Wang Qinggang, He Brian Lingfeng, Zhang Jin, Huang Yande, Kleintop Brent, Raglione Thomas
Analytical and Bioanalytical Development, Bristol-Myers Squibb Company, One Squibb Drive, New Brunswick, NJ 08903, USA.
Analytical and Bioanalytical Development, Bristol-Myers Squibb Company, One Squibb Drive, New Brunswick, NJ 08903, USA.
J Pharm Biomed Anal. 2015;111:288-96. doi: 10.1016/j.jpba.2015.04.005. Epub 2015 Apr 15.
Drug degradation that occurs in HPLC analysis, during either sample preparation or chromatographic separation, can greatly impact method robustness and result accuracy. In this work, we report a case study of drug dimerization in HPLC analysis where proximate causes were attributed to either the LC columns or the HPLC instrument. Solution stress studies indicated that the same pseudo-dimeric degradants could also be formed rapidly when the compound was exposed to certain oxidative transition metal ions, such as Cu(II) and Fe(III). Two pseudo-dimeric degradants were isolated from transition metal stressed samples and their structures were elucidated. A degradation pathway was proposed, whereby the degradation was initiated through transition metal-induced single electron transfer oxidation. Further studies confirmed that the dimerization was induced by trace transition metals in the HPLC flow path, which could arise from either the stainless steel frits in the LC column or stainless steel tubing in the HPLC instrument. Various procedures to prevent transition metal-induced drug degradation were explored, and a general strategy to mitigate such risks is briefly discussed.
在高效液相色谱（HPLC）分析中，无论是样品制备过程还是色谱分离过程中发生的药物降解，都可能极大地影响方法的稳健性和结果的准确性。在本研究中，我们报告了一个HPLC分析中药物二聚化的案例研究，其中直接原因归因于液相色谱柱或HPLC仪器。溶液应力研究表明，当该化合物暴露于某些氧化态过渡金属离子，如铜（II）和铁（III）时，同样的假二聚体降解产物也能迅速形成。从过渡金属胁迫样品中分离出两种假二聚体降解产物，并阐明了它们的结构。提出了一种降解途径，即降解通过过渡金属诱导的单电子转移氧化引发。进一步的研究证实，二聚化是由HPLC流路中的痕量过渡金属诱导的，这些过渡金属可能来自液相色谱柱中的不锈钢烧结板或HPLC仪器中的不锈钢管路。探索了各种防止过渡金属诱导药物降解的方法，并简要讨论了减轻此类风险的一般策略。
