An Unexpected Degradation Pathway of a 1,2,4-Triazolo[4,3-a]pyridine Derivative: The Formation of 2 Cationic Pseudodimers of an 11β-Hydroxysteroid Dehydrogenase Type 1 Inhibitor Drug Candidate in a Stressed Capsule Formulation

Degradation of an active pharmaceutical ingredient (API), a 2-(3-(1-(4-chlorophenyl)cyclopropyl)-[1,2,4]triazolo[4,3-a]pyridin-8-yl)propan-2-ol hydrochloride salt, was observed in a capsule formulation stressed at 50°C or 40°C/75% relative humidity conditions for 1 month. Two unknown degradants were identified as cationic pseudodimers of the API via accurate mass liquid chromatography-mass spectrometry and 1- and 2-dimensional NMR analyses. A plausible degradation pathway of the API was postulated which led to the identification of 2 key N-oxide degradants in the stressed capsule formulation at trace levels. It was hypothesized that the N-oxide degradants could be protonated and undergo further transformation so as to react with another API free base to form pseudodimeric N-oxide intermediates, followed by protonation/dehydration to yield the cationic pseudodimers of the API. The proposed degradation pathway was further supported by formulation screening studies: (1) the removal of magnesium stearate (base/lubricant) from the formulation to reduce the formation of API free base, which is susceptible to oxidation to form N-oxides; (2) the replacement of API hydrochloride salt by its free base form to eliminate the proton source for protonation of the N-oxides so as to prevent their further transformation; and (3) the addition of anti-oxidants to minimize the oxidation of API free base to N-oxides.