AAPS PharmSciTech

, 5:20 | Cite as

Two-stage optimization process for formulation of chitosan microspheres



The objective of the present study was to optimize the concentration of a chitosan solution, stirring speed, and concentration of drug having different aqueous solubility for the formulation of chitosan microspheres. Chitosan microspheres (unloaded and drug loaded) were prepared by the chemical denaturation method and were subjected to measurement of morphology, mean particle size, particle size distribution, percentage drug entrapment (PDE), drug loading, and drug release (in vitro). Morphology of the microspheres was dependent on the level of independent process parameters. While mean particle size of unloaded microspheres was found to undergo significant change with each increase in concentration of chitosan solution, the stirring rate was found to have a significant effect only at the lower level (ie, 2000 to 3000 rpm). Of importance, spherical unloaded micropheres were also obtained with a chitosan solution of concentration less than 1 mg/mL. Segregated unloaded microspheres with particle size in the range of 7 to 15 μm and mean particle size of 12.68 μm were obtained in the batch prepared by using a chitosan solution of 2 mg/mL concentration and stirring speed of 3000 rpm. The highest drug load (μg drug/mg microspheres) was 50.63 and 13.84 for microspheres containing 5-fluorouracil and methotrexate, respectively. While the release of 5-fluorouracil followed Higuchi's square-root model, methotrexate released more showly with a combination of first-order kinetics and Higuchi's square-root model. The formation of chitosan microspheres is helped by the use of differential stirring. While an increase in the concentration of water-soluble drug may help to increase PDE and drug load over a large concentration range, the effect is limited in case of water insoluble drugs.


optimization chitosan microspheres 5-fluorouracil methotrexate 


  1. 1.
    Thanoo BC, Sunny MC, Jayakrishnan A. Cross-linked chitosan microspheres: preparation and evaluation as a matrix for the controlled release of pharmaceuticals.J Pharm Pharmacol. 1992;44:283–286.CrossRefPubMedGoogle Scholar
  2. 2.
    Ko JA, Park HJ, Hwang SJ, Park JB, Lee JS. Preparation and characterization of chitosan microparticles intended for controlled drug delivery.Int J Pharm 2002;249(1–2):165–174.CrossRefPubMedGoogle Scholar
  3. 3.
    Kumbar SG, Kulkami AR, Aminabhavi TM. Crosslinked chitosan microspheres for encapsulation of diclofenac sodium: effect of crosslinking agent.J Microencapsul. 2002;19(2):173–180.CrossRefPubMedGoogle Scholar
  4. 4.
    Yoshino T, Machida Y, Onishi H, Nagai T. Preparation and characterization of chitosan microspheres containing doxifluridine.Drug Dev Ind Pharm, 2003;29(4):417–427.CrossRefPubMedGoogle Scholar
  5. 5.
    Berthold A, Cremer K, Kreuter J. Preparation and characterization of chitosan microspheres as drug carrier for prednisolone sodium phosphate as model for antiinflammatory drugs.J Control Release. 1996;39:17–25.CrossRefGoogle Scholar
  6. 6.
    He P, Davis SS, Illum L. Sustained release chitosan microspheres prepared by novel spray drying methods.J Microencapsul. 1999;16(3):343–355.CrossRefPubMedGoogle Scholar
  7. 7.
    Filipovic-Grcic J, Perissutti B, Moneghini M, Voinovich D, Martinac A, Jalsenjak I. Spray-dried carbamazepine-loaded chitosan and HPMC microspheres: preparation and characterisation.J Pharm Pharmacol. 2000;55(7) 921–931.CrossRefGoogle Scholar
  8. 8.
    Singh UV, Udupa N. Methotrexate loaded chitosan and chitin microspheres—in vitro characterization and pharmacokinetics in mice bearing Ehrlich ascites carcinoma.J Microencapsul. 1998;15(5):581–594.CrossRefPubMedGoogle Scholar
  9. 9.
    Akabuja J, Bergisadi N. Effect of formulation variables on cisplatin loaded chitosan microsphere properties.J Microencapsul. 1999;16(6):697–703.CrossRefGoogle Scholar
  10. 10.
    Al-Helw AA, Al-Angary AA, Mahrous GM, Al-Dardari MM. Preparation and evaluation of crosslinked chitosan microspheres containing phenobarbitone.J Microencapsul. 1998;15(3):373–382.CrossRefPubMedGoogle Scholar
  11. 11.
    Dubey R, Parikh JR, Parikh RH. Effect of heating temperature and time on pharmaceutical characteristics of albumin microspheres containing 5-fluorouracil.AA PSPharm Sci Tech. 2002;3(1) article 13.Google Scholar
  12. 12.
    Shukla PG, Kalidhass B, Shah A, Palashkar DV. Preparation and characterization of microcapsules of water soluble pesticide monocrotophs using polyurethane as carrier material.J Microencapsul. 2002; 19(3):293–304.CrossRefPubMedGoogle Scholar
  13. 13.
    Nam YS, Park TG. Protein loaded biodegradable microspheres based on PLGA-protein biconjugates.J Microencapsul. 1999;16(5):625–637.CrossRefPubMedGoogle Scholar
  14. 14.
    Aiedeh K, Gianasi E, Orienti I, Zecchi V. Chitosan microcapsules as controlled release systems for insulin.J Microencapsul. 1997;14(5):567–576.CrossRefPubMedGoogle Scholar
  15. 15.
    Jeyanthi R, Mehta RC, Thanoo BC, Deluca PP. Effect of processing parameters on the properties of peptide-containing PLGA microspheres.J Microencapsul. 1997;14(2):163–174.CrossRefPubMedGoogle Scholar
  16. 16.
    Denkbas EB, Seyyal M, Piskins E. 5-Fluorouracil loaded chitosan micropheres for chemoembolization.J Microencapsul. 1999;16(6):741–749.CrossRefPubMedGoogle Scholar
  17. 17.
    Benoit P. Preparation and characterization of 5-fluorouracil-loaded microparticles as biodegradable anticancer drug carriers.J Pharm Pharmacol. 1995;47:108–114.CrossRefPubMedGoogle Scholar
  18. 18.
    Tomlinson E. Passive and active vectoring with microparticles: localisation and drug release.J Control Release, 1985;2:385–391.CrossRefGoogle Scholar
  19. 19.
    Sato T, Kanke M, Schroeder HG, Deluca PP. Porous biodegradable microspheres for controlled drug delivery. I. Assessment of processing conditions and solvent removal techniques.Pharm Res. 1988;5(1):21–30.CrossRefPubMedGoogle Scholar

Copyright information

© American Association of Pharmaceutical Scientists 2004

Authors and Affiliations

  1. 1.AR College of Pharmacy & GH Patel Institute of PharmacyVallabh VidyanagarIndia

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