Separation and characterization of impurities and isomers in cefpirome sulfate by liquid chromatography/tandem mass spectrometry and a summary of the fragmentation pathways of oxime‐type cephalosporins

Abstract

Rationale: Although the identification of degradation products of cefpirome sulfate has been reported, there has been no report concerning the impurities in bulk samples of this compound. To meet the requirements of the International Council for Harmonization of Technical Requirements for Pharmaceuticals for Human Use, the structures of impurities whose content are over 0.1% need to be confirmed. Thus, characterization of the impurities in cefpirome sulfate bulk samples is critical for controlling the production of this drug. Methods: The structures of cefpirome sulfate impurities were investigated using two-dimensional liquid chromatography (LC) coupled to electrospray ionization tandem mass spectrometry. In the first LC dimension, a Kromasil 100-5C18 column (4.6 mm × 250 mm, 5 μm) was used, and the mobile phases were 0.03 M ammonium dihydrogen phosphate solution and acetonitrile. In the second dimension, the column was a Shimadzu Shim-pack GISS C18 column (50 mm × 2.1 mm, 1.9 μm), and the mobile phases were 10 mM ammonium formate solution and methanol. An ion trap time-of-flight mass spectrometer operated in both positive and negative ion mode was employed in this study. Results: Nine impurities and isomers in cefpirome sulfate, eight of which were previously unknown, were separated and characterized. Structures were proposed for the eight unknown compounds based on the MS n fragmentation data. The degradation behavior of cefpirome sulfate was also studied. Conclusions: Based on the characterization of impurities and isomers, this study could be used to improve the quality control of the cefpirome sulfate drug recommended in pharmacopoeias. The degradation behavior of cefpirome sulfate provides a basis for the selection of storage conditions. 1 | INTRODUCTION Cefpirome sulfate, a fourth-generation semi-synthetic cephalosporin, has been described in the Japanese Pharmacopoeia and the Korean Pharmacopoeia. 1,2 It is highly active against Enterobacteriaceae, Pseudomonas aeruginosa, Klebsiella spp. and Streptococcus pneumoniae and is frequently used for the treatment of various infections such as pneumonia and sepsis, as well as urinary tract infections and intraabdominal infections among adult patients. 3-7 However, common adverse symptoms of the fourth-generation cephalosporins are nonspecific circulatory disorders (chills, tachycardia, hypertension, nausea, dyspnea, cold perspiration, weak concentration, and

Impurity profile and spectrum characteristics of the isomers in cefamandole nafate using high‐ performance liquid chromatography/high‐performance size exclusion chromatography tandem ion trap/time‐of‐flight mass spectrometry

“…Online liquid chromatography/mass spectrometry (LC/MS) has been applied as an identification tool for structural identification of the impurities in drugs. A volatile mobile phase is required for the ionization process in LC/MS analysis 3,4 . However, non‐volatile mobile phases are usually used in the official analytical method of pharmacopoeia using HPLC.…”

“…A volatile mobile phase is required for the ionization process in LC/MS analysis. 3,4 However, non-volatile mobile phases are usually used in the official analytical method of pharmacopoeia using HPLC. Two-dimensional LC/MS developed over the past decade has overcome the contradiction.…”