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Multicriteria optimization and Quality by Design concept in development of ultrahigh pressure liquid chromatographic and micellar liquid chromatographic methods for investigation of cilazapril and hidrochlorothiazide stability

dc.contributor.advisorZečević, Mira
dc.contributor.otherOtašević, Biljana
dc.contributor.otherProtić, Ana
dc.contributor.otherMalenović, Anđelija
dc.contributor.otherUzunović, Alija
dc.creatorŠljivić, Jasmina
dc.date.accessioned2020-02-27T11:22:37Z
dc.date.available2020-02-27T11:22:37Z
dc.date.available2020-07-03T09:47:20Z
dc.date.issued2019-10-11
dc.identifier.urihttp://eteze.bg.ac.rs/application/showtheses?thesesId=7295
dc.identifier.urihttps://nardus.mpn.gov.rs/handle/123456789/12130
dc.identifier.urihttps://fedorabg.bg.ac.rs/fedora/get/o:21073/bdef:Content/download
dc.identifier.urihttp://vbs.rs/scripts/cobiss?command=DISPLAY&base=70036&RID=2048398434
dc.description.abstractCilazapril je potentan dugodjelujući inhibitor angiotenzin-konvertirajućeg enzima. On je prolijek cilazaprilata koji je ujedno i njegov aktivni metabolit. Hidrohlorotiazid je tiazidni diuretik koji inhibira reapsorpciju natrija i hlorida iz bubrežnih tubula i istovremeno povećava izlučivanje kalija. Cilazapril i hidrohlorotiazid se koriste kao monoterapija, ali i u kombinaciji pri čemu pokazuju sinergistički antihipertenzivni efekat. Procjena efikasnosti, kvaliteta i bezbijednosti farmaceutskog doziranog oblika podrazumijeva ispitivanje njegove hemijske stabilnosti pri različitim uslovima čuvanja. Ovo se prvenstveno odnosi na stabilnost aktivnih farmaceutskih supstanci koja ovisi o hemijskoj strukturi, a ispituje se sprovođenjem studija forsirane degradacije. Cilj studija forsirane degradacije je praćenje degradacionih proizvoda, utvrđivanje puteva njihovog nastanka i razvoj stability-indicating metode. Simultano razdvajanje cilazaprila, hidrohlorotiazida i njihovih degradacionih proizvoda u toku jedne hromatografske analize za što kraće vrijeme je veoma zahtjevan zadatak jer se ispitivani analiti značajno razlikuju po lipofilnosti i apsorpcionim karakteristikama. Složenost ispitivanog sistema je zahtijevala primjenu metodologije multikriterijumskog odlučivanja korištenjem centralnog kompozicionog dizajna i Derringer-ove funkcije poželjnih odgovora. Razvijena je gradijentna stabilityindicating RP UHPLC metoda za razdvajanje cilazaprila, hidrohlorotiazida i njihovih degradacionih proizvoda. Validacija optimizovane RP HPLC metode je izvršena u cilju potvrde njene primjenljivosti u rutinskim analizama...sr
dc.description.abstractCilazapril is a potent long-acting angiotensin-converting enzyme inhibitor. It is a prodrug of cilazaprilat which is also its active metabolite. Hydrochlorothiazide is a thiazide diuretic which inhibits sodium and chloride reabsorption from kidney tubules and simultaneously increases potassium secretion. Cilazapril and hydrochlorothiazide are used as monotherapy, but also in combination, showing a synergistic antihypertensive effect. The evaluation of efficiency, quality and safety of the pharmaceutical dosage form implies an investigation of its chemical stability under various storage conditions. This primarily relates to the stability of active pharmaceutical substances that depend on the chemical structure which is tested by conducting a forced degradation study. The aim of the forced degradation studies is the monitoring of degradation products, establishment of the paths of their formation and the development of stability-indicating method. Simultaneous separation of cilazapril, hydrochlorothiazide and their degradation products during one chromatographic analysis for a shorter time is a very demanding task because the analyzed analytes differ significantly by lipophilicity and absorption characteristics. The complexity of the investigated system required the application of multicriteria decision-making methodology using central composite design and Derringer's desirable responses function. A gradient stability-indicating RP UHPLC method was developed for the separation of cilazapril, hydrochlorothiazide and their degradation products. The validation of the optimized RP HPLC method was performed to confirm its applicability in routine analyzes...en
dc.formatapplication/pdf
dc.languagesr
dc.publisherУниверзитет у Београду, Фармацеутски факултетsr
dc.rightsopenAccessen
dc.rights.urihttps://creativecommons.org/licenses/by-nc-nd/4.0/
dc.sourceУниверзитет у Београдуsr
dc.subjectcilazaprilsr
dc.subjectcilazaprilen
dc.subjecthydrochlorothiazideen
dc.subjectstability-indicating methoden
dc.subjectgradient UHPLCen
dc.subjectisocratic micellar HPLCen
dc.subjectmulticriteria optimizationen
dc.subjectgrid point searchen
dc.subjectAQbDen
dc.subjectindirect modelingen
dc.subjectrobustness testingen
dc.subjecthidrohlorotiazidsr
dc.subjectstability-indicating metodasr
dc.subjectgradijentna UHPLCsr
dc.subjectizokratska micelarna HPLCsr
dc.subjectmultikriterijumska optimizacijasr
dc.subjectpretraga čvorova mrežesr
dc.subjectAQbDsr
dc.subjectindirektno modelovanjesr
dc.subjecttestiranje robusnostisr
dc.titlePrimena multikriterijumskie optimizacije i koncepta dizanja kvaliteta u razvoju metoda tečne hromatografije pod ultravisonim pritiskom i micelarne tečne hromatografije za praćenje stabilnosti cilazaprila i hidrohlorotiazidasr
dc.title.alternativeMulticriteria optimization and Quality by Design concept in development of ultrahigh pressure liquid chromatographic and micellar liquid chromatographic methods for investigation of cilazapril and hidrochlorothiazide stabilityen
dc.typedoctoralThesisen
dc.rights.licenseBY-NC-ND
dc.identifier.fulltexthttp://nardus.mpn.gov.rs/bitstream/id/24142/IzvestajKomisije22211.pdf
dc.identifier.fulltexthttps://nardus.mpn.gov.rs/bitstream/id/24141/Disertacija.pdf
dc.identifier.fulltexthttps://nardus.mpn.gov.rs/bitstream/id/24142/IzvestajKomisije22211.pdf
dc.identifier.fulltexthttp://nardus.mpn.gov.rs/bitstream/id/24141/Disertacija.pdf
dc.identifier.rcubhttps://hdl.handle.net/21.15107/rcub_nardus_12130


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