Quantification of Trace Levels of Active Oxygen in Pharmaceutical Excipients

Abstract

Pharmaceutical drug products contain various excipients in combination with the active pharmaceutical ingredient (API), and those excipients have the potential to have as impurities reactive oxygen species that can react directly with the API and lead to oxidative degradation. Such degradation can impact long-term stability of the drug product, reduce drug product purity, limit shelf life, and increase time to market. Peroxy compounds are a common class of such reactive impurities, but there is an absence in the literature of a method for detection of total peroxide level in pharmaceutical excipients when the identity of the peroxy contaminant is not known. In this thesis, novel modifications were made to the 1966 ASTM E 299-08 method for enhanced and robust detection of active oxygen in pharmaceutical excipients. The modified ASTM E 299-08 method was evaluated using spiked solutions of hydrogen peroxide, a hydroperoxide compound, and a peroxide compound. Liquid and solid excipients were then evaluated for active oxygen levels to demonstrate the utility and breadth of the modified method to cover a wide range of excipients. The polyethylene glycol (PEG) class of compounds was chosen for more in-depth evaluation due to their susceptibility to autoxidation and the existence of various molecular weight grades of PEG compounds. PEG 1000 was chosen along with lestaurtinib (CEP-701) to prepare a novel drug product, which was evaluated on stability for active oxygen and assay impurity levels. The results showed that the modified ASTM E 299-08 method successfully quantified both the total active oxygen levels and the CEP-701 peroxy impurity levels, which agreed with those obtained by an HPLC assay method. The modified ASTM E 299-08 method has important applicability in the pharmaceutical industry as a method that can be used for preliminary screening of excipients and new formulations to predict potential oxidative degradation reactions.