Enantiomers Of Basic Drugs Research Articles

Carboxymethylated maltodextrin as a chiral selector for the separation of some basic drug enantiomers using capillary electrophoresis

In this work, carboxymethylated maltodextrin (Cm-MD) was successfully synthesized as an efficient anionic chiral selector and applied for the enantiomer separation of some basic drugs including tramadol, venlafaxine, verapamil, hydroxyzine, citalopram, fluoxetine, and amlodipine by capillary electrophoresis (CE). The synthesized chiral selector was characterized by the nuclear magnetic resonance and Fourier transform infrared spectrophotometry. Under the optimized Cm-MD modified CE conditions (background electrolyte: phosphate buffer (pH 5.0, 50 mM) containing 5% (w/v) Cm-MD; applied voltage: 20 kV; and capillary column temperature: 25 °C), successful enantiomer separation of all studied chiral drugs were observed. By comparison of Cm-MD and MD for enantiomer separation of the model drugs, it was revealed that Cm-MD exhibits a higher resolution in comparison to the MD modified CE. This enhanced resolution could be attributed to the electrostatic interactions between the cationic drugs and anionic Cm-MD and opposite direction mobility of the host-guest complex relative to the chiral analyte. The optimized Cm-MD modified CE method was successfully used for the assay of the enantiomers of citalopram and venlafaxine in commercial tablets. The proposed method showed the linear range of 5.0–150.0 mg/L and 10.0–150.0 mg/L for both enantiomers of citalopram and venlafaxine, respectively. The limits of quantification were 5.0 and 10.0 mg/L for the enantiomers of citalopram and venlafaxine, respectively. The limit of detection for all enantiomers was found to be < 3.0 mg/L. Intra- and inter-day RSDs (n = 4) were less than 9.7%. The relative errors were less than 9.4% for all enantiomers. The obtained results in this research show that Cm-MD as a new, efficient and inexpensive chiral selector can be used for enantiomer separation of basic drugs using the CE technique.

Enantioseparation of basic drugs by reverse phase high-performance liquid chromatography system using carboxymethyl-β-cyclodextrin as chiral mobile phase additive.

A rapid and efficient method was developed for enantioseparation of basic drugs, using carboxymethyl-β-cyclodextrin (CM-β-CD) as chiral mobile phase additive, rather than involving costly chiral column in high-performance liquid chromatography (HPLC) system. Four of the six basic drug enantiomers investigated were successfully separated. The highest resolution reaches 2.15 for threo-(1S,2S)-2-amino-l-p-nitrophenyl-1,3-propanediol. The effects of the organic modifier, pH value, concentration of chiral additive, column temperature, and flow rate of mobile phase on the enantioseparation of analytes were researched. The apparent formation constants of inclusion and the thermodynamic parameters were evaluated to explain the mechanism of chiral recognition.

Separation of enantiomers of chiral basic drugs with amylose- and cellulose- phenylcarbamate-based chiral columns in acetonitrile and aqueous-acetonitrile in high-performance liquid chromatography with a focus on substituent electron-donor and electron-acceptor effects

In this study, amylose- and cellulose-phenylcarbamate-based chiral columns with different chiral-selector (CS) chemistries were compared to each other for the separation of enantiomers of basic chiral analytes in acetonitrile and aqueous-acetonitrile mobile phases in HPLC. For two chemistries the amylose-based columns with coated and immobilized CSs were also compared. The comparison of CSs containing only electron-donating or electron-withdrawing substituents with those containing both electron-donating and electron-withdrawing substituents showed opposite results for the studied set of chiral analytes in the case of amylose and cellulose derivatives. Along with the chemistry of CS the focus was on the behavior of polysaccharide phenylcarbamates in acetonitrile versus aqueous acetonitrile as eluents. In agreement with earlier results, it was found that in contrast to the commonly accepted view, polysaccharide phenylcarbamates do not behave as typical reversed-phase materials for basic analytes either. In the range of water content in the mobile phase of up to 20–30% v/v the behavior of these CSs is similar to hydrophilic interaction liquid chromatography (HILIC)-type adsorbents. This means that with increasing water content in the mobile phase up to 20–30% v/v, the retention of analytes mostly decreases. The important finding of this study is that the separation efficiency improves for most analytes when switching from pure acetonitrile to aqueous acetonitrile. Therefore, in spite of reduced retention, the separation of enantiomers improves and thus, the HILIC-range of mobile phase composition, offering shorter analysis time and better peak resolution, is advantageous over pure polar-organic solvent mode. Interesting examples of enantiomer elution order (EEO) reversal were observed for some analytes based on the content of water in the mobile phase on Lux Cellulose-1 and Lux Amylose-2 columns.

A novel open-tubular capillary electrochromatography using carboxymethyl-β-cyclodextrin functionalized gold nanoparticles as chiral stationary phase.

Enantioselective open tubular capillary electrochromatography with carboxymethyl-β-cyclodextrin conjugated gold nanoparticles as stationary phase was developed. This novel open tubular column was fabricated through layer-by-layer self-assembly of gold nanoparticles on a 3-mercaptopropyl-trimethoxysilane-modified fused-silica capillary and subsequent surface functionalization of the gold nanoparticles through self-assembly of 6-mercapto-β-cyclodextrin. The 6-mercapto-β-cyclodextrin was firstly synthesized and determined by extensive spectroscopic data. Scanning electron microscopy, energy dispersive X-ray analysis spectroscopy, and electroosmotic flow experiments were carried out to characterize the prepared open tubular column. Then, the separation effectiveness of the open tubular column was verified by two pairs of ɑ-tetralones derivatives enantiomers and two pairs of basic drug enantiomers (tramadol hydrochloride and zopiclone) as mode analytes. Factors that influence the enantioseparation were optimized, and under the optimized conditions, satisfactory separation results were obtained for the four enantiomers: compound A, compound B, tramadol hydrochloride, and zopiclone with resolutions of 3.79, 1.56, 1.03, 1.60, respectively. For the combination of gold nanoparticles and negatively charged carboxymethyl-β-cyclodextrin, the open tubular column exhibited wider separation range for neutral and basic drugs. Moreover, the repeatability and stability of the column were studied through the run-to-run and day-to-day investigations.

Application of Guanidine Hcl to Improve Enantioseparation of a Model Basic Drug, Cetirizine, By Capillary Electrophoresis Using Sulfated Β-Cyclodextrin.

A common approach in resolving enantiomers of chiral basic drugs by capillary electrophoresis (CE) is to use cyclodextrins (especially their anionic derivatives) as chiral selector in the acidic buffer (pH ≤ 3) in normal or reversed (carrier) mode. Then, some organic modifiers are added to the buffer solution if the resolution is not satisfactory. In case of cetirizine (CTN), applying the same approach, i.e. a reversed mode capillary zone electrophoresis (CZE) method with an acidic buffer and sulfated-β-cyclodextrine (S-bCD) as chiral selector, was failed and no complete enantioseparation was achieved. Different organic modifiers, like urea and triethylamine HCl, were used to improve chiral resolution which led to partial resolution of the two peaks. Then, guanidine HCl at a concnetration of 100 mM was added to the running buffer and an acceptable resolution of the enantiomers of the drug was obtained. The method was successfully applied to determine optical purity of a levo-cetirizine (l-CTN) sample.

Effect of basic and acidic additives on the separation of some basic drug enantiomers on polysaccharide-based chiral columns with acetonitrile as mobile phase.

The separation of enantiomers of 16 basic drugs was studied using polysaccharide-based chiral selectors and acetonitrile as mobile phase with emphasis on the role of basic and acidic additives on the separation and elution order of enantiomers. Out of the studied chiral selectors, amylose phenylcarbamate-based ones more often showed a chiral recognition ability compared to cellulose phenylcarbamate derivatives. An interesting effect was observed with formic acid as additive on enantiomer resolution and enantiomer elution order for some basic drugs. Thus, for instance, the enantioseparation of several β-blockers (atenolol, sotalol, toliprolol) improved not only by the addition of a more conventional basic additive to the mobile phase, but also by the addition of an acidic additive. Moreover, an opposite elution order of enantiomers was observed depending on the nature of the additive (basic or acidic) in the mobile phase.

Combination of capillary electrophoresis, molecular modelling and nuclear magnetic resonance to study the interaction mechanisms between single-isomer anionic cyclodextrin derivatives and basic drug enantiomers in a methanolic background electrolyte

In order to improve our knowledge of the mechanisms of enantiomer recognition pattern in nonaqueous systems, an approach combining nonaqueous CE (NACE), molecular modelling and NMR was undertaken. Bupivacaine and propranolol were selected as model compounds and their interactions with two single-isomer highly charged β-CD derivatives, namely heptakis(2,3-di-O-methyl-6-O-sulfo)-β-CD (HDMS-β-CD) and heptakis(2,3-di-O-acetyl-6-O-sulfo)-β-CD (HDAS-β-CD), were studied. The CD-bupivacaine complexes were evaluated by 2-D Rotating-frame Overhauser Effect SpectroscopY (ROESY) experiments. From these experiments, it can be assumed that inclusion complexes are not formed, whatever the CD derivative used. Molecular modelling was performed at the RHF/MINI-1 or B3LYP/6-31G(d) level. External as well as inclusion type complexes with the alkyl chain of propranolol into both CD cavities were located. Interaction energies calculated for bupivacaine and propranolol correlated with the enantiomer migration order observed in the NACE experiments using both anionic CD derivatives. The interaction of propranolol with HDMS-β-CD or HDAS-β-CD gives rise to a family of external and inclusion complexes in which some are more probably obtained.

Evaluation of chlorine containing cellulose‐based chiral stationary phases for the LC enantioseparation of basic pharmaceuticals using polar non‐aqueous mobile phases

The discrimination ability of three cellulose-based chiral stationary phases (CSPs) was evaluated towards the enantiomers of basic drugs, using ACN as the main solvent in polar organic mobile phases. The study was focused on CSPs containing cellulose tris(3-chloro-4-methylphenylcarbamate) (3-Cl-4-MePC), cellulose tris(4-chloro-3-methylphenylcarbamate) (4-Cl-3-MePC) or cellulose tris(3,5-dichlorophenylcarbamate) (3,5-diClPC) as the chiral selector. The behaviour of these CSPs was studied systematically in order to investigate the influence of the presence and position of the chlorine substituents on the phenylcarbamate moieties on the retention and resolution of the enantiomers. The evaluation was made with three different generic mobile phases, namely ACN/0.1%DEA/0.1% TFA (DEA, diethylamine), ACN/0.1%DEA/0.2% FA and ACN/0.1%DEA/0.2%AcA, deduced from the previous study. The nature of the acidic additive and of the chiral selector was found to be particularly important for the retention and enantioresolution of these basic compounds. High-resolution values could be obtained for most studied enantiomers with these CSPs, clearly demonstrating the interest of using them in combination with polar organic mobile phases. However, significant differences in enantioresolution between the CSPs have been observed for many compounds, indicating that these phases seem to be quite complementary.

Enantioselective Separation of Basic Drugs by CE with Polygalacturonic Acid as a Novel Chiral Selector

Polygalacturonic acid, a linear high molecular weight homopolysaccharide was investigated as a chiral selector in capillary zone electrophoresis for the separation of enantiomers of basic drugs. The choices of running buffer pH and concentration of chiral selector were found to be important for the improvement of enantioselectivity. The effects of background electrolyte concentration and the capillary temperature on the separation were also examined. Enantioseparations were carried out in the acidic conditions using 1.5% polygalacturonic acid (w/v) in a 40 mM phosphate buffer under an applied voltage of 15 kV. The optimization of these separations was dependent on the nature of the analytes and could be achieved by the proper choice of experimental conditions. A brief mechanism of enantiorecognition by polygalacturonic acid was also given.

Separation of Enantiomeric Basic Drugs by Microemulsion Electrokinetic Chromatography with Chiral 2-Octanol as the Oil Core

The effects of oil substitution on separation of the enantiomers of basic drugs by microemulsion electrokinetic chromatography (MEEKC) have been studied. The presence of the chiral oils (S)-(+)-2-octanol or (R)-(-)-2-octanol in the microemulsion droplets seemed to have a very important effect on the mechanism of chiral separation. The importance of hydrogen bonding between the β-amino proton of the test solutes [(±)-ephedrine, (±)-norephedrine, and DL-propranolol] and the hydroxyl oxygen of the chiral selector (chiral 2-octanol) is suggested. Addition of methanol to the chiral MEEKC system had a large effect on this hydrogen bonding and thus on chiral discrimination, probably because competition of between the solutes and the methanol for binding to the hydrogen-bonding site on the chiral selector in the microemulsion system. The order of elution of the (±)-norephedrine enantiomers can be reversed by switching from (S)-2-octanol to (R)-2-octanol in the microemulsion system.

Influence of the nature of the electrolyte on the chiral separation of basic compounds in nonaqueous capillary electrophoresis using heptakis(2,3-di- O-methyl-6- O-sulfo)-β-cyclodextrin

The influence on the enantiomeric resolution of the nature of the cationic BGE component (sodium, ammonium or potassium) and that of the anionic component (chloride, formate, methanesulfonate or camphorsulfonate) as well as the concentration of heptakis(2,3-di- O-methyl-6- O-sulfo)-β-cyclodextrin (HDMS-β-CD), the selected chiral selector, was studied in nonaqueous capillary electrophoresis (NACE). For this purpose, two D-optimal designs with 33 and 26 experimental points were applied. Three β-blockers (atenolol, celiprolol and propranolol) and three local anesthetics (bupivacaine, mepivacaine and prilocaine) were selected as basic model compounds. Both cationic and anionic BGE components were found to have a deep impact on the enantiomeric resolution of the investigated analytes but it is the cationic component that has shown the strongest influence. Indeed, in some cases, the change of the latter led to a complete loss of enantioresolution. Based on the observed results, two NACE systems were recommended, namely ammonium formate and potassium camphorsulfonate in a methanolic solution containing HDMS-β-CD and acidified with formic acid, in order to separate efficiently the enantiomers of basic drugs.

Separation of basic drug enantiomers by capillary electrophoresis using chicken alpha1-acid glycoprotein: insight into chiral recognition mechanism.

Recombinant chicken alpha(1)-acid glycoprotein (alpha(1)-AGP) was prepared by the Escherichia coli expression system and completely deglycosylated alpha(1)-AGP (cd-alpha(1)-AGP) was obtained by treatments of native alpha(1)-AGP with a mixture of endoglycosidase and N-glycosidase. The average molecular masses of chicken alpha(1)-AGP, cd-alpha(1)-AGP and recombinant alpha(1)-AGP were estimated to be about 29 200, 21 700 and 20 700, respectively, by matrix-assisted laser desorption-time of flight-mass spectrometry. We compared the chiral recognition ability of chicken alpha(1)-AGP, cd-alpha(1)-AGP and recombinant alpha(1)-AGP using them as chiral selectors in capillary electrophoresis. The chicken alpha(1)-AGP showed higher resolution for eperisone, pindolol and tolperisone than cd-alpha(1)-AGP or recombinant alpha(1)-AGP. Recombinant alpha(1)-AGP still showed chiral recognition for three basic drugs tested. By addition of propranolol as a competitor in the separation solution in CE, no enantioseparations of three basic drugs were observed with chicken alpha(1)-AGP, cd-alpha(1)-AGP or recombinant alpha(1)-AGP. These results reveal that the protein domain of the chicken alpha(1)-AGP is responsible for the chiral recognition ability, and that the chiral recognition site(s) for basic drugs exists on the protein domain.

Separation of basic drug enantiomers by capillary electrophoresis using methylated glucuronyl glucosyl β-cyclodextrin as a chiral selector

Separations of basic drug enantiomers by capillary electrophoresis have been investigated using methylated glucuronyl glucosyl β-cyclodextrin (Me GUG β-CD) as the chiral selector in the background electrolyte. Methylation was performed by reaction with methyl iodide, barium oxide, and barium hydroxide in dimethylformamide, varying the reaction temperature and time. The resulting Me GUG β-CD derivatives differed in their degree of substitution and were characterized using matrix-assisted laser desorption ionization time-of-flight mass spectra. Among the Me GUG β-CD derivatives prepared, the one with a degree of substitution of 2.8 showed the highest resolution abilities for basic drug enantiomers. Chiral resolution of 16 basic drugs was attained using the Me GUG β-CD derivative (10 mM solution in 40 mM sodium phosphate buffer at pH 3.5). The chiral recognition abilities of Me GUG β-CD were compared with those of GUG β-CD. Me GUG β-CD showed higher resolution for bupivacaine, clorprenaline, isoprenaline, pindolol, salbutamol, and terbutaline than GUG β-CD, while GUG β-CD showed higher resolution for atenolol, chlorpheniramine, dimethindene, homochlorcyclizine, ketamine, piperoxan, promethazine, propranolol, trimetoquinol, and verapamil than Me GUG β-CD. Thus, Me GUG β-CD and GUG β-CD can be complementarily used for the resolution of basic drug enantiomers.

Separation of basic drug enantiomers by capillary zone electrophoresis using glucuronyl glucosyl beta-cyclodextrin as a chiral selector.

Separations of basic drug enantiomers have been investigated using glucuronyl glucosyl beta-cyclodextrin (GUG beta-CD) as a chiral selector in the background electrolyte by capillary zone electrophoresis. The effects of GUG beta-CD concentration and running buffer pH on the migration times and resolution of 16 basic drug enantiomers were precisely examined using a linear polyacrylamide-coated capillary. High resolution of 16 basic drug enantiomers was generally attained with a running buffer pH 2.5 or 3.5 containing 10 mM GUG beta-CD. Next, we compared the chiral resolution abilities of GUG beta-CD with those of beta-CD and maltosyl beta-CD (G2 beta-CD). GUG beta-CD showed higher resolution for basic drug enantiomers tested than beta-CD and G2 beta-CD. This could be due to that hydrogen bonding or ionic interactions of uncharged and charged glucuronyl glucosyl groups of GUG beta-CD with an analyte could stabilize the inclusion complex.

Separation of basic drug enantiomers by capillary zone electrophoresis using glucuronyl glucosyl β-cyclodextrin as a chiral selector

Separations of basic drug enantiomers have been investigated using glucuronyl glucosyl beta-cyclodextrin (GUG beta-CD) as a chiral selector in the background electrolyte by capillary zone electrophoresis. The effects of GUG beta-CD concentration and running buffer pH on the migration times and resolution of 16 basic drug enantiomers were precisely examined using a linear polyacrylamide-coated capillary. High resolution of 16 basic drug enantiomers was generally attained with a running buffer pH 2.5 or 3.5 containing 10 mM GUG beta-CD. Next, we compared the chiral resolution abilities of GUG beta-CD with those of beta-CD and maltosyl beta-CD (G2 beta-CD). GUG beta-CD showed higher resolution for basic drug enantiomers tested than beta-CD and G2 beta-CD. This could be due to that hydrogen bonding or ionic interactions of uncharged and charged glucuronyl glucosyl groups of GUG beta-CD with an analyte could stabilize the inclusion complex.

Separation of basic drug enantiomers by capillary electrophoresis using ovoglycoprotein as a chiral selector: Comparison of chiral resolution ability of ovoglycoprotein and completely deglycosylated ovoglycoprotein

Separations of basic drug enantiomers by capillary electrophoresis (CE) using ovoglycoprotein (OGCHI) as a chiral selector are described. The effects of running buffer pH and 2-propanol content on the migration times and resolution of basic drug enantiomers were examined using a linear polyacrylamide-coated capillary. High resolution of basic drug enantiomers was attained using a mixture of 50 mM sodium phosphate buffer (pH 4.5–6.0) and 2-propanol (5–30%) including 50 νM OGCHI. It was found that ionic and hydrophobic interactions could work for the recognition of basic drug enantiomers. Further, we compared the chiral resolution ability of OGCHI with that of completely deglycosylated OGCHI (cd-OGCHI) using them as chiral selectors in CE. OGCHI showed higher resolution for basic drug enantiomers tested than cd-OGCHI. The results suggest that the chiral recognition site(s) for OGCHI exists on the protein domain of OGCHI.

Chiral resolution of basic drugs by capillary electrophoresis with new glycosaminoglycans

New glycosaminoglycans, fucose-containing glycosaminoglycan (FGAG) and depolymerized holothurian glycosaminoglycan (DHG), were investigated as chiral additives for the separation of drug enantiomers by capillary electrophoresis. The average molecular masses of FGAG and DHG were estimated to be about 59 000 and 14 000, respectively. A variety of basic drug enantiomers were resolved using 10 m M phosphate buffer, pH 5.0, containing 3% FGAG or DHG. Since chiral recognition properties of FGAG and DHG are different, some drug enantiomers were only separated by using FGAG or DHG. With regard to comparison of chiral recognition abilities of FGAG and DHG with other chiral selectors, tolperisone and eperisone enantiomers were not separated with α- or β-cyclodextrin, or heparin as the chiral additives, but were separated with FGAG and DHG. The results obtained reveal that FGAG and DHG are useful as the chiral selectors for separations of drug enantiomers by CE, and that they could be complementarily used with other chiral additives.

ChemInform Abstract: Separation of Basic Drug Enantiomers by Capillary Electrophoresis with New Glycosaminoglycan.

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Separation of basic drug enantiomers by capillary zone electrophoresis using ovoglycoprotein as a chiral selector

The utilization of crude ovomucoid from chicken egg whites (OMCHI) for the separation of drug enantiomers as a chiral selector in capillary zone electrophoresis (CZE) proved to be unsatisfactory. Because only about 10% ovoglycoprotein (OGCHI), which is responsible for chiral recognition ability, was included in crude OMCHI, we investigated the utilization of OGCHI as a chiral selector in CZE. To avoid protein adsorption on the wall, two kinds of modified capillaries, a vinyl capillary and a linear polyacrylamide-coated capillary, were employed. Separations of basic drug enantiomers were achieved by optimizing the concentrations of OGCHI and running buffer, running buffer pH, and the nature and content of organic modifier. The present method was successfully applied to the assay of eperisone enantiomers.

Separation of Basic Drug Enantiomers by Capillary Electrophoresis with New Glycosaminoglycan

Abstract A new fucose-containing glycosaminoglycan was investigated as the chiral additive for the separation of basic drug enantiomers by capillary electrophoresis. Tolperisone and eperisone enantiomers were not separated with α- or β-cyclodextrin, or heparin as the chiral additive, but were separated with the new fucose-containing glycosaminoglycan. A variety of basic drug enantiomers were resolved using 2-5%(w/w) solution of the glycosaminoglycan in 10 mM phosphate buffer (final pH 5.0).