Integrating quantum chemical descriptors and Monte Carlo simulations for analytical quality assurance of...

The sterilization of antineoplastic agents remains a critical challenge due to the high sensitivity of active pharmaceutical ingredients (APIs) to ionizing radiation. This study proposes a virtual validation protocol (VVP)-introduced here as a conceptual, computational screening framework rather than a regulatory recognized validation procedure-intended to support analytical quality assurance by prioritizing and guiding experimental stability testing rather than replacing it, thereby reducing the reliance on extensive trial-and-error laboratory work. Obtained results identify mercaptopurine as a significant outlier due to the "trap effect" induced by its sulfur-containing structure (Z_eff  = 14.20 at 0.015 MeV), which causes rapid radiation reducing. In line with the ISO 11137 dose homogeneity principle (± 10% acceptance criterion), a computationally derived packaging-thickness threshold of 1.80 mm is predicted for mercaptopurine, subject to experimental confirmation. In contrast, compounds with lower effective atomic numbers, such as capecitabine, permit greater packaging flexibility, with thickness limits up to 3.80 mm. Additionally, the projected adiabatic temperature rise remains below 37 °C in all cases, well beneath the thresholds of conventional thermal sterilization, indicating that the process avoids thermal degradation and can be regarded as a "cold" process in the thermal sense. This thermal finding concerns heat-induced damage only; preservation of chemical integrity against direct radiolysis is a separate question that requires experimental confirmation. This approach provides a sustainable, cost-effective, and non-destructive roadmap for pharmaceutical quality control.

The protocol integrates density functional theory (DFT) and Monte Carlo (MCNPX) simulations. Molecular structures were optimized at the ωB97XD/def2TZVP level to determine spectroscopic behaviors and evaluate chemical reactivity through HOMO-LUMO energy gaps. Simultaneously, radiation interaction parameters were modeled across a 0.015-15 MeV energy range and validated against theoretical XCOM data.