title: Characterization of a solid state reaction product from a lyophilized formulation of a cyclic heptapeptide. A novel example of an excipient-induced oxidation.
abstract: OBJECTIVE
  To elucidate the structure of a degradation product arising from a lyophilized formulation of a cyclic heptapeptide, and to provide a mechanism to account for its formation.
  
  
  METHODS
  Preparative HPLC was used to isolate the degradate in quantities sufficient for structural studies. A structure assignment was made on the basis of the compounds spectroscopic properties (UV, MS, NMR) and the results of amino acid analysis.
  
  
  RESULTS
  The degradate was identified as a benzaldehyde derivative arising from the oxidative deamination of an aminomethyl phenylalanine moiety. The extent of formation of this product is influenced by the amount of mannitol used as an excipient in the formulation. A mechanism is proposed whereby reducing sugar impurities in mannitol act as an oxidizing agent via the intermediacy of Schiff base adducts which subsequently undergo tautomerization and hydrolysis.
  
  
  CONCLUSIONS
  Reducing sugar impurities in mannitol are responsible for the oxidative degradation of the peptide via a mechanism that involves Schiff base intermediates. This mechanism may be a potential route of degradation of other arylmethyl amines in mannitol-based formulations.
authors.affiliation: Merck Research Laboratories, West Point, Pennsylvania 19486, USA.
authors.forename: D C
authors.initials: DC
authors.lastname: Dubost
authors.forename: M J
authors.initials: MJ
authors.lastname: Kaufman
authors.forename: J A
authors.initials: JA
authors.lastname: Zimmerman
authors.forename: M J
authors.initials: MJ
authors.lastname: Bogusky
authors.forename: A B
authors.initials: AB
authors.lastname: Coddington
authors.forename: S M
authors.initials: SM
authors.lastname: Pitzenberger
mesh_terms: D001547:Benzaldehydes / Q000737:chemistry*; D004355:Drug Stability; D004356:Drug Storage; D005079:Excipients / Q000737:chemistry*; D009682:Magnetic Resonance Spectroscopy; D009842:Oligopeptides / Q000737:chemistry*; D010084:Oxidation-Reduction; D010456:Peptides, Cyclic / Q000737:chemistry*; D010975:Platelet Aggregation Inhibitors / Q000737:chemistry*; D019039:Platelet Glycoprotein GPIIb-IIIa Complex / Q000037:antagonists & inhibitors*; D053778:Thiazolidines
chemical_list: D001547:Benzaldehydes; D005079:Excipients; D009842:Oligopeptides; D010456:Peptides, Cyclic; D010975:Platelet Aggregation Inhibitors; D019039:Platelet Glycoprotein GPIIb-IIIa Complex; D053778:Thiazolidines; C083231:MK 0852