Oxidative degradation in pharmaceuticals: Mechanism and stabilization of a spray-dried amorphous drug - A case study

Abstract

Drug formulations such as spray drying are often required to improve the physicochemical properties and bioavailability of hydrophobic drugs. However, excipients often carry contaminants/ impurities and may also increase moisture levels in solid formulations, which can have detrimental effects on the drugs, including drug degradation and stability. Hence, achieving adequate shelf life of drug products has been among the most challenging issues for pharmaceuticals. Here we report a case study where we systematically studied the oxidative degradation of a pharmaceutical compound GENE-A, spray-dried and dispersed in hydroxypropyl methylcellulose-acetate succinate polymer matrix. Three different oxidative degradation products were observed, and their mechanisms of formation were investigated via forced degradation studies. Finally, we used several antioxidants based on their mechanisms of action to reduce/ prevent the drug degradation process. Propyl gallate alone and in combination with Ethylenediaminetetraacetic acid completely prevented the formation of two degradation products, whereas there was no significant impact observed on the third one. The results showed that both metal chelators and free radical terminators most effectively prevented drug degradation. This study may address some of the key issues that pharmaceutical companies encounter and offer appropriate solutions to counter the oxidative degradation process of pharmaceuticals.

Keywords: Antioxidants; Drug stability; Forced degradation; Oxidative degradation; Pharmaceuticals; Spray-dried formulations.