Elucidating the pathways of degradation of denagliptin
Corresponding Author
Biren K. Joshi
Analytical Sciences, Chemical Development, Five Moore Drive, PO Box 13398, GlaxoSmithKline, RTP, North Carolina 27709
Analytical Sciences, Chemical Development, Five Moore Drive, PO Box 13398, GlaxoSmithKline, RTP, North Carolina 27709. Telephone: 919-483-3468; Fax: 919-483-0443.Search for more papers by this authorBeverly Ramsey
Product Development, Pharmaceutical Development, Five Moore Drive, PO Box 13398, GlaxoSmithKline, RTP, North Carolina 27709
Search for more papers by this authorByron Johnson
Analytical Sciences, Chemical Development, Five Moore Drive, PO Box 13398, GlaxoSmithKline, RTP, North Carolina 27709
Search for more papers by this authorDaniel E. Patterson
Synthetic Chemistry, Chemical Development, Five Moore Drive, PO Box 13398, GlaxoSmithKline, RTP, North Carolina 27709
Search for more papers by this authorJeremiah Powers
Synthetic Chemistry, Chemical Development, Five Moore Drive, PO Box 13398, GlaxoSmithKline, RTP, North Carolina 27709
Search for more papers by this authorKevin L. Facchine
Analytical Sciences, Chemical Development, Five Moore Drive, PO Box 13398, GlaxoSmithKline, RTP, North Carolina 27709
Search for more papers by this authorMartin Osterhout
Synthetic Chemistry, Chemical Development, Five Moore Drive, PO Box 13398, GlaxoSmithKline, RTP, North Carolina 27709
Search for more papers by this authorMichael P. LeBlanc
Analytical Sciences, Chemical Development, Five Moore Drive, PO Box 13398, GlaxoSmithKline, RTP, North Carolina 27709
Search for more papers by this authorRenetta Bryant-Mills
Product Development, Pharmaceutical Development, Five Moore Drive, PO Box 13398, GlaxoSmithKline, RTP, North Carolina 27709
Search for more papers by this authorRoyston C.B. Copley
Analytical Chemistry, GlaxoSmithKline, NFSP (N), Third Avenue, Harlow, Essex CM19 5AW, UK
Search for more papers by this authorScott L. Sides
Analytical Sciences, Chemical Development, Five Moore Drive, PO Box 13398, GlaxoSmithKline, RTP, North Carolina 27709
Search for more papers by this authorCorresponding Author
Biren K. Joshi
Analytical Sciences, Chemical Development, Five Moore Drive, PO Box 13398, GlaxoSmithKline, RTP, North Carolina 27709
Analytical Sciences, Chemical Development, Five Moore Drive, PO Box 13398, GlaxoSmithKline, RTP, North Carolina 27709. Telephone: 919-483-3468; Fax: 919-483-0443.Search for more papers by this authorBeverly Ramsey
Product Development, Pharmaceutical Development, Five Moore Drive, PO Box 13398, GlaxoSmithKline, RTP, North Carolina 27709
Search for more papers by this authorByron Johnson
Analytical Sciences, Chemical Development, Five Moore Drive, PO Box 13398, GlaxoSmithKline, RTP, North Carolina 27709
Search for more papers by this authorDaniel E. Patterson
Synthetic Chemistry, Chemical Development, Five Moore Drive, PO Box 13398, GlaxoSmithKline, RTP, North Carolina 27709
Search for more papers by this authorJeremiah Powers
Synthetic Chemistry, Chemical Development, Five Moore Drive, PO Box 13398, GlaxoSmithKline, RTP, North Carolina 27709
Search for more papers by this authorKevin L. Facchine
Analytical Sciences, Chemical Development, Five Moore Drive, PO Box 13398, GlaxoSmithKline, RTP, North Carolina 27709
Search for more papers by this authorMartin Osterhout
Synthetic Chemistry, Chemical Development, Five Moore Drive, PO Box 13398, GlaxoSmithKline, RTP, North Carolina 27709
Search for more papers by this authorMichael P. LeBlanc
Analytical Sciences, Chemical Development, Five Moore Drive, PO Box 13398, GlaxoSmithKline, RTP, North Carolina 27709
Search for more papers by this authorRenetta Bryant-Mills
Product Development, Pharmaceutical Development, Five Moore Drive, PO Box 13398, GlaxoSmithKline, RTP, North Carolina 27709
Search for more papers by this authorRoyston C.B. Copley
Analytical Chemistry, GlaxoSmithKline, NFSP (N), Third Avenue, Harlow, Essex CM19 5AW, UK
Search for more papers by this authorScott L. Sides
Analytical Sciences, Chemical Development, Five Moore Drive, PO Box 13398, GlaxoSmithKline, RTP, North Carolina 27709
Search for more papers by this authorAbstract
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. © 2010 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci 99:3030–3040, 2010
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