Radiochemical Modeling of Gamma Sterilization Risk in ACE Inhibitors Using Chromatographic and Monte Carlo Parameters

Gamma irradiation presents a significant challenge for chemically labile pharmaceuticals due to the risk of degradation and reduced efficacy. This study introduces a novel dual-index framework to quantitatively assess the gamma sterilization risk of three ACE inhibitors (benazepril, quinapril and cilazapril) by integrating chromatographic degradation data with Monte Carlo-based radiation interaction metrics. Forced degradation experiments were conducted under acidic, basic, oxidative, photolytic, and thermal conditions, and degradation behavior was evaluated using reverse-phase liquid chromatography (RPLC). Based on normalized degradation profiles a compound-specific Chemical Fragility Index (CFI) was determined with cilazapril showing the highest fragility (CFI = 0.572), followed by quinapril (0.539) and benazepril (0.081).Monte Carlo simulations (MCNPX v2.7.0) were used to compute key gamma interaction parameters (kerma, dose rate, effective atomic number, and energy absorption buildup factor) at 1.25 MeV, leading to the development of the Physics Energy Deposition Index (PEDI). Benazepril exhibited the highest energy deposition potential, while cilazapril showed minimal interaction. By combining CFI and PEDI a unified Radiosterilization Risk Score (RRS) was derived, identifying quinapril as the most vulnerable compound, followed by benazepril and cilazapril.This integrated methodology is the first to quantitatively link chromatographic degradation behavior with radiation physics, offering a predictive and transferable tool for early-stage sterilization compatibility screening across pharmaceutical classes. The CFI–PEDI–RRS framework supports rational sterilization strategy development while reducing reliance on destructive testing.