Use of polystyrene nanoparticles to enhance enantiomeric separation of propranolol by capillary electrophoresis with Hp-beta-CD as chiral selector

We describe the use of polystyrene (PS) nanoparticles to manipulate chiral selectivity of propranolol analysis by capillary electrophoresis, by dispersing PS nanoparticles into the run buffer employing hydroxypropyl-β-cyclodextrin (HP-β-CD) as chiral selector. Distinct separational differences are observed between the buffer containing PS nanoparticles and buffer without, when changing separating conditions including PS nanoparticles concentration, pH, buffer concentration, HP-β-CD concentration and when adding an organic additive. Selectivity improvements are reflected by changes in the observed mobility as a result of interactions between the propranolol enantiomers and HP-β-CD governing the absorption process on the PS particles surface. The presence of PS nanoparticles increases the enantioseparation at low particle concentration in the presence of HP-β-CD as a chiral selector.     

Enantioseparation Of Aromatic Dipeptides Using Carboxymethyl-β-Cyclodextrin Polymer As Chiral Selector By Capillary Electrophoresis

ABSTRACT

Chiral separation of peptides is of interest because of the different biological activity of enantiomers. In this report, several underivatized dipeptides with benzene moieties were optically resolved by employing carboxymethyl-β-cyclodextrin polymer(CM-β-CD polymer) as chiral selector. The effects of different cyclodextrin types, selector concentration, buffer pH, and organic additive were examined. Selector concentration and buffer pH played significant roles in resolution. Enantioseparation was found to be negatively influenced by adding the organic additive into running buffer and even completely lost at the organic additive content of 16%. It was also noted that the dipeptides with short chain in the vicinity of the second chiral carbon atom showed better chiral resolution by using CM-β-CD polymer than by using either carboxyethyl-β-CD or succinylated-β-CD. Simultaneous chiral separation of a mixture of DL-Ala-DL-Phe and DL-Leu-DL-Phe was also obtained using 27 mg/ml CM-β-CD polymer in the running buffer at pH5.12.     

Comparative NMR and MS studies on the mechanism of enantioseparation of propranolol with heptakis(2,3-diacetyl-6-sulfo)-β-cyclodextrin in capillary electrophoresis with aqueous and non-aqueous electrolytes

In our recent studies, the reversal of the enantiomer migration order (EMO) was observed with heptakis (2,3-dimethyl-6-sulfo)-β-CD (HDMS-β-CD) when aqueous electrolyte was changed with nonaqueous electrolyte in CE. One-dimensional rotating frame nuclear Overhauser effect spectroscopy experiments prevailed that an inclusion complex was formed between the analyte and the chiral selector in the aqueous buffer, whereas an external complex resulted when a methanolic electrolyte was employed. In the case of the similarly substituted heptakis (2,3-diacetyl-6-sulfo)-β-CD (HDAS-β-CD), the external complex was observed in the aqueous buffer but an inclusion complex was formed in methanolic electrolyte. In contrast to heptakis (2,3-dimethyl-6-sulfo)-β-CD, no reversal of the enantiomer migration order was observed with HDAS-β-CD. In the present study, further mechanisms of enantioselective recognition and separation of propranolol enantiomers with HDAS-β-CD were investigated by using different techniques of nuclear magnetic resonance spectroscopy and high-resolution mass spectrometry. To the best of our knowledge, enantioselective nuclear Overhauser effect was observed for the first time in this study.     

Separation of chiral drugs with sulfobutylether-β-cyclodextrin bycapillary zone electrophoresis

IntroductionChaedcyclodextrlnswerefirstIntroducedby几rabelforchlralseparationofamlnoacids,andthechargedCDcommonlyusednowdaysarecarboxymethyl－p－CD（CM－p－CD）,p－CD－phosphate,Y－CD－phosphate,sulfobutylether－p－cyclodextrln（SBE－p－CD）etc．...     

6-O-(2-hydroxybutyl)-β-CD as a chiral selector for nonaqueous capillary electrophoretic separation of chiral drugs

6-O-(2-hydroxybutyl)-β-CD, as a new β-cyclodextrin (β-CD) derivative, was successfully synthesized. It was used as a chiral selector to separate six chiral drugs, including propranolol, anisodamine, promethazine, ketoconazole, benzhexol, and fenfluramine in nonaqueous capillary electrophoresis (NACE). The effects of the organic solvent, the electrolytes, the concentrations of cyclodextrin derivatives, and the pH of the buffer on the chiral resolution (Rs) were investigated. The baseline separation of enantiomers, including propranolol (Rs = 2.26), anisodamine (Rs = 2.31), promethazine (Rs = 2.42), ketoconazole (Rs = 2.56), benzhexol (Rs = 3.38), and fenfluramine (Rs = 3.04), could be achieved using a buffer of 100 mmol · L^t−1 citric acid and 50 mmol · L^t−1 Tris (hydroxymethyl) aminomethane (Tris) at pH 4.6 containing 100 mmol · L^t−1 6-O-(2-hydroxybutyl)-β-CD in formamide (FA).     

Chiral Separation of Ibuprofen and Terbutaline by Nonaqueous Capillary Electrophoresis with Conductance Detection

IntroductionThe separation of chiral substances is a chal-lenge task to analytical chemistry and pharmaceuti-cal chemistry.HPLC[1] and GC[2 ] are the commonchiral separation techniques.Unfortunately,theyare time- consuming and strenuous.In addition,thechiral separation columns are expensive and thebaseline separation is hard to be obtained.Recently,the researches of chiral separationwith capillary electrophoresis have been active[3 ,4 ] .However,the instrument with an optical detectorcosts …     

毛细管区带电泳对手性药物盐酸美西律和盐酸异博定的对映体分离

应用环糊精-毛细管区带电泳体系对手性药物盐酸美西律和盐酸异博定的对映体分离进行了研究。结果表明, 在所研究的手性选择剂α-环糊精, β-环糊精, 二甲基-β-环糊精, 羟丙基β-环糊精和γ-环糊精中, 羟丙基β-环糊精对所研究的手性药物分离效果较好。对盐酸美西律和盐酸异博定的最佳羟丙基-β-环糊精浓度分别为30mmol/L和9mmol/L, 最佳缓冲溶液浓度为100mmol/L Tris-H3PO4(pH2.3)。向缓冲溶液中加入0.05%羟丙基纤维素(HPLC)可改善分离。盐酸美西律获得了接近基线的手性分离, 而盐酸异博定亦获得了较好的分离。     

Optimized Conditions of Enantioseparation of β-Blockers by CZE Using Carboxymethyl-β-Cyclodextrin as Chiral Selector

Capillary zone electrophoresis was used for the enantiomeric separation of six β-blocking drug substances with β-cyclodextrin (β-CD) and its derivatives as chiral selectors employing an uncoated capillary. The effects of pH value and composition of the background electrolyte (BGE), the capillary temperature and running voltage have been investigated. The results showed that β-CD type, concentration and pH value have a strong influence on the efficiency of the chiral separation. Carboxymethyl-β-cyclodextrin (CM-β-CD) gave a baseline enantiomeric separation for six β-blocking drug substances under optimal conditions, whereas the β-CD, hydroxypropyl-β-cyclodextrin (HP-β-CD) showed no chiral recognition. The potential and capillary temperature did not have a great effect on enantiomer resolution.     

新型三唑类抗真菌活性化合物毛细管电泳手性拆分及手性识别机理分子模拟研究

研究了7种新型三唑类抗真菌活性化合物的毛细管电泳法手性分离,利用计算机辅助分子模拟技术研究拆分机理。考察了8种中性环糊精手性添加剂,只有2,6-二甲基-β-环糊精对7种活性化合物都有手性识别能力。在30mmol/L NaH2PO4缓冲液中含2,6-二甲基-β-环糊精30mmol/L,用H3PO4调至pH 2.2,温度20℃,电压20kV,在此条件下7种活性化合物都能达到手性分离,其中4种活性化合物能达到基线分离(Rs>1.5)。应用计算机辅助分子模拟软件Discovery Studio 2.5/Sybyl/Gold模拟2,6-二甲基-β-环糊精与7种活性化合物主客体包结过程,并计算相互结合能,探讨手性识别机理,发现拆分结果与结合能的差异有关,结合能差异越大拆分结果越好。     

Optimization and Parameter Study for Chiral Separation by Capillary Electrophoresis

Orthogonal design and uniform design were used for the optimization of separation of enantiomers using 2,6-di-O-methyl-β-cyclodextrin (DM-β-CD) as a chiral selector by capillary zone electrophoresis. The concentration of DM-β-CD, buffer pH, running voltage, and capillary temperature were selected as variable parameters, their different effects on peak resolution were studied by the design methods. It was concluded that orthogonal design offers a rapid and efficient means for testing the importance of individual parameters and for determining the optimum operating conditions. However, for a large number of both factors and levels, uniform design is more efficient. The effect of addition of methanol and citric acid buffer on the separation of enantiomers was also examined.     

Enantiomeric Separation of β-Amino Alcohols by Capillary Electrophoresis Using DM-β-CD as Chiral Selector

Enantiomeric separations of several β-amino alcohol drugs, i.e., phenylephrine, epinephrine, norepinephrine, synephrine, and chlorprenaline were performed by capillary electrophoresis using DM-β-CD as a chiral selector. Five test solutes were baseline resolved in six minutes. The effects of DM-β-CD concentration, pH value, ionic strength of the buffer, and the type of β-CDs on resolution were investigated. The results indicated that DM-β-CD is suitable for enantiomeric separation of β-amino alcohols containing a phenyl group on the chiral atom. Enantiorecognition mechanisms for test solutes are also discussed.     

Zeolitic imidazolate framework-67–modified open-tubular column with cyclodextrin for enantioseparation in capillary electrochromatography

The histidine-modified zeolitic imidazolate framework [His-ZIF-67] was prepared with the histidine, 2-methylimidazole, and Co²⁺ under ambient temperature. His-ZIF-67 was bonded via a glycidyl methacrylate copolymer to the internal surface of capillary and then functionalized with the NH₂-β-cyclodextrin (NH₂-β-CD). The materials were characterized by field emission scanning electron microscopy, high-resolution transmission electron microscopy, thermogravimetric analysis, Fourier transform infrared spectroscopy, N₂ adsorption–desorption isotherm, X-ray diffraction, and X-ray photoelectron spectroscopy. In comparison with the NH₂-β-CD@capillary, the NH₂-β-CD@His-ZIF-67@capillary-coated column shows significantly enhanced resolution for chiral molecules. The NH₂-β-CD@His-ZIF-67@capillary column achieved the baseline separation of amlodipine and metoprolol (the resolution of amlodipine: 1.70; metoprolol: 1.50) and the partial separation of atenolol and propranolol (the resolution of atenolol: 1.03; propranolol: 0.60). These were attributed to the histidine modification and the features of ZIF-67, including an excellent surface area and the abundant porosity. The pH and proportion of organic modifier in the buffer were crucial for enantioseparation performance and were evaluated in detail. The fabricated NH₂-β-CD@His-ZIF-67@capillary-coated column showed good stability and repeatability (relative standard deviation <6.3%). The molecular modeling with AutoDock and grand canonical ensemble was carried out to evaluate the interactions between chiral stationary phase and racemic drugs.     

Synthesis and application of a novel single-isomer mono-6-deoxy-6-(3R,4R-dihydroxypyrrolidine)-β-cyclodextrin chloride as a chiral selector in capillary electrophoresis

A novel positively charged single-isomer of β-cyclodextrin, mono-6-deoxy-6-(3R,4R-dihydroxypyrrolidine)-β-CD chloride (dhypy-CDCl), was synthesized and employed as a chiral selector for the first time in capillary electrophoresis (CE) for the enantioseparation of anionic and ampholytic acids. The effects of the running buffer pH, chiral selector concentration, analyte structure and organic modifier on the enantioseparation were studied in detail. The chiral selectivity and resolution for most of the studied analytes decreased as the buffer pH increased in the range of 6.0–9.0. Increasing selector concentration led to decreased effective mobility, increased chiral selectivity and resolution for most of the studied analytes. Moreover, the hydroxyl groups located on the dihydroxypyrrolidine substituent of the dhypy-CDCl could have influence on the chiral separation.     

Determination of aminoglutethimide enantiomers in pharmaceutical formulations by capillary electrophoresis using methylated-β-cyclodextrin as a chiral selector and computational calculation for their respective inclusion complexes

A capillary electrophoretic method for the separation of the aminoglutethimide (AGT) enantiomers using methylated-β-cyclodextrin (M-β-CD) as chiral selector is described. Several parameters affecting the separation were studied, including the type and concentration of chiral selector, buffer pH, voltage and temperature. Good chiral separation of the racemic mixture was achieved in less than 9 min with resolution factor Rs = 2.1, using a fused-silica capillary and a background electrolyte (BGE) of tris-phosphate buffer solution (50 mmol L⁻¹, pH 3.0) containing 30 mg mL⁻¹ of M-β-CD. The separation was carried out in normal polarity mode at 25 °C, 16 kV and using hydrostatic injection. Acceptable validation criteria for selectivity, linearity, precision, and accuracy/recovery were included. The proposed method was successfully applied to the assay of AGT enantiomers in pharmaceutical formulations. The computational calculations for the inclusion complexes of the R- and S-AGT-M-β-CD rationalized the reasons for the different migration times between the AGT enantiomers.     

基于非手性离子液体的毛细管电泳法拆分3种手性药物

建立了以非手性离子液体1-正丁基-3-甲基咪唑氯(［BMIM］Cl)为手性分离的添加剂、β-环糊精作为手性选择剂的毛细管区带电泳(CZE)分离扑尔敏、氯霉素前体和氧氟沙星3种对映体的方法,并与未添加［BMIM］Cl的CZE分离情况进行了对比研究。发现［BMIM］Cl对手性药物的拆分有协同作用,不仅能够增加对映体的分离度,还能有效地抑制毛细管内壁对样品分子的吸附作用,改善峰形。采用离子液体辅助手性选择剂(尤其是环糊精)的CZE改进方法,为其他毛细管电泳难以分离的手性药物的分离分析提供了新的方法。     

Analysis of repaglinide enantiomers in pharmaceutical formulations by capillary electrophoresis using 2,6-di-o-methyl-β-cyclodextrin as a chiral selector

This study used the general applicability of 2,6-didi-o-methyl-β-cyclodextrin (DM-β-CD) as the chiral selector in capillary electrophoresis for fast and efficient chiral separation of repaglinide enantiomers. A systematic study of the parameters affecting separation was performed with UV detection at 243 nm. The optimum conditions were determined to be 1.25% (w/v) DM-β-CD in 20 mM sodium phosphate (pH 2.5) as the running buffer and separation voltage at 20 kV. DM-β-CD had the best enantiomer resolution properties under the tested conditions, whereas other β-cyclodextrins showed inferior performances or no performance. The proposed method had a linear calibration curve in the concentration range of 12.5-400 μg/mL. The limit of detection was 100 ng/mL. The intra-day and inter-day precisions were 2.8 and 3.2%, respectively. Recoveries of 97.9-100.9% were obtained. The proposed method was fast and convenient, and was determined to be efficient for separating enantiomers and applicable for analyzing repaglinide enantiomers in quality control of pharmaceutical production.     

竞争包结法研究β-环糊精及其两种衍生物对一些手性脂肪族客体分子的识别作用

以酚酞作为光谱探针 ,采用紫外 可见光谱滴定法测定了 β 环糊精 (β CD)、单 (6 氧 α 麦芽糖 ) β 环糊精 (6 G2 β CD )和单 [2 氧 (2 羟丙基 ) ] β 环糊精 (2 HP β CD )在 2 5℃时 ,pH =10 5缓冲液中(0 0 2 5mol/L)与几种脂肪族手性客体分子所形成超分子配合物的稳定常数 .结果表明 ,多种弱相互作用力协同作用于环糊精的配位过程 ,主 客体间的尺寸匹配决定所形成配合物的稳定性 .环糊精衍生物的取代基影响主体的配位能力 ,对于尺寸较小的客体分子配位能力的大小一般为 2 HP β CD >β CD >6 G2 β CD .另一方面 ,3种环糊精主体化合物对一些脂肪族客体分子也表现出一定的手性识别能力 ,对 (+ ) 异构体给出相对较强的键合能力 ,其中 ,2 HP β CD对 (+ ) /(- ) 樟脑的配位选择性为 1 2 5 .     

Enantiomeric separation of (R, S)-naproxen by recycling high speed counter-current chromatography with hydroxypropyl-β-cyclodextrin as chiral selector

Recycling high speed counter-current chromatography (HSCCC) was successfully applied to resolution of (R, S)-naproxen (NAP) using hydroxypropyl-β-cyclodextrin (HP-β-CD) as chiral selector. The two-phase solvent system composed of n-hexane-ethyl acetate-0.1 mol L(-1) phosphate buffer solution with pH=2.67 (8:2:10, v/v/v) was selected. Influence factors for the chiral separation process were investigated, including concentration of HP-β-CD, equilibrium temperature and pH of aqueous phase. Suitable elution mode was selected for HSCCC enantioseparation of (R, S)-NAP. Under optimum separation conditions, 29 mg of (R, S)-NAP was separated using preparative recycling HSCCC with the molar ratio HP-β-CD/NAP racemate 83:1. Technical details for recycling elution mode were discussed as for chiral HSCCC separation. The purities of both (S)-NAP and (R)-NAP were over 99.5% as determined by HPLC. Enantiomeric excess of (S)-NAP and (R)-NAP reached 99.4%. Recovery for NAP enantiomers from HSCCC fractions was 82-89%, yielding 13 mg of (S)-NAP and 12 mg of (R)-NAP.     

Configurational stability of 9-hydroxyrisperidone. Kinetics and mechanism of racemization

The configurational stability of 9-hydroxyrisperidone, an atypical antipsychotic, was studied under acidic, basic and physiological conditions. The analysis of 9-hydroxyrisperidone was performed using a recently validated chiral capillary electrophoretic method developed using a dual cyclodextrin mode (hydroxypropylated-β-CD and sulfated-α-CD). The kinetic parameters (rate constants, half-lives, and apparent free energy barriers) of the racemization were calculated through a mathematical model of the first-order reaction. The influences of the pH, the temperature, the nature and the concentration of the buffer, and the presence of an organic co-solvent were investigated. The fastest racemizations were observed under acidic conditions with high phosphate buffer concentrations and high temperatures. Under these conditions, the cyclodextrins (β-CD, methyl- β-CD, or hydroxypropylated-β-CD) added to both enantiomers in various molar ratios were not able to retard the racemization. Finally, the mechanism of racemization was investigated using nuclear magnetic resonance (NMR) and the proton–deuterium exchange of the proton H₉ borne by the chiral carbon has proven the presence of an imine–enamine tautomerism.     

高效液相色谱手性流动相添加剂分离乳酸对映体

分别将β-环糊精、2,6－二甲基－β－环瑚精和2,3,6－三甲基－β－环糊精作为手性流动相添加剂,系统地研究了D,L-乳酸在反相HPLC系统中的拆分,考察了流动相种类,pH值和手性流动相添加剂的浓度对手性分离的影响,建立了甲基化β-环糊精动态手性固定相分离乳酸对映体的方法。