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.