Impurity profiling of Cefteram pivoxil based on Fourier transform ion cyclotron resonance MS.

Abstract Profiling impurities for the active pharmaceutical ingredients (APIs) is an indispensable step in drug development process. Nowadays, high resolution mass spectrometry is the first choice for determining the chemical formula of organic impurities. However, merely base on the accurate mass to screen the formula is obviously not a flawless method. In this paper, a reliable strategy based on Fourier transform ion cyclotron resonance mass spectrometry (FT-ICR MS) was presented to profile the related impurities. Firstly, Cefteram pivoxil was subjected to forced degration under hydrolytic (acidic and basic), oxidative, photolytic and thermal conditions according to ICH guidelines. Then, a highly specific and efficient HPLC-FT-ICR MS compatible method was developed and it was used to separate and characterize the process related substances and the major degradation products in Cefteram pivoxil. Next, isotopic fine structures (IFSs) of all impurities were acquired to decisively determine their elemental composition. Finally, the possible chemical structures of impurities were predicted by combining the information of accurate mass, retention time, IFSs and characteristic fragmentation ions. As a result, a total of 20 related substances including 6 process related substances and 14 degradation products were identified and characterized. To the best of our knowledge, 13 of these related substances were not reported in the previous literature. It indicates that the developed strategy is accurate and standard independent to determine the chemical formulae of organic impurities in APIs. In conclusion, the impurity profiles obtained in this study are critical to the quality control and stability study of Cefteram pivoxil. Moreover, the developed method can be used as a versatile workflow to profile the impurities in APIs in the future, especially for the unknown impurities.