Comparison of the acid stability of azithromycin and erythromycin A.
In acidic aqueous media, erythromycin A is rapidly degraded via intramolecular dehydration to form erythromycin-6.9-hemiketal and then anhydroerythromycin, both of which possess little antimicrobial activity. Azithromycin, a new azalide antibiotic, has a methyl-substituted nitrogen in place of the carbonyl at the 9a position of the aglycone ring, thus blocking the internal dehydration pathway. As a result, azithromycin decomposition occurs primarily via acid-catalysed hydrolysis of the ether bond to the neutral cladinose sugar. Rate constants and the time for 10% decay (T1/10) were determined for both azithromycin and erythromycin A at pH2 using various levels of acetonitrile cosolvent and constant ionic strength. Semi-log plots of the decay rate constants versus the reciprocal of the solution dielectric constants were used to extrapolate to totally aqueous conditions. In solution at 37 degrees C and pH2 with ionic strength mu = 0.02, azithromycin was degraded with a T1/10 of 20.1 min while erythromycin underwent 10% decay in only 3.7 sec. The activation energy for hydrolysis of the ether bond connecting cladinose to azithromycin was 25.3 kcal/mol while the internal dehydration reaction of erythromycin had an activation energy of 15.6 kcal/mol. A solution stability profile was generated for azithromycin over the pH range of 1.0 to 4.1 at 30 degrees C. Stability was found to improve ten-fold for each unit increase in pH.
Fiese
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Central Research Division, Pfizer Inc. Groton, CT 06340.
Steffen
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D000097:Acetonitriles / Q000493:pharmacokinetics; D017963:Azithromycin; D002851:Chromatography, High Pressure Liquid; D004355:Drug Stability; D004917:Erythromycin / Q000031:analogs & derivatives* / Q000493:pharmacokinetics*; D006863:Hydrogen-Ion Concentration; D006868:Hydrolysis
D000097:Acetonitriles; D004917:Erythromycin; D017963:Azithromycin