Radiosterilization dosimetry by electron-spin resonance spectroscopy: Cefotetan

As an alternative to heat and gas exposure sterilization, ionizing radiation is gaining interest as a sterilization process for medicinal products. Nevertheless, essentially for economic profit, unauthorized and uncontrolled use of radiation processes may be expected. In this context, it is necessary to find methods of distinguishing between irradiated and nonirradiated pharmaceuticals. In the absence of suitable detection methods, our attention was focused on electron-spin resonance (ESR) spectrometry. A third generation cephalosporin, cefotetan, was chosen as a model; this antibiotic is a potential candidate for radiation treatment due to its thermosensitivity. While the ESR spectra of a nonirradiated sample presents no signal, a nonsymmetrical signal, dependent on the irradiation dose, is found in irradiated samples. The number of free radicals was estimated by comparing the second integral from radiosterilized samples and a diphenylpicryl hydrazyl reference. Estimation of the number of free radicals gives 7×1017 radicals g−1 at 20 kGy (1.1×1016 radicals in 15 mg). From this result, the G-value (number of radicals (100 eV)−1) could be estimated as 0.6. Decay of radicals upon storage were modeled using a bi-exponential function. The limit of detection of free radicals after irradiation at 25 kGy is up to two years. This result agrees with those obtained on other cephalosporins. Aside from qualitative detection, ESR spectrometry can be used for dose estimation. Linear regression is applicable for doses lower than 20 kGy. Since the radiation dose selected must always be based upon the bioburden of the products and the degree of sterility required (EN 552 and ANSI/AAMI/ISO 11137), 25 kGy could no longer be accepted as a “routine” dose for sterilizing a pharmaceutical. Doses in the 5–20 kGy range could be investigated and linear regression appeared to be the least expensive route to follow. The best results for the integration of the curves were obtained with exponential functions.