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Preparative Enantioseparation of Racemic Aromatic Acids and Aminoalcohol Drugs by Counter-Current Chromatography

Author: ZhengZuo
Tutor: YanJiZhong
School: Zhejiang University of Technology
Course: Medicinal Chemistry
Keywords: High speed counter-current chromatography Chiralseparation Closed loop recycling mode Multiple dual mode Hydroxypropyl-β-cyclodextrin Dialkyl tartrate
CLC: O657.7
Type: Master's thesis
Year: 2013
Downloads: 58
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Abstract


This work concentrates on the application of a variety of elution modes in improving enantioseparation of racemic2-arylpropionic acids by high speed counter-current chromatography (HSCCC), including closed loop recycling elution mode and multiple dual mode elution, which could be used to make up its disadvantage to some extent. The comparison of high-speed counter-current chromatography and high performance liquid chromatography in preparative enantioseparation of racemic drug was discussed. Dialkyl L-tartrate was used as chiral selector for enantioseparation of three aminalcohol racemic drugs by analytical HSCCC. The five racemates were used:2-phenylpropionic acid (2-PPA), naproxen (NAP), propranolol, propafenone and alprenolol.1. The enantioseparation of2-PPA was established by using high performance liquid chromatography (HPLC) with hydroxypropyl--(3-cyclodextrin (HP-β-CD) as the chiral mobile phase additive and a C18reversed-phase column as the stationary phase. Influence factors for peak resolution were investigated, and the mechanism of inclusion complex between HP-(3-CD and2-PPA was studied by HPLC. Experimental results showed that the stoichiometry between the cyclodextrin host and the guest molecule was1:1.2. Closed loop recycling mode (CLRM) HSCCC was applied in resolution of2-PPA using HP-β-CD as chiral selector. The two-phase solvent system composed of n-hexane-ethyl acetate-0.1mol/L phosphate buffer solution (5:5:10, v/v/v) was selected. Influence factors for the chiral separation process were investigated and thermodynamic parameters of2-PPA-HP-β-CD inclusion complex were calculated. Langmuirian isotherm for the2-PPA enantiomers in two phase solvent system was investigated.40mg of (±)-2-PPA was separated using preparative recycling HSCCC. Resolution factor for2-PPA enantiomers was improved from0.90to1.15when CLRM HSCCC was used.3. HPLC and HSCCC were compared in preparative enantioseparation of2-PPA when HP-β-CD was used as chiral mobile phase additive. Experimental results showed that as for enantioseparation of40mg of (±)-2-PPA racemate, the two methods exhibit its advantages and disadvantages. The separation time of preparative HPLC was only75min with peak resolution Rs=0.63and reagents of chromatographic grade used while the separation time of HSCCC need340min, peak resolution was relatively little higher Rs=0.90and large cost of reagents. The peak resolution for HSCCC could be obtained with RS=1.10when recycling elution mode was used, but its separation time needs650min.4. Multiple dual mode (MDM) HSCCC was applied to resolution of NAP and2-PPA using HP-β-CD as chiral selector. The two-phase solvent systems consisting of n-hexane-ethyl acetate-0.1mol/L phosphate buffer pH2.67containing0.1mol/L HP-β-CD (7.5:2.5:10for NAP and7:3:10for2-PPA, v/v/v) were used. Conventional multiple dual mode and modified multiple dual mode were compared according to peak resolution under current separation mechanism. The influence of elution time after the first phase inversion and number of cycles for multiple dual mode were investigated. Peak resolution of NAP and2-PPA increased from0.62to1.05and0.72to0.84respectively under optimum multiple dual mode elutions.5. Dialkyl L-tartrate was used as chiral selector for enantioseparation of three aminoalcohol racemic drugs by analytical HSCCC, including propranolol, propafenone and alprenolol. A two-phase solvent system chloroform:aqueous (1:1, v/v) consisting of a chloroform solution of0.1mol/L dihexyl L-tartrate/dibutyl L-tartrate in organic phase and a0.05mol/L acetate buffer aqueous solution of0.1mol/L boric acid was used for enantioseparation of propranolol/propafenone. Influence factors for the chiral separation process were investigated. Langmuirian isotherm for the propafenone enantiomers in the two phase solvent system was investigated.

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CLC: > Mathematical sciences and chemical > Chemistry > Analytical Chemistry > Instrument analysis ( physics and physical chemistry ) > Chromatographic analysis
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