New clopidogrel napadisilate salt and its solid dispersion with improved stability and bioequivalence to the commercial clopidogrel bisulphate salt in beagle dogs

• Published in: International journal of pharmaceutics 2011-08, Vol.415 (1), p.129-139
• Main Authors: Kim, Yong-Il, Kim, Kyung Soo, Suh, Kwee-Hyun, Shanmugam, Srinivasan, Woo, Jong Soo, Yong, Chul Soon, Choi, Han-Gon
• Format: Article
• Language: English
• Subjects: Administration, Oral; Animals; Beagle; Bioavailability; Bioequivalence; Biological and medical sciences; Biological Availability; Chromatography, High Pressure Liquid; Clopidogrel napadisilate; Crystallization; Dogs; Drug Compounding; Drug Stability; drugs; General pharmacology; Male; Medical sciences; Molecular Structure; Pharmaceutical technology. Pharmaceutical industry; Pharmacology. Drug treatments; Platelet Aggregation Inhibitors - blood; Platelet Aggregation Inhibitors - chemistry; Platelet Aggregation Inhibitors - pharmacokinetics; Powder Diffraction; silica; Solid dispersion; Solubility; spray drying; Stability; Tablets; Tandem Mass Spectrometry; Therapeutic Equivalency; Ticlopidine - analogs & derivatives; Ticlopidine - blood; Ticlopidine - chemistry; Ticlopidine - pharmacokinetics; X-Ray Diffraction
• ISSN: 0378-5173; 1873-3476
• DOI: 10.1016/j.ijpharm.2011.05.059

Stability (A) and pharmacokinetics (B and C) of clopidogrel bisulphate (commercial salt) and clopidogrel napadisilate-loaded solid dispersion; (B) clopidogrel; (C) SR26334. The purpose of this study was to develop a novel clopidogrel napadisilate-loaded solid dispersion with improved stability and bioequivalence to the clopidogrel bisulphate-loaded commercial product. Clopidogrel napadisilate prepared in this study appeared as a white crystalline powder unlike clopidogrel base. However, this salt did not improve the solubility of clopidogrel, even with improved stability compared to clopidogrel bisulphate. To improve the solubility of clopidogrel napadisilate, a novel clopidogrel napadisilate-loaded solid dispersion was prepared by the spray-drying technique using HPMC and colloidal silica, and the physicochemical properties, dissolution and bioavailability in beagle dogs were evaluated compared to the clopidogrel bisulphate-loaded commercial product. The solid dispersion composed of clopidogrel napadisilate, HPMC and colloidal silica at a weight ratio of 11.069/3/3.5 improved solubility by 6.5-fold compared to clopidogrel napadisilate, even if it did not improve drug solubility compared to clopidogrel bisulphate. However, unlike clopidogrel bisulphate, this formulation improved the stability of clopidogrel. Furthermore, the clopidogrel napadisilate solid dispersion-loaded tablet showed similar dissolution to the clopidogrel bisulphate-loaded commercial product and was bioequivalent to the commercial product in beagle dogs. Thus, this clopidogrel napadisilate-loaded solid dispersion could be a promising candidate for improving the stability and bioavailability of clopidogrel.