Gerhard K. E. Scriba

Cyclodextrins in capillary electrophoresis enantioseparations – Recent developments and applications

Capillary EKC has been established as a versatile and robust CE method for the separation of enantiomers. Within the chiral selectors added to the BGE CDs continue as the most widely used selectors due to their structural variety and commercial availability. This is reflected in the large number of practical applications of CDs to analytical enantioseparations that have been reported between January 2006 and January 2008, the period of time covered by this review. Most of these applications cover aspects of life sciences such as drug analysis, bioanalysis, environmental analysis, or food analysis. Moreover, new CD derivatives have been developed in an attempt to achieve altered enantioselectivities and to further broaden the application range. Finally, efforts will be summarized that aim at an understanding of the molecular level of the chiral recognition between CDs and the analytes.

Selected fundamental aspects of chiral electromigration techniques and their application to pharmaceutical and biomedical analysis.

While capillary electrophoresis has been established as a major enantioseparation technique within the last decade, the potential of capillary electrochromatography is still studied extensively. This review summarizes recent applications of electromigration techniques with regard to the enantioseparation of chiral drugs. The first part discusses the general aspects of migration models and the enantiomer migration order. The application of capillary electrophoresis to chiral pharmaceutical analysis considers recent literature on: (1) chiral resolutions of non-racemic mixtures of enantiomers for the development of assays and the determination of the stereochemical purity of the drugs, (2) chiral separations of compounds in pharmaceutical formulations and products, and (3) enantioseparations of drugs in biological samples. A shorter section devoted to chiral electrochromatography discusses some fundamental aspects as well as the application to the chiral analysis of drugs including bioanalysis.

Recent advances in electrodriven enantioseparations

Capillary electromigration techniques have developed into significant analytical separation tools especially for enantioseparations. While CE can be considered a mature technique as documented by its wide applications, CEC is still in a developmental state despite many research efforts. The success of stereospecific CE separation methods is due to the high specificity and flexibility of the technique as well as the availability of many types of chiral selectors. Thus, numerous methods have been developed for the analysis of chiral compounds in chemical, biochemical, pharmaceutical, environmental, and forensic sciences. However, most reported applications deal with pharmaceuticals. The search for new chiral selectors also continued despite the fact that most applications were performed using cyclodextrins. Furthermore, CE has been combined with spectroscopic and molecular modeling studies in attempts to understand the interactions between chiral selectors and analytes. The present review focuses on recent examples of mechanistic aspects of capillary enantioseparations with regard to mathematical modeling of enantioseparations, investigations of the analyte-complex structures as well as new chiral selectors and applications of chiral analyses by CE and CEC. It covers the literature published between January 2011 and August 2012.

Chiral Recognition Mechanisms in Analytical Separation Sciences

Chiral recognition phenomena play an important role in nature as well as analytical separation sciences. In chromatography and capillary electrophoresis, enantiospecific interactions between a chiral selector and the enantiomers of an analyte resulting in transient diastereomeric complexes are required in order to achieve enantioseparations. The formation of the complexes is driven by ionic interactions, ion–dipole or dipole–dipole interactions, H-bonds, van der Waals interactions and π–π interactions. Due to the structural variety of chiral selectors applied in separation sciences, different mechanisms and structural features contribute to the chiral recognition processes. Besides structure–separation relationship studies in HPLC and CE spectroscopic techniques including NMR spectroscopy, circular dichroism and vibrational circular dichroism spectroscopy as well as molecular modeling methods have significantly contributed to the understanding of the enantiospecific recognition of enantiomers by chiral selectors. The present review briefly illustrates the current models of the enantiospecific recognition on a structural basis of various chiral selectors including polysaccharide derivatives, cyclodextrins, cyclofructan derivatives, macrocyclic glycopeptides, proteins, Pirkle-type selectors, ion exchangers, polymers, crown ethers, ligand exchangers, calixarenes, aptamers, micelles forming agents and ionic liquids.

Fundamental aspects of chiral electromigration techniques and application in pharmaceutical and biomedical analysis

Capillary electromigration techniques are often considered ideal methods for the analysis of chiral compounds due to the high resolution power and flexibility of the technique. Therefore, especially capillary electrophoresis using a chiral selector in the background electrolyte, also termed electrokinetic chromatography, has found widespread acceptance in analytical enantioseparations of drug compounds in pharmaceuticals and biological media. Moreover, mechanistic studies on analyte complexation by the chiral selectors have continuously been conducted in an effort to rationalize enantioseparation phenomena. These studies combined capillary electrophoresis with spectroscopic techniques such as nuclear magnetic resonance and/or molecular modeling. The present review focuses on recent examples of mechanistic aspects of capillary electromigration enantioseparations and summarizes recent applications of chiral pharmaceutical and biomedical analysis published between January 2009 and August 2010.

Advances in-capillary electrophoretic enzyme assays

In recent years, capillary electrophoresis (CE) has become a frequently used tool for enzyme assays due to its well-recognized advantages such as high separation efficiency, short analysis time, small sample and chemicals consumption. The published applications cover all aspects of enzyme characterization and analysis including the determination of the enzyme activity, substrate and modulator characterization and identification, as well as the investigation of enzyme-mediated metabolic pathways of bioactive molecules. The CE assays may be classified into two general categories: (1) pre-capillary assays where the reactions are performed offline followed by CE analysis of the substrates and products and (2) online assays when the enzyme reaction and separation of the analytes are performed in the same capillary. In online assays, the enzyme may be either immobilized or in solution. The latter is also referred to as electrophoretically mediated microanalysis (EMMA). The present review will highlight the literature of CE-based enzyme assays from 2006 to November 2009. One section will be devoted to applications of microfluidic devices.

Chiral recognition in separation science – an update

Stereospecific recognition of chiral molecules is an important issue in various aspects of life sciences and chemistry including analytical separation sciences. The basis of analytical enantioseparations is the formation of transient diastereomeric complexes driven by hydrogen bonds or ionic, ion-dipole, dipole-dipole, van der Waals as well as π-π interactions. Recently, halogen bonding was also described to contribute to selector-selectand complexation. Besides structure-separation relationships, spectroscopic techniques, especially NMR spectroscopy, as well as X-ray crystallography have contributed to the understanding of the structure of the diastereomeric complexes. Molecular modeling has provided the tool for the visualization of the structures. The present review highlights recent contributions to the understanding of the binding mechanism between chiral selectors and selectands in analytical enantioseparations dating between 2012 and early 2016 including polysaccharide derivatives, cyclodextrins, cyclofructans, macrocyclic glycopeptides, proteins, brush-type selectors, ion-exchangers, polymers, crown ethers, ligand-exchangers, molecular micelles, ionic liquids, metal-organic frameworks and nucleotide-derived selectors. A systematic compilation of all published literature on the various chiral selectors has not been attempted.

A rapid and efficient microwave-assisted synthesis of hydantoins and thiohydantoins

The present paper describes studies on the synthesis of the antiepileptic drug phenytoin, and of structurally related derivatives. First, the influence of the solvent has been investigated in the microwave-assisted synthesis of the drug, resulting in a yield improvement and a cleaner reaction. Second; a two-step reaction is described to synthesize selectively and in high yields phenytoin. The first step consists in microwave activation of the reaction of benzil with thiourea, the second step includes the conversion of the resulting 2-thiohydantoin to phenytoin using hydrogen peroxide. Moreover, microwave activation is a very convenient method for the synthesis of 3-alkylated phenytoin derivatives, resulting in a much more selective method than the previously reported procedure using alkylating agents

Recent advances in capillary electrophoretic migration techniques for pharmaceutical analysis (2013-2015)

This review updates and follows‐up a previous review by highlighting recent advancements regarding capillary electromigration methodologies and applications in pharmaceutical analysis. General approaches such as quality by design as well as sample injection methods and detection sensitivity are discussed. The separation and analysis of drug‐related substances, chiral CE, and chiral CE‐MS in addition to the determination of physicochemical constants are addressed. The advantages of applying affinity capillary electrophoresis in studying receptor–ligand interactions are highlighted. Finally, current aspects related to the analysis of biopharmaceuticals are reviewed. The present review covers the literature between January 2013 and December 2015.

Human skin permeation of neutral species and ionic species: Extended linear free‐energy relationship analyses

The permeability, K(p), of some ionized solutes (including nine acids and nine bases) through human epidermis membrane was measured in this work. Combined with the experimental K(p) data set for neutral species created by Abraham and Martins and reliable K(p) data for ionic species from the literature, a linear free-energy relationship (LFER) analysis was conducted. The values of log K(p) for 118 compounds have been correlated with solute descriptors to yield an LFER equation that incorporates neutral species and ionic species, with R(2) = 0.861 and SD = 0.462 log units. The equation can be used to predict K(p) for neutral species and ionic species, as well as partly ionized solutes. Predicted values for the passive permeation of the sodium ion and the tetraethylammonium ion are in good accord with the experimental values. It was observed that neutral acids and bases are more permeable than their ionized forms, and that the ratio depends on the actual structure. The correlation between human skin permeation and water-organic solvent/artificial membrane partitions was investigated by comparison of the coefficients in the LFER equations. Partition into cerasome is a reasonable model for partition into skin, and using cerasome as a surrogate for the partitioning process, we separate permeation into partition and diffusion processes. We show that the poor permeability of ionic species is largely due to slow diffusion through the stratum corneum. This is especially marked for a number of protonated base cations.