Abstract：
The Food and Drug Administration (FDA) recently reported a new nitrosamine impurity in sitagliptin that was named nitroso-STG-19 (NTTP), whose acceptable intake limit was extremely low at 37 ng per day. In addition, NTTP was found to be a degradation impurity in sitagliptin tablets, which was formed by the reaction of 3-(trifluoromethyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazine hydrochloride and nitrite salts introduced via excipients. Consequently, the NTTP content in tablets was larger than that in active pharmaceutical ingredients (APIs). To control the impurity, an ultra-performance liquid chromatography coupled with tandem mass spectrometry (UPLC-MS/MS) procedure for the detection of NTTP in sitagliptin phosphate tablets and APIs was developed and validated. Furthermore, a derivatization method for the detection of nitrite salts at lower concentration was developed to select applicable excipients to decelerate the generation of NTTP. During validation of the analytical procedure for NTTP, the quantitation limit (LOQ) of NTTP was 56 ppb (0.056 ng mL-1), the linear correlation coefficient was 0.9998, and recoveries of NTTP in spiked samples ranged from 95.5% to 105.2%, indicating that the method is rapid, sensitive and accurate for an NTTP test. In the nitrite salt detection method, the LOQ was 0.21 ng mL-1, and recoveries of NTTP in spiked samples ranged from 87.6% to 107.8%, indicating a sensitive and accurate method, suitable for screening appropriate pharmaceutical excipients.
摘要：
美国食品和药物管理局（FDA）最近报道了西格列汀中一种新的亚硝胺杂质，命名为亚硝基-STG-19（NTTP），其可接受的摄入量限值极低，为每天37ng。此外,发现NTTP是西格列汀片中的降解杂质，其通过3-(三氟甲基)-5,6,7,8-四氢-[1,2,4]三唑并[4,3-a]吡嗪盐酸盐与经由赋形剂引入的亚硝酸盐的反应形成。因此,片剂中的NTTP含量高于活性药物成分（API）。为了控制杂质，开发并验证了超高效液相色谱-串联质谱(UPLC-MS/MS)方法,用于检测磷酸西格列汀片剂和API中的NTTP.此外，开发了一种用于检测低浓度亚硝酸盐的衍生方法,以选择适用的赋形剂来减缓NTTP的产生.在验证NTTP的分析程序期间，NTTP的定量限（LOQ）为56ppb（0.056ngmL-1），线性相关系数为0.9998,加标样品中NTTP的回收率为95.5%~105.2%,表明该方法快速，敏感和准确的NTTP测试。在亚硝酸盐检测方法中，LOQ为0.21ngmL-1，加标样品中NTTP的回收率为87.6％至107.8％，指示灵敏和准确的方法，适合筛选合适的药用辅料。
