Degradation Kinetics and Isomerization of Cefdinir, a New Oral Cephalosporin, in Aqueous Solution. 2. Hydrolytic Degradation Pathway and Mechanism for β-Lactam Ring Opened Lactones

Hydrolysis of cefdinir leads to pH-dependent isomerizations and beta-lactam ring-opening. Lactam ring opened gamma-lactones were produced as a mixture of four diastereoisomers based on the lactone methyl, and C-6 isomerizations in acidic to neutral solutions. Cefdinir and its 7-epimer were hydrolyzed to clarify the pathway leading to these lactones and the mechanism of C-6 epimerization with the aid of chiral separation techniques. Chiral separation using a bovine serum albumin column was employed to detect the beta-lactam ring opened products of cefdinir and its 7-epimer; the C-6 and C-7 isomerization was thereby observed; however, it was found to be pH-dependent at pH > or = 9. Optical activity detection applied to the lactones produced from cefdinir and its 7-epimer demonstrated that the corresponding peaks of these lactones were enantiomeric pairs. In addition, the smallest rate constant at pH 4 was observed for C-6 epimerization of the lactones, and it was found to proceed without deprotonation at C-6 by 1H-NMR spectroscopy. From the results of these studies, a plausible mechanism for C-6 epimerization has been proposed. Additionally, it was confirmed that two degradation pathways were involved during hydrolysis of cefdinir to the lactone.