Oxygen-Dependent Accelerated Stability Modeling of Drug Products.

Abstract

A new formalism for accelerating the determination of shelf life with respect to temperature, relative humidity (when applicable), and oxygen concentration is proposed and exemplified for liquid sesame oil and formulated tablets of chlorpromazine. An oxygen-sensitivity parameter, C, is added to the moisture-modified Arrhenius equation with the reference condition being the atmospheric oxygen level (21% O₂). The resultant modified Arrhenius equation is used in conjunction with isoconversion, where rate determinations are focused only on the behavior to a specification limit. With sesame oil oxidation, peroxides are generated showing temperature and oxygen concentration terms that are independent of each other with a C term of approximately one. With chlorpromazine tablets, an N-oxide and a sulfoxide are formed with nonlinear kinetics. The degradant growth dependencies on temperature, relative humidity, and percent oxygen were found to be independent and consistent with the proposed moisture and oxygen-modified Arrhenius equation with C terms less than one. This inefficiency in oxidation suggests that indirect oxidation occurs, implicating the formation of reactive oxygen species in the reaction process. The models are in good agreement with real-time data for both case studies.