N‐Methylation and N‐Formylation of a Secondary Amine Drug (Varenicline) in an Osmotic Tablet

Significant degradation of the amine‐based smoking cessation drug varenicline tartrate in an early development phase osmotic, controlled‐release (CR) formulation yields predominantly two products: N‐methylvarenicline (NMV) and N‐formylvarenicline (NFV). NMV is produced by reaction of the amine moiety with both formaldehyde and formic acid in an Eschweiler‐Clarke reaction, while NFV is formed by reaction of formic acid alone with varenicline. This represents the first report of these reactions occurring on storage of solid pharmaceutical formulations. Both formaldehyde and formic acid are formed from oxidative degradation of polyethylene glycol (PEG) used in an osmotic coating through a process heavily dependent on the physical state of the PEG. When the concentration of PEG in the coating is sufficiently low, the PEG remains phase compatible with the other component of the coating (cellulose acetate) such that its degradation (and the resulting drug reactivity) is effectively eliminated. Antioxidants in the coating and oxygen scavengers in the packaging also serve to prevent the PEG degradation, and consequently provide for drug stability. © 2007 Wiley‐Liss, Inc. and the American Pharmacists Association J Pharm Sci 97:1499-1507, 2008