The kinetics of the alkaline degradation of daptomycin

• Published in: Journal of pharmaceutical sciences Vol. 90; no. 8; pp. 1066 - 1075
• Main Authors: Muangsiri, Walaisiri, Kirsch, Lee E.
• Format: Journal Article
• Language: English
• Published: New York Elsevier Inc 01.08.2001; John Wiley & Sons, Inc; Wiley; American Pharmaceutical Association
• Subjects: Alkalies - chemistry; Anti-Bacterial Agents - chemistry; Antibacterial agents; Antibiotics. Antiinfectious agents. Antiparasitic agents; Biological and medical sciences; Buffers; Chromatography, High Pressure Liquid; daptomycin; Daptomycin - chemistry; drug stability; ester hydrolysis; General pharmacology; Hydrogen-Ion Concentration; Hydrolysis; Kinetics; lipopeptide antibiotic; Medical sciences; peptide degradation pathway; pH-rate profile; Pharmacology. Drug treatments; Physicochemical properties. Structure-activity relationships; Salts; Solutions; Surface Tension; Temperature; Water; daptomycin; ester hydrolysis; pH–rate profile; lipopeptide antibiotic; peptide degradation pathway; drug stability; Degradation; Hydrolysis; Ester; Antibiotic; Stability; Salt effect; Daptomycin; Temperature effect; pH; Surface tension; Degradation product; Physicochemical properties
• ISSN: 0022-3549; 1520-6017
• DOI: 10.1002/jps.1060

The aqueous degradation of daptomycin, a lipopeptide antibiotic, was investigated as a function of substrate concentration (0.5–10.0 mM), pH (9.0–10.5), buffer concentration (0.06–0.20 M borate, glycinate, or carbonate buffers), temperature (20–50°C), and ionic strength (0.1–0.8). The primary degradation pathway was determined by electrospray‐mass spectroscopy (ES‐MS), Fourier transform infrared (FTIR), and fluorescence spectroscopy to be hydrolysis of the ester linkage between the C‐terminus (kynurenine) and the side chain of the fourth residue (threonine). The reaction was first order with respect to time; however, the reaction order with respect to substrate concentration was <1 at substrate concentrations >1 mM. Insignificant buffer effect was observed. The reaction was subject to specific base catalysis. Activation parameters were Ea = 13.6 kcal/K·mol, ΔH‡ = 13.0 kcal/K·mol, and ΔS‡ = −19.2 eu. The positive primary salt effect was observed with negative deviation at high concentration of salt. The magnitude of the salt effect depended on salt identities in the order sodium < potassium < calcium chloride. © 2001 Wiley‐Liss, Inc. and the American Pharmaceutical Association J Pharm Sci 90:1066–1075, 2001