Skip to main content
SpringerLink
Log in

Preparation and Optimization of Resveratrol Nanosuspensions by Antisolvent Precipitation Using Box-Behnken Design

  • Research Article
  • Published:
AAPS PharmSciTech Aims and scope Submit manuscript

Abstract

Resveratrol, a natural polyphenolic component, has inspired considerable interest for its extensive physiological activities. However, the poor solubility of resveratrol circumscribes its therapeutic applications. The purpose of this study was to optimize and prepare resveratrol nanosuspensions using the antisolvent precipitation method. The effects of crucial formulation and process variables (drug concentration, stabilizer, and surfactant contents) on particle size were investigated by utilizing a three-factor three-level Box-Behnken design (BBD) to perform this experiment. Different mathematical polynomial models were used to identify the impact of selected parameters and to evaluate their interrelationship for predictive formulation purposes. The optimal formulation consisted of drug 29.2 (mg/ml), polyvinylpyrrolidone (PVP) K17 0.38%, and F188 3.63%, respectively. The morphology of nanosuspensions was found to be near-spherical shaped by scanning electron microscopy (SEM) observation. The X-ray powder diffraction (XRPD) and differential scanning calorimetry (DSC) analysis confirmed that the nanoparticles were in the amorphous state. Furthermore, in comparison to raw material, resveratrol nanosuspensions showed significantly enhanced saturation solubility and accelerated dissolution rate resulting from the decrease in particle size and the amorphous status of nanoparticles. Meanwhile, resveratrol nanosuspensions exhibited the similar antioxidant potency to that of raw resveratrol. The in vivo pharmacokinetic study revealed that the C max and AUC0→∞ values of nanosuspension were approximately 3.35- and 1.27-fold greater than those of reference preparation, respectively. Taken together, these results suggest that this study provides a beneficial approach to address the poor solubility issue of the resveratrol and affords a rational strategy to widen the application range of this interesting substance.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6

Similar content being viewed by others

REFERENCES

  1. Amri A, Chaumeil J, Sfar S, Charrueau C. Administration of resveratrol: what formulation solutions to bioavailability limitations? J Controlled Release. 2012;158(2):182–93.

    Article  CAS  Google Scholar 

  2. Baur JA, Sinclair DA. Therapeutic potential of resveratrol: the in vivo evidence. Nat Rev Drug Discovery. 2006;5(6):493–506.

    Article  CAS  Google Scholar 

  3. Fan E, Zhang L, Jiang S, Bai Y. Beneficial effects of resveratrol on atherosclerosis. J Med Food. 2008;11(4):610–4.

    Article  CAS  PubMed  Google Scholar 

  4. Newa M, Bhandari KH, Kim JO, Im JS, Kim JA, Yoo BK, et al. Enhancement of solubility, dissolution and bioavailability of ibuprofen in solid dispersion systems. Chem Pharm Bull. 2008;56(4):569–74.

    Article  CAS  PubMed  Google Scholar 

  5. Kesisoglou F, Panmai S, Wu Y. Nanosizing—oral formulation development and biopharmaceutical evaluation. Adv Drug Delivery Rev. 2007;59(7):631–44.

    Article  CAS  Google Scholar 

  6. Chingunpituk J. Nanosuspension technology for drug delivery. Walailak J Sci Technol (WJST). 2011;4(2):139–53.

    Google Scholar 

  7. Sinha B, Müller RH, Möschwitzer JP. Bottom-up approaches for preparing drug nanocrystals: formulations and factors affecting particle size. Int J Pharm. 2013;453(1):126–41.

    Article  CAS  PubMed  Google Scholar 

  8. Keck CM, Müller RH. Drug nanocrystals of poorly soluble drugs produced by high pressure homogenisation. Eur J Pharm Biopharm. 2006;62(1):3–16.

    Article  CAS  PubMed  Google Scholar 

  9. Chen H, Khemtong C, Yang X, Chang X, Gao J. Nanonization strategies for poorly water-soluble drugs. Drug Discovery Today. 2011;16(7):354–60.

    Article  CAS  PubMed  Google Scholar 

  10. Li X-S, Wang J-X, Shen Z-G, Zhang P-Y, Chen J-F, Yun J. Preparation of uniform prednisolone microcrystals by a controlled microprecipitation method. Int J Pharm. 2007;342(1):26–32.

    Article  CAS  PubMed  Google Scholar 

  11. Bilati U, Allémann E, Doelker E. Development of a nanoprecipitation method intended for the entrapment of hydrophilic drugs into nanoparticles. Eur J Pharm Sci. 2005;24(1):67–75.

    Article  CAS  PubMed  Google Scholar 

  12. Lu Z, Cheng B, Hu Y, Zhang Y, Zou G. Complexation of resveratrol with cyclodextrins: solubility and antioxidant activity. Food Chem. 2009;113(1):17–20.

    Article  CAS  Google Scholar 

  13. Pawar VK, Singh Y, Meher JG, Gupta S, Chourasia MK. Engineered nanocrystal technology: in-vivo fate, targeting and applications in drug delivery. J Controlled Release. 2014;183:51–66.

    Article  CAS  Google Scholar 

  14. Kim S, Ng WK, Dong Y, Das S, Tan RB. Preparation and physicochemical characterization of trans-resveratrol nanoparticles by temperature-controlled antisolvent precipitation. J Food Eng. 2012;108(1):37–42.

    Article  CAS  Google Scholar 

  15. Zhang X-P, Le Y, Wang J-X, Zhao H, Chen J-F. Resveratrol nanodispersion with high stability and dissolution rate. LWT–Food Sci Technol. 2013;50(2):622–8.

    CAS  Google Scholar 

  16. Cheel J, Antwerpen PV, Tůmová L, Onofre G, Vokurková D, Zouaoui-Boudjeltia K, et al. Free radical-scavenging, antioxidant and immunostimulating effects of a licorice infusion (Glycyrrhiza glabra L.). Food Chem. 2010;122(3):508–17.

    Article  CAS  Google Scholar 

  17. Caddeo C, Manconi M, Fadda AM, Lai F, Lampis S, Diez-Sales O, et al. Nanocarriers for antioxidant resveratrol: formulation approach, vesicle self-assembly and stability evaluation. Colloids Surf, B. 2013;111:327–32.

    Article  CAS  Google Scholar 

  18. Patravale V, Kulkarni R. Nanosuspensions: a promising drug delivery strategy. J Pharm Pharmacol. 2004;56(7):827–40.

    Article  CAS  PubMed  Google Scholar 

  19. Matteucci ME, Hotze MA, Johnston KP, Williams RO. Drug nanoparticles by antisolvent precipitation: mixing energy versus surfactant stabilization. Langmuir. 2006;22(21):8951–9.

    Article  CAS  PubMed  Google Scholar 

  20. Horn D, Rieger J. Organic nanoparticles in the aqueous phase—theory, experiment, and use. Angew Chem Int Edit. 2001;40(23):4330–61.

    Article  CAS  Google Scholar 

  21. Dalvi SV, Dave RN. Controlling particle size of a poorly water-soluble drug using ultrasound and stabilizers in antisolvent precipitation. Ind Eng Chem Res. 2009;48(16):7581–93.

    Article  CAS  Google Scholar 

  22. Raghavan S, Trividic A, Davis A, Hadgraft J. Crystallization of hydrocortisone acetate: influence of polymers. Int J Pharm. 2001;212(2):213–21.

    Article  CAS  PubMed  Google Scholar 

  23. Thorat AA, Dalvi SV. Liquid antisolvent precipitation and stabilization of nanoparticles of poorly water soluble drugs in aqueous suspensions: recent developments and future perspective. Chem Eng J. 2012;181:1–34.

    Article  Google Scholar 

  24. Kind M. Colloidal aspects of precipitation processes. Chem Eng Sci. 2002;57(20):4287–93.

    Article  CAS  Google Scholar 

  25. Patel D, Chaudhary P, Mohan S, Khatri H. Enhancement of glipizide dissolution rate through nanoparticles: formulation and in vitro evaluation. J Sci Technol. 2012;7(4):20.

    Google Scholar 

  26. Yang Z-Y, Le Y, Hu T-T, Shen Z, Chen J-F, Yun J. Production of ultrafine sumatriptan succinate particles for pulmonary delivery. Pharm Res. 2008;25(9):2012–8.

    Article  CAS  PubMed  Google Scholar 

  27. Shah B, Kakumanu VK, Bansal AK. Analytical techniques for quantification of amorphous/crystalline phases in pharmaceutical solids. J Pharm Sci. 2006;95(8):1641–65.

    Article  CAS  PubMed  Google Scholar 

  28. Rabinow BE. Nanosuspensions in drug delivery. Nat Rev Drug Discovery. 2004;3(9):785–96.

    Article  CAS  Google Scholar 

  29. Xia D, Quan P, Piao H, Piao H, Sun S, Yin Y, et al. Preparation of stable nitrendipine nanosuspensions using the precipitation–ultrasonication method for enhancement of dissolution and oral bioavailability. Eur J Pharm Sci. 2010;40(4):325–34.

    Article  CAS  PubMed  Google Scholar 

  30. Marier J-F, Vachon P, Gritsas A, Zhang J, Moreau J-P, Ducharme MP. Metabolism and disposition of resveratrol in rats: extent of absorption, glucuronidation, and enterohepatic recirculation evidenced by a linked-rat model. J Pharmacol Exp Ther. 2002;302(1):369–73.

    Article  CAS  PubMed  Google Scholar 

  31. Jia L, Wong H, Cerna C, Weitman SD. Effect of nanonization on absorption of 301029: ex vivo and in vivo pharmacokinetic correlations determined by liquid chromatography/mass spectrometry. Pharm Res. 2002;19(8):1091–6.

    Article  CAS  PubMed  Google Scholar 

  32. Varshosaz J, Tabbakhian M, Mohammadi MY. Formulation and optimization of solid lipid nanoparticles of buspirone HCl for enhancement of its oral bioavailability. J Liposome Res. 2010;20(4):286–96.

    Article  CAS  PubMed  Google Scholar 

Download references

ACKNOWLEDGMENTS

This work was supported by grants obtained from the National Nature Science Foundation of China (Nos. 81102820 and 81373896), Major National Science and Technology Programs (No. 2011ZXJ09102B), and Shanghai Municipality Science and Technology Commission (No. 14JC1491300).

Disclosure

The authors report no conflicts of interest in this work.

Author information

Authors and Affiliations

  1. Department of Pharmaceutics, College of Pharmacy, Shandong University, 44 Wenhua Xilu, Jinan, 250012, People’s Republic of China

    Jifu Hao & Zhongxi Zhao

  2. College of Pharmacy, Taishan Medical University, Taian, 271016, People’s Republic of China

    Jifu Hao, Jing Zhao, Jimei Zhang & Qiankui Li

  3. Department of Scientific Research and Teaching, The Central Hospital of Taian, Taian, 271016, People’s Republic of China

    Yun Gao

  4. Department of Pharmacy, Changhai Hospital, Second Military Medical University, Shanghai, 200433, People’s Republic of China

    Jiyong Liu

Authors
  1. Jifu Hao
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Yun Gao
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Jing Zhao
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Jimei Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Qiankui Li
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Zhongxi Zhao
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Jiyong Liu
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding authors

Correspondence to Zhongxi Zhao or Jiyong Liu.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Hao, J., Gao, Y., Zhao, J. et al. Preparation and Optimization of Resveratrol Nanosuspensions by Antisolvent Precipitation Using Box-Behnken Design. AAPS PharmSciTech 16, 118–128 (2015). https://doi.org/10.1208/s12249-014-0211-y

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1208/s12249-014-0211-y

KEY WORDS

Search

Navigation