Many methods used across the pharmaceutical industry for analysis of active pharmaceutical ingredients (APIs) and drug products are based on high-pressure liquid chromatography (HPLC) and non-volatile mobile phases that are incompatible with mass spectrometry (MS). This makes the direct analysis of APIs and their related impurities difficult as it requires tedious fractionation and isolation prior to offline analysis by high-resolution mass spectrometry (HRMS). An online alternative that allows for direct impurity analysis is adding a second dimension LC to desalt the sample before sending it to the MS. Effluent containing salt from the first dimension is diverted to waste while the remaining effluent is sent to the MS. This allows for both removal of non-MS friendly salts and improved separation, making the online analysis of impurities by HRMS and HRMS/MS possible. 2D-LC-HRMS/MS methods were developed for the analysis of small molecule drugs at Merck. Full HRMS spectra and HRMS/MS data were collected to elucidate structures of low-level impurities of interest. 

2D-LC-HRMS/MS for direct structural characterization of small molecule drugs

Macromolecular Chemistry: The Second Century

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ACS Spring 2020 National Meeting & Expo

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