Mechanism for the Degradation of Erythromycin A and Erythromycin A 2'-Ethyl Succinate in Acidic Aqueous Solution

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• 作者：Abdolreza Hassanzadeh ; Jill Barber ; Gareth A. Morris ; Peter A. Gorry
• 刊名：Journal of Physical Chemistry A
• 出版年：2007
• 出版时间：October 11, 2007
• 年：2007
• 卷：111
• 期：40
• 页码：10098 - 10104
• 全文大小：181K
• 年卷期：v.111,no.40(October 11, 2007)
• ISSN：1520-5215

文摘

A major drawback of the antibiotic erythromycin A is its extreme acid sensitivity, leading to rapid inactivationin the stomach. The accepted model for degradation in aqueous acidic solution has erythromycin A inequilibrium with erythromycin A enol ether and degrading to anhydroerythromycin A. We report a detailedkinetic study of the acidic degradation of erythromycin A and of erythromycin A 2'-ethyl succinate (themarket-leading pediatric prodrug), investigating the reaction rates and degradation products via NMR. Thisreveals that the accepted mechanism is incorrect and that both the enol ether and the anhydride are in equilibriumwith the parent erythromycin. By implication, both the anhydride and enol ether are antibacterially inactivereservoirs for the parent erythromycin. The actual degradation pathway is the slow loss of cladinose fromerythromycin A (or erythromycin A 2'-ethyl succinate), which is reported here for the first time in a kineticstudy. The kinetic analysis is based on global, nonlinear, simultaneous least-squares fitting of time courseconcentrations for all species across multiple datasets to integrated rate expressions, to provide robust estimatesof the rate constants.