Isolation and Structure Elucidation of the Major Degradation Products of Cefaclor Formed Under Aqueous Acidic Conditions

Abstract

The aqueous acidic degradation of the oral cephalosporin cefaclor was investigated. A number of degradation products were isolated and characterized. The degradation products can be loosely classified into three categories: thiazole derivatives, pyrazine derivatives, and simple hydrolysis or rearrangement products. Degradation pathways are proposed that involve (1) hydrolysis of the beta-lactam carbonyl with subsequent rearrangement, (2) ring contraction of the six-membered cephem nucleus to five-membered thiazole derivatives through an episulfonium ion intermediate, and (3) attack of the primary amine of the phenylglycyl side chain on the "masked aldehyde" at carbon-6 to form fluorescent substituted pyrazines.

Isolation and Structure Elucidation of the Major Degradation Products of Cefaclor in the Solid State

“…Other characteristics of thiazole, pyrazine, and other substructures are described in our accompanying paper. 2 Among the products of the present degradation, however, were seven compounds in which the fundamental structure of the parent antibiotic survived. In five of these compounds, the -lactam was intact, as shown by the presence of a peak near 1770 cm -1 in the infrared (IR) spectrum.…”

“…Two of these (3 and 13) were previously isolated from acidic degradations. 2 Spectroscopic data for these compounds are presented in Table 2.…”

“…Cefaclor degrades under aqueous conditions to many compounds, some of which have been characterized and found to arise from only a few distinct pathways. 1,2 The degradation pathways of cefaclor in the solid state might be expected to differ from those observed in solution, but these pathways have not yet been delineated.…”

“…Many of the peaks with retention times of 42 to 55 min are associated with UV spectra characteristic of substituted 2-hydroxy-3-phenylpyrazines. 2 Thus, the formation of substituted pyrazines that occurs under acidic aqueous conditions also occurs during solid-state degradation, although to a much smaller extent. Analysis of the chromatograms and UV spectra revealed that most of the degradation products present in the sample of cefaclor stressed at 40°C and 75% RH and in the sample aged at room temperature for 14 years are present in the 85°C-stressed sample.…”

A critical review on the use of modern sophisticated hyphenated tools in the characterization of impurities and degradation products

“…There are series of papers by Görög et al involving characterization of IMPs of a number of drug molecules [66][67][68][69]. Baertschi et al reported degradation behavior of cefaclor in multiple papers [70][71][72], highlighting the use of conventional approach in the characterization of almost 30 DPs of the drug. The authors employed in silico prediction using GENOA software, literature support and data generated from UV, mass, and NMR studies to assign structures to this large number of DPs.…”