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

Abstract

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 degrade at 40 degrees C (75% relative humidity) and at 85 degrees C. The profile of degradation products formed under these conditions is qualitatively similar to the profile of degradation products observed in samples of cefaclor aged for 14 years at room temperature, although some products found in the sample degraded at 85 degrees C are not formed at the lower temperatures. Using preparative reversed-phase high-performance liquid chromatography (rp-HPLC) and a combination of spectroscopic methods, we have isolated and characterized 17 of these degradation products. Some of these products were also isolated from studies of aqueous degradations. The major products appear to have arisen from five distinct pathways: (1) isomerization of the double bond in the dihydrothiazine ring; (2) decarboxylation; (3) ring contraction of the cephem 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 oxidation at carbon 4 is particularly important at ambient temperatures and is unique to the solid-state degradation.

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

“…The recent study by Vilanova et al 24 describing a major pathway of cefaclor degradation under neutral conditions provides an excellent start to exploring these degradation pathways. The major solid-state degradation pathways described by Dorman et al 21 lead to multiple degradation products, many of which are not formed under aqueous conditions. Together, the aqueous and solid-state degradation investigations reveal some of the diverse degradation chemistry of the the cefaclor molecule.…”

Hydrates and Solid-State Reactivity: A Survey of β-Lactam Antibiotics

“…Compounds containing the b-lactam core are known to react and degrade both in aqueous solutions and in the solid-state with one of the major routes of degradation being hydrolysis of the b-lactam ring. 6,7 The solid-state stability of these materials depends heavily on the crystallinity of the compounds and the conditions under which they are stored. [8][9][10] However, the data in the literature suggest that even hydrates of b-lactams, where water is a putative reactant in degradation, can be remarkably stable in the solid-state and provide the opportunity to make products with room-temperature stability of years.…”

Forced Degradation Studies

“…But intermediate studies (6months) can be performed at conditions lesser than that used in accelerated studies. After stability studies the separation, identification and quantitation are carried out [18,19].…”