CHARACTERIZATION OF A SOLID-STATE REACTION-PRODUCT FROM A LYOPHILIZEDFORMULATION OF A CYCLIC HEPTAPEPTIDE - A NOVEL EXAMPLE OF AN EXCIPIENT-INDUCED OXIDATION

Purpose. To elucidate the structure of a degradation product arising f rom a lyophilized formulation of a cyclic heptapeptide, and to provide a mechanism to account for its formation. Methods. Preparative HPLC w as used to isolate the degradate in quantities sufficient for structur al studies. A structure assignment was made on the basis of the compou nds spectroscopic properties (UV, MS, NMR) and the results of amino ac id analysis. Results. The degradate was identified as a benzaldehyde d erivative arising from the oxidative deamination of an aminomethyl phe nylalanine moiety. The extent of formation of this product is influenc ed 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 oxidat ive degradation of the peptide via a mechanism that involves Schiff ba se intermediates. This mechanism may be a potential route of degradati on of other arylmethyl amines in mannitol-based formulations.