Comparative stability of cephalosporins in aqueous solution: Kinetics and mechanisms of degradation

Abstract

The acidic, neutral, and alkaline degradations of six therapeutically useful cephalosporins (cephalothin, cephaloridine, cephaloglycin, cephalexin, cephradine, and cefazolin), 7‐aminocephalosporanic acid, 7‐aminodeacetoxycephalosporanic acid, and some 7‐substituted derivatives were followed by high‐pressure liquid chromatographic, UV spectrometric, iodometric, and hydroxamic acid assays. The pH‐rate profiles were determined at 35° and μ = 0.5. The acidic degradation pathway for the 3‐acetoxymethyl and 3‐pyridinylmethyl derivatives was the specific hydrogenion‐catalyzed hydrolysis of the β‐lactam bonds. The β‐lactam hydrolyses of these antibiotics exhibited half‐lives of about 25 hr at pH 1.0 and 35°. The acetyl functions of 3‐acetoxymethylcephalosporins were hydrolyzed eight times faster than their β‐lactam moieties to yield the corresponding deacetyl intermediates, which were rapidly converted to the lactones. Deacetoxycephalosporins were fairly acid stable; e.g., cephalexin and cephradine were about 25 times more stable than cephalothin, cephaloridine, and cephaloglycin and about 180 times more stable than ampicillin at pH 1.0. In the neutral degradation of 3‐acetoxymethyl compounds, the competitive reactions of the direct water attack and intramolecular catalysis by the side‐chain amido upon the β‐lactams were proposed. The pH‐rate profiles near pH 8 for cephaloglycin, cephalexin, and cephradine could be explained by the intramolecular‐nucleophilic attack of the side‐chain α‐amino group upon the β‐lactam carbonyls to produce diketopiperazine‐type compounds. The reactivity of the cephalosporins in the hydroxideion‐catalyzed degradation was influenced significantly by the C‐3 methylene substituents. Copyright © 1976 Wiley‐Liss, Inc., A Wiley Company