ISOLATION AND STRUCTURE ELUCIDATION OF THE MAJOR DEGRADATION PRODUCTSOF CEFACLOR IN THE SOLID-STATE

Cefaclor is a beta-lactam antibiotic that degrades slowly under normal storage conditions to several minor products. To obtain samples large enough to permit structure elucidation, cefaclor was allowed to degra de at 40 degrees C (75% relative humidity) and at 85 degrees C. The pr ofile of degradation products formed under these conditions is qualita tively similar to the profile of degradation products observed in samp les of cefaclor aged for 14 years at room temperature, although some p roducts found in the sample degraded at 85 degrees C are not formed at the lower temperatures. Using preparative reversed-phase high-perform ance liquid chromatography (rp-HPLC) and a combination of spectroscopi c methods, we have isolated and characterized 17 of these degradation products. Some of these products were also isolated from studies of aq ueous degradations. The major products appear to have arisen from five distinct pathways: (1) isomerization of the double bond in the dihydr othiazine ring; (2) decarboxylatlon; (3) ring contraction of the cephe m nucleus to thiazole structures; (4) oxidative attack at carbon 4 of the dihydrothiazine ring; and (5) intramolecular attack of the primary amine of the side chain on either the beta-lactam carbonyl to form 3- phenyl-2,5-diketopiperazines or the ''masked aldehyde'' at carbon 6 to form 2-hydroxy-3-phenylpyrazine derivatives. The pathway involving ox idation at carbon 4 is particularly important at ambient temperatures and is unique to the solid-state degradation.