betadex and 18-crown-6

In this work, chiral separation of enantiomers of three amino acids was achieved using capillary electrophoresis technique with α-cyclodextrin (αCD) as a running buffer additive. Only tryptophan has exhibited baseline separation in the presence of αCD, while the enantiomers of the other two amino acids, phenylalanine and tyrosine, were only partially separated. The addition of 18-crown-6 (18C6) as a second additive imparted only slight improvement to the separation of all enantiomers. On the other hand, all three racemic amino acid mixtures demonstrated no indication of separation when the larger cavity cyclodextrin members, β- and γCD, are used as running buffer chiral additives. However, remarkable improvements in the separation of the enantiomers of phenylalanine and tyrosine were obtained when 18C6 is used together with βCD as a running buffer additive. Surprisingly, tryptophan enantiomers were not separated by the dual additive system of cyclodextrin and crown ether. Using electrospray ionization mass spectrometry (ESI-MS), all amino acids were found to form stable binary complexes with individual hosts as well as ternary compounds involving the crown ether and the cyclodextrin. Furthermore, we used molecular dynamics (MD) simulations to build a clear picture about the interaction between the guest and the hosts. Most of these complexes remained stable throughout the simulation times, and the molecular dynamics study allowed better understanding of these supramolecular assemblies.

Topics: alpha-Cyclodextrins; Amines; Amino Acids; Amino Acids, Aromatic; beta-Cyclodextrins; Crown Ethers; Electrophoresis, Capillary; Phenylalanine; Stereoisomerism; Tryptophan; Tyrosine

Using capillary electrophoresis (CE) three chiral primary amine compounds 1-aminoindan (AI), 1-(1-naphthyl)ethylamine (NEA) and 1,2,3,4-tetrahydro-1-naphthylamine (THAN), exhibited only partial or no separation when β-cyclodextrin (βCD) was used as chiral selector. The use of 18-crown-6 (18C6) as a second additive with βCD resulted in an enhanced separation. A molecular modeling study, using molecular mechanics and the semiempirical PM6 calculations, was used to help explaining the mechanism of the enantiodifferentiation and to predict the separation process. Optimization of the structures of the complexes by the PM6 method indicate that the poor separation obtained in the presence of the βCD chiral selector alone is due to the small binding energy differences (ΔΔE) of 4.7, 1.1 and 1.2 kcal mol(-1) for AI, NEA and THAN, respectively. In the presence of 18C6 it was suggested that a sandwich compound between 18C6, amine and βCD is formed. Theoretical calculations show that a significant increase in the binding energy is obtained for the sandwich compounds indicating strong hydrophobic and van der Waals interactions that show enhanced enantiodifferentiation.

Topics: Amines; beta-Cyclodextrins; Computer Simulation; Crown Ethers; Electrophoresis, Capillary; Models, Chemical; Stereoisomerism

The antimalarial drug primaquine (PQ) and its contaminant, the positional isomer quinocide (QC) have been successfully separated using capillary electrophoresis with either beta-cyclodextrin (beta-CD) or 18-crown-6 ether (18C6) as chiral mobile phase additive. The interactions of the drugs with cyclodextrins and 18C6 were studied by the semiempirical method (Parametric Model 3) PM3. Theoretical calculations for the inclusion complexes of PQ and QC with alpha-CD, beta-CD and 18C6 were performed. Data from the theoretical calculations are correlated and discussed with respect to the electrophoretic migration behavior. More stable complexes are predicted for the PQ-beta-CD and PQ-18C6 complexes. The coelution of PQ and QC when alpha-CD was used as buffer additive can be explained by their comparable stabilities of the inclusion complex formed, while significant differences in the complexation stabilities of the drugs with beta-CD is responsible for their separation. The stronger hydrogen bonding in PQ-18C6 system is responsible for the separation between PQ and QC when 18C6 was used as chiral mobile phase additive.

Topics: Aminoquinolines; beta-Cyclodextrins; Crown Ethers; Drug Stability; Electrophoresis, Capillary; Models, Molecular; Primaquine

A capillary zone electrophoretic method has been developed and validated for the determination of the impurity quinocide (QC) in the antimalarial drug primaquine (PQ). Different buffer additives such as native cyclodextrins and crown ethers were evaluated. Promising results were obtained when either beta-cyclodextrin (beta-CD) or 18-crown-6 ether (18C6) were used. Their separation conditions such as type of buffer and its pH, buffer additive concentration, applied voltage capillary temperature and injection time were optimized. The use of 18C6 offers slight advantages over beta-CD such as faster elution times and improved resolution. Nevertheless, migration times of less than 5 min and resolution factors (R(s)) in the range of 2-4 were obtained when both additives were used. The method was validated with respect to selectivity, linearity, limits of detection and quantitation, analytical precision (intra- and inter-day variability) and repeatability. Concentrations of 2.12 and 2.71% (w/w) of QC were found in pharmaceutical preparations of PQ from two different manufacturers. A possible mechanism for the successful separation of the isomers is also discussed.

Topics: Aminoquinolines; Antimalarials; beta-Cyclodextrins; Crown Ethers; Drug Contamination; Electrophoresis, Capillary; Humans; Hydrogen-Ion Concentration; Linear Models; Primaquine; Reference Standards; Sensitivity and Specificity; Tablets; Temperature; Time Factors

Stability constants of K, Na, Ca, and Ba with 18-crown-6, K, Na, Li with sulfated beta-cyclodextrin and K, Li, Ca, Mg, Sr, and Ba ions with ([2-hydroxy-1,1-bis(hydroxymethyl) ethyl]-amino)-1-propanesulfonic acid (TAPS) were determined by capillary electrophoresis and computed using a general least squares minimizing program CELET. The results for 18-crown-6 agreed well with those evaluated by graphical methods or reported in the literature. Previously unknown stability constants of sulfated beta-cyclodextrins and TAPS determined for alkali and alkaline earth metals show that sulfated beta-cyclodextrin interacts with monovalent metals allowing to manipulate their effective mobility. It interacts stronger with divalent metal cations. TAPS, as zwitterionic buffer widely used in various analytical, biochemical and other applications, forms complexes with alkali and alkaline earth cations, and although the stability constants are rather low, the equilibria should be taken into account when TAPS is used and metal cations are present in solution at the same time.

Topics: beta-Cyclodextrins; Buffers; Cations; Crown Ethers; Cyclodextrins; Electrolytes; Electrophoresis, Capillary; Ethers, Cyclic; Metals; Molecular Structure

A non-chiral crown ether (18-crown-6) along with beta-cyclodextrin (beta-CD) was used to achieve enantioselective separations of primary amino compounds in capillary electrophoresis. In this new method, the amino group of these compounds is protonated in a low pH separation buffer and forms a selective host-guest complex with the crown ether (amino compound+18-crown-6). The hydrophobic portion of the host-guest complex is then incorporated into the cavity of the beta-cyclodextrin. The amino compound is sandwiched between the crown ether and the cyclodextrin (18-crown-6+amino compound+beta-CD) and thus determines or enhances the enantioselective recognition. It is postulated that the formation of this sandwich results in a more selective chiral interaction between the molecule and beta-cyclodextrin. The chiral recognition is dependent upon the formation of this sandwich complex. This method has been used to achieve enantioselectivity of primary amino compounds with a wide variety of substitutions.

Topics: Amines; Amino Acids; Amino Alcohols; beta-Cyclodextrins; Crown Ethers; Cyclodextrins; Electrophoresis, Capillary; Ethers, Cyclic; Stereoisomerism