Analiza degradacije lipoglikodepsipeptidnog antibiotika ramoplanina tekućinskom kromatografijom i spektrometrijom masa

doctoral thesis

• Title (english): Degradation study of lipoglycodepsipeptide antibiotic ramoplanin by liquid chromatography and mass spectrometry
• Author: Dubravka Stražić Novaković
• Mentor: Nives Galić (mentor)
• Committee member: Iva Juranović Cindrić (predsjednik povjerenstva)
• Committee member: Šime Ukić (član povjerenstva)
• Committee member: Ines Primožič (član povjerenstva)
• Granter: University of Zagreb; Faculty of Science; (Department of Chemistry); Zagreb
• Defense date and country: 2024-06-12, Croatia
• Scientific / art field, discipline and subdiscipline: NATURAL SCIENCES; Chemistry
• Universal decimal classification (UDC): 54 - Chemistry. Crystallography. Mineralogy

Abstract

U borbi protiv bakterijske rezistencije, ciklički lipoglikodepsipeptid ramoplanin pojavio se kao novi obećavajući antibiotski lijek. U ovom radu je razvijena, validirana i upotrjebljena metoda tekućinske kromatografije za praćenje stabilnosti ramoplanina, u čvrstom stanju i u otopini. Studija forsirane razgradnje provedena je podvrgavanjem uzorka različitim stresnim uvjetima (kisela i bazična hidroliza, oksidacija, vlaga, temperatura i svjetlo) te su opaženi razgradni produkti razjašnjeni spektrometrijom masa. Istraživanje je otkrilo kako je hidroliza laktonskog prstena najvažniji degradacijski put molekule. Međutim, opaženi su i drugi značajni putevi degradacije. Nadalje, ramoplanin je formuliran u vodenim otopinama koristeći nekoliko različitih pomoćnih tvari te je provedena stabilitetna studija pri 25 °C/60 % RV i 40 °C/75 % RV. Među ispitanim pomoćnim tvarima, polisorbat 20, Kolliphor® RH 40 i kolin klorid pokazali su važan stabilizacijski učinak na degradaciju ramoplanina.

Abstract (english)

In the fight against antimicrobial resistance, a cyclic lipoglycodepsipeptide ramoplanin emerged as a new promising antibacterial regimen. In the present work, an LC method was developed, validated and used during stability testing of ramoplanin, in solid state and in solution. Forced degradation study was performed by subjecting the sample to different stress conditions (acid and base hydrolysis, oxidation, humidity, heat and light) and the observed degradation products were elucidated using mass spectrometry. The study revealed that the most significant degradation path of the molecule is hydrolysis of its lactone ring. However, other significant degradation routs were also observed. Furthermore, ramoplanin was formulated in aqueous solutions using several different excipients and a stability study was conducted at 25 °C/60 % RH and 40 °C/75 % RH. Among the tested excipients, polysorbate 20, Kolliphor® RH 40 and choline chloride were found to have an important stabilizing effect on the degradation of ramoplanin.

• Keywords: polipeptidni antibiotik; pomoćne tvari; razgradni produkti; spektrometrija masa; stabilitet; tekućinska kromatografija
• Keywords (english): degradation products; excipients; liquid chromatography; mass spectrometry; polypeptide antibiotic; stability testing
• Language: croatian
• URN:NBN: urn:nbn:hr:217:270151
• Promotion: 2024
• 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: 108, XXXIII str. ; 30 cm
• File origin: Born digital
• Access conditions: Embargoed access; Embargo expiration date: 2026-06-13
• Created on: 2024-06-21 12:30:40