Trial of novel solid dispersion system with improved bioavailability and stability to clopidogrel napadisilate monohydrate

Abstract

In order to enhance the bioavailability and stability of poorly aqueous soluble clopidogrel napadisilate monohydrate, solid dispersion was prepared by spray-drying via surface-attached method. Solid dispersion system was prepared with various weight ratios of clopidogrel napadisilate monohydrate/HPMC/tween 80. The dissolution of the drug in the solid dispersion was evaluated compared with drug powder at pH 1.2, pH 4.0, pH 6.8 and water. The crystallinity of the drug in solid dispersion was evaluated using SEM, PXRD and DSC. The stability of the drug in solid dispersion was estimated at 50℃/75 %RH for 6 weeks compared to clopidogrel napadisilate monohydrate and clopidogrel bisulfate. The bioavailability in rats was evaluated and compared to drug powder. The aqueous solubility of solid dispersion, possessing clopidogrel napadisilate monohydrate/HPMC/tween 80 in a weight ratio of (5:1.25:1.25), was increased 4.65-fold compared to drug powder. The dissolution rate was significantly enhanced in solid dispersion compared to drug powder. SEM, PXRD and DSC showed that crystallinity of solid dispersions was not changed to amorphous form. In stability test of these solid dispersions, hydrolyzed degradant and racemized degradant were decreased compared to clopidogrel bisulfate and drug content was not decreased compared to clpidogrel napadisilate monohydrate in spite of increased water content due to HPMC. The bioavailability of the drug in rat was significantly enhanced with solid dispersion as AUC and Cmax became higher. Thus, the clopidogrel napadisilate monohydrate loaded-solid dispersion could be a useful system to enhance the bioavailability of poorly aqueous soluble clopidogrel napadisilate monohydrate and stability in storing for long period of time as compared to clopidogrel bisulfate.