Impact of gamma irradiation and ethylene oxide sterilisation on the stability of crystalline and amorphous drug solids

Terminal sterilisation is a critical process for pharmaceutical products intended for parenteral or invasive administration, yet conventional sterilisation approaches can compromise thermolabile or chemically sensitive drug substances. In this study, the compatibility of crystalline and amorphous solid forms of five drug substances (betamethasone dipropionate (BMD), estradiol (E2), itraconazole (ITZ), vismodegib (VDG), and zolmitriptan (ZMT)) with sterilising gamma irradiation and ethylene oxide (EtO) cycles was evaluated in terms of chemical and physical stability. Physical stability was assessed by visual inspection of crystalline powders and amorphous solids pre- and post-sterilisation and by differential scanning calorimetry (DSC) to characterise the melting behaviour of crystalline drugs, and glass transition and recrystallisation events in amorphous forms. Chemical stability was examined using reverse phase-high-performance liquid chromatography (RP-HPLC), liquid chromatography-mass spectrometry (LC-MS), and proton nuclear magnetic resonance spectroscopy (¹H-NMR). Gamma irradiation and EtO preserved the chemical integrity of BMD, E2, ITZ, and VDG. A reversible colour change observed for ITZ was attributed to radical formation as confirmed by gentle heating, HPLC and LC-MS. E2 demonstrated alterations in crystallinity and thermal behaviour after sterilisation, despite maintaining chemical integrity. ZMT exhibited pronounced sensitivity to sterilisation: gamma irradiation induced physical softening and oxidative degradation, particularly in the amorphous form, while EtO sterilisation induced ZMT hydroxyethylation, as confirmed by LC-MS identification of multiple alkylated derivatives. Overall, sterilisation compatibility was governed primarily by molecular structure rather than the drug solid-state. These findings provide an insight for selecting sterilisation strategies and facilitate the translation of crystalline and amorphous pharmaceutical solids toward clinical application.

Ethylene oxide; Gamma irradiation; Physicochemical stability; Solid-state characterisation; Terminal sterilisation.