Abstract
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.
Similar content being viewed by others
References
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.
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.
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.
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.
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.
He P, Davis SS, Illum L. Sustained release chitosan microspheres prepared by novel spray drying methods.J Microencapsul. 1999;16(3):343–355.
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.
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.
Akabuja J, Bergisadi N. Effect of formulation variables on cisplatin loaded chitosan microsphere properties.J Microencapsul. 1999;16(6):697–703.
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.
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.
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.
Nam YS, Park TG. Protein loaded biodegradable microspheres based on PLGA-protein biconjugates.J Microencapsul. 1999;16(5):625–637.
Aiedeh K, Gianasi E, Orienti I, Zecchi V. Chitosan microcapsules as controlled release systems for insulin.J Microencapsul. 1997;14(5):567–576.
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.
Denkbas EB, Seyyal M, Piskins E. 5-Fluorouracil loaded chitosan micropheres for chemoembolization.J Microencapsul. 1999;16(6):741–749.
Benoit P. Preparation and characterization of 5-fluorouracil-loaded microparticles as biodegradable anticancer drug carriers.J Pharm Pharmacol. 1995;47:108–114.
Tomlinson E. Passive and active vectoring with microparticles: localisation and drug release.J Control Release, 1985;2:385–391.
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.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Dubey, R.R., Parikh, R.H. Two-stage optimization process for formulation of chitosan microspheres. AAPS PharmSciTech 5, 5 (2004). https://doi.org/10.1208/pt050105
Received:
Accepted:
Published:
DOI: https://doi.org/10.1208/pt050105