Abstract
The objective of the present investigation was to improve the dissolution rate of Rofecoxib (RXB), a poorly water-soluble drug by solid dispersion technique using a water-soluble carrier, Poloxamer 188 (PXM). The melting method was used to prepare solid dispersions. A 32 full factorial design approach was used for optimization wherein the temperature to which the melt-drug mixture cooled (X 1) and the drug-to-polymer ratio (X 2) were selected as independent variables and the time required for 90% drug dissolution (t90) was selected as the dependent variable. Multiple linear regression analysis revealed that for obtaining higher dissolution of RXB from PXM solid dispersions, a low level ofX 1 and a high level ofX 2 were suitable. The differential scanning calorimetry and x-ray diffraction studies demonstrated that enhanced dissolution of RXB from solid dispersion might be due to a decrease in the crystallinity of RXB and PXM and dissolution of RXB in molten PXM during solid dispersion preparation. In conclusion, dissolution enhancement of RXB was obtained by preparing its solid dispersions in PXM using melting technique. The use of a factorial design approach helped in identifying the critical factors in the preparation and formulation of solid dispersion.
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References
Amidon GL, Lennernas H, Shah VP, Crison JR. A theoretical basis for a biopharmaceutic drug classification: the correlation of in vitro drug product dissolution and in vivo bioavailability.Pharm Res. 1995;12:413–420.
Garad SD. How to improve the bioavailability of poorly soluble drugs.Am Pharm Rev. 2004;7: Available at: http://www.varianinc.com. cn/products/dissolution/shared/ir2004_5.pdf. Accessed April 5, 2007.
Nokhodchi A, Javadzadeh Y, Reza M, Barzegar Jalali M. The effect of type and concentration of vehicles on the dissolution rates of a poorly water soluble drug (indomethacin) from liquisolid compacts.J Pharm Pharm Sci. 2005;8:18–25.
Chiou WL, Rigelman S. Pharmaceutical application of solid dispersion system.J Pharm Sci. 1971;60:1281–1302.
Serajuddin A. Solid dispersion of poorly water soluble drugs: early promises, subsequent problems and recent breakthroughs.J Pharm Sci. 1999;88:1058–1066.
Leuner C, Dressman J. Improving drug solubility for oral delivery using solid dispersions.Eur J Pharm Biopharm. 2000;50:47–60.
Sekiguchi K, Obi N. Studies on absorption of eutectic mixture-I.Chem Pharm Bull (Tokyo). 1961;9:866–872.
Liu C, Liu C, Desai KGH. Enhancement of dissolution rate of valdecoxib using solid dispersions with polyethylene glycol 4000.Drug Dev Ind Pharm. 2005;31:1–10.
Verheyen S, Blaton N, Kinget R, Van den Mooter G. Mechanism of increased dissolution of diazepam and temazepam from polyethylene glycol 6000 solid dispersions.Int J Pharm. 2002;249:45–58.
Hirasawa N, Ishise S, Miyata H. An attempt to stabilize nivaldipine solid dispersion by the use of ternary systems.Drug Dev Ind Pharm. 2003;29:997–1004.
Karavas E, Ktistis G, Xenakis A, Georgarakis E. Miscibility behavior and formation mechanism of stabilized felodipine-polyvinylpyrrolidone amorphous solid dispersions.Drug Dev Ind Pharm. 2005;31:473–489.
Hirasawa N, Danij K, Haruna M, Otsuka A. Physicochemical characterization and drug release studies of naproxen solid dispersions using lactose as a carrier.Chem Pharm Bull (Tokyo). 1998;46: 1027–1030.
Zheng Y, Haworth IS, Zuo Z, Chow MS, Chow AH. Physicochemical and structural characterization of Quercetin-β-Cyclodextrin complexes.J Pharm Sci. 2005;94:1079–1089.
Rawat S, Jain SK. Rofecoxib-beta-cyclodextrin inclusion complex for solubility enhancement.Pharmazie. 2003;58:639–641.
Okimoto K, Miyake M, Ibuki R, Yasumura M, Ohnishi N, Nakai T. Dissolution mechanism and rate of solid dispersion particles of nivaldipine with hydroxypropylmethylcellulose.Int J Pharm. 1997;159:85–93.
Chutimaworapan S, Ritthidej GC, Yonemochi E, Oguchi T, Yamamoto K. Effect of water soluble carriers on dissolution characteristics of nifedipine solid dispersions.Drug Dev Ind Pharm. 2000;26:1141–1150.
Chen Y, Zhang G, Neilly J, Marsh K, Mawhinney D, Sanzgiri Y. Enhancing the bioavailability of ABT-963 using solid dispersion containing Pluronic F-68.Int J Pharm. 2004;286:69–80.
Mehta K, Kislalioglu S, Phuapradit W, Malick W, Shah N. Multi-unit controlled release systems of Nifedipine and Nifedipine:Pluronic F-68 solid dispersions: characterization of release mechanisms.Drug Dev Ind Pharm. 2002;28:275–285.
Schmolks IR. Poloxamers in controlled drug delivery. In: Tarcha PJ, ed.Polymers for Controlled Drug Delivery. Boca Raton, FL: CRC Press; 2000:189–214.
Seo A, Holm P, Kristensen HG, Schaefer T. The preparation of agglomerates containing solid dispersions of diazepam by melt agglomeration in a high shear mixer.Int J Pharm. 2003;259:161–171.
Saettone MF, Giannacini B, Delmonte G, Campigli V, Tota G, La Marca F. Solubilization of tropicamide by poloxamers:physicochemical data and activity data in rabbits and humans.Int J Pharm. 1988;43:67–76.
Passerini N, Albertini B, Gonzalez-Rodriguez ML, Cavallari C, Rodriguez L. Preparation and characterization of ibuprofen-poloxamer 188 granules obtained by melt granulation.Eur J Pharm Sci. 2002;15:71–78.
Kwon GS. Polymeric micelles for delivery of poorly water-soluble compounds.Crit Rev Ther Drug Carrier Syst. 2003;20:357–403.
Yong CS, Yang CH, Rhee JD, et al. Enhanced rectal bioavailability of ibuprofen in rats by poloxamer 188 and menthol.Int J Pharm. 2004;269:169–176.
Merck & Go, Inc. Vioxx (Rofecoxib tablets and oral suspension). In: Walsh P, ed.Physicians Desk Reference. 57th ed. Montvale, NJ: Thomson-PDR; 2003:2120–2125.
Mukherjee D, Nissen SE, Topol E. Risk of cardiovascular events associated with selective COX-2 inhibitors.JAMA. 2001;286:954–959.
Chavanpatil M, Dawre FD, Shakleya DS, Vavia PR. Enhancement of oral bioavailability of Rofecoxib using β-Cyclodextrin.J Incl Pheno Macro Chem. 2002;44:145–149.
Bolton S, Charles S.Pharmaceutical Statistics. New York, NY: Marcel Dekker Inc; 2004.
Franz RM, Browne JE, Lewis AR. Experiment design, modeling and optimization strategies for product and process development. In: Libermann HA, Reiger MM, Banker GS, eds.Pharmaceutical Dosage Forms: Disperse Systems. vol. 1. New York, NY: Marcel Dekker Inc; 1988:427–519.
Kapsi SG, Ayers JW. Processing factors in development of solid solution formulation of itraconazole for enhancement of drug dissolution and bioavailability.Int J Pharm. 2001;229:193–203.
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Published: April 13, 2007
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Shah, T.J., Amin, A.F., Parikh, J.R. et al. Process optimization and characterization of poloxamer solid dispersions of a poorly water-soluble drug. AAPS PharmSciTech 8, 29 (2007). https://doi.org/10.1208/pt0802029
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DOI: https://doi.org/10.1208/pt0802029