Nitrogen dioxide sterilization of a set of five ophthalmic active pharmaceutical ingredients: Impact on impurity profile and content

Literature about sterilization of pharmaceutical substances is limited. The aim of this study was to evaluate the effect of nitrogen dioxide (NO 2 ) sterilization, a new emerging technology, on five different ophthalmic active pharmaceutical ingredients, i.e., tetracycline hydrochloride, aciclovir, dexamethasone, methylprednisolone, and triamcinolone. The NO 2 process concentrations tested were 5, 10, and 20 mg/L. The applied temperature was 21 °C and the relative humidity 30 %. The process cycle consisted of two pulses with a dwell time of 10 min each. Non-processed samples were used as a blank. The effect of the sterilization method was assessed by high performance liquid chromatography coupled to an ultraviolet/visible detector, used for the quantitative analysis of the degradation products and the relative content of the evaluated ophthalmic medicines. For tetracycline hydrochloride and aciclovir, an increase of impurities was observed by increasing the NO 2 concentration. The maximum permissible NO 2 concentrations were estimated to be 10 mg/L and 2.5 mg/L, respectively, considering the requirement for the impurities to be within the limit stated in the European Pharmacopoeia (Ph. Eur.). For both compounds, samples subjected to 20 mg/L NO 2 demonstrated a significant difference in content compared to the non-processed sample. For methylprednisolone, dexamethasone, and triamcinolone, impurities complied with the limits of the Ph. Eur. for each NO 2 concentration and relative contents were not significantly affected. Sterilization of tetracycline hydrochloride and aciclovir with NO 2 is not recommended due to extensive degradation. NO 2 sterilization of methylprednisolone, dexamethasone, and triamcinolone could find its application within the aseptic processing procedure of related pharmaceuticals. • Effect of the gas sterilant nitrogen dioxide studied on 5 ophthalmic drugs. • Content and impurity profile determined with HPLC. • Degradation of tetracycline hydrochloride and aciclovir upon nitrogen dioxide treatment. • No pronounced effect on methylprednisolone, dexamethasone and triamcinolone.