Improved pharmacokinetics of AMG 517 through co-crystallization part 1: Comparison of two acids with corresponding amide co-crystals

✍ Scribed by Mary K. Stanton; Ron C. Kelly; Adria Colletti; Y.-H. Kiang; Meghan Langley; Eric J. Munson; Matthew L. Peterson; John Roberts; Mary Wells

• Publisher: John Wiley and Sons
• Year: 2010
• Tongue: English
• Weight: 326 KB
• Volume: 99
• Category: Article
• ISSN: 0022-3549
• DOI: 10.1002/jps.22181

✦ Synopsis

The dissolution and pharmacokinetics (PK) of two carboxylic acid co-crystals (cinnamic acid and benzoic acid) with the corresponding amide co-crystals (cinnamamide and benzamide) of AMG 517 were investigated. Powder and intrinsic dissolution studies were performed in fasted simulated intestinal fluid (FaSIF). Suspension formulations in 1% polyvinylpyrrolidone K25 in water were administered orally at 100 mg/kg to rats. The four cocrystals were found to have faster intrinsic and powder dissolution rates in FaSIF than the free base. This correlated with a 2.4-to 7.1-fold increase in the area under the concentration-time curve in rat PK investigations. When contrasting the acid to its corresponding amide co-crystal, cinnamamide shows improvement over cinnamic acid, while benzamide and benzoic acid perform similarly.