Green Catalysis Center, College of Chemistry, Zhengzhou University, 100 Science Road, Zhengzhou, 450001, China.
Jiyuan Branch, Henan Tobacco Corporation, 38 Huanghe Road, Jiyuan, 459000, China.
Rapid Commun Mass Spectrom. 2021 Aug 30;35(16):e9129. doi: 10.1002/rcm.9129.
Tebipenem pivoxil (TBPM-PI) has been developed as the first oral carbapenem drug in the world to treat otolaryngological and respiratory infections in pediatric patients. Due to its structural properties and external factors, some related impurities, which may cause side effects in patients, might be formed during the synthesis and storage of TBPM-PI. It was vital to rapidly separate and identify the related impurities to guarantee the safe use of TBPM-PI.
A method using ultra-high-performance liquid chromatography (UHPLC) coupled with quadrupole time-of-flight tandem mass spectrometry (QTOF-MS/MS) was developed to separate and detect TBPM-PI and related impurities in an oral pharmaceutical formulation. LC/MS and MS/MS spectra of these compounds in the formulation were acquired to confirm their elemental compositions and propose their structures based on LC/MS data and fragmentation pathways of available reference substances.
LC/MS parameters and MS/MS fragmentation pathways of reference substances of TBPM-PI and related impurities were summarized in detail. Based on this, a total of 23 related impurities were found and characterized in the oral pharmaceutical formulation. Eight of these were verified by comparison with reference substances and the structures of the other 15 were proposed for the first time. In addition, four of these compounds were produced by the reaction of excipients and pre-existing related impurities.
A UHPLC/QTOF-MS method was established and used for the separation and identification of 23 related impurities in a TBPM-PI oral pharmaceutical formulation. Moreover, it was proved that new related impurities could be produced by the reaction of excipients in the pharmaceutical formulation and related impurities in the corresponding active pharmaceutical ingredient (API).
替比培南匹伏酯（TBPM-PI）已被开发为全球首个治疗儿科耳鼻喉和呼吸道感染的口服碳青霉烯类药物。由于其结构特性和外部因素，在 TBPM-PI 的合成和储存过程中可能会形成一些相关杂质，这些杂质可能会导致患者产生副作用。快速分离和鉴定相关杂质对于保证 TBPM-PI 的安全使用至关重要。
采用超高效液相色谱（UHPLC）-四级杆飞行时间串联质谱（QTOF-MS/MS）法，建立了一种分离和检测口服制剂中 TBPM-PI 及相关杂质的方法。对制剂中这些化合物的 LC/MS 和 MS/MS 图谱进行了采集，以确认其元素组成，并根据 LC/MS 数据和现有参考物质的裂解途径，提出其结构。
详细总结了 TBPM-PI 及相关杂质的参考物质的 LC/MS 参数和 MS/MS 裂解途径。在此基础上，在口服制剂中发现并鉴定了 23 种相关杂质。其中 8 种通过与参考物质的比较得到验证，其余 15 种为首次提出。此外，其中 4 种化合物是由辅料与预存在的相关杂质反应生成的。
建立了一种 UHPLC/QTOF-MS 方法，用于分离和鉴定 TBPM-PI 口服制剂中的 23 种相关杂质。此外，还证明了药物制剂中的辅料和相应的活性药物成分（API）中的相关杂质可以反应生成新的相关杂质。
