title: Elucidating the pathways of degradation of denagliptin.
abstract: Stress testing or forced degradation studies of denagliptin (1) tosylate in solution and solid-state, its blends with excipients, and capsules were conducted in order to elucidate degradation pathways, aid formulation development, and generate data to support regulatory filings. In solution, denagliptin was stressed in acid, water, and base using organic cosolvents. In the solid-state, denagliptin was stressed under heat, humidity, and light. Blends of denagliptin with various excipients were stressed under heat and humidity in order to evaluate whether tablet was a viable dosage form. Capsules were stressed under heat, humidity, and light. It was found that denagliptin was stable in the solid-state, but degraded in solution, in blends with all excipients, and in capsules predominantly by cyclization to (3S,7S,8aS) amidine (2), which epimerized to (3S,7S,8aR) amidine (3). (3S,7S,8aR) amidine (3) subsequently hydrolyzed to the corresponding diketopiperazine (4). The purpose of this manuscript is to discuss the results of stress testing studies conducted during the development of denagliptin and the elucidation of its key degradation pathway.
authors.affiliation: Analytical Sciences, Chemical Development, Five Moore Drive, PO Box 13398, GlaxoSmithKline, RTP, North Carolina 27709, USA. bkj71882@gsk.com
authors.forename: Biren K
authors.initials: BK
authors.lastname: Joshi
authors.forename: Beverly
authors.initials: B
authors.lastname: Ramsey
authors.forename: Byron
authors.initials: B
authors.lastname: Johnson
authors.forename: Daniel E
authors.initials: DE
authors.lastname: Patterson
authors.forename: Jeremiah
authors.initials: J
authors.lastname: Powers
authors.forename: Kevin L
authors.initials: KL
authors.lastname: Facchine
authors.forename: Martin
authors.initials: M
authors.lastname: Osterhout
authors.forename: Michael P
authors.initials: MP
authors.lastname: Leblanc
authors.forename: Renetta
authors.initials: R
authors.lastname: Bryant-Mills
authors.forename: Royston C B
authors.initials: RC
authors.lastname: Copley
authors.forename: Scott L
authors.initials: SL
authors.lastname: Sides
mesh_terms: D000578:Amidines / Q000737:chemistry; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy; D054873:Dipeptidyl-Peptidase IV Inhibitors; D004355:Drug Stability; D004791:Enzyme Inhibitors / Q000737:chemistry*; D005079:Excipients / Q000737:chemistry; D006358:Hot Temperature; D006801:Humans; D009682:Magnetic Resonance Spectroscopy; D008958:Models, Molecular; D010649:Phenylalanine / Q000031:analogs & derivatives* / Q000737:chemistry; D011759:Pyrrolidines / Q000737:chemistry*
chemical_list: D000578:Amidines; D054873:Dipeptidyl-Peptidase IV Inhibitors; D004791:Enzyme Inhibitors; D005079:Excipients; D011759:Pyrrolidines; D010649:Phenylalanine; C551147:denagliptin