Structure elucidation and risk assessment of degradation products in gamma irradiated rubber closures

Abstract

Gamma-ray irradiation has been widely applied in large-scale industrial pharmaceutical packages sterilization however, high-energy rays may result in degradation of packaging materials comprising polymers and additives. These degradation products (DPs) can migrate into drugs, reducing their efficacy and safety. Therefore, a holistic study about structure elucidation and toxicity assessment of DPs is necessary. In this work, the effect of γ irradiation on rubber closures and additives was investigated by supercritical fluid extraction (SFE) coupled with UHPLC-QTOF MS and GC-MS. Comprehensive DPs were screened and identified by high-resolution mass spectrum and the potential degradation way was proposed. However, as there is no standard present for these DPs, Density-functional theory (DFT) was incorporated to verify degradation way and their structures by analyzing energy barriers and thermodynamic parameters. The initial step of the degradation mechanism was determined and structures and intensity difference of isomers were validated to be consistent experimentally and theoretically. Then based on toxicity prediction consistency by three (Q)SAR tools, the risk of DPs was evaluated and most DPs were negative for carcinogenicity and mutagenicity but positive for developmental toxicity. 7,9-di-tert-butyl-1-oxaspiro [4,5] deca-6,9-dien-2,8-dione was predicted to be carcinogenic in consensus which should be focused on in the further leachable study. Finally, risk assessment in the simulated lyophilized drug showed that exposure of all DPs was within the threshold. The present work addresses the structure elucidation of DPs, especially Irganox 1076, and helps to access a deeper insight into the safety evaluation of rubber closures with more confidence.