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

Abstract

Literature about sterilization of pharmaceutical substances is limited. The aim of this study was to evaluate the effect of nitrogen dioxide (NO₂) sterilization, a new emerging technology, on five different ophthalmic active pharmaceutical ingredients, i.e., tetracycline hydrochloride, aciclovir, dexamethasone, methylprednisolone, and triamcinolone. The NO₂ 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 NO₂ concentration. The maximum permissible NO₂ 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 NO₂ 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 NO₂ concentration and relative contents were not significantly affected. Sterilization of tetracycline hydrochloride and aciclovir with NO₂ is not recommended due to extensive degradation. NO₂ sterilization of methylprednisolone, dexamethasone, and triamcinolone could find its application within the aseptic processing procedure of related pharmaceuticals.