title: 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.
authors.affiliation: Pharmaceutical Development, Bristol-Myers Squibb Company, One Squibb Dr., New Brunswick, New Jersey 08903, USA. sherif.badawy@bms.com
authors.forename: S
authors.initials: S
authors.lastname: Badawy
authors.forename: M
authors.initials: M
authors.lastname: Hussain
authors.forename: F
authors.initials: F
authors.lastname: Zhao
authors.forename: Q
authors.initials: Q
authors.lastname: Ye
authors.forename: Y
authors.initials: Y
authors.lastname: Huang
authors.forename: V
authors.initials: V
authors.lastname: Palaniswamy
mesh_terms: D001711:Biotransformation / Q000187:drug effects; D002626:Chemistry, Pharmaceutical; D003346:Corticotropin-Releasing Hormone / Q000037:antagonists & inhibitors*; D004355:Drug Stability; D006868:Hydrolysis; D019999:Pharmaceutical Solutions / Q000737:chemistry* / Q000378:metabolism* / Q000494:pharmacology; D011720:Pyrazoles / Q000737:chemistry* / Q000378:metabolism* / Q000494:pharmacology; D012995:Solubility; D014227:Triazines / Q000737:chemistry* / Q000378:metabolism* / Q000494:pharmacology
chemical_list: C547926:4-(bis(2-methoxyethyl)amino)-2,7-dimethyl-8-(2-methyl-4-methoxyphenyl)pyrazolo(1,5-a)-1,3,5-triazine; D019999:Pharmaceutical Solutions; D011720:Pyrazoles; D014227:Triazines; D003346:Corticotropin-Releasing Hormone