Prisilna razgradnja atazanavira i nirmatrelvira

master's thesis

• Title (english): Forced degradation of atazanavir and nirmatrelvir
• Author: Luka Večenaj
• Mentor: Šime Ukić (mentor)
• Committee member: Šime Ukić (predsjednik povjerenstva)
• Committee member: Matija Cvetnić (član povjerenstva)
• Committee member: Dajana Kučić Grgić (član povjerenstva)
• Granter: University of Zagreb; Faculty of Chemical Engineering and Technology; Zagreb
• Defense date and country: 2024-04-30, Croatia
• Scientific / art field, discipline and subdiscipline: NATURAL SCIENCES; Chemistry

Abstract

U zadnjih nekoliko desetljeća razvoj farmaceutika i njihova primjena u medicini su znatno poboljšali kvalitetu ljudskog života. No, uslijed njihove proizvodnje i korištenja dospijevaju u okoliš gdje predstavljaju opasnost za organizme u njemu. Farmaceutici, njihovi metaboliti i nusprodukti u okolišu mogu biti vrlo postojani i akumulirati se što može rezultirati visokim koncentracijama koje djeluju toksično na cijeli ekosustav. Zbog toga potrebno je istražiti njihovu stabilnost i postojanost u okolišu te istražiti moguće razgradne produkte koji pri tome nastaju. U ovom radu ispitana je stabilnost i ponašanje dvaju farmaceutika, atazanavira i nirmatrelvira, provođenjem testova prisilne razgradnje. Prisilna razgradnja se provodila na 0,003 mM otopini atazanavira i 0,1 mM otopini nirmatrelvira u uvjetima: lužnate hidrolize s
1,0 M NaOH na sobnoj temperaturi tijekom 24 h, kisele hidrolize s 1,0 M HCl na sobnoj temperaturi tijekom 24 h, oksidacijskom razgradnjom s 30% H2O2 na sobnoj temperaturi tijekom 24 h, termičko razgradnjom pri temperaturama od 30 i 40 °C tijekom 7 dana, neutralne hidrolize na sobnoj temperaturi (25 °C) tijekom 7 dana i fotolitičke razgradnje djelovanjem UV svjetlosti jačine 600 W/m^2 pri 25 °C tijekom 6 sati. Analize svih uzoraka su se provodile na HPLC-u te su u tu svrhu razvijene i validirane HPLC metode. Za razvijene metode utvrđeno je da zadovoljavaju sve kriterije validacije: linearnost s koeficijentom determinacije većim od 0,9900, točnost s analitičkim povratom između 70 i 130% te preciznost s RSD vrijednostima manjim od 10%. Rezultati ispitivanja prisilne razgradnje pokazali su očekivanu stabilnost ispitivanih spojeva pri većini primijenjenih uvjeta.

Abstract (english)

In recent decades, the development of pharmaceuticals and their use in medicine have significantly improved quality of human life. However, as a result of their production and use, they end up in the environment, where they pose a risk to the organisms living in it. Pharmaceuticals, their metabolites and degradation products can be very persistent and accumulate in the environment, which can lead to high concentrations that have a toxic effect on the ecosystem. For this reason, it is necessary to investigate their stability and persistence in the environment as well as the possible degradation products that are formed. In this work, the stability and behavior of two pharmaceuticals, atazanavir and nirmatrelvir, were tested by forced degradation experiments. Forced degradation was performed with a 0.003 mM solution of atazanavir and a 0.1 mM solution of nirmatrelvir under the following conditions: alkaline hydrolysis in the presence of a 1.0 M NaOH solution at room temperature for a period of 24 hours, acid hydrolysis in the presence of a 1.0 M HCl solution at room temperature over a period of 24 hours, oxidation in the presence of a 30% H2O2 solution at room temperature over a period of 5 hours, thermal decomposition at 30 °C and 40 °C over a period of 7 days, neutral hydrolysis at room temperature (25 °C) over a period of 7 days and photolytic decomposition under UV light at 600 W/m^2 at 25 °C over a period of 6 hours. HPLC methods were developed and validated for analysis of atazanavir and nirmatrelvir.
The developed methods were found to fulfill all validation criteria: linearity with a coefficient of determination above 0.9900, accuracy with recoveries between 70 and 130% and precision with RSD values of less than 10%. The results of the forced degradation tests showed the expected stability of the tested compounds under most of the applied conditions.

• Keywords: atazanavir; nirmatrelvir; prisilna razgradnja
• Keywords (english): atazanavir; nirmatrelvir; forced degradation
• Language: croatian
• URN:NBN: urn:nbn:hr:149:079140
• Project: Number: IP-2022-10-2822; Title: Okolišni aspekti SARS-CoV-2 antivirotika; Title: Environmental Aspects of SARS-CoV-2 Antiviral Substances; Acronym: EnA-SARS; Leader: Šime Ukić; Jurisdiction: Croatia; Funder: HRZZ; Funding stream: IP
• Study programme: Title: Chemical Engineering - Graduate study; Study programme type: university; Study level: graduate; Academic / professional title: sveučilišni/a magistar/magistra inženjer/inženjerka kemijskog inženjerstva (sveučilišni/a magistar/magistra inženjer/inženjerka kemijskog inženjerstva)
• Type of resource: Text
• File origin: Born digital
• Access conditions: Open access
• Created on: 2024-05-06 12:07:38