Priprava, karakterizacija i stabilnost supramolekulskih sustava nabumetona i derivata β-ciklodekstrina u čvrstom stanju i otopini

doctoral thesis

• Title (english): Preparation, characterization, and stability of supramolecular systems of nabumetone and β-cyclodextrin derivatives in the solid state and in solution
• Author: David Klarić
• Mentor: Nives Galić (mentor)
• Committee member: Ines Primožič (predsjednik povjerenstva)
• Committee member: Željka Soldin (član povjerenstva)
• Committee member: Šime Ukić (član povjerenstva)
• Granter: University of Zagreb; Faculty of Science; (Department of Chemistry); Zagreb
• Defense date and country: 2024-10-16, Croatia
• Scientific / art field, discipline and subdiscipline: NATURAL SCIENCES; Chemistry
• Universal decimal classification (UDC): 54 - Chemistry. Crystallography. Mineralogy

Abstract

Nabumeton je nesteroidni protuupalni predlijek slabe topljivosti koja se može poboljšati kompleksiranjem s ciklodekstrinima. Detaljno je istražen utjecaj β-ciklodekstrina i njegovih hidroksipropiliranih, nasumično metiliranih i sulfobutiliranih derivata na topljivost nabumetona u vodi i simuliranim biorelevantnim medijima (želučani, duodenalni i intestinalni medij). Inkluzijski kompleksi nabumetona i različitih β-ciklodekstrina u otopini okarakterizirani su spektrofluorimetrijom, izotermnom titracijskom kalorimetrijom i spektrometrijom masa te je određen sastav kompleksa i termodinamičke veličine (log K, ΔrH°, ΔrS°, i ΔrG°). Na temelju rezultata solubilizacijskih istraživanja odabrani su pogodni binarni sustavi NAB:CD koji su u čvrstom stanju pripravljeni mehanokemijskom aktivacijom te detaljno okarakterizirani primjenom tehnika DSC, FT-IR i PXRD. Nakon određivanja topljivosti te brzine i opsega otapanja nabumetona in vitro, odabrani su sustavi NAB:CD optimalnih karakteristika, koji su podvrgnuti eksperimentima prisilne razgradnje, studijama dugotrajne stabilnosti te studijama fotostabilnosti. Stabilnost je praćena razvijenim i validiranim metodama tekućinske kromatografije. Strukture razgradnih produkata predložene su temeljem rezultata tandemne spektrometrije masa (HRMS/MS). Postignuti rezultati dobar su temelj za razvoj novih terapijskih oblika nabumetona poboljšanih svojstava.

Abstract (english)

Nabumetone is a NSAID prodrug with poor solubility that can be improved by complexing with cyclodextrins. The influence of β-cyclodextrin and its hydroxypropylated, randomly methylated, and sulfobutylated derivatives on the solubility of nabumetone in water and simulated biorelevant media (gastric, duodenal and intestinal media) was investigated in detail. The characterization of inclusion complexes of nabumetone and various β-cyclodextrins in solution was carried out using spectrofluorimetry, isothermal titration calorimetry, and mass spectrometry, and the complex stoichiometry and thermodynamic parameters (log K, ΔrH°, ΔrS° and ΔrG°) were determined. Based on the results of phase-solubility analysis, suitable binary systems NAB:CD were selected and prepared in the solid state by mechanochemical activation. They were characterized in detail using DSC, FT-IR, and PXRD techniques. Based on the determination of solubility and dissolution rate of nabumetone in vitro, NAB:CD systems with optimal characteristics were selected, and subjected to forced degradation experiments, long- term stability studies, and photostability studies. Stability was monitored by developed and validated liquid chromatography methods. Degradation product structures were proposed based on the results of tandem mass spectrometry experiments (HRMS/MS). The obtained results are a good basis for the development of new pharmaceutical formulations of nabumetone with improved properties.

• Keywords: ciklodekstrini; inkluzijski kompleksi; nabumeton; stabilnost; topljivost
• Keywords (english): cyclodextrins; inclusion complexes; nabumetone; solubility; stability
• Language: croatian
• URN:NBN: urn:nbn:hr:217:759313
• Promotion: 2024
• Project: Number: IP-2022-10-6033; Title: Priprava, karakterizacija i biokompatibilnost novih supramolekulskih kompleksa lijek/ciklodekstrin i lijek/dekstrinske nanospužve s poboljšanim svojstvima; Title: Preparation, characterization and biocompatibility studies of novel drug/cyclodextrin and drug/dextrin-based nanosponge supramolecular complexes with enhanced functionality; Acronym: DrugCD.com; Leader: Nives Galić; Jurisdiction: Croatia; Funder: Hrvatska zaklada za znanost; Funding stream: Research Projects
• Study programme: Title: Doctoral study; Study programme type: university; Study level: postgraduate; Academic / professional title: doktor/doktorica u području prirodnih znanosti (doktor/doktorica u području prirodnih znanosti)
• Type of resource: Text
• Extent: 153, XCI str. ; 30 cm
• File origin: Born digital
• Access conditions: Open access
• Created on: 2024-10-28 13:28:54