Ultra-performance liquid chromatography tandem mass spectrometry for the rapid, simultaneous analysis of ziprasidone and its impurities.

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 C18 (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-1 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.

Application of parallel artificial membrane permeability assay technique and chemometric modeling for blood-brain barrier permeability prediction of protein kinase inhibitors.

Aim: This study aims to investigate the passive diffusion of protein kinase inhibitors through the blood-brain barrier (BBB) and to develop a model for their permeability prediction. Materials & methods: We used the parallel artificial membrane permeability assay to obtain logPe values of each of 34 compounds and calculated descriptors for these structures to perform quantitative structure-property relationship modeling, creating different regression models. Results: The logPe values have been calculated for all 34 compounds. Support vector machine regression was considered the most reliable, and CATS2D_09_DA, CATS2D_04_AA, B04[N-S] and F07[C-N] descriptors were identified as the most influential to passive BBB permeability. Conclusion: The quantitative structure-property relationship-support vector machine regression model that has been generated can serve as an efficient method for preliminary screening of BBB permeability of new analogs.

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Electrochemical and theoretical study on interaction between erlotinib and DNA.

A comprehensive investigation of tyrosine kinase inhibitor erlotinib (ERL) electrochemical behavior and interaction with DNA was performed with the aim to clarify its redox mechanism and to determine the mode of binding. Irreversible oxidation and reduction processes of ERL on glassy carbon electrode were investigated using three voltammetric techniques CV, DPV, SWV in pH range between 2.0 and 9.0. Oxidation was established as an adsorption-controlled process, while the reduction manifested diffusion-adsorption mixed controlled process in acidic medium and adsorption became predominant in the neutral solutions. According to the determined number of transferred electrons and protons, oxidation and reduction mechanism of ERL are proposed. To follow the interaction between ERL and DNA, the multilayer ct-DNA electrochemical biosensor was incubated in ERL solutions concentrations ranged from 2 × 10-7 M to 5 × 10-5 M (pH 4.6) for 30 min. SWV measurements have shown the decrease in deoxyadenosine peak current as a consequence of ERL increased concentration and binding to ct-DNA. The calculated value of binding constant was K = 8.25 × 104 M-1. Molecular docking showed that ERL forms hydrophobic interactions when docked into minor groove, as well as when intercalated, and molecular dynamics analysis predicted the stability of obtained complexes. These results together with voltammetric studies imply that the intercalation could be more dominant way ERL binding to DNA compared to minor groove binding.