Određivanje razgradnih produkata amino i amidino supstituiranih 2-benzotiazola

master's thesis

• Title (english): Determination of degradation products of amino and amidino substituted 2-benzothiazoles
• Author: Ema Pavić
• Mentor: Dragana Mutavdžić Pavlović (mentor)
• Committee member: Dragana Mutavdžić Pavlović (predsjednik povjerenstva)
• Committee member: Marijana Hranjec (član povjerenstva)
• Committee member: Lidija Furač (član povjerenstva)
• Granter: University of Zagreb; Faculty of Chemical Engineering and Technology; Zagreb
• Defense date and country: 2021-09-14, Croatia
• Scientific / art field, discipline and subdiscipline: NATURAL SCIENCES; Chemistry

Abstract

Definiranje stabilnosti lijekova ponajviše se svodi na određivanje neželjenih svojstava uzrokovanih razgradnim produktima i onečišćenjima koji smanjuju kvalitetu, sigurnost i djelotvornost lijeka. U svrhu točnog određivanja procesa proizvodnje, uvjeta skladištenja i transporta, važno je ispitati kako se kvaliteta farmaceutskog proizvoda mijenja pod utjecajem različitih okolišnih čimbenika. Prije početka komercijalne uporabe farmaceutski aktivnih tvari potrebno je, uz ispitivanje stabilnosti, procijeniti njihova svojstva koja mogu imati značajan utjecaj na žive organizme i okoliš. Tek nakon provedenih ispitivanja, farmaceutski aktivni spojevi mogu prijeći u fazu ispitivanja potencijalne implementacije u novim farmaceutskim proizvodima. Jedan od načina ispitivanja stabilnosti jest podvrgavanje aktivnih tvari ekstremnim kemijskim i okolišnim uvjetima, tzv. ispitivanje prisilne razgradnje. Cilj ovog rada bio je odrediti strukturu i svojstva razgradnih produktata dva derivata 2-fenilbenzotiazola. Uzorci spojeva LD-4, IUPAC naziva 2-(4-amidinofenil)-6-aminobenzotiazol-klorid, i LD-5, IUPAC naziva 2-(4-aminofenil)-6-(imidazolin-2-il)benzotiazol-mesilat, ispitivani su u uvjetima kisele hidrolize (0,5 M HCl), bazne hidrolize (0,5 M NaOH), oksidacije peroksidom
(10 % H2O2), povišene temperature (80 ˚C i 100 ˚C) i UV/VIS svjetla (500 Wh/m^2), a identifikacija produkata provedena je pomoću tekućinskog kromatografa visoke djelotvornosti povezanim sa spektrometrom masa visoke razlučivosti (HPLC-QTOF). Na osnovu dobivenih spektara masa određena je struktura razgradnih produkata i predložen razgradni put osnovnih spojeva. Na temelju određene strukture razgradnih produkata procijenjene su vrijednosti razvojne toksičnosti, mutagenosti i biakumulacijskog faktora pomoću T.E.S.T. softverskog programa.

Abstract (english)

Definifing the stability of drugs is mostly reduced to determining the adverse properties caused by degradation products and contaminants that reduce the quality, safety and efficiency of the drug. In order to accurately determine the production process, as well as storage and transport conditions, it is important to examine how the quality of the pharmaceutical product changes under the influence of various environmental factors. Before commencing commercial use of pharmaceutically active substances, it is necessary, in addition to stability testing, to evaluate their properties which may have a significant effect on living organisms and the environment. Only after the tests have been performed, can the pharmaceutically active compounds enter the testing phase of potential implementation in new pharmaceutical products. One way to test stability is to subject the active substances to extreme chemical and environmental conditions, the so-called forced decomposition test. The aim of this study was to determine the structure and properties of degradation products of two 2-phenylbenzothiazole derivates. Samples of the compounds LD-4, IUPAC called
2-(4-amidinophenyl)-6-aminobenzothiazole chloride, and LD-5, IUPAC called
2-(4-aminophenyl)-6-(imidazolin-2-yl)benzothiazole mesylate, were tested under conditions of acid hydrolysis (0,5 M HCl), basic hydrolysis (0,5 M NaOH), peroxide oxidation (10 % H2O2), elevated temperatures (80 ˚C i 100 ˚C) and UV/VIS light (500 Wh/m^2), and product identification was performed using a high performace liquid chromatograph connected to a high resolution mass spectrometer (HPLC-QTOF). Based on the obtained mass spectra, the structure of degradation products was determined and the degradation pathway of basic compounds was proposed. Based on the specific structure of degradation products, the values of developmental toxicity, mutagenicity and bioaccumulation factor were estimated using T.E.S.T. software program.

• Keywords: benzotiazol; prisilna razgradnja; razgradni produkti; tekućinska kromatografije visoke djelotvornosti; razvojna toksičnost; mutagenost; bioakumulacijski faktor
• Keywords (english): benzothiazole; forsed degradation; degradation products; high performace liquid chromatography; developmental toxicity; mutagenicity; bioaccumulation factor
• Language: croatian
• URN:NBN: urn:nbn:hr:149:911714
• Project: Number: IP-2018-01-4379; Title: Istraživanje antioksidativnog djelovanja benzazolskog skeleta u dizajnu novih antitumorskih agensa; Acronym: AntioxPot; Leader: Marijana Hranjec; Jurisdiction: Croatia; Funder: HRZZ; Funding stream: IP
• Study programme: Title: Chemical Engineering - Graduate study; Study programme type: university; Study level: graduate; Academic / professional title: magistar/magistra inženjer/inženjerka kemijskog inženjerstva (magistar/magistra inženjer/inženjerka kemijskog inženjerstva)
• Type of resource: Text
• File origin: Born digital
• Access conditions: Open access; Embargo expiration date: 2022-12-01
• Created on: 2023-04-11 11:35:51