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The new drug ODE-TFV and flavonoids chiral resolution of

Author: SunYaNan
Tutor: MaChen
School: Beijing Union Medical College
Course: Drug analysis
Keywords: chiral separation chiral stationary phase chiral mobile phase ODE-TFV flavonoids enantiomers
CLC: R917
Type: Master's thesis
Year: 2013
Downloads: 19
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Abstract


Living organisms are based on a plethora of chiral molecules and often display different biological responses to drug enantiomers when they are dosed separately.It is not uncommon for one enantiomer to be active while the other is toxic in biological systems.Thus,the FDA has required evaluation of each enantiomer in developing stereoisomeric drugs.As a result,the pharmaceutical industry has raised its emphasis on the generation of enantiomerically pure compounds before undertaking pharmacokinetic, metabolic,physiological and toxicological evaluation in the search for drugs with greater therapeutic benefits and low toxicity.Enantioselective chromatography using HPLC has become the most widely utilized technique in the context of obtaining limited quantities of pure enantiomers quickly,particularly in drug discovery.In this paper,the separation of the new drugs ODE-TFV and14kinds of flavonoids has been investigated by means of chiral stationary phase (CSP) or by the use of chiral mobile phase method (CMPA) respectively.Chapter2, A HPLC method was developed for the new drug ODE-TFV on chiral columns Chiralcel OZ-H.The influence of different alcohol modifier in the mobile phase on the chiral recognition was studied and the difference of the pH in mobile phase and flow rate on Chiralcel OZ-H was compared.The final conditions as follows,mobile phase:n-hexane/ethanol/diethylamine/trifluoroacetic acid(82/16/0.1/0.025, V/V/V/V);The flow rate was set at1mL·min-1;the column temperature was35℃.The UV detection was carried out at260nm,Rs=2.1. Methodology validation results show good linearity with in the test ranges of0.542to108.4μg/mL for ODE-TFV (R).The precision of ODE TFV (R) were1.8%(0.542μg/mL),0.8%(10.84μg/mL).At the same time,the detection limit and the quantitative limit were0.2μg/mL and0.4μg/mL,respectively.The method was quick、sensitive and valid.It can apply to make sure the quality of ODE-TFV.Chapter3, Using high performance liquid chromatography (HPLC) method,14kinds of flavonoids compounds were investigated, main content is divided into two parts.To perform chiral separation of14flavonoids racemates, a simple and effective method was developed by using SBE-β-CD as a mobile-phase additive in HPLC system. The effects of different factors on the chiral separation were investigated. The analysis was carried out on Kromasil100-5C18(250mm×4.6mm,5μm), The mobile phase consisted of acetonitrile and a solution added with10mmol/L SBE-β-CD (containing20mmol/L KH2PO4,at pH2.0adjusted with phosphoric acid aqueous solution)20:80,V/V. The flow rate was set at1mL/min,the column temperature was25℃. The results show that,Using sulfonated butylether-β-cyclodextrin (SBE-P-CD) as a mobile-phase additive can separate five racemates,for respectively,dihydrogendaidzin、naringenin、alpinetin、 hesperetin and equol. When HP-β-CD was as mobile-phase additive,the four compounds can successfully enantioseparated,for respectively,dihydrogendaidzin^homoeriodictyo、alpinetin and equol.The final condition as follows, The mobile phase consisted of acetonitrile and a solution added with25mmol/L HP-P-CD (containing20mmol/LKH2PO4)20:80, V/V. This two method might be applied to separate various types of flavanoids enantiomers in the chemical structure.13kinds of chiral separation of flavonoids were successfully enantioseparated on Chiralpak AD-H and Chiralcel OZ-H,only Rotenone was not enantioseparated.The influence of different alcohol modifier in the mobile phase on the chiral recognition was studied and the difference between chiral recognition of racemic flavonoids on Chiralpak AD-H and Chiralcel OZ-H was compared.The final chromate graphic conditions on Chiralpak AD-H and Chiralcel OZ-H chiral column, mobile phase I hexane/isopropyl nlcohol/trifluoroacetic acid (TFA)(75/25/0.1); mobile phase II:hexane/ethanol/irifluoroacetic acid (75/25/0.1); Flow rate was0.5mLmin"’; column temperature was35℃; detection wavelength was290nm. The results show that the different ethanol additive on Chiralpak AD-H has the different influence; however, isopropyl alcohol is slightly superior to ethanol on the cellulose chiral column Chiralcel OZ-H. Overall, the amylose chiral column and the cellulose chiral column has certain complementation for the chiral separation of flavonoids.The results of the two chiral column were different, so concluded that the separation mechanism is also drfferent.Due to the mechanism of chiral resolution is not very clear, it need to constantly attempt and research.This research provide the foundation data for the exploration in this field.

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