Elucidating the pathways of degradation of denagliptin.
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.
Joshi
Biren K
BK
Analytical Sciences, Chemical Development, Five Moore Drive, PO Box 13398, GlaxoSmithKline, RTP, North Carolina 27709, USA. bkj71882@gsk.com
Ramsey
Beverly
B
Johnson
Byron
B
Patterson
Daniel E
DE
Powers
Jeremiah
J
Facchine
Kevin L
KL
Osterhout
Martin
M
Leblanc
Michael P
MP
Bryant-Mills
Renetta
R
Copley
Royston C B
RC
Sides
Scott L
SL
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*
D000578:Amidines; D054873:Dipeptidyl-Peptidase IV Inhibitors; D004791:Enzyme Inhibitors; D005079:Excipients; D011759:Pyrrolidines; D010649:Phenylalanine; C551147:denagliptin