Discussion on the dimerization reaction of penicillin antibiotics.

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 ß-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 ß-lactam of another molecule. These findings can lead to a polymer control approach to maintaining penicillin antibiotics in an active formulation.

Discussion on the dimerization reaction of penicillin antibiotics / 药物分析学报

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 under-standing 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.

Simple Fluorescence Assay for Triethylamine Based on the Palladium Catalytic Dimerization of Benzofuran-2-boronic Acid.

Although benzofuran-2-boronic acid hardly emits fluorescence, it can be rapidly converted to a highly fluorescent benzofuran dimer after mixing with a palladium catalyst and amine. We found that a fluorescence enhancement accompanying dimerization was quantitatively promoted upon increasing the concentration of amine. In the present study, we developed a simple fluorescence assay for amines based on the promotive effect. As the result of a fluorescence measurement of the reaction mixture of 19 kinds of typical amines, it was found that tertiary amines including triethylamine (TEA) provided a significant fluorescence enhancement. Finally, the fluorogenic reaction could be applied to develop a high-throughput fluorescent microplate assay for TEA with the limit of detection (blank + 3SD) of 0.091 µM.