The separation and characterization of the unknown degradation product of second-generation antipsychotic drug ziprasidone are essential for defining the genotoxic potential of the compound. The aim of this study was to develop a simple UHPLC method coupled with tandem mass spectrometry (MS/MS) for chemical characterization of an unknown degradant, and the separation and quantification of ziprasidone and its five main impurities (I-V) in the raw material and pharmaceuticals. Chromatographic conditions were optimized by experimental design. The MS/MS fragmentation conditions were optimized individually for each compound in order to obtain both specific fragments and high signal intensity. A rapid and sensitive UHPLC-MS/MS method was developed. All seven analytes were eluted within the 7 min run time. The best separation was obtained on the Acquity UPLC BEH C (50 × 2.1 mm × 1.7 μm) column in gradient mode with ammonium-formate buffer (10 mm; pH 4.7) and acetonitrile as mobile phase, with the flow rate of 0.3 mL min and at the column temperature of 30°C. The new UHPLC-MS/MS method was fully validated and all validation parameters were confirmed. The fragmentation pathways and chemical characterization of an unknown degradant were proposed and it was confirmed that there are no structural alerts concerning genotoxicity.
Ziprasidone is the second generation antipsychotic drug with unique multipotent G-protein-coupled (GPCR) receptor binding profile. Since ziprasidone is a highly lipophilic and unstable compound, development of efficient method for a concurrent assay of ziprasidone and its main impurities was a very challenging task. The UHPLC-MS/MS method that we developed for simultaneous determination of ziprasidone and its main impurities (BITP, Chloroethyl-chloroindolinone, Zip-oxide, Zip-dimer, and Zip-BIT) was compared with some other related HPLC-UV methods of our own and other authorship. An increase of the mobile phase pH value from 2.5 to 4.7 units in the examined analytical methods influenced elution order of the investigated compounds. It was found out that the UHPLC-MS/MS method is more selective and sensitive than the earlier developed HPLC-UV method. Similar to our earlier HPLC-UV method, the UHPLC-MS/MS method is linear with a correlation coefficient (r) above 0.99 for all the analysed compounds, but with a negligibly lower precision and accuracy. Finally, with shorter analysis time, smaller column size and reduction of solvent consumption, UHPLC-MS/MS is assumed as a greener method than HPLC-UV for the ziprasidone purity assay. After transfer of the UHPLC-MS/MS method to the UHPLC-DAD system, suitability of the UHPLC-DAD method for routine control of ziprasidone and its main impurities is examined and confirmed based on the retained good selectivity, resolution and short analysis time.
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