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Chemometric approach to the development of HPLC/UV and HPLC/MS methods for determination and stability testing of torasemide and its impurities

dc.contributor.advisorŽivanović, Ljiljana
dc.contributor.otherZečević, Mira
dc.contributor.otherLaušević, Mila
dc.creatorJović, Žarko M.
dc.date.accessioned2016-01-05T12:49:45Z
dc.date.available2016-01-05T12:49:45Z
dc.date.issued2013-03-18
dc.identifier.urihttp://eteze.bg.ac.rs/application/showtheses?thesesId=195
dc.identifier.urihttps://fedorabg.bg.ac.rs/fedora/get/o:5442/bdef:Content/download
dc.identifier.urihttp://vbs.rs/scripts/cobiss?command=DISPLAY&base=70036&RID=43566607
dc.identifier.urihttp://nardus.mpn.gov.rs/123456789/3132
dc.descriptionTorasemid je diuretik Henleove petlje sa sličnim dejstvom kao furosemid. Koristi se u stanjima edema udruženim sa srčanom bolešću, uključujući i plućni edem, kao i u slučajevima oboljenja bubrega i jetre. Takoñe se koristi u tretmanu hipertenzije, samostalno ili u kombinaciji sa drugim antihipertenzivima. Torasemid ostvaruje dejstvo u uzlaznom, debljem kraku Henleove petlje inhibirajući tubularnu reapsorpciju natrijuma (Na+) i hlora (Cl-) ograničavanjem natrijum/hlorid/kalijum prenosnog sistema. U kontroli kvaliteta farmaceutskih proizvoda testovi identifikacije i odreñivanja sadržaja aktivne supstance i nečistoća su veoma važni sa ciljem da se obezbedi visok kvalitet proizvoda, bez promena u hemijskim, farmakološkim ili toksikološkim karakteristikama. Prema ICH smernicama, sve nečistoće prisutne u farmaceutskom doziranom obliku u količini većoj od 0.1% moraju se ispitati. Za istovremeno odreñivanje torasemida i njegovih nečistoća razvijene su nove, osetljive i pouzdane HPLC/UV i HPLC/MS metode. Kompletno hromatografsko ponašanje ispitivanih supstanci i pronalaženje optimalnih hromatografskih uslova ostvareno je uz upotrebu eksperimentalnog dizajna. Frakcioni faktorski dizajn je korišćen za izbor varijabli koji značajno utiču na hromatografsko razdvajanje. Puni faktorski dizajn je korišćen za optimizaciju tih varijabli kako bi se postiglo zadovoljavajuće razdvajanje izmeñu ispitivanih supstanci u najkraćem mogućem vremenu trajanja analize. Nakon toga, obe metode su uspešno validirane u skladu sa ICH smernicama i primenjene za ispitivanje farmaceutskog doziranog oblika, torasemid tableta. Kako u literaturi postoji nedostatak informacija o degradacionom mehanizmu torasemida, to su aktivna farmaceutska supstanca torasemid i farmaceutski dozirani oblik (torasemid tablete) podvrgnuti studijama forsirane degradacije sa ciljem da se identifikuju potencijalni degradacioni proizvodi i ustanovi mogući degradacioni put i sveukupna stabilnost torasemida. Studija je sprovedena u skladu sa ICH smernicama, a uzorci su izlagani uslovima hidrolize (kisele, bazne i neutralne), oksidacije, fotolize i termalne degradacije. Za karakterizaciju nastalih degradacionih proizvoda primenjene su HPLC/UV i HPLC/MSn tehnike. Kvadrupolni i jonski trap maseni analizatori su korišćeni da se ustanovi način fragmentacije degradacionih proizvoda...sr
dc.descriptionTorasemide is a loop diuretic with actions similar to those of furosemide. Torasemide is used for edema associated with heart failure, including pulmonary edema, and with renal and hepatic disorders. It is also used in the treatment of hypertension, either alone or with other antihypertensives. It acts in the ascending limb of the loop of Henle by inhibiting tubular reapsorption of sodium and chloride and interacting with the sodium/chloride/potassium co-transport system. In the quality control of pharmaceutical products identification and quantification of the active ingredient and its impurities is very important in order to achieve a high quality of the product, without change in chemical, pharmacological and toxicological properties. According to ICH guidelines, determination of impurities present in pharmaceutical dosage forms above 0.1% is necessary. A new, sensitive and reliable HPLC/UV and HPLC/MS methods for simultaneous determination of torasemide and its impurities were developed. The complete chromatographic behavior and optimal chromatographic conditions were evaluated with the assistance of experimental design. The fractional factorial design was used for selection of variables which significantly influence the chromatographic separation of the investigated substances. Full factorial design was used for optimization of these variables in order to achieve satisfactory resolution between all investigated substances with the shortest possible analysis time. Afterwards, both analytical methods were successfully validated in accordance with ICH guidelines and the applicability of the proposed methods on the torasemide tablet dosage form has been demonstrated. As the degradation mechanism of torasemide has been lacking in the literature, torasemide active pharmaceutical ingredient and torasemide tablets drug product were subjected to forced degradation studies in order to identify the potential degradation products and establish the possible degradation pathways and intrinsic stability of the drug. The study was performed according to ICH guidelines and samples were exposed to hydrolysis (acid, base and neutral), oxidation, photolysis and thermal degradationen
dc.formatapplication/pdf
dc.languagesr
dc.publisherУниверзитет у Београду, Фармацеутски факултетsr
dc.rightsAutorstvo-Nekomercijalno-Bez prerade 3.0 Srbija (CC BY-NC-ND 3.0)
dc.sourceУниверзитет у Београдуsr
dc.subjectTorasemidsr
dc.subjectTorasemideen
dc.subjectTečna hromatografijasr
dc.subjectMasena spektroskopijasr
dc.subjectValidacija metodesr
dc.subjectFrakcioni faktorski dizajnsr
dc.subjectPuni faktorski dizajnsr
dc.subjectCentralni kompozicioni dizajnsr
dc.subjectDeringerova funkcija poželjnih odgovorasr
dc.subjectForsirana degradacijasr
dc.subjectDegradacioni proizvodisr
dc.subjectLiquid chromatographyen
dc.subjectMass spectroscopyen
dc.subjectMethod validationen
dc.subjectFractional factorial designen
dc.subjectFull factorial designen
dc.subjectCentral composite designen
dc.subjectDerringer’s desirability functionen
dc.subjectForced degradationen
dc.subjectDegradation productsen
dc.titleHemometrijski pristup u razvoju HPLC/UV i HPLC/MS metoda za određivanje i ispitivanje stabilnosti torasemida i nečistoćasr
dc.titleChemometric approach to the development of HPLC/UV and HPLC/MS methods for determination and stability testing of torasemide and its impuritiesen
dc.typePhD thesis
dcterms.abstractЖивановић, Љиљана; Лаушевић, Мила; Зечевић, Мира; Јовић, Жарко М.; Хемометријски приступ у развоју ХПЛЦ/УВ и ХПЛЦ/МС метода за одређивање и испитивање стабилности торасемида и нечистоћа; Хемометријски приступ у развоју ХПЛЦ/УВ и ХПЛЦ/МС метода за одређивање и испитивање стабилности торасемида и нечистоћа;


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