Drugs In Capillary Electrophoresis Research Articles

Use of chiral ionic liquid as additive for synergistic enantioseparation of basic drugs in capillary electrophoresis

This work presents a synergistic system for enantioseparation in capillary electrophoresis (CE) with a chiral ionic liquid (CIL) based on D-10-camphorsulfonic acid as additive and carboxymethyl-β-cyclodextrin (CM-β-CD) as the chiral selector. The proposed method showed excellent enantioseparation performance towards sixteen chiral drugs. In contrast to the single CM-β-CD system, the notably improved resolution (Rs) and selectivity factor (α) of model drugs were observed in synergistic system. Several key parameters such as CIL concentration, CM-β-CD concentration, buffer pH and separation voltage were investigated, after which Statistical Product and Service Solutions (SPSS) was used to prove the potential synergistic effect. The nuclear magnetic resonance (NMR) results further demonstrated the function of the CIL and the superiority of synergistic system. Finally, chiral impurity determination of chlorpheniramine maleate sample was successfully carried out using the established method.

Investigation of the enantioselectivity of tetramethylammonium-lactobionate chiral ionic liquid based dual selector systems toward basic drugs in capillary electrophoresis.

Recently, chiral ionic liquids (CILs) have received increasing interest in chiral separation by CE. Nevertheless, the lack of deep perception of the specific mechanism about CILs in CE for enantioseparation still perplexes a legion of researchers, despite the strenuous efforts. In this paper, a lactobionic acid based ionic liquid, tetramethylammonium-lactobionate (TMA-LA) was applied for the first time in CE to establish dual selector system with clindamycin phosphate (CP) for enantiomeric separation. Compared to single CP system or single TMA-LA system significantly improved separations of seven tested rameric drugs (propranolol, nefopam, citalopram, chlorphenamine, metoprolol, bisoprolol, and esmolol) were observed in the dual selector systems. Several crucial parameters such as type and proportion of organic modifier, buffer composition and pH, and concentration of TMA-LA/CP were systematically investigated to achieve satisfied enantioseparation. Meanwhile, molecular modeling was applied to demonstrate the chiral recognition mechanism of the TMA-LA/CP dual-selector separation system using the molecular docking software Autodock, which well supported the experimental results. The existence of TMA-LA/CP complex may give rise to a higher discriminatory ability against the enantiomers, indicating the reason of improved separation in TMA-LA/CP system. All the influence factors evaluated by means of Statistical Product and Service Solutions (SPSS) to research the influences on the chiral separation system.

Enantioseparation by Capillary Electrophoresis Using Cyclodextrins in an Amino Acid-Based Ionic Liquid Running Buffer.

For enantioseparations of chiral drugs in capillary electrophoresis, chiral ionic liquids (CIL) can be employed instead of traditional running buffer containing a chiral selector. CILs can be applied solely or in addition to the often used cyclodextrin derivatives. Here the separation of phenethylamines, especially of ephedrine, is described using tetrabutylammonium L-argininate (125mM) in phosphate buffer (75mM, pH1.5) in addition to β-cyclodextrin (30mM). Using this dual-chiral running buffer system ephedrine, pseudoephedrine and methylephedrine, but not norephedrine, could be easily resolved.

Study of the enantioselectivity and recognition mechanism of chiral dual system based on chondroitin sulfate D in capillary electrophoresis.

Several chiral reagents including cyclodextrins (CDs) and derivatives, crown ethers, proteins, chiral surfactants, and polymers have been involved in dual-selector systems for enantioseparation of a series of compounds by capillary electrophoresis (CE). In this paper, chondroitin sulfate D-based dual-selector system (CSD/CM-β-CD)was firstly established and investigated for the enantioseparation of six basic racemic drugs in capillary electrophoresis. Compared to the single-selector systems, synergistic effect and significantly improved separations for all tested analytes were observed in CSD/CM-β-CD system. The effect of several parameters, such as buffer pH, chiral selector concentration, and applied voltage, was systematically optimized. Meanwhile, to investigate the possible chiral recognition mechanisms in CSD/CM-β-CD synergistic system, we tried to apply the molecular docking method to simulate the host-guest binding procedures of the polysaccharide-based dual system for the first time. The difference in binding free energy was found to correspond to the chiral selectivity factor. The existence of CSD-CM-β-CD complex may give rise to a higher discriminatory ability against the enantiomers, indicating the synergistic effect in CSD/CM-β-CD system. Graphical abstract ᅟ.

Synergistic effect of field enhanced sample injection on micelle to solvent stacking in capillary electrophoresis

Injection of a sodium dodecyl sulfate micellar plug prior to the sample solution induced transient micellar phase extraction of cationic drugs in capillary electrophoresis. Micelle to solvent stacking mechanism was utilized by preparing the sample in aqueous organic solvent. Synergism was achieved with field enhanced sample injection that allowed larger sample loads. Micelle to solvent stacking occurred concurrently with the enhanced injection after the fast moving analytes electrophoretically migrated into the micellar plug. This was different from stacking combinations with field enhancement where the electric field strength difference was involved in analyte focusing. Using a sample diluent that had one-tenth the conductivity of the background solution, the strategy afforded thousands-fold improvements in peak height and LODs (S/N=3) of as low as 1.1ng/mL. The results were repeatable and linear. Adaptability to real sample analysis was evaluated using spiked urine sample after minimal sample clean-up.

Micelle to solvent stacking of tricyclic psychiatric drugs in capillary electrophoresis

A capillary electrophoresis (CE) method with UV-detection based on preconcentration with on-line micelle to solvent stacking (MSS) was optimized and validated to the simultaneous determination of tricyclic psychiatric drugs in urine samples. Sample preparation was based on liquid–liquid extraction (LLE) of analyzed drugs from biological samples. The electrophoretic conditions were: separation buffer composed of 40mM sodium dihydrogen phosphate (pH 3.7) and 60% methanol (v/v), uncoated fused silica capillary (75μm i.d.×57cm length), UV spectrophotometric detection at 254nm, injection time 90s at 3.45kPa, applied voltage 25kV, and temperature 22°C. The advantage of proposed MSS strategy is its improved limit of detection of analytes compared to traditional CE technique. This is important for the analysis of drugs presented at very low concentration in biological samples. The developed CE method allows determination of psychotropic drugs at ng/ml level in human urine. This is the first report, presenting the possibility of determination of these drugs in urine samples by MSS–CE.

Evaluation of clarithromycin lactobionate as a novel chiral selector for enantiomeric separation of basic drugs in capillary electrophoresis

Nowadays, macrocyclic antibiotics are presenting an increasing number of enantioseparation applications. The macrocyclic antibiotics used as chiral selectors in capillary electrophoresis (CE) include the ansamycins and the glycopeptides. The macrolides, another important class of macrocyclic antibiotics, have been reported as a new type of chiral selectors recently. In this study, clarithromycin lactobionate (CL), belonging to the group of macrolide antibiotics, was first investigated for its potential as a novel chiral selector in CE for enantiomeric separation of several basic drugs. As observed, CL allowed excellent separation of the enantiomers of metoprolol, atenolol, propranolol, bisoprolol, esmolol, ritodrine, and amlodipine, as well as partial enantioresolution of labetalol and nefopam. In addition, CL possesses advantages such as high solubility and low viscosity in the solvent and very weak UV absorption. In the course of this study, it was found that both migration times and enantioseparation of the basic drugs were influenced by several experimental parameters, e.g. selector concentration, the composition and pH of the BGE, the type and concentration of organic modifier, and applied voltage. Thus, the effects of these factors were systematically investigated, and satisfactory enantioseparations of the studied drugs were achieved at the buffer pH range of 7.3-7.5 using 12.5 mM borax buffer with 50% v/v methanol, 60 mM CL, and 20 kV applied voltage. Moreover, comparison of the influences of the studied parameters was further investigated by means of Statistical Product and Service Solutions (SPSS) in this article.

Evaluation of the enantioselectivity of glycogen-based dual chiral selector systems towards basic drugs in capillary electrophoresis

Several chiral reagents including cyclodextrins (CDs) and derivatives, crown ethers, proteins, chiral surfactants and polymers have been involved in dual selector systems for enantioseparation of a series of chiral compounds by capillary electrophoresis (CE). In comparison to the chiral reagents above-mentioned, there is no report concerning the use of polysaccharides in dual chiral CE system. In this paper we first investigate the enantioselectivity of polysaccharide-based dual selector systems towards some chiral drugs. During our recent work, glycogen belonging to the class of branched polysaccharides has been used as a novel chiral selector in CE. In this study, three glycogen-based dual chiral CE systems have been established for enantiomeric separations of several racemic basic drugs consisting of duloxetine, cetirizine, citalopram, sulconazole, laudanosine, amlodipine, propranolol, atenolol and nefopam. These three dual systems combined glycogen (neutral polysaccharide) with chondroitin sulfate A (CSA, ionic polysaccharide), β-CD and HP-β-CD, respectively. It was found that the dual system of glycogen/CSA exhibited good enantioselective properties toward the tested drugs. More importantly, compared to the single selector systems, synergistic effect was observed when glycogen was used with CSA for most of the analytes. This indicated the enhancement of enantioseparation observed for these analytes in glycogen/CSA system might be due to some favorable interaction effects between glycogen and CSA. Moreover, in order to evaluate the stereoselectivity of glycogen/CSA, the influences of buffer pH and selector concentration on enantioseparation of the studied drugs were also investigated.

Comparison of chiral separation of basic drugs in capillary electrophoresis and liquid chromatography using neutral and negatively charged cyclodextrins

Liquid chromatography (LC) and capillary electrophoresis (CE) are very widely used as chiral separation methods. In this publication we try to find if the results obtained in CE and LC with the chiral selector added to the electrolyte and the mobile phase, respectively, can be used as tools for studying weak stereoselective interactions, and how this information can be useful for optimizing chiral separation processes. The manuscript presents a systematic comparison of chiral discrimination of model compounds in HPLC and CE using neutral and negatively charged cyclodextrins. The enantiomeric separation of basic chiral pharmaceuticals such as pheniramine, brompheniramine, metoxyphenamine, cyclopentolate, doxylamine and ketamine was investigated in capillary electrophoresis (CE) and liquid chromatography (HPLC) using negatively charged sulfated-beta-cyclodextrin (S-beta-CD) and neutral cyclodextrins (CDs). The apparent stability constants between the model compounds and cyclodextrins were estimated in both techniques. We discuss the influence of the stability constant and K1/K2 ratio of the investigated complexes on chiral separation obtained in both techniques.

A novel QSPR study of normalized migration time for drugs in capillary electrophoresis by new descriptors: Quantum chemical investigation

Some drugs' migration time (MT) has been studied employing quantitative structure-property relationship using new descriptors that are able to predict MT value with high accuracy. MT property modeling of the drugs was established as a function of the new theoretically derived descriptors applying multiple linear regressions and partial least-squares regression. The genetic algorithm was used to select those variables that resulted in the best-fitted models. To select a set of descriptors that are most relevant to MT, illustrating the affecting degree for the affinity of different descriptors, the linear models with 1-14 variables were constructed and were then investigated based on F-value, squared regression coefficients of cross-validated (Q2), adjusted R2 (R2adj) and standard error of estimate (S) statistical parameters. Finally, the best model with ten variables was selected. Statistical parameters of the test set, such as standard deviation error in test, were 0.559 and 0.616, while relative error of test was equal to 7.648 and 8.497% for multiple linear regressions and partial least-squares models, respectively, confirming the good predictive ability of the model. Since the capillary lengths were not the same for the drugs in the data set, MT values were normalized based on a specific capillary before modeling, which is also one of the advantages of this method, enabling us to use the model for different capillary lengths.

Effect of structure modification of chondroitin sulfate C on its enantioselectivity to basic drugs in capillary electrophoresis

The effect of structure modification of chondroitin sulfate C on its enantioselectivity to several representative basic drugs in capillary electrophoresis was investigated. Chemical desulfation showed no remarkable decrease in selectivity, whereas depolymerization with chondroitinase ABC resulted in complete loss of selectivity. Comparison with chondroitin sulfate A indicated considerable decrease in selectivity with this isomer. The great retention of enantioselectivity in the desulfated derivative suggests that the selectivity comes from the difference of the magnitude of an interaction in the multipoint mechanism between a part of the drug molecule and a functional group in chondroitin sulfate C other than the sulfate group. The sulfate group is not considered to play a major role for chiral separation. The complete loss of selectivity by depolymerization is consistent with a general tendency of lower selectivity in smaller saccharides, and the priority of chondroitin sulfate C to chondroitin sulfate A suggests the importance of the hydroxyl group at C 4 in the galactosamine residue. During the course of this work we observed heavy tailing of the peaks of basic drugs in some batches of uncoated fused-silica capillaries under acidic conditions and solved this problem by doubly coating capillaries with Polybrene followed by chondroitin sulfate C. On the other hand, we demonstrated the usefulness of a special technique which uses a short, wider bore PTFE tube-attached capillary for the study of the effect of depolymerization, in order to minimize sample amount.