Effects of Ionizing Radiations on the Stability of Selected Drugs and their Formulations

Abstract

Efficacious pharmaceuticals with adequate shelf life are essential for the well-being of humans, equally on the Earth and in the space. Space medical records outline the cases of reduced pharmaceutical efficacy during several space missions. One of the possible reasons could be the physicochemical instability of pharmaceuticals in the presence of the space environment, which could result in reduced potency, efficacy and safety of the drug. Space is brimming with different types of radiations, which penetrate inside the spacecraft despite the shielding material. Such radiations can alter the stability of pharmaceuticals during long duration space missions. The literature reporting the space radiation effects on the pharmaceuticals is scarce in a public domain. Right now, the medicines from the International Space Station are replaced before their expiration. For longer duration missions to Mars or to any other asteroid, there will not be any chance of replacement of medicines. Hence, it is desired that medicines maintain their shelf-life throughout the space mission. The systematic real-time stability studies in a space radiation environment are challenging owing to restricted space/volume and difficulty in reimbursement. The ground-based simulation studies can be useful to predict the influence of space radiations on the stability of the pharmaceuticals. Based upon these facts, the main objective of the present preliminary work was to investigate the effect of different types of ionizing radiations on the stability of diclofenac, ciprofloxacin, metoprolol and amlodipine API and their marketed formulations such as tablets, eye/ear drops, injections. The samples were irradiated by protons, neutrons (thermal and fast), gamma and heavy ion (56Fe) radiations with their different doses. The samples were also irradiated with UV-visible radiation to compare the effect of selected ionizing radiations with photodegradation. The physical stability was examined through organoleptic evaluation and the chemical stability was evaluated by FTIR and HPLC. Significant colour changes were observed in drugs/formulations after proton, gamma and UV-visible irradiations. FTIR spectra of control and irradiated drugs were in full agreement with each other and there were no changes in the characteristic absorption bands except in amlodipine. Wherein, the FTIR spectrum of proton irradiated amlodipine API showed one additional absorption band at 1728 cm-1 due to the presence of radiolytic products. The HPLC analysis revealed that the proton irradiated diclofenac, ciprofloxacin, metoprolol and amlodipine API degraded up to 17.47, 6.81, 13.57 and 10.53%, respectively. Whereas, gamma irradiated diclofenac, ciprofloxacin, metoprolol and amlodipine API aqueous solution showed up to 6.40, 6.67, 0.50 and 21.23% drug degradation, respectively. The HPLC chromatograms for the proton irradiated diclofenac, ciprofloxacin, metoprolol and amlodipine tablets exhibited up to 0.90, 0.11, 1.32 and 0.97% total radiolytic products, respectively. Gamma irradiated diclofenac injections showed 0.20% radiolytic products whereas gamma irradiated ciprofloxacin injections and drops exhibited 3.71 and 2.13% degradation, respectively. No physical or chemical changes were observed after neutron and 56Fe irradiation. The radiolytic profiles for proton irradiated and gamma irradiated samples were compared with photodegraded samples to identify the presence of radiation generated unique degradation products. This comparison showed that a few impurities were new and not observed in photodegraded samples. Further, the structures of major radiolytic products of amlodipine were elucidated using LC-MS/MS. Two new impurities were found in the amlodipine API aqueous solution as a result of gamma irradiation. The drug degradation pathways were postulated by proposing the plausible mechanism of formation. The results of the present study are important to report as they provide evidence that ionizing radiation exposure can lead to drug degradation. However, more systematic studies are essential using large numbers of drugs and even higher energy of radiations in order to predict the space radiation impact on the drugs. The study can be useful to select appropriate steps to maintain drug stability before future long duration space missions