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.

青霉素是临床上最重要的抗生素之一。药物杂质谱的控制是确保药物安全的重要组成部分。这在青霉素中尤为重要，其中聚合可导致聚合物作为被动皮肤过敏反应的引发剂。目前对青霉素聚合的理解是基于与氨基的反应，但尚未报道全面的机理理解。在这里，我们使用理论计算和色谱柱切换 - LC/MS 技术来研究青霉素二聚化。分别选择氨苄青霉素和苄青霉素作为侧链有或没有氨基的代表性青霉素。我们确定了可能发生这种情况的四种途径，并给出了每个反应过程的能垒图。对于 6 侧链中没有氨基的苄青霉素，二聚模式 A 是主要模式，其中一个分子的 2-羧基与另一个分子的 β-内酰胺反应。然而，在 6 侧链中具有氨基的氨苄青霉素有利于二聚化模式 C，其中一个分子的氨基攻击另一个分子的 β-内酰胺。这些发现可以导致一种聚合物控制方法来维持活性制剂中的青霉素抗生素。