The Use of Antibiotics as Chiral Selectors in Capillary Electrophoresis: A Review.

Chirality is becoming an essential issue in modern pharmaceutical research as regulatory agencies emphasize the safety and efficiency of enantiomers in drug development. The development of efficient and reliable chiral separation methods became a necessity in the last 30 years, and capillary electrophoresis (CE), due to its relatively low costs and "green" features, is attracting increased attention. Cyclodextrin (CD) and their derivatives are the most frequently used chiral selectors (CSs) in CE, however, the use of antibiotics as CSs represents an interesting alternative. Various classes of antibiotics (aminoglycosides, ansamycins, glycopeptides, lincosamides, macrolides, tetracyclines) have been used more or less successfully for the enantio-separation of pharmaceuticals. Antibiotics offer the possibility of a multitude of potential interactions (electrostatic, inclusion, hydrogen bonding, etc.) due to their chemical diversity, allowing the enantio-separation of analytes with a wide range of structural characteristics. This article aims to review the application of various classes of antibiotics in the CE enantio-separation of pharmaceuticals. Antibiotic physiochemical characteristics, variables impacting enantio-separation, advantages, and disadvantages when certain antibiotics are used as CSs in CE are also explored.

Chiral separation in the class of proton pump inhibitors by chromatographic and electromigration techniques: An overview.

Proton pump inhibitors (PPIs) are benzimidazole-derivative chiral sulfoxides, frequently used in the treatment of gastric hyperacidity-related disorders. Due to their stereoselective metabolism, the eutomeric forms of PPIs can present a more advantageous pharmacokinetic profile by comparison with the distomers or racemates. Moreover, two representatives of the class are used in therapy both as racemates and as pure enantiomers (esomeprazole, dexlansoprazole). A relatively large number of enantioseparation methods employed for the stereoselective determination of PPIs from pharmaceutical, biological, and environmental matrices were published in the past three decades. The purpose of the current overview is to provide a systematic survey of the available chiral separation methods published since the introduction of PPIs in the therapy up to the present. Analytical and bioanalytical methods using different chromatographic and electromigration techniques reported for the enantioseparation of omeprazole, lansoprazole, pantoprazole, rabeprazole, ilaprazole, and tenatoprazole are included. The analytical conditions of the presented methods are summarized in three comprehensive tables, while a critical discussion of the applied techniques, possible mechanism of enantiorecognition, and future perspectives on the topic are also presented.

The Use of Dual Cyclodextrin Chiral Selector Systems in the Enantioseparation of Pharmaceuticals by Capillary Electrophoresis: An Overview.

Cyclodextrin (CD) derivatives are the most efficient and frequently used chiral selectors (CSs) in capillary electrophoresis (CE). There are situations when the use of a single CD as CS is not enough to obtain efficient chiral discrimination of the enantiomers; in these cases, sometimes this problem can be resolved using a dual CD system. The use of dual CD systems can often dramatically enhance enantioseparation selectivity and can be applied for the separation of many analytes of pharmaceutical interest for which enantioseparation by CE with another CS systems can be problematic. Usually in a dual CD system an anionic CD is used together with a neutral one, but there are situations when the use of a cationic CD with a neutral one or the use of two neutral CDs or even two ionized CDs can be an efficient solution. In the current review we present general aspects of the use of dual CD systems in the analysis of pharmaceutical substances. Several examples of applications of the use of dual CD systems in the analysis of pharmaceuticals are selected and discussed. Theoretical aspects regarding the separation of enantiomers through simultaneous interaction with the two CSs are also explained. Finally, advantages, disadvantages, potential and new direction in this chiral analysis field are highlighted.

Chiral discrimination of amlodipine from pharmaceutical products using capillary electrophoresis

The present work describes the development of a capillary electrophoresis (CE) method for the chiral discrimination of amlodipine (AML) enantiomers using cyclodextrine (CD) derivatives as chiral selectors. A large number of native and derivatized, neutral and ionized CD derivatives were screened to find the optimal chiral selector; and carboximethyl-β-CD (CM-β-CD) was selected for the enantiomeric discrimination. A factorial analysis study was performed by orthogonal experimental design in which several factors were varied at the same time to optimize the separation method. The optimized method (25 mM phosphate buffer, pH = 9.0, 15 mM CM-β-CD, 15 ºC, + 25 kV, 30 mbar/1 second, detection wavelength 230 nm) was successfully applied for the baseline separation of AML enantiomers within 5 minutes. Successful validation and application of the proposed CE method suggest its routine use in enantioselective control of AML in pharmaceutical preparations.

Chiral separation of lansoprazole and rabeprazole by capillary electrophoresis using dual cyclodextrin systems.

Novel capillary electrophoresis methods using CDs as chiral selectors were developed and validated for the chiral separation of lansoprazole and rabeprazole, two proton pump inhibitors. Fourteen different neutral and anionic CDs were screened at pH 4 and 7 in the preliminary analysis. Sulfobutyl-ether-ß-CD with a degree of substitution of 6.5 and 10 at neutral pH proved to be the most suitable chiral selector for both compounds. Various dual CD systems were also compared, and the possible mechanisms of enantiomer separation were investigated. A dual selector system containing sulfobutyl-ether-ß-CD degree of substitution 6.5 and native γ-CD proved to be the most adequate system for the separations. Method optimization was carried out using an experimental design approach, performing an initial fractional factorial screening design, followed by a central composite design to establish the optimal analytical conditions. The optimized methods (25 mM phosphate buffer, pH 7, 10 mM sulfobutyl-ether-ß-CD/20 mM γ-CD, +20 kV voltage; 17°C temperature; 50 mbar/3 s injection, detection at 210 nm for lansoprazole; 25 mM phosphate buffer, pH 7, 15 mM sulfobutyl-ether-ß-CD/30 mM γ-CD, +20 kV voltage; 18°C temperature; 50 mbar/3 s injection, detection at 210 nm for rabeprazole) provided baseline separation for lansoprazole (Rs = 2.91) and rabeprazole (Rs = 2.53) enantiomers with favorable migration order (in both cases the S-enantiomers migrates first). The optimized methods were validated according to current guidelines and proved to be reliable, linear, precise, and accurate for the determination of 0.15% distomer as chiral impurity in dexlansoprazole and dexrabeprazole samples.

Analytical methodologies for the determination of ticagrelor.

Ticagrelor is an orally administered platelet aggregation inhibitor with a cyclopentyl-triazolopyrimidine structure; it is a selective reversible P2Y12 receptor antagonist, which prevents P2Y12-mediated and ADP-mediated platelet activation and aggregation. It is used to reduce the rate of cardiovascular death, myocardial infarction and stroke in patients with acute coronary syndrome or history of myocardial infarction. Several analytical methods have been published for the determination of ticagrelor in pharmaceuticals and biological materials by spectrophotometry, high-performance liquid chromatography with ultraviolet detection and liquid chromatography coupled with tandem mass spectrometry. The purpose of the current review is to provide a systematic survey of the analytical techniques used for the determination of ticagrelor since its introduction in therapy until today.

Development of a generic method for the determination of proton-pump inhibitors by capillary zoneelectrophoresis

A generic capillary zone electrophoresis method was developed for the analysis of four proton pump inhibitors: omeprazole, pantoprazole, lansoprazole and rabeprazole. During preliminary analysis screening of phosphate buffers at different pH levels was performed, in order to determine the optimum pH domain suitable for the simultaneous determination of all studied compounds. A face centered central composite design was employed for the optimization of separation conditions. The effect of buffer concentration, pH and applied voltage was studied; resolution between peaks and migration time of the last compound were considered as responses. Other factors as system temperature, injection parameters, capillary length, were held constant during the optimization process. The optimized conditions consisted of 40mM phosphate background electrolyte at pH 5.0, +25 kV applied voltage and 20 °C temperature. The migration order of the analytes was as follows: rabeprazole, omeprazole, lansoprazole and pantoprazole. Full resolution of all analytes was achieved within 9 minutes. The method was validated and proved to be suitable in terms of repeatability, sensitivity, linearity, accuracy and robustness. Determinations from commercially available pharmaceutical formulation were performed for omeprazole; good reproducibility and recovery were obtained.

Enantioselective analysis of fluoxetine in pharmaceutical formulations by capillary zone electrophoresis.

Fluoxetine is an antidepressant, a selective serotonin reuptake inhibitor (SSRI) used primarily in the treatment of major depression, panic disorder and obsessive compulsive disorder. Chiral separation of racemic fluoxetine is necessary due to its enantioselective metabolism. In order to develop a suitable method for chiral separation of fluoxetine, cyclodextrin (CD) modified capillary electrophoresis (CE) was employed. A large number of native and derivatized, neutral and ionized CD derivatives were screened to find the optimal chiral selector. As a result of this process, heptakis(2,3,6-tri-O-methyl)-ß-CD (TRIMEB) was selected for enantiomeric discrimination. A factorial analysis study was performed by orthogonal experimental design in which several factors are varied at the same time to optimize the separation method. The optimized method (50 mM phosphate buffer, pH = 5.0, 10 mM TRIMEB, 15 °C, + 20 kV, 50 mbar/1 s, detection at 230 nm) was successful for baseline separation of fluoxetine enantiomers within 5 min. Our method was validated according to ICH guidelines and proved to be sensitive, linear, accurate and precise for the chiral separation of fluoxetine.

Simultaneous determination of atorvastatin and ezetimibe from combined pharmaceutical products by micellar electrokinetic capillary chromatography

Abstract A rapid and sensitive micellar electrokinetic capillary chromatography method with UV photodiode-array detection was developed for the simultaneous determination of atorvastatin and ezetimibe in fixed dose drug combination. Experimental conditions such as buffer concentration and pH, surfactant concentration, system temperature, applied voltage, injection parameters were optimized in order to improve the efficiency of the separation. The best results were obtained when using fused silica capillary (48 cm length X 50 µm ID) and 25 mM borate buffer electrolyte at pH 9.3 containing 25 mM SDS, + 30 kV applied voltage, 20 ºC system temperature. The separation was achieved in approximately 2 minutes, with a resolution of 7.02, the order of migration being atorvastatin followed by ezetimibe. The analytical performance of the method was verified with regard to linearity, precision, robustness and the limit of detection and quantification were calculated.

[Phytopharmacological review of bathurst burr (Xanthium spinosum L.)]. / A szúrós szerbtövis (Xanthium spinosum L.) növényfaj fitofarmakológiai áttekintése.

Bathurst burr (Xanthium spinosum L.) is an invasive species that is also known as a medicinal plant. Our goal is to make known the plant and its therapeutic effects in larger scale. The plant has been used in the Romanian folk medicine for urinary problems and various prostate diseases. The most important substances in Xanthii spinosi herba are: flavones and their derivates (quercetin, pendulin, iocein, centaurin and patuletin), polyphenols (caffeic- and chlorogenic acid and their derivates), sesquiterpene lactones (xanthinin, xanthatin-xanthanol-xanthumin derivates), diterpenes (atractyloside and derivates) and phytosterols (sitosterol, stigmasterol). The beneficial effect of the herb was proved in the 80's by Petcu and his collaborators. The plants infusion and tincture had positive effects on induced benign prostate hyperplasia in rats. The antibacterial and antifungal properties of the plant are attributed to the sesquiterpene lactone, xanthatin. Our preliminary experiments showed the presence of the xanthatin in the toluol, chloroform, methanol and ethanol extracts.

Study of the Electrophoretic Behavior of Cephalosporins by Capillary Zone Electrophoresis.

PURPOSE: The aim of the study was the characterization of the electrophoretic behavior of cephalosporins from different generation having different structural characteristics in order to develop a rapid, simple and efficient capillary electrophoretic method for their identification and simultaneous separation from complex mixtures. METHODS: Ten cephalosporin derivatives (cefaclor, cefadroxil, cefalexin, cefazolin, cefoxitin, cefuroxime, cefoperazone, cefotaxime, ceftazidime, ceftriaxone) were analyzed by capillary zone electrophoresis using different background electrolyte solutions at different pH values. Electrophoretic mobilities of the analytes were calculated, the influence of the electrophoretic parameteres on the separation was established and the analytical conditions were optimized. RESULTS: Taking into consideration their structural and chemical properties cephalosporins can be detected over a pH range between 6 and 10. The best results were obtained using a buffer solution containing 25 mM disodium hydrogenophosphate - 25 mM sodium dihydrogenophosphate, at a pH - 7.00, + 25 kV voltage at a temperature of 25 °C, UV detection at 210 nm. Using the optimized analytical conditions we achieved the simultaneous baseline separation for seven cephalosporins in less then 10 minutes. CONCLUSION: Using the described optimized electrophoretic procedures, capillary electrophoresis can be used for the identification and determination of cephalosporins in formulated pharmaceutical products and for their separation from complex mixtures.

Simultaneous determination of loratadine, desloratadine and cetirizine by capillary zone electrophoresis.

PURPOSE: The aim of the study was the development of a simple and rapid analytical procedure for the determination of the most frequently used antihistamine derivatives. METHODS: A capillary zone electrophoretic method was developed for the simultaneous separation of loratadine, desloratadine and cetirizine. Efforts were focused primarly on the optimisation of the experimental parameters: buffer composition and concentration, buffer pH, applied voltage, temperature, injection pressure and time. RESULTS: The optimised parameters for the separation were: 25 mM buffer electrolyte, buffer pH 2.5, voltage + 25 kV, temperature 25 °C, injection pressure 50 mbar, injection time 3 seconds, capillary 48 cm (effective length 40 cm) x 50 µm, detection at 240 nm. Under these conditions, the analysis time was below 5 minutes, the order of migration being: desloratadine, cetirizine and loratadine. The developed method was validated in terms of linearity, limits of detection and quantification, intra- and inter-day precision, selectivity and robustness. CONCLUSION: Capillary zone electrophoresis proved to be a suitable method for the simulatneous determination of the three studied antihistamine derivatives.

Thin layer chromatographic analysis of Beta-lactam antibiotics.

PURPOSE: The paper describes some thin layer chromatographic procedures that allow simple and rapid separation and identification of penicillins and cephalosporins from complex mixtures. METHODS: Using silicagel GF254 as stationary phase and selecting different mobile phases we succeeded in the separation of the studied beta-lactamins. Our aim was not only to develop a simple, rapid and efficient method for their separation but also the optimization of the analytical conditions. RESULTS: No system will separate all the beta-lactams, but they could be identified when supplementary information is used from color reactions and/or by using additional chromatographic systems. CONCLUSIONS: The right combination of solvent system and detection method allows the identification of the studied penicillins and cephalosporins and can be successfully used in the preliminary analysis beta-lactam antibiotics. CONCLUSION: The right combination of solvent system and detection method allows the identification of the studied penicillins and cephalosporins and can be successfully used in the preliminary analysis beta-lactam antibiotics.