Dubost D C, Kaufman M J, Zimmerman J A, Bogusky M J, Coddington A B, Pitzenberger S M
Merck Research Laboratories, West Point, Pennsylvania 19486, USA.
Pharm Res. 1996 Dec;13(12):1811-4. doi: 10.1023/a:1016024923002.
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.
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.
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.
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.
阐明一种环七肽冻干制剂产生的降解产物的结构，并提供其形成机制。
采用制备型高效液相色谱法分离出足够用于结构研究的降解产物。基于化合物的光谱性质（紫外、质谱、核磁共振）和氨基酸分析结果进行结构鉴定。
降解产物被鉴定为一种由氨甲基苯丙氨酸部分氧化脱氨产生的苯甲醛衍生物。该产物的形成程度受制剂中用作辅料的甘露醇用量的影响。提出了一种机制，即甘露醇中的还原糖杂质通过席夫碱加合物中间体作为氧化剂，随后经历互变异构和水解。
甘露醇中的还原糖杂质通过涉及席夫碱中间体的机制导致肽的氧化降解。该机制可能是基于甘露醇的制剂中其他芳基甲基胺降解的潜在途径。
