Rourick R A, Volk K J, Klohr S E, Spears T, Kerns E H, Lee M S
Bristol-Myers Squibb Pharmaceutical Research Institute, Analytical Research and Development Department, Wallingford, CT 06492-7660, USA.
J Pharm Biomed Anal. 1996 Sep;14(12):1743-52. doi: 10.1016/0731-7085(96)01843-2.
Structural information on drug degradants and impurities can serve to accelerate the drug discovery and development cycle. Traditional structure elucidation methodologies for obtaining this information are often slow and resource-consuming; therefore, LC/MS profiling and LC/MS/MS substructural analysis methodologies have been developed to rapidly and accurately elucidate structures of impurities and degradants. This work is a further development of methodologies used for the elucidation of degradation products of paclitaxel [K.J. Volk et al., Proc. 9th AAPS Ann. Meeting, 1994, p.29]. In this study cefadroxil was used as a model compound for the evaluation of a predictive strategy for the production and elucidation of impurities and degradants induced by acid, base, and heat, using LC/MS and LC/MS/MS profiling methodology, resulting in an LC/MS degradant database which includes information on molecular structures, chromatographic behavior, molecular weight, UV data, and MS/MS substructural information. Furthermore, libraries such as this can provide a predictive foundation for pre-clinical development work involving drug stability, synthesis, and monitoring.
关于药物降解产物和杂质的结构信息有助于加速药物发现和开发周期。用于获取此类信息的传统结构解析方法通常耗时且资源消耗大；因此，液相色谱/质谱（LC/MS）分析和液相色谱/串联质谱（LC/MS/MS）子结构分析方法已被开发出来，以快速、准确地解析杂质和降解产物的结构。这项工作是对用于阐明紫杉醇降解产物的方法的进一步发展[K.J. Volk等人，《第9届美国药学协会年会论文集》，1994年，第29页]。在本研究中，头孢羟氨苄被用作模型化合物，采用LC/MS和LC/MS/MS分析方法，评估由酸、碱和热诱导产生的杂质和降解产物的预测策略，从而建立了一个LC/MS降解产物数据库，其中包括分子结构、色谱行为、分子量、紫外数据和MS/MS子结构信息等。此外，这样的数据库可为涉及药物稳定性、合成和监测的临床前开发工作提供预测基础。
