Understanding of cabotegravir degradation through isolation and characterization of key degradation products and kinetic studies

Abstract

Cabotegravir is a novel human immunodeficiency virus integrase enzyme inhibitor used for prevention and treatment of HIV infection. The combinational final dosage form, as extended release injection suspension in combination with rilpivirine and as cabotegravir tablets (for lead-in therapy), was recently approved in Canada, EU and in USA and is currently seeking approval also in other countries. The subject of this investigation was to study the degradation of cabotegravir under different stress conditions as per the International Council for Harmonization (ICH) guidelines. The drug substance was found to be stable in thermal, photolytic and basic stress conditions, but degraded under acidic and oxidative stress conditions. It was determined that four main degradation products of cabotegravir are formed in forced degradation studies. All four main degradation products were isolated using preparative chromatography and subjected to NMR and HRMS analysis in order to determine their structure. We proposed degradation pathways of cabotegravir under acidic stress conditions in solution based on the structure of isolated degradation products, cabotegravir degradation kinetic studies and degradation studies on two isolated key degradation products. Moreover, degradation pathway to predominant oxidation degradation product is proposed based on the adduct of cabotegravir and peroxide species, which was identified by LC-HRMS analysis. This is the first report to the best of our knowledge that describes characterized cabotegravir forced degradation impurities and provides insights into its degradation pathways.

Keywords: Cabotegravir; Characterization; Degradation product; Identification; Stress testing.