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Degradation pathways of a corticotropin-releasing factor antagonist in solution and solid states.

Abstract：

:Stability of the 1,3,5-triazine derivative (1), a corticotropin-releasing factor inhibitor, was studied in acidic solutions and in solid formulations. Degradant structures were elucidated using liquid chromatography/mass spectrometry (LC/MS) and nuclear magnetic resonance (NMR). Compound 1 was found to undergo hydrolysis via two pathways. Pathway 1 involves three hydrolysis steps of the triazine ring. Pathway 2 proceeds through hydroxy substitution of the amino group on the triazine ring followed by its hydrolysis, eventually resulting in the formation of the same degradant as pathway 1. Stability of 1 in the tablets was dependent on the manufacturing process and degradation appeared to proceed more rapidly in amorphous regions created during processing. Pathways 1 and 2 were observed in the tablets and degradation rate was enhanced at high humidity condition. In addition to pathways 1 and 2, degradation in the tablet formulations was found to proceed through a third pathway involving nucleophilic displacement of the ether methoxy group by the triazine N-3. The resulting imidazolidinium intermediate was found to undergo a series of hydrolytic steps finally leading to the same end degradant as pathways 1 and 2. This intermediate was observed at a lower concentration in the tablet at the high humidity conditions and at very low concentrations in acidic solutions.

journal_name

J Pharm Sci

journal_title

Journal of pharmaceutical sciences

authors

Badawy S,Hussain M,Zhao F,Ye Q,Huang Y,Palaniswamy V

doi

10.1002/jps.21637

subject

Has Abstract

pub_date

2009-08-01 00:00:00

pages

2636-47

issue

8

eissn

0022-3549

issn

1520-6017

pii

S0022-3549(16)33029-5

journal_volume

98

pub_type

杂志文章

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