Improved Pharmacokinetics of AMG 517 Through Co-Crystallization Part 1: Comparison of Two Acids With Corresponding Amide Co-crystals

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 flui...

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Published in:Journal of pharmaceutical sciences 2010-09, Vol.99 (9), p.3769-3778
Main Authors: Stanton, Mary K., Kelly, Ron C., Colletti, Adria, Kiang, Y.-H., Langley, Meghan, Munson, Eric J., Peterson, Matthew L., Roberts, John, Wells, Mary
Format: Article
Language:English
Subjects:
Animals
Benzamides - chemistry
Benzoic Acid - chemistry
Benzothiazoles - chemistry
Benzothiazoles - pharmacokinetics
Biological and medical sciences
Cinnamates - chemistry
co-crystals
Crystallization
Crystallography, X-Ray
dissolution
General pharmacology
Male
Medical sciences
Pharmaceutical technology. Pharmaceutical industry
pharmacokinetics
Pharmacology. Drug treatments
Pyrimidines - chemistry
Pyrimidines - pharmacokinetics
Rats
Rats, Sprague-Dawley
Solubility
TRPV Cation Channels - antagonists & inhibitors
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Summary: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 100mg/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. © 2009 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci 99:3769–3778, 2010
ISSN:0022-3549
1520-6017
DOI:10.1002/jps.22181