Određivanje podeonih koeficijenata i solvatohromnih parametara malih organskih molekula primenom tankoslojne hromatografije i hemometrije

Abstract

Cilj ove disertacije bio je razvoj metoda tankoslojne hromatografije zaodređivanje podeonih koeficijenata, pre svega oktanol-voda (logKOW), zemljište-voda(logKOC), vazduh-voda (logKAW) i solvatohromnih (A, B i S) parametara malihorganskih molekula na osnovu kojih se, primenom pristupa lineranih odnosa energijesolvatacije (LSER), mogu dalje proceniti: stepen aporpcije u gastrointestinalnom traktu(% Abs), raspodela u sistemu krv-koža (logPskin), voda-koža (logKP, logKSC) i krvmoždana-barijera(log BBB).Za određivanje datih parametara izvorne metode su vremenski zahtevne,podrazumevaju veliku količinu analita i imaju ograničeni radni opseg. Zbog toga su uvelikoj meri zamenjene različitim hromatografskim tehnikama, pre svega visokoefikasnomtečnom hromatografijom (HPLC). Međutim, tankoslojna hromatografija imaniz prednosti nad HPLC metodom. To je jednostavna, brza, jeftina metoda, koja koristimale količine analita i reagenasa. Do sada nije sistematski ispitivana njena primena uodređivanju pomenutih parametara.U okviru ove disertacije primenjeni su različiti reverezno-fazni i normalno-faznihromatografski sistemi na skupu od 70 organskih jedinjenja malih molekulskih masa, ukombinaciji sa različitim kalibracionim tehnikama: univarijantna regresija (OLS),regresija glavnih komponenata (PCR), regresija metodom delimičnih najmanjihkvadrata (PLS). Pri tome je izvršena selekcija hromatografskih sistema i definisanjeradnih opsega za svaki od proučavanih pariticionih koeficijenata te, tipova organskihjedinjenja na koja se dati izbor hromatografskih uslova može primeniti. Razvijenipostupci su okarakterisani parametrima preciznosti, tačnosti, prediktivne moći i ostalimparametarima validacije modela

The aim of this thesis was the development of thin-layer chromatographicmethods for the determination of partition coefficients, primarily octanol-water(logKow), soil-water (logKOC), air-to-water (logKAW ) and Abraham’s solvatochromicparameters of small organic molecules which can be further used to estimate: thegastrointestinal tract absorption (%Abs), the blood to skin distribution (logPskin), water- skin (logKP, logKsc) and the blood to brain partition (logBBB).Original methods used to determine the aforementioned parameters are timeconsuming, involve a large amount of the analyte and have limited working range.Therefore, they are, to a large extent, replaced by various chromatographic techniques,especially high-performance liquid chromatography. However, thin-layerchromatography has a number of advantages over HPLC method. It is simple, fast,inexpensive method that uses small amounts of analytes and reagents. So far itsapplication in the determination of the parameters mentioned above has not beensystematically studied.In the scope of this dissertation, several reversed-phase and normal-phasechromatographic systems were applied on a set of 70 organic compounds of lowmolecular weight in order to determine the partitioning as well as solvatochromicparameters, in combination with a variety of calibration methods: univariate regression(OLS), principal component regression (PCR), partial least squares regression (PLS).For each of the studied pratitioning coefficients careful selection and definition ofchromatographic systems, operating conditions, working ranges and the types of organiccompounds on which the developed method could be applied have been done.The developed methods were fruther characterized by the parameters ofprecision, accuracy, predictive power, and other parameters of the model validation