Chiral Separation Ability Research Articles

Cellulose as a membrane material for optical resolution

Applications of l-Glu molecularly imprinted cellulose membranes to chiral separation were studied. LiCl, which was adopted to dissolve cellulose into solvent, N,N-dimethylactamide (DMAc), worked well as a print molecule to construct recognition sites toward Li+ (or LiCl). The chiral separation ability was greatly dependent on LiCl. The permselectivity was increased with the LiCl concentration and asymptotically reached the maximum value at higher LiCl concentration region. The affinity constants between LiCl and LiCl recognition sites in both control and l-Glu molecularly imprinted membranes were determined to be 65 mol−1 dm3.

Evaluation of the chiral separation ability of single-isomer cationic β-cyclodextrins in capillary electrophoresis.

Eight single-isomer ammonium-β-cyclodextrin derivatives with different side chains were successfully developed as chiral selectors for the chiral separation of selected racemates in capillary electrophoresis. The number of substituted groups at N-atom as well as the alkyl chain length greatly influenced the chiral separation. With the numbers of hydroxylalkyl groups at N-atom growing, the aqueous solubility of resolving agents were distinctly decreased and chiral separation ability was also significantly reduced. The apparent complex stability constants between CDs and analytes were further determined. The best enantioseparations of hydroxyl acids was achieved with the use of mono-6(A) -(3-hydroxypropyl)-1-ammonium-β-cyclodextrin chloride and mono-6(A) -(3-methoxypropyl)-1-ammonium-β-cyclodextrin chloride. The nuclear magnetic resonance experiments were carried out using them with mandelic acid as guest molecules, revealing the inclusion pattern as well as electrostatic interactions and hydrogen bonding interactions as additional chiral driving force. The contribution of potential interaction sites in the sidearm could enhance the enantioseparations.

Enantioseparation and Determination of Propranolol in Human Plasma on a New Derivatized β-Cyclodextrin-Bonded Phase by HPLC

A 6-azido-β-cyclodextrin was synthesized and derivatized with p-nitrophenyl isocyanate as chiral ligand. Then the ligand was chemically bonded to mesoporous SBA-15 via a ‘Click Chemistry’ reaction of the azido group with alkynyl group. A new p-nitrophenylcarbamoylated β-cyclodextrin bonded SBA-15 chiral stationary phase (NPCSP) for HPLC was thus obtained. The new stationary phase was first used for enantioseparation of propranolol in human plasma under the polar organic solvent mode. The effects of methanol content, concentration of glacial acetic acid/triethylamine in mobile phase and the temperature on the enantioseparation were studied in detail. The optimized chromatographic conditions were as follows: mobile phase was acetonitrile/methanol/glacial acetic acid/triethylamine (90/10/1.25/2.25, V/V) at 288 K, with a flow rate of 0.5 mL min−1, an injection volume of 20 μL and detection wavelength at 290 nm. The resolution was 2.04 with a short run time (< 15 min) under the optimal conditions. The content of propranolol in plasma was quantitatively measured by HPLC-MS under selected ion monitoring mode ([M + H]+ m/z 260.10) with hydrochlorothiazide as an internal standard. The good linear relationship was observed in the range of 2.5−50 μg L−1. The detection limits were 1 μg L−1 according to S/N = 3 for both enantiomers. The experimental results showed that the chiral stationary phase exhibited excellent chiral separation ability to propranolol. The analytical method for propranolol enantiomers was sensitive, accurate, simple and fast, which was can be for the determination of propranolol in plasma and related pharmacokinetic studies.

Enantioselective Separation of Racemic Amlodipine by Two-Phase Chiral Extraction Containing O,O′-Dibenzoyl-(2S,3S)-Tartaric Acid as Chiral Selector

A two-phase chiral extraction system containing O,O′-dibenzoyl-(2S,3S)-tartaric acid ((+)-DBTA) in 1-decanol organic phase and aqueous phase was developed for the chiral resolution of amlopidine. The effects of extractant concentration, equilibrium time, and pH of the aqueous phase on the separation performance were investigated. The results indicated that the system afforded a strong chiral separation ability; the (+)-DBTA showed a higher recognition ability toward (S)-amlodipine than the (R)-amlodipine. Upon a single extraction, the enantiomeric excess (%) of (S)-amlodipine could be enriched to 24.27%. The product recovery ratio was 0.74. The distribution ratios for (S)-amlodipine (D S ), (R)-amlodipine (D R ) and separation factor (α) were 1.28, 0.78, and 1.64, respectively. Therefore, the pH and concentration of the extractant have the great effects on chiral separation ability. Two-phase chiral extraction has great significance for preparative separation of (S)-amlodipine; it can also be used to design and scale up the enantioselective separation process.

Chromatographic Properties of a “Comb-like” Chiral Stationary Phase Prepared via Atom Transfer Radical Polymerization

A “comb-like” chiral stationary phase was developed using surface-initiated technique via atom transfer radical polymerization (ATRP). Chlorinated silica gel was produced as the ATRP initiator in a one-step reaction with thionyl chloride. This initiation method results in a hydrolytically stable initial Si–C bond for poly(glycidyl methacrylate) (pGMA) chains grafted on the surface of silica gel. β-Cyclodextrin (β-CD) was immobilized on the pGMA chains with ring opening reaction to prepare the chiral stationary phase. This “comb-like” chiral stationary phase with the different pGMA chain length was evaluated by enatioseparation of structurally diverse racemic compounds under reversed-phase high-performance liquid chromatography. The chromatographic results demonstrate the effective chiral separation ability of the new chiral stationary phase.

Cellulose 2,3-Di(p-chlorophenylcarbamate) Bonded to Silica Gel for Resolution of Enantiomers

In this study, 6-azido-2,3-di(p-chlorophenylcarbamoylated) cellulose was synthesized and bonded onto aminized silica gel to obtain a new chiral stationary phase. Enantioselectivity of the chiral stationary phase and Chiralcel OF suggested promising chiral separation ability of the new cellulose chiral stationary phase. In addition, the effect of trifluoroacetic acid, diethylamine on enantioselectivity and retention factors on the chiral stationary phase in high performance liquid chromatography was investigated. Experimental results revealed that resolution increased as the trifluoroacetic acid concentration increased to 0.3% while resolution declined as the diethylamine concentration increased. Therefore, the optimal concentrations of trifluoroacetic acid and diethylamine were determined to be 0.3 and 0.1%, respectively. In most cases, trifluoroacetic acid shortened the retention of the first eluted enantiomer while it increased the retention of the other. For acidic compounds, with the existence of diethylamine in the mobile phase, the retention of both enantiomers decreased. But for basic compounds, the retention of both enantiomers increased.

Chiral Polyurea with L-Lysinyl Residue Aimed for Optical Resolution

Novel polyurea was synthesized from lysinyl residue, L-lysine-4-nitroanilide (L-Lys-4-NA) and 1,4-phenylene diisocyanate (1,4-PDI). The polyurea thus prepared gave durable self-standing membranes. The polyurea was converted into molecular recognition materials by using Z-D-Glu or Z-L-Glu as a print molecule. The Z-D-Glu molecularly imprinted membrane adsorbed the D-isomer of Glu in preference to the corresponding L-isomer and vice versa. Even though the polyurea consisted of L-lysinyl residue, both Z-D-Glu and Z-L-Glu worked as print molecules to construct molecular (chiral) recognition sites in the membrane. Those two types of molecularly imprinted membrane show chiral separation abilities, adopting a concentration gradient or an applied potential difference as a driving force for membrane transport.

Polymeric pseudo-liquid membranes from poly(octadecyl methacrylate)

The novel liquid membrane system, which is named polymeric pseudo-liquid membrane, was constructed from poly(octadecyl methacrylate) (PC18MA), which showed a rubbery state under operating conditions, as a membrane matrix, and dibenzo-18-crown-6 (DB18C6) for the transport of KCl or O-allyl-N-(9-anthracenylmethyl)cinchonidinium bromide (AAMC) for that of racemic mixture of phenylglycine (Phegly) as a carrier. The results of KCl transport revealed that KCl transport was attained by carrier-diffusion mechanism even though membrane matrix was composed of polymeric material. The polymeric pseudo-liquid membrane containing chiral carrier AAMC showed optical resolution ability, in other words, the membrane selectively transported l-Phegly and its permselectivity toward l-Phegly reached 1.48 at the operating temperature of 40°C. Chiral separation ability was greatly dependent on the operating temperature and a wide range of permselectivity from l-isomer to d-isomer permselectivity was attained by adjusting the operating temperature. The present study revealed that the polymeric pseudo-liquid membrane is a promising membrane system in membrane separation.

Synthesis and application of a chiral ionic liquid functionalized β‐cyclodextrin as a chiral selector in capillary electrophoresis

A novel chiral ionic liquid functionalized β-cyclodextrin, 6-O-2-hydroxpropyltrimethylammonium-β-cyclodextrin tetrafluoroborate ([HPTMA-β-CD][BF4]), was synthesized and used as a chiral selector in capillary electrophoresis. [HPTMA-β-CD][BF4] not only increased the solubility in aqueous buffer in comparison with the parent compound, but also provided a stable reversal electroosmotic flow, and the enantioseparation of eight chiral drugs was examined in phosphate buffer containing [HPTMA-β-CD][BF4] as the chiral selector. The effects of the [HPTMA-β-CD][BF4] concentration and the background electrolyte pH were studied. Moreover, the chiral separation abilities of β-CD and [HPTMA-β-CD][BF4] were compared and possible mechanisms for the chiral recognition of [HPTMA-β-CD][BF4] are discussed.

Polysulfones with Phenylalanine Derivatives as Chiral Selectors – Membranes for Chiral Separation

Polysulfone with a derivative of phenylalanyl residue as a chiral selector (PSf-Ac-D-Phe or PSf-Ac-L-Phe) were prepared by polymer reaction of benzylamine-modified polysulfones with N-a-acetyl-D-phenylalanine or N-a-acetyl-L-phenylalanine. Both polysulfones having a chiral selector gave durable self-standing membranes. The specific rotations of those polymers revealed that the chiral selectors were successfully introduced into the polysulfone. PSf-Ac-D-Phe membrane incorporated L-Glu in preference to D-Glu and vice versa. The chiral separation ability was studied by applying a concentration gradient as a driving force for membrane transport. Permselectivities for those two types of membrane reflected their adsorption selectivities. PSf-Ac-D-Phe membrane selectively transported L-Glu and vice versa. Predicted permselectivities by adopting membrane resistance coincided with the observed ones.

Polyurea Bearing L-Lysinyl Residue as a Chiral Building Block and Its Application to Optical Resolution

Chial polyureas were prepared from L-Lys-OEt and 2,4-TDI. The optimum polyaddition conditions were determined as follows: [L-Lys-OEt] = 2.08 x 10-1 mol dm-3 and [2,4-TDI] = 2.50 x 10-1 mol dm-3 ([L-Lys-OEt]/[2,4-TDI] = 0.83). The polyuera thus obtained gave a durable self-standing membrane and it was directly converted into molecular recognition membranes by applying an alternative molecular imprinting. The D-isomer molecularly imprinted membrane adsorbed the D-isomer in preference to the L-isomer and vice versa. In the present study, two types of print molecule, such as Z-D-Glu and Z-L-Glu, worked as print molecules though the polyurea consisted of L-lysinyl residue. Those two types of molecularly imprinted membrane showed chiral separation ability. The membrane, which was molecularly imprinted by the D-isomer and preferentially incorporated the D-isomer into the membrane, selectively transported the D-isomer and vice versa.

Separation mechanism of chiral stationary phase based on quinine and crown ether for the direct stereoselective separation of amino acids

A novel chiral stationary phase combining quinine and crown ether (QN-CR CSP) was developed to separate amino acid enantiomers. This CSP showed good enantioselectivity for some amino acids. Since the synergistic effect of ion exchange and complexation in chiral recognition of amino acids, a new adsorption isotherm was built. Using the method of frontal analysis by characteristic point (FACP), the adsorption isotherms of tryptophan (Trp) under different mobile phase conditions were determined and fitted the proposed adsorption isotherm model well. With the increase of the competition between metal cationic and amino to crown ether, the equilibrium constant of complexing adsorption was found increased. The chiral separation ability was decreased. The adsorption isotherm improved the understanding of the retention behavior of amino acids on QN-CR CSP, which was also benefit to optimize the structure of the stationary phase.

Chiral separation with molecularly imprinted polysulfone-aldehyde derivatized nanofiber membranes☆

Molecularly imprinted membranes (MIPMs) and molecularly imprinted nanofiber membranes (MINFMs) were prepared from polysulfone with aldehyde (PSf-CHO-05 or PSf-CHO-10) and N-α-benzyloxycarbonyl-d-glutamic acid (Z-d-Glu) or N-α-benzyloxycarbonyl-l-glutamic acid (Z-l-Glu) as a print molecule. Those two types of molecularly imprinted membrane, such as MIPMs and MINFMs, incorporated the enantiomer, of which absolute configuration was same as that of the print molecule, in preference to the corresponding antipode. In other words, the membranes imprinted by the d-isomer preferentially adsorbed the d-isomer and vice versa. Those two types of membrane showed chiral separation ability by membrane transport. Against expectation, transport of the enantiomer preferentially adsorbed in the membrane was retarded, in other words, the enantiomer less adsorbed in the membrane was selectively transported. The fluxes through the molecularly imprinted nanofiber membranes gave one to two orders of magnitude higher than those of usual molecularly imprinted membranes without depression of permselectivity. The present study demonstrated that molecularly imprinted nanofiber membrane gave high flux without depression of permselectivity. A breakthrough in membrane separation would be realized by adopting molecularly imprinted nanofiber membranes.

Chitin Nanofiber Membranes for Chiral Separation

Nanofiber membranes for chiral separation were prepared from chitin, which is the most abundant natural amino polysaccharide. The membrane showed chiral separation ability by adopting concentration gradient as a driving force for membrane transport. In other words, the chitin nanofiber membrane selectively transported the D-isomer of glutamic acid (Glu), phenylalanine (Phe), and lysine (Lys) from the corresponding racemic amino acid mixtures.

Enantioselective extraction of mandelic acid enantiomers by aqueous two-phase systems of polyethylene glycol and ammonium sulfate containing β-cyclodextrin as chiral selector

A new chiral separation technology, aqueous two-phase extraction, was proposed for the separation of racemic mandelic acid. The distribution behavior of mandelic acid enantiomers was investigated in aqueous two-phase systems composed of polyethylene glycol and ammonium sulfate containing β-cyclodextrin as chiral selector. The influences of the pH, the mass fraction of polyethylene glycol and ammonium sulfate, the polymerization degree of polyethylene glycol, the initial concentration of β-cyclodextrin, mandelic acid enantiomers and extractive temperature on the distribution behavior were studied respectively. The results show that β-cyclodextrin is inclined to recognize L-enantiomer; under the optimized conditions, the separation factor reaches 2.46 and the enantiomeric excess is 42.13% in the top phase and 40.43% in the bottom phase, respectively. Aqueous two phase chiral-extraction with strong chiral separation ability, plays great role in preparative separation of racemic compounds and is important for the development of aqueous two phase extraction technique.

Enantioselective partitioning of 2-phenylpropionic acid enantiomers in a biphasic recognition chiral extraction system

This work reports enantioselective partitioning of 2-phenylpropionic acid enantiomers in a biphasic recognition chiral extraction (BRCE) system combining hydrophobic L- iso-butyl tartrate in organic phase and hydrophilic hydroxypropyl-β-cyclodextrin in aqueous phase which preferentially recognize S-enantiomer and R-enantiomer, respectively. In BRCE system, the concentrations of the extractants and 2-phenylpropionic acid enantiomers, the types of organic solvents and extractants, pH and temperature all exert a considerable influence on the biphasic recognition process. The two-dimensional interpolation method is utilized to explore the influence of the concentrations of selectors and enantiomers on distribution ratios and separation factors in single stage BRCE systems. High separation factors are obtained at low pH value under condition that the concentrations of HP-β-CD and L- iso-butyl tartrate are about 0.1 mol/L and 0.2 mol/L, respectively. BRCE is of strong chiral separation ability. From monophasic recognition chiral extraction (MRCE) system into BRCE system, the separation factor increases from 1.08 to 1.69.

Equilibrium Studies on Liquid-Liquid Reactive Extraction of Phenylsuccinic Acid Enantiomers Using Hydrophilic β-CD Derivatives Extractants

This paper deals with the enantioseparation of phenylsuccinic acid (H 2A) enantiomers by liquid-liquid reactive extraction using β-CD derivatives as aqueous selectors. Cyclodextrin and its derivatives can interact with guest molecules selectively to form complexes with different stabilities. Cyclodextrin derivatives are not soluble in organic liquids, but highly soluble in water. In this work, hydroxypropyl- β-cyclodextrin (HP- β-CD), hydroxyethyl- β-cyclodextrin (HE- β-CD) and methyl- β-cyclodextrin (Me- β-CD) were selected as chiral selectors in aqueous phase for the reactive extraction of phenylsuccinic acid enantiomers from organic phase to aqueous phase. The results show that the efficiency of the extraction depends, often strongly, on a number of process variables, including the types of organic solvents and β-CD derivatives, the concentrations of the extractants and H 2A enantiomers, pH and temperature. HP- β-CD, HE- β-CD and Me- β-CD have stronger recognition abilities for R-phenylsuccinic acid than for S-phenylsuccinic acid. Among the three kinds of β-CD derivatives, HP- β-CD has the strongest separation ability. Excellent enantioseparation was achieved under the optimal conditions of pH of 2.5 and temperature of 5°C with a maximum enantioselectivity ( a) of 2.38. Reactive extraction of enantiomers with hydrophilic β-CD derivatives is of strong chiral separation ability and can be hopeful for separations of various enantiomers at a large-scale.

Transformation of Intact Chicken Feathers into Chiral Separation Membranes

Intact chicken feathers, most of which are currently discarded by incineration, were decayed by Meiothermus ruber H328 at the moderate aerobic conditions of 60°C so that they could be utilized as raw materials. The degraded chicken feather thus obtained was converted into membranes in the presence of reducing agent of 1-octanethiol. The membrane showed chiral separation ability; in other words, it transported the D-isomer of Glu and Phe, and the L-isomer of Lys from the corresponding racemic amino acid mixtures.

Optical resolution with membranes derived from marine polymers

Optical resolution with membranes derived from marine polymersNovel polyion-lipid complexes were prepared from quaterinized chitosan (QCh), which was a derivative of marine (natural) polymer, and three types of anionic amphiphile, such as sodium 1-dodecanesulfate (C12SNa), sodium 1-tetradecanesulfate (C14SNa), and sodium 1-hexadecanesulfate (C16SNa). Those complexes gave durable self-standing membranes. The QCh-lipid complex membranes prepared in the present study showed chiral separation ability; in other words, they selectively transported L-Lys from racemic mixture of Lys adopting a concentration gradient as a driving force for membrane transport. Permselectivity of QCh-C12S membrane toward L-Lys was determined to be 3.31 under the concentration difference of 1.0 × 10−3 mol dm−3. From transport experiments and adsorption studies, it was revealed that the permselectivity was dominantly determined by diffusivity selectivity. It is expected that the present study would open a door to novel materials.

Separation of flurbiprofen enantiomers by biphasic recognition chiral extraction

Based on our previous work, this paper reports enantioselective partitioning of flurbiprofen enantiomers in a biphasic recognition chiral extraction (BRCE) system combining a hydrophobic l-tartrate in organic phase and hydrophilic β-cyclodextrin derivative in aqueous phase which preferentially recognize R-enantiomer and S-enantiomer, respectively. The studies performed involve an enantioselective extraction in a biphasic system, where flurbiprofen enantiomers form four complexes with β-cyclodextrin derivative and l-tartrate, respectively. In these biphasic resolutions, the concentrations of the extractants and flurbiprofen enantiomers, the types of organic solvents and extractants, pH and temperature all exert a considerable influence on the biphasic recognition process. The maximum enantioselectivity for flurbiprofen enantiomers is 1.24 at the pH of 2.5, 5 °C, the flurbiprofen initial concentration of 0.0001 mol/L and the ratio of 2:1 of [ l- iso-butyl tartrate] to [TM-β-CD]. By changing the monophasic recognition chiral extraction (MRCE) system into BRCE system, the enantioselectivities are greatly improved. Biphasic recognition chiral extraction is of strong chiral separation ability, and can be hopeful for separations of various enantiomers at a large-scale.