Razvoj hromatografskih metoda za određivanje sadržaja, stepena čistoće i retencionih karakteristika ziprasidona primenom eksperimentalnog dizajna
Development of chromatographic methods for determination of ziprasidone content, related substances and retention characteristics using experimental design
Author
Čarapić, Marija R.Mentor
Agbaba, DanicaCommittee members
Nikolić, KatarinaMarković, Bojan
Tešić, Živoslav Lj.
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Show full item recordAbstract
Ziprasidon je novi atipični antipsihotik, derivat benzoizotiazol
piperazinilindolona koji se koristi u tretmanu šizofrenije i akutnim manijačnim
epizodama povezanim sa bipolarnim poremećajima. Primarno deluje kao antagonista
serotoninskih i dopaminskih receptora, i kao inhibitor preuzimanja noradrenalina.
Ziprasidon ima jedinstven profil vezivanja za receptore što doprinosi terapijskim
efektima i slabije izraženim neželjenim dejstvima.
U ovoj doktorskoj disertaciji izvršen je razvoj i optimizacija metoda reverznofazne
tečne hromatografije za određivanje sadržaja i retencionh karakteristika
ziprasidona i njegovih nečistoća (I-V) različite polarnosti primenom više metoda
eksperimentalnog dizajna. Izvršeno je ispitivanje kvantitativnog odnosa strukture i
retencije analiziranih jedinjenja u sistemu reverzno-fazne tečne hromatografije pod
visokim pritiskom - RP-HPLC (Reverse-Phase High Performance Liquid
Chromatography) i formiran je QSRR (Quantitative Structure Retention Relationship)
mode...l na osnovu kojeg je moguće predvideti retenciju novih derivata ziprasidona. U
toku optimizacije RP-HPLC metode detektovana je nepoznata nečistoća čija je struktura
karakterisana masenom spektrometrijom.
Optimizacija RP-HPLC-UV metode je izvršena u dve faze: optimizacijom
mobilne faze i ispitivanjem selektivnosti RP stacionarnih faza, pri odabranim
eksperimentalnim uslovima, u odnosu na ziprasidon i njegove nečistoće. Ispitan je uticaj
temperature stacionarne faze, pH, koncentracije pufera i organskog modifikatora na
rezoluciju i faktore selektivnosti kritičnih parova. Optimalni hromatografski uslovi za
razdvajanje složene smeše ispitivanih supstanci su dobijeni primenom linearne
regresione metode parcijalno najmanjih kvadrata - PLS (Partial Least Squares) i
nelinearne metode veštačkih neuronskih mreža sa višeslojnim perceptronom - ANNMLP
(Artificial Neural Network - Multilayer Perceptrons)...
Ziprasidone is a novel atypical antipsychotic drug, benzisothiazol piperazinyl
indolone derivative, which is used for the treatment of schizophrenia and for the acute
maniac or mixed episodes associated with bipolar disorder. Primarily, it acts through the
serotonergic and dopaminergic receptor antagonism, but also as an inhibitor of the
norepinephrine reuptake. Ziprasidone has a unique human receptor binding profile
which may be related to its clinical effectiveness with a low propensity for side effects.
In the framework of this doctoral dissertation, development and optimization of
reversed phase liquid chromatographic methods for determination of ziprasidone
content, related substances and retention characteristics of ziprasidone and its impurities
(I-V), significantly different in polarity, were performed with use of several methods of
experimental design. Quantitative Structure Retention Relationships (QSRR) of these
compounds in RP-HPLC system were performed and appropriate math...ematical QSRR
models able to predict retention of new ziprasidone derivatives were developed. During
the optimization of the RP-HPLC method, an unknown impurity has been detected,
which was successfully characterized with use of tandem mass spectrometry.
Optimization of the RP-HPLC-UV method was performed in two stages:
optimization of mobile phase and investigation of selectivity of RP columns under
selected experimental conditions towards ziprasidone and its five main impurities and
the unknown impurity. The influence of different chromatographic factors (buffer pH,
column temperature, buffer and organic modifier concentration) on the resolution and
selectivity factors of critical peak pairs were investigated. The optimal chromatographic
conditions for the separation of complex mixture of investigated substances were
obtained with use of the Partial Least Square (PLS) regression analysis and non-linear
statistical method Multi Layer Perceptron Artificial Neural Networks - ANN-MLP...