Određivanje onečišćenja i razgradnih produkata ceritiniba

doctoral thesis

• Title (english): Determination of ceritinib impurities and degradation products
• Author: Mia Antolčić
• Mentor: Nives Galić (mentor)
• Committee member: Ines Primožič (predsjednik povjerenstva)
• Committee member: Šime Ukić (član povjerenstva)
• Committee member: Iva Juranović Cindrić (član povjerenstva)
• Granter: University of Zagreb; Faculty of Science; (Department of Chemistry); Zagreb
• Defense date and country: 2021-06-11, Croatia
• Scientific / art field, discipline and subdiscipline: NATURAL SCIENCES; Chemistry
• Universal decimal classification (UDC): 54 - Chemistry. Crystallography. Mineralogy

Abstract

Ceritinib je djelatna tvar lijeka za terapiju bolesnika s metastaziranim karcinomom pluća nemalih stanica pozitivnih na kinazu anaplastičnog limfoma. Upotrebom tekućinske kromatografije visoke djelotvornosti spregnute s trostrukim kvadrupolnim analizatorom masa, razvijena je i validirana metoda za kvantitativno određivanje potencijalno genotoksičnih onečišćenja ceritiniba. Metoda je selektivna, specifična, linearna u rasponu od 1 μg L–1 (granica kvantifikacije) do 10 μg L–1, ponovljiva i robusna. Točnost metode potvrđena je određivanjem analitičkog povrata, čija je vrijednost bila u rasponu od 81,0 % do 107,3 %. Otopine uzoraka stabilne su minimalno 48 sati pri temperaturi od 4 °C. Također je razvijena metoda tekućinske kromatografije visoke djelotvornosti za analizu organskih onečišćenja ceritinib djelatne tvari, te je ista korištena za analizu nastalih razgradnih produkata ceritiniba. Razgradnja ceritiniba postignuta je pri povišenoj temperaturi, te u oksidacijskim, kiselim, i bazičnim uvjetima uz zagrijavanje. Predložene su strukture i pripadajući fragmenti 7 nastalih razgradnih produkata (RP1-RP7) korištenjem spektrometra masa visokog razlučivanja, Q-TOF.·

Abstract (english)

Ceritinib is an active pharmaceutical ingredient of a drug used for treatment of anaplastic lymphoma kinase-positive metastatic non-small cell lung cancer. A method for quantitation of potentially genotoxic contaminants in ceritinib was developed and validated using ultra-high performance liquid chromatography coupled with mass detection with triple quadrupole analyzer. The developed method is selective, specific, linear from 1 μg L–1 (quantification limit) to 10 μg L–1, with adequate repeatability and robustness. Accuracy was determined by percentage recovery method, with obtained values between 81,0 % - 107,3 %. Sample solutions are stable for at least 48 hours when stored at 4 °C. A method for organic impurities determination in ceritinib was developed using Ultra-high performance liquid chromatography. This method was also used for separation of degradation products that were obtained using stress conditions (high temperature, oxidative, acidic, and basic environment). Structures of fragments and 7 new degradation products (RP1-RP7) were proposed using high resolution mass detection, Q-TOF.

• Keywords: ceritinib; djelatna tvar; genotoksika; identifikacija; lijek; onečišćenje; razgradnja
• Keywords (english): active ingredient; ceritinib; degradation; drug; genotoxic; identification; impurity
• Language: croatian
• URN:NBN: urn:nbn:hr:217:748219
• Promotion: 2021
• Study programme: Title: Doctoral study in chemistry; Study programme type: university; Study level: postgraduate; Academic / professional title: doktor/doktorica znanosti, područje prirodnih znanosti, polje kemija (doktor/doktorica znanosti, područje prirodnih znanosti, polje kemija)
• Type of resource: Text
• Extent: 99 str. ; 30 cm
• File origin: Born digital
• Access conditions: Open access; Embargo expiration date: 2023-06-11
• Created on: 2021-06-24 11:54:59