title: Forced degradation of fentanyl: identification and analysis of impurities and degradants.
abstract: Fentanyl, N-(1-phenethylpiperidin-4-yl)-N-phenylpropionamide is a rapid-acting, powerful opioid analgesic used extensively for anesthesia and chronic pain management. A forced degradation study of fentanyl active pharmaceutical ingredient (API) was performed using light, acid, base, heat and oxidation. Under acidic conditions, fentanyl was shown to degrade to N-phenyl-1-(2-phenylethyl)-piperidin-4-amine (PPA(1)). Fentanyl was stable to light exposure and base treatment with no degradation observed. Oxidation with hydrogen peroxide produced fentanyl N-oxide by rapidly oxidizing the nitrogen on the piperidine ring. Five degradants were formed during thermal degradation of fentanyl. The two known degradants included propionanilide (PRP(2)) and norfentanyl (NRF(3)). The three unknown degradants were first identified by mass using LC/MS, and postulated compounds were synthesized and confirmed by LC/MS and (1)H NMR. These degradants were identified as 1-phenethylpyridinium salt (1-PEP(4)), 1-phenethyl-1H-pyridin-2-one (1-PPO(5)), and 1-styryl-1H-pyridin-2-one (1-SPO(6)). In addition to the seven degradants, three known process impurities, acetyl fentanyl, pyruvyl fentanyl and butyryl fentanyl were also detected by reverse-phase high performance liquid chromatography (HPLC) with UV detection. All degradants and impurities were identified and confirmed using authentic materials. Method validation was performed for the assay of fentanyl and its related compounds in accordance to ICH guideline Q2(R1), and the method was demonstrated to be specific, linear (r>0.999 for fentanyl assay and r>0.996 for related compounds), accurate (recovery>99.6% for fentanyl assay and recovery>91.0 for related compounds), precise (%RSD<0.8% for fentanyl assay and <4.8% for related compounds), sensitive (limit of detection=0.08 microg/mL or 0.016% of nominal concentration), robust and suitable for its intended use. The chemical structures for the degradants and impurities were submitted to three in silico toxicity programs to identify any structural alerts.
authors.affiliation: Analytical Research and Development, Alexza Pharmaceuticals, 2091 Stierlin Court, Mountain View, CA 94043, United States. agarg@alexza.com
authors.forename: Anuradha
authors.initials: A
authors.lastname: Garg
authors.forename: Dennis W
authors.initials: DW
authors.lastname: Solas
authors.forename: Lori H
authors.initials: LH
authors.lastname: Takahashi
authors.forename: James V
authors.initials: JV
authors.lastname: Cassella
mesh_terms: D004340:Drug Contamination; D004355:Drug Stability; D005283:Fentanyl / Q000737:chemistry*; D057230:Limit of Detection; D010084:Oxidation-Reduction; D010782:Photolysis
chemical_list: D005283:Fentanyl