Mechanistic Studies of the N-formylation of Edivoxetine, a Secondary Amine-Containing Drug, in a Solid Oral Dosage Form.
Edivoxetine (LY2216684 HCl), although a chemically stable drug substance, has shown the tendency to degrade in the presence of carbohydrates that are commonly used tablet excipients, especially at high excipient:drug ratios. The major degradation product has been identified as N-formyl edivoxetine. Experimental evidence including solution and solid-state investigations, is consistent with the N-formylation degradation pathway resulting from a direct reaction of edivoxetine with (1) formic acid (generated from decomposition of microcrystalline cellulose or residual glucose) and (2) the reducing sugar ends (aldehydic carbons) of either residual glucose or the microcrystalline cellulose polymer. Results of labeling experiments indicate that the primary source of the formyl group is the C1 position from reducing sugars. Presence of water or moisture accelerates this degradation pathway. Investigations in solid and solution states support that the glucose Amadori Rearrangement Product does not appear to be a direct intermediate leading to N-formyl degradation of edivoxetine, and oxygen does not appear to play a significant role. Solution-phase studies, developed to rapidly assess propensity of amines toward Maillard reactivity and formylation, were extended to show comparative behavior with example systems. The cyclic amine systems, such as edivoxetine, showed the highest propensity toward these side reactions.
Eli Lilly and Company, Lilly Research Laboratories, Small Molecule Design and Development, Indianapolis, Indiana 46285. Electronic address: hoaglund-hyzercs@lilly.com.
Cherokee S
CS
Hoaglund Hyzer
Eli Lilly and Company, Lilly Research Laboratories, Small Molecule Design and Development, Indianapolis, Indiana 46285.
Michele L
ML
Williamson
Eli Lilly and Company, Lilly Research Laboratories, Small Molecule Design and Development, Indianapolis, Indiana 46285.
Patrick J
PJ
Jansen
Eli Lilly and Company, Lilly Research Laboratories, Small Molecule Design and Development, Indianapolis, Indiana 46285.
Michael E
ME
Kopach
Eli Lilly and Company, Lilly Research Laboratories, Small Molecule Design and Development, Indianapolis, Indiana 46285.
R Brian
RB
Scherer
Eli Lilly and Company, Lilly Research Laboratories, Small Molecule Design and Development, Indianapolis, Indiana 46285.
Steven W
SW
Baertschi
D000284:Administration, Oral; D018759:Adrenergic Uptake Inhibitors / Q000008:administration & dosage / Q000737:chemistry; D004304:Dosage Forms; D004339:Drug Compounding / Q000379:methods*; D009025:Morpholines / Q000008:administration & dosage* / Q000737:chemistry*; D010626:Phenylethyl Alcohol / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000737:chemistry
D018759:Adrenergic Uptake Inhibitors; D004304:Dosage Forms; D009025:Morpholines; C568831:alpha-((5-fluoro-2-methoxyphenyl)methyl)-alpha-(tetrahydro-2H-pyran-4-yl)-2-morpholinemethanol; D010626:Phenylethyl Alcohol
analysis; analytical chemistry; chemical stability; chromatography; excipients; mass spectrometry; oxidation; polymer chemical degradation; solid dosage form; solid state stability