The possible dimerization of penicillins both with and without amino groups in the C-6 side chain were analyzed theoretically and experimentally.
2.
Four different dimerization pathways were simulated via computational chemistry, and the dominant dimerization reaction was identified.
3.
The theoretical results were verified by liquid chromatograph-mass spectrometry(LC-MS)analysis.
4.
The understanding of penicillin dimerization mechanism facilitates analyses of polymers in samples and possible discovery of dominant polymers.
Abstract
Penicillins are one type of the most important antibiotics used in the clinic. Control of drug impurity profiles is an important part of ensuring drug safety. This is particularly important in penicillins where polymerization can lead to polymers as elicitors of passive cutaneous anaphylaxis. The current understanding of penicillin polymerization is based on reactions with amino groups, but no comprehensive mechanistic understanding has been reported. Here, we used theoretical calculations and column switching - LC/MS techniques to study penicillin dimerization. Ampicillin and benzylpenicillin were selected as representative penicillins with or without amino groups in the side chain, respectively. We identified four pathways by which this may occur and the energy barrier graphs of each reaction process were given. For benzylpenicillin without an amino group in the 6-side chain, dimerization mode A is the dominant mode, where the 2-carboxyl group of one molecule reacts with the β-lactam of another molecule. However, ampicillin with an amino group in the 6-side chain favors dimerization mode C, where the amino group of one molecule attacks the β-lactam of another molecule. These findings can lead to a polymer control approach to maintaining penicillin antibiotics in an active formulation.
