Chiral Separation Of Basic Drugs Research Articles

Design and synthesis of naphthalene-based chiral strong cation exchangers and their application for chiral separation of basic drugs.

In continuation of our efforts to synthesize a highly dedicated strong cation exchanger, we introduce four chiral stationary phases based on a laterally substituted naphthalene core featuring chiral 2-aminocyclohexansulfonic acid as the chiral cation-exchange site. The selectors were modified with two different terminal units, which enabled immobilization to the silica support by thiol-ene radical reaction or azide-yne click chemistry. The chromatographic parameters of these chiral stationary phases were determined using a set of chiral amines, mainly from the family of β-blocker pharmaceuticals. The chiral stationary phases immobilized by means of click chemistry were found to be superior to those possessing the sulfide linker to the silica support. The chromatographic results and visualization of density functional theory-calculated conformations of the selectors hint at a combination of a steric and electronic effect of the triazole ring in the course of chiral resolution of the target analytes.

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.

Retraction Note: (S)-(+)-2-Octanol as a Chiral Oil Core for the Microemulsion Electrokinetic Chromatographic Separation of Chiral Basic Drugs

Retraction Note: (S)-(+)-2-Octanol as a Chiral Oil Core for the Microemulsion Electrokinetic Chromatographic Separation of Chiral Basic Drugs

(S)-(+)-2-Octanol as a Chiral Oil Core for the Microemulsion Electrokinetic Chromatographic Separation of Chiral Basic Drugs

The enantiomeric separation of basic drugs was successfully demonstrated by using a novel chiral microemulsion electrokinetic chromatography (MEEKC). An interesting finding was that the chiral oil core ((S)-(+)-2-octanol) within the microemulsion droplets appeared to play an important role in the chiral separation mechanism. In addition, the enantioselectivity of the analyte-selector complex could be influenced by methanol, through an interaction with the complex. The chiral resolution (R(s)) and partition coefficient were strongly influenced by the concentration of methanol, pH, the concentration of chiral oil and the concentration of a cosurfactant. Under the optimized microemulsion conditions, the baseline separation of (+/-)-ephedrine (R(s) = 2.7), and the partial separations of (+/-)-norephedrine (R(s) = 1.3), (+/-)-synephrine (R(s) = 1.4) and (+/-)-propranolol (R(s) = 1.3), could be achieved.

Application of capillary electrophoresis with field-amplified sample injection for the detection of new adrenoreceptor antagonist enantiomers in plasma in the low ng/mL concentration range.

Throughout the separation of chiral basic drugs by capillary electrophoresis (CE) with neutral hydroxypropyl-beta-cyclodextrin (HP-beta-CD) as chiral selector, the sensitivity of detection has been improved by using field-amplified sample injection (FASI). In the present work, this on-line stacking method has been used to detect low ng/mL levels of cationic enantiomers of a new adrenoreceptor antagonist in plasma. A systematic study of the parameters affecting on-line concentration of these enantiomers (nature of the preinjection plug, composition of sample solvent, injection times of water and sample plugs) has been performed enabling the detection sensitivity of antagonist enantiomers to be improved by 180 times compared with usual hydrodynamic injection. The quantification of each adrenoreceptor antagonist enantiomer in plasma samples was then performed in the 2-100 ng/mL (or 8-400 nM) concentration range after a solid-phase extraction step. Using this FASI-CE-UV procedure, the limit of quantification (LOQ) for each enantiomer was in the low ng/mL concentration range (3 ng/mL or 10 nM).

Chiral separation of basic drugs by capillary electrophoresis with carboxymethylcyclodextrins

Capillary electrophoresis (CE) with carboxymethylated β- or γ-cyclodextrins was used to achieve the rapid enantiomeric separation of a set of basic drugs. The enantiomers of 12 chiral amino-containing pharmaceutical compounds belonging to various therapeutic categories were analyzed by CE using an uncoated 60 cm×75 μm I.D. silica capillary. Several experimental parameters such as the nature, concentration and pH of the buffer, nature and concentration of the anionic cyclodextrin and temperature were studied in order to optimize the enantiomeric separation. The variation of the solute partition coefficient for the chiral selector, the enantioselectivity and resolution factors are used to assess the quality of the chiral separation. It is shown that the solute affinity for the chiral selector is not related to its enantioresolution factor. None of the two cyclodextrin selectors used was able to separate the whole set of basic drugs.

Efficient applications of capillary electrophoresis–tandem mass spectrometry to the analysis of adrenoreceptor antagonist enantiomers using a partial filling technique

Throughout the separation of chiral basic drugs by capillary electrophoresis (CE) with neutral hydroxypropyl-β-cyclodextrin (HP-β-CD) as chiral selector, the sensitivity of detection can be improved by using tandem mass spectrometric (MS–MS) detection with a partial filling technique rather than with UV spectrometric detection. Prior to sample injection, the capillary was partly filled with HP-β-CD dissolved in volatile ammonium formate buffer (pH 4, ionic strength 50 m M). The effects of modifying the HP-β-CD concentration in the selector zone and the length of the separation zone on the enantioresolution and the signal-to-noise ratio of the pseudo-molecular MH + ion were investigated. For a given selector zone length, as the concentration of the neutral cyclodextrin increases, the resolution between enantiomers becomes higher (the opposite of the behavior of the signal-to-noise ratio) and then reaches an optimum value. The decrease of the selector zone length lowered the resolution between the enantiomers but increased peak efficiencies and signal-to-noise ratio values. Accordingly, partial capillary filling at 80% (v/v) and 10 m M concentration of HP-β-CD was selected as a suitable compromise between resolution and sensitivity of MS detection. Limits of detection for each adrenoreceptor antagonist enantiomer were 5 ng/ml (0.02 μ M) in CE–MS–MS instead of 150 ng/ml (0.60 μ M) in CE–UV, which enhances sensitivity by a factor of 30.

Enhancement of second-migrating enantiomer peak symmetry of basic drugs by using dual-cyclodextrin system in capillary electrophoresis

Today, chiral separations of cationic drugs by capillary electrophoresis are generally carried out by adding negatively charged cyclodextrins (CDs) to the running buffer while anionic or neutral drug separations require the use of dual-CD systems (mixtures of neutral and charged CDs). Chiral separation of some basic drugs (idazoxan, efaroxan, milnacipran) has been studied by using mixtures of sulfated-beta-CD (S-beta-CD) and hydroxypropyl-gamma-CD (HP-gamma-CD). The influence of the following parameters (nature and concentration of neutral CD, concentration of S-gamma-CD) on many separation factors (electrophoretic mobility, selectivity, efficiency, asymmetry factor, resolution) demonstrated that dual-CD systems are useful for chiral separation of basic drugs in order to improve the symmetry of the second-migrating enantiomer. Indeed, the neutral CD reduces the extent of electromigration dispersion by mobility tuning. Finally, the 0.5 mg/mL S-beta-CD/5 mg/mL HP-gamma-CD dual system has allowed the chiral separation of idazoxan, efaroxan and milnacipran enantiomers in less than 9 min.

Enhancement of second-migrating enantiomer peak symmetry of basic drugs by using dual-cyclodextrin system in capillary electrophoresis.

Today, chiral separations of cationic drugs by capillary electrophoresis are generally carried out by adding negatively charged cyclodextrins (CDs) to the running buffer while anionic or neutral drug separations require the use of dual-CD systems (mixtures of neutral and charged CDs). Chiral separation of some basic drugs (idazoxan, efaroxan, milnacipran) has been studied by using mixtures of sulfated-beta-CD (S-beta-CD) and hydroxypropyl-gamma-CD (HP-gamma-CD). The influence of the following parameters (nature and concentration of neutral CD, concentration of S-gamma-CD) on many separation factors (electrophoretic mobility, selectivity, efficiency, asymmetry factor, resolution) demonstrated that dual-CD systems are useful for chiral separation of basic drugs in order to improve the symmetry of the second-migrating enantiomer. Indeed, the neutral CD reduces the extent of electromigration dispersion by mobility tuning. Finally, the 0.5 mg/mL S-beta-CD/5 mg/mL HP-gamma-CD dual system has allowed the chiral separation of idazoxan, efaroxan and milnacipran enantiomers in less than 9 min.

Separation of chiral basic drugs with sulfobutyl-β-cyclodextrin in capillary electrophoresis

Separation of the enantiomers of 22 chiral basic drugs not previously separated with sulfobutyl-β-cyclodextrin (SBE-β-CD) as a chiral selector has been investigated by capillary zone electrophoresis. By dissolving the drug in Britton-Robinson buffer then optimization of selector concentration, pH, and amount injected, the enantiomers of 19 drugs were successfully separated, two for the first time.

Study on the chiral separation of basic drugs by capillary zone electrophoresis using β-CD and derivatized β-CDs as chiral selectors

Capillary zone electrophoresis was used for the enantiomeric separation of racemic ketamine, anisodamine and isoprenaline with β-cyclodextrin (β-CD) and β-cyclodextrin derivatives as chiral selectors employing an uncoated capillary. The β-CD types and concentrations have strong influence on the efficiency of the chiral separation. The effects of the pH and composition of the background electrolyte (BGE), the amphiphilic compound in the BGE and the capillary temperature on the mobility and chiral separation have been studied. 2,6-di- O-carboxymethyl-β-cyclodextrin (CM-β-CD) gave a baseline enantiomeric separation for the basic drugs under study, whereas the β-CD and its glutamic acid derivative, under the same experimental conditions, were poor in stereoselectivity and gave just partial chiral separation. Moreover, the acetic diamine derivative, gelatin derivative and phosphate ester derivative showed no chiral recognition. The tetraethylammonium bromide and tetrabutylammoniun bromide added to the BGE could improve the chiral separation but the hexadecyltrimethylammonium bromide made the chiral separation worse while using β-CD as chiral selector. Lower capillary temperatures were more favorable for the chiral resolution.

Ultra-fast chiral separation of basic drugs by capillary electrophoresis

Chiral separation-methods development is usually very time-consuming, due to the diversity in chemical structures of pharmaceutical drug substances as well as the suitable separation conditions and the problem to choose the appropriate chiral selector. This paper shows an ultra-fast, capillary electrophoresis based screening procedure which was developed for chiral separation of several basic pharmaceuticals using dimethyl-β-cyclodextrin as chiral selector. Complete enantiomeric separations of basic drugs (metaproterenol and isoproterenol) were achieved as fast as in 40–50 s, with an R.S.D. for the absolute migration time reproducibility of less than 0.75%. The peak efficiency of the separations was usually over one million theoretical plates per meter, which correspond to an efficiency generation rate above 30 000 plates/m s.

Chiral separation of basic drugs by capillary zone electrophoresis with cyclodextrin additives.

The enantiomers of a series of basic drugs were separated in capillary zone electrophoresis (CZE) in phosphate buffers, pH 3, containing beta-cyclodextrin or one of its derivatives as chiral selectors and uncoated fused silica capillaries thermostated at 15 degrees C. The nature of the cationic component of the background electrolyte was found to have a significant influence on achiral resolution and peak symmetry. The best results were obtained with triethanolamine, which was then used to adjust the buffer pH in all further experiments. The effects on chiral resolution of the nature and concentration of cyclodextrin, of the addition of methanol, and of capillary temperature were studied. Maximum resolution was obtained at a particular cyclodextrin concentration for each analyte, depending on the affinity of the analyte for this cyclodextrin. On the basis of the results, the effects of methanol addition and temperature on enantiomeric resolution could be explained and predicted. Numerous chiral separations are presented and suggestions for the rapid optimization of CZE enantioseparations with cyclodextrin additives are given.

Chiral separation of basic drugs using cyclodextrins as chiral pseudo-stationary phases in capillary electrophoresis

Capillary electrophoresis was used for the chiral resolution of basic racemic drugs in general and in particular for dimethindene and four possible metabolites. Conditions for optimum enantioselectivity and resolution were determined by changing the cyclodextrin type, cyclodextrin concentration, pH of the run buffer, applied current and capillary temperature.

Chiral separation of basic drugs using cyclodextrin-modified capillary zone electrophoresis

Capillary zone electrophoresis (CZE) was successfully applied to the chiral separation of basic drugs after addition of a suitable cyclodextrin chiral selector to the electrophoresis buffer. Commercially avaliable cyclodextrins (α- β-, and γ-cyclodextrin and heptakis(2,6-dl-O-methyl)-β-cyclodextrin) were evaluated for their enantioselectrivity toward 10 compounds having rather complex molecular structures. In contrast to liquid chromatographic attempts, the enantiomers of all racemates investigated could be resolved with a resolution of more than 1.4, except for one (R S 1.1), and showed theoretical plate numbers up to 265,000 with good peak shapes