Multikriterijumski pristup modelovanja HPLC metode za određivanje zolpidem-tartarata i degradacionih proizvoda
Multicriteria approach to development of HPLC method fordetermination of Zolpidem tartrate and degradation products
Doktorand
Malešević, Marija P.Mentor
Živanović, LjiljanaČlanovi komisije
Zečević, MiraLaušević, Mila
Metapodaci
Prikaz svih podataka o disertacijiSažetak
Zolpidem 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...
Zolpidem 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...