exhibit several problems for administration related to delivery control, low solubility, and low oral bioavailability. Due to mentioned reasons, several inorganic materials (anionic clays and mesoporous materials) as host, have been tested to support the min order to overcome these drawbacks. Among these materials, layered zinc hydroxide (LZH) has been used in recent years. In the present research, naproxen (Np) was intercalated into the interlayer space of LZH using anion exchange method. From the PXRD results, it was found that Np anions were successfully incorporated on LZH and the basal spacing of LZH increased from 9.57 to 22.09 Å, indicating that Np was intercalated into the interlayer space of LZHs as a monolayer. FTIR study exhibits the vibrations bands of the functional groups of Np and of the LZH, confirming the intercalation. TG analysis confirms that the intercalated Np drug in the form of nanohybrid is thermally more stable than its Np salt. SEM images illustrated that the LZH precursor has a plate-like structure transformed into the uniform structure when the nanohybrid is formed. In vitro drug release experiments at a pH of 7.4 phosphate buffer solutions and a pH of 4.8 acetate buffer solution showed controlled release profiles with Np anions as a non-steroidal anti-inflammatory model drug. In the following, the results of cytotoxicity assay showed that Np–LZH nanohybrid affected cell viability in a dose and time-dependent mode. According to the results, synthesized LZH can act as a host network and accept Np as a guest in its structure and release the drug in a more controlled manner and over a longer period of time.


Layered zinc hydroxide Naproxen Nanohybrid Cytotoxicity activity Controlled release 





Layered zinc hydroxide


Layered zinc hydroxide containing the anionic form of the drug naproxen


Phosphate buffer solution


Drug delivery system


Layered double hydroxides


Layered hydroxide salt


Polyvinyl alcohol


Polyethylene glycols


Monomethoxy poly-(ethylene glycol)


3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide


Scanning electron microscope


Brunauer, Emmet, and Teller


Barrett, Joyner, and Halenda




Standard deviation


Thermogravimetric analysis


Fourier transform infrared spectroscopy


Powder X-ray diffraction


Joint Committee on Powder Diffraction Standards


Simultaneous thermal analysis


Dimethyl sulfoxide



  1. 1.
    M. Hrubý, S.K. Filippov, P. Štěpánek, Smart polymers in drug delivery systems on crossroads: Which way deserves following? Eur. Polym. J. 65, 82–97 (2015)CrossRefGoogle Scholar
  2. 2.
    S. Bamrungsap, Z. Zhao, T. Chen, L. Wang, C. Li, T. Fu, W. Tan, Nanotechnology in therapeutics: a focus on nanoparticles as a drug delivery system. Nanomedicine 7, 1253–1271 (2012)CrossRefGoogle Scholar
  3. 3.
    T.M. Allen, P.R. Cullis, Liposomal drug delivery systems: from concept to clinical applications. Adv. Drug Deliv. Rev. 65, 36–48 (2013)CrossRefGoogle Scholar
  4. 4.
    J. Siepmann, N.A. Peppas, Modeling of drug release from delivery systems based on hydroxypropyl methylcellulose (HPMC). Adv. Drug Deliv. Rev. 64, 163–174 (2012)CrossRefGoogle Scholar
  5. 5.
    K. Kataoka, A. Harada, Y. Nagasaki, Block copolymer micelles for drug delivery: design, characterization and biological significance. Adv. Drug Deliver. Rev. 64, 37–48 (2012)CrossRefGoogle Scholar
  6. 6.
    Y. Qiu, K. Park, Environment-sensitive hydrogels for drug delivery. Adv. Drug Deliv. Rev. 64, 49–60 (2012)CrossRefGoogle Scholar
  7. 7.
    N. Bhattarai, J. Gunn, M.Q. Zhang, Chitosan-based hydrogels for controlled, localized drug delivery. Adv. Drug Deliv. Rev. 62, 83–99 (2010)CrossRefGoogle Scholar
  8. 8.
    C. Alvarez-Lorenzo, B. Blanco-Fernandez, A.M. Puga, A. Concheiro, Crosslinked ionic polysaccharides for stimuli-sensitive drug delivery. Adv. Drug Deliv. Rev. 65, 1148–1171 (2013)CrossRefGoogle Scholar
  9. 9.
    N. Zhang, P.R. Wardwell, R.A. Bader, Polysaccharide-based micelles for drug delivery. Pharmaceutics 5, 329–352 (2013)CrossRefGoogle Scholar
  10. 10.
    M.J. Lawrence, G.D. Rees, Microemulsion-based media as novel drug delivery systems. Adv. Drug Deliv. Rev. 64, 175–193 (2012)CrossRefGoogle Scholar
  11. 11.
    W.M. Kriven, S.Y. Kwak, M.A. Wallig, Bio-resorbable nanoceramics for gene and drug delivery. MRS Bull. 29, 33–37 (2004)CrossRefGoogle Scholar
  12. 12.
    F.Q. Tang, L.L. Li, D. Chen, Mesoporous silica nanoparticles: synthesis, biocompatibility and drug delivery. Adv. Mater. 24, 1504–1534 (2012)CrossRefGoogle Scholar
  13. 13.
    P.P. Yang, S.L. Gai, J. Lin, Functionalized mesoporous silica materials for controlled drug delivery. Chem. Soc. Rev. 41, 3679–3698 (2012)CrossRefGoogle Scholar
  14. 14.
    F. Alexis, E.M. Pridgen, R. Langer, O.C. Farokhzad, Nanoparticle technologies for cancer therapy. Handb. Exp. Pharmacol. 197, 55–86 (2010)CrossRefGoogle Scholar
  15. 15.
    P.R. Wei, S.H. Cheng, W.N. Liao, K.C. Kao, F.C. Weng, C.H. Lee, Synthesis of chitosan-coated near-infrared layered double hydroxide nanoparticles for in vivo optical imaging. J. Mater. Chem. 22, 5503–5513 (2012)CrossRefGoogle Scholar
  16. 16.
    L.N.M. Ribeiro, A.C.S. Alcântara, M. Darder, P. Aranda, F.M. Araújo-Moreira, E. Ruiz-Hitzky, Pectin-coated chitosan-LDH bionanocomposite beads as potential systems for colon-targeted drug delivery. Int. J. Pharm. 463, 1–9 (2014)CrossRefGoogle Scholar
  17. 17.
    W. Stahlin, H.R. Oswald, The crystal structure of zinc hydroxide nitrate, Zn5(OH)8(NO3)2·2H2O. Acta Crystallogr. Sect. B 26, 860 (1970)CrossRefGoogle Scholar
  18. 18.
    R.Z. Ma, Z.P. Liu, K. Takada, K. Fukuda, Y. Ebina, Y. Bando, K. Sasaki, Tetrahedral Co(II) coordination in α-type cobalt hydroxide: Rietveld refinement and X-ray absorption spectroscopy. Inorg. Chem. 45, 3964–3969 (2006)CrossRefGoogle Scholar
  19. 19.
    A. Moezzi, A. McDonagh, A. Dowd, M. Cortie, Zinc hydroxyacetate and its transformation to nanocrystalline zinc oxide. Inorg. Chem. 52, 95–102 (2012)CrossRefGoogle Scholar
  20. 20.
    S.H. Hussein-Al-Ali, M. Al-Qubaisi, M.Z. Hussein, M. Ismail, Z. Zainal, M.N. Hakim, Controlled-release formulation of antihistamine based on cetirizine zinc-layered hydroxide nanocomposites and its effect on histamine release from basophilic leukemia (RBL-2H3) cells. Int. J. Nanomed. 7, 3351–3363 (2012)CrossRefGoogle Scholar
  21. 21.
    M. Meyn, K. Beneke, G. Lagaly, Anion-exchange reactions of hydroxy double salts. Inorg. Chem. 32, 1209 (1993)CrossRefGoogle Scholar
  22. 22.
    G.R. Williams, J. Crowder, J.C. Burley, A.M. Fogg, The selective intercalation of organic carboxylates and sulfonates into hydroxy double salts. J. Mater. Chem. 22, 13600–13611 (2012)CrossRefGoogle Scholar
  23. 23.
    V. Laget, C. Hornick, P. Rabu, M. Drillon, R. Ziessel, Molecular magnets: hybrid organic-inorganic layered compounds with very long-range ferromagnetism. Coord. Chem. Rev. 178, 1533–1553 (1998)CrossRefGoogle Scholar
  24. 24.
    R. Rojas, C. Barriga, M.A. Ulibarri, P. Malet, V. Rives, Layered Ni(II)-Zn(II) hydroxyacetates. Anion exchange and thermal decomposition of the hydroxysalts obtained. J. Mater. Chem. 12, 1071–1078 (2002)CrossRefGoogle Scholar
  25. 25.
    L. Xu, Y.S. Ding, C.H. Chen, L. Zhao, C. Rimkus, R. Joesten, S. Suib, 3D flowerlike α-nickel hydroxide with enhanced electrochemical activity synthesized by microwave-assisted hydrothermal method. Chem. Mater. 20, 308–316 (2007)CrossRefGoogle Scholar
  26. 26.
    M. Louer, D. Louer, D. Grandjean, Structural studies of hydroxyl nitrate nickel and zinc I. Structural classification. Acta Crystallogr. B 29(8), 1696–1703 (1973)CrossRefGoogle Scholar
  27. 27.
    W.K. Hu, D. Noréus, Alpha nickel hydroxides as lightweight nickel electrode materials for alkaline rechargeable cells. Chem. Mater. 15, 974–978 (2003)CrossRefGoogle Scholar
  28. 28.
    V. Gupta, T. Kusahara, H. Toyama, S. Gupta, N. Miura, Potentiostatically deposited nanostructured α-Co(OH)2: a high performance electrode material for redox-capacitors. Electrochem. Commun. 9, 2315–2319 (2007)CrossRefGoogle Scholar
  29. 29.
    S. Inoue, S. Fujihara, Liquid–liquid biphasic synthesis of layered zinc hydroxides intercalated with long-chain carboxylate ions and their conversion into ZnO nanostructures. Inorg. Chem. 50, 3605–3612 (2011)CrossRefGoogle Scholar
  30. 30.
    S. Saha, S. Ray, R. Acharya, R.K. Chatterjee, J. Chakraborty, Magnesium, zinc and calcium aluminium layered double hydroxide-drug nanohybrids: a comprehensive study. Appl. Clay Sci. 135, 493–509 (2017)CrossRefGoogle Scholar
  31. 31.
    M.I. Carretero, Clay minerals and their beneficial effects upon human health. Rev. Appl. Clay Sci. 21, 155–163 (2002)CrossRefGoogle Scholar
  32. 32.
    M. del Arco, E. Cebadera, S. Gutiérrez, C. Martín, M.J. Montero, V. Rives, J. Rocha, M.A. Sevilla, Mg, Al layered double hydroxides with intercalated indomethacin: synthesis, characterization and pharmacological study. J. Pharm. Sci. 93, 1649–1658 (2004)CrossRefGoogle Scholar
  33. 33.
    M. del Arco, S. Gutiérrez, C. Martín, V. Rives, J. Rocha, Synthesis and characterization of layered double hydroxides (LDH) intercalated with non-steroidal anti-inflammatory drugs (NSAID). J. Solid State Chem. 177, 3954–3962 (2004)CrossRefGoogle Scholar
  34. 34.
    J.H. Yang, Y.S. Han, M. Park, T. Park, S.J. Hwang, J.H. Choy, New inorganic-based drug delivery system of indole-3-acetic acid-layered double hydroxide nanohybrids with controlled release rate. Chem. Mater. 19, 2679–2685 (2007)CrossRefGoogle Scholar
  35. 35.
    V. Ambrogi, G. Fardella, G. Grandolini, M. Nocchetti, L. Perioli, Effect of hydrotalcite-like compounds on the aqueous solubility of some poorly water-soluble drugs. J. Pharm. Sci. 92, 1407–1418 (2003)CrossRefGoogle Scholar
  36. 36.
    J.H. Yang, Y.S. Han, M. Park, T. Park, S.J. Hwang, J.H. Choy, New inorganic-based drug delivery system of indole-3-acetic acid-layered metal hydroxide nanohybrids with controlled release rate. Chem. Mater. 19, 2679–2685 (2007)CrossRefGoogle Scholar
  37. 37.
    J.H. Choy, S.Y. Kwak, J.Y. Jeong, J.S. Park, Inorganic layered double hydroxides as nonviral vectors. Angew. Chem. Int. Ed. Engl. 39, 4041–4045 (2000)CrossRefGoogle Scholar
  38. 38.
    F.A.L. Ahmad, Z.H. Mohd, S. Johnson, C.W. Charng, A. Rohana, Release behavior and toxicity profiles towards A549 cell lines of ciprofloxacin from its layered zinc hydroxide intercalation compound. Chem. Cent. J. 7, 119 (2013)CrossRefGoogle Scholar
  39. 39.
    S.H.H. Al Ali, M. Al-Qubaisi, M.Z. Hussein, Z. Zainal, M.N. Hakim, Preparation of hippurate-zinc layered hydroxide nanohybrid and its synergistic effect with tamoxifen on HepG2 cell lines. Int. J. Nanomed. 6, 3099–3111 (2011)CrossRefGoogle Scholar
  40. 40.
    R. Munirah, Z.H. Mohd, Y. Khatijah, Preparation and characterization of an anti-inflammatory agent based on a zinc-layered hydroxide-salicylate nanohybrid and its effect on viability of Vero-3 cells. Int. J. Nanomed. 8, 297–306 (2013)Google Scholar
  41. 41.
    S.M. Mohsin, M.Z. Hussein, S.H. Sarijo, S. Fakurazi, P. Arulselvan, T.Y. Hin, Synthesis of (cinnamate-zinc layered hydroxide) intercalation compound for sunscreen application. Chem. Cent. J. 7, 26 (2013)CrossRefGoogle Scholar
  42. 42.
    H. Nabipour, M. Hossaini Sadr, N. Thomas, Synthesis, characterization and sustained release properties of layered zinc hydroxide intercalated with amoxicillin trihydrate. J. Exp. Nanosci. 10(16), 1269–1284 (2015)CrossRefGoogle Scholar
  43. 43.
    G. Bettinetti, M. Sorrenti, A. Negri, M. Setti, P. Mura, F. Melani, Interaction of naproxen with alpha-cyclodextrin and its noncyclic analog maltohexaose. Pharm. Res. 16, 689 (1999)CrossRefGoogle Scholar
  44. 44.
    M. Wei, S.H. Shi, J. Wang, Y. Li, X. Duan, Studies on the intercalation of naproxen into layered double hydroxide and its thermal decomposition by in situ FT-IR and in situ HT-XRD. J. Solid State Chem. 177, 2534–2541 (2004)CrossRefGoogle Scholar
  45. 45.
    M.R. Berber, K. Minagawa, M. Katoh, T. Mori, M. Tanaka, Nanocomposites of 2-arylpropionic acid drugs based on Mg–Al layered double hydroxide for dissolution enhancement. Eur. J. Pharm. Sci. 35, 354–360 (2008)CrossRefGoogle Scholar
  46. 46.
    D. Carriazo, M. del Arco, C. Martín, C. Ramos, V. Rives, Influence of the inorganic matrix nature on the sustained release of naproxen. Microporous Mesoporous Mater. 130, 229–238 (2010)CrossRefGoogle Scholar
  47. 47.
    M. del Arco, A. Fernández, C. Martín, V. Rives, Release studies of different NSAIDs encapsulated in Mg, Al, Fe-hydrotalcites. Appl. Clay Sci. 42, 538–544 (2009)CrossRefGoogle Scholar
  48. 48.
    W.G. Hou, Z.L. Jin, Synthesis and characterization of naproxen intercalated Zn–Al layered double hydroxides. Colloid Polym. Sci. 285, 1449–1454 (2007)CrossRefGoogle Scholar
  49. 49.
    S.S.D. Richardson-Chong, R. Patel, G.R. Williams, Intercalation and controlled release of bioactive ions using a hydroxy double salt. Ind. Eng. Chem. Res. 51, 2913–2921 (2012)CrossRefGoogle Scholar
  50. 50.
    L. Poul, N. Jouini, F. Fiévet, Layered hydroxide metal acetates (metal = zinc, cobalt, and nickel): elaboration via hydrolysis in polyol medium and comparative study. Chem. Mater. 12, 3123–3132 (2000)CrossRefGoogle Scholar
  51. 51.
    S.S.D. Richardson-Chong, R. Patel, G.R. Williams, Intercalation and controlled release of bioactive ions using a hydroxy double salt. Ind. Eng. Chem. Res. 51, 2913–2921 (2012)CrossRefGoogle Scholar
  52. 52.
    T. Xia, M. Kovochich, J. Brant, M. Hotze, J. Sempf, T. Oberley, C. Sioutas, J.I. Yeh, M.R. Wiesner, A.E. Nel, Comparison of the abilities of ambient and manufactured nanoparticles to induce cellular toxicity according to an oxidative stress paradigm. Nano Lett. 6, 1794–1807 (2006)CrossRefGoogle Scholar
  53. 53.
    B. Soltani, H. Nabipour, N. Ahmadi Nasab, Fabrication, controlled release, and kinetic studies of indomethacin—layered zinc hydroxide nanohybrid and its effect on the viability of HFFF2. J. Dispers. Sci. Technol. 39(8), 1200–1207 (2018). CrossRefGoogle Scholar
  54. 54.
    H. Morioka, H. Tagaya, M. Karasu, J. Kadokawa, K. Chiba, Effects of zinc on the New preparation method of hydroxy double salts. Inorg. Chem. 38, 4211–4216 (1999)CrossRefGoogle Scholar
  55. 55.
    R. Rojas, M.C. Palena, A.F. Jimenez-Kairuz, R.H. Manzo, C.E. Giacomelli, Modeling drug release from a layered double hydroxide–ibuprofen complex. Appl. Clay Sci. 62–63, 15–20 (2012)CrossRefGoogle Scholar
  56. 56.
    S.B. Khan, K.A. Alamry, N.A. Alyahyawi, A.M. Asiri, M.N. Arshad, H.M. Marwani, Nanohybrid based on antibiotic encapsulated layered double hydroxide as a drug delivery system. Appl. Biochem. Biotechnol. 175(3), 1412–1428 (2015)CrossRefGoogle Scholar

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© Springer Science+Business Media, LLC, part of Springer Nature 2019

Authors and Affiliations

  1. 1.State Key Laboratory of Fire ScienceUniversity of Science and Technology of ChinaHefeiPeople’s Republic of China

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