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Multicriteria approach to development of HPLC method fordetermination of Zolpidem tartrate and degradation products

dc.contributor.advisorŽivanović, Ljiljana
dc.contributor.otherZečević, Mira
dc.contributor.otherLaušević, Mila
dc.creatorMalešević, Marija P.
dc.date.accessioned2016-01-05T12:49:44Z
dc.date.available2016-01-05T12:49:44Z
dc.date.issued2013-02-14
dc.identifier.urihttp://eteze.bg.ac.rs/application/showtheses?thesesId=199
dc.identifier.urihttps://fedorabg.bg.ac.rs/fedora/get/o:5449/bdef:Content/download
dc.identifier.urihttp://vbs.rs/scripts/cobiss?command=DISPLAY&base=70036&RID=43566863
dc.identifier.urihttp://nardus.mpn.gov.rs/123456789/3130
dc.descriptionZolpidem tartarat je nebenzodijazepinski sedativ i hipnotik, koji se koristi za kratkotrajnu terapiju nesanice. Njegovi efekti se manifestuju vezivanjem za benzodiazepinsko vezujuće mesto na GABAA receptoru u CNS-u. Zolpidem baza, koji farmaceutski aktivan deo molekula, podleže laganoj hidrolizi u kiselim i baznim rastvorima usled nestabilnosti tercijarne amidne funkcionalne grupe prisutne u njegovoj strukturi. Proizvodi ove hidrolize su zolpacid i dimetilamin. Oksozolpidem, zolpiridin i zolpaldehid su takoñe potencijalni degradacioni proizvodi zolpidem-tartarata. Kako prisustvo degradacionih proizvoda može da utiče na hemijske, farmaceutske i toksikološke osobine doziranog oblika, prema ICH smernicama moraju da se ispituju sve nečistoće prisutne u doziranom obliku u količini većoj od 0.1%. Zbog toga je razvijena nova, brza RP-HPLC metoda za odreñivanje zolpidem-tartarata i ključnih degradacionih proizvoda. Kako na hromatografsko ponašanje analiziranih supstanci mogu da utiču različiti eksperimentalni faktori odlučeno je da se razvoj i optimizacija metode sprovedu uz pomoć eksperimentalnog dizajna. Frakcioni faktorski dizajn je korišćen da se detektuju sve promenljive koje značajno utiču na hromatografsku metodu, centralni kompozicioni dizajn je korišćen za optimizaciju tih promenljivih, a multikriterijumski princip odlučivanja u formi Deringerove funkcije je primenjen za postizanje odgovarajućeg kompromisa izmeñu različitih hromatografskih ciljeva, kao što su zadovoljavajuća rezolucija izmeñu svih ispitivanih supstanci uz najkraće moguće trajanje hromatografske analize. Nakon toga, metoda je uspešno validirana u skladu sa ICH smernicama i primenjena za ispitivanje komercijalno dostupnih zolpidem-tartarat film-tableta. Kako je pregled literature pokazao nedostatak informacija o degradacionom mehanizmu zolpidem-tartarata, sledeći cilj ovog rada je bio da se ispita stabilnost zolpidem-tartarata i mogućnost nastajanja novih degradacionih proizvoda, sprovoñenjem studije forsirane degradacije sa aktivnom supstancom zolpidem tartaratom i farmaceutskim doziranim oblikom zolpidem-tartarat film-tabletama, što bi omogućilo identifikovanje potencijalnih degradacionih proizvoda i posledično utvrñivanje degradacionog puta i sveobuhvatne stabilnosti leka...sr
dc.descriptionZolpidem tartrate is a non-benzodiazepine sedative-hypnotic agent, used in the short-term management of insomnia. Its effects are expressed by binding to the benzodiazepine-binding site of the GABAA receptor in the CNS. Zolpidem base, which is pharmacological active part of the molecule, undergoes slow degradation in acidic solutions, due to instability of the tercial amide moiety present in the zolpidem structure. Products of that acid hydrolysis are zolpacid and dimethylamine. Oxozolpidem, zolpyridine and zolpaldehyde are also potential degradation products of zolpidem. The presence of degradation products could affect chemical, pharmaceutical and toxicological properties of the pharmaceutical dosage form. Therefore, determination of degradation products present in pharmaceutical dosage forms above 0.1 % level is necessary, according to ICH guidelines. A new, rapid RP-HPLC method for determination of zolpidem tartrate and degradation products was developed. Since the chromatographic behaviour of analysed substances may be influenced by various experimental parameters, it was decided that the development and optimization of the method would be carried out by employing experimental design methodology. The fractional factorial design was used to detect all variables which significantly influenced the chromatographic procedure, central composite design was used for optimisation of these variables and multicriteria decision approach by means of Derringer’s desirability function was applied for reaching a suitable compromise among different chromatographic goal such as satisfactory resolution between all analysed compounds with the shortest possible analysis time. Afterwards, the method was successfully validated in accordance with ICH guideline and subsequently applied to the analysis of commercially available zolpidem tartrate film-tablets. As the literature search revealed lack of information on degradation mechanism of zolpidem tartrate, another objective of this work was to analyse the stability of zolpidem tartrate and possibility of formation of new degradation products by conduction of forced degradation study with active pharmaceutical ingredient zolpidem tartrate and drug product zolpidem tartrate film tablets, which would help identify the potential degradation products and consequently establish the possible degradation pathways and intrinsic stability of the drug...en
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.subjectZolpidem-tartarat, Tečna hromatografija, Frakcioni faktorski dizajn, Centralni kompozicioni dizajn, Deringerova funkcija poželjnih odgovora, Forsirana degradacija, Degradacioni proizvodi, LC–MSsr
dc.subjectZolpidem tartrate, Liquid chromatography, Fractional factorial design, Central composite design, Derringer’s desirability function, Forced degradation, Degradation products, LC–MSen
dc.titleMultikriterijumski pristup modelovanja HPLC metode za određivanje zolpidem-tartarata i degradacionih proizvodasr
dc.titleMulticriteria approach to development of HPLC method fordetermination of Zolpidem tartrate and degradation productsen
dc.typePhD thesis
dcterms.abstractЖивановић, Љиљана; Зечевић, Мира; Лаушевић, Мила; Малешевић, Марија П.; Мултикритеријумски приступ моделовања ХПЛЦ методе за одређивање золпидем-тартарата и деградационих производа; Мултикритеријумски приступ моделовања ХПЛЦ методе за одређивање золпидем-тартарата и деградационих производа;


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