Journal
JOURNAL OF PHARMACEUTICAL SCIENCES
Volume 107, Issue 6, Pages 1633-1641Publisher
ELSEVIER SCIENCE INC
DOI: 10.1016/j.xphs.2018.02.009
Keywords
degradation product; formulation; NMR spectroscopy; mass spectroscopy; stability
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Degradation of an active pharmaceutical ingredient (API), a 2-(3-(1-(4-chlorophenyl)cyclopropyl)-[1,2,4] triazolo[4,3-alpyridin-8-yl)propan-2-ol hydrochloride salt, was observed in a capsule formulation stressed at 50 degrees C or 40 degrees 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. (C) 2018 American Pharmacists Association (R) . Published by Elsevier Inc. All rights reserved.
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