Chemistry: electrical and wave energy – Processes and products – Electrophoresis or electro-osmosis processes and electrolyte...
Reexamination Certificate
1999-04-22
2001-08-07
Warden, Jill (Department: 1743)
Chemistry: electrical and wave energy
Processes and products
Electrophoresis or electro-osmosis processes and electrolyte...
C204S455000, C204S601000, C204S605000, C210S198200, C210S634000, C210S635000, C210S656000, C095S082000, C095S088000
Reexamination Certificate
active
06270640
ABSTRACT:
The development of this invention was partially funded by the Government through a grant from the National Institutes of Health, number GM-39844. The Government has certain rights in this invention.
This invention pertains to methods and compositions useful in chiral separations of enantiomeric mixtures, particularly to the use of polymerized chiral micelles in such separations.
Chiral Separations
The separation of enantiomeric mixtures into individual optical isomers is one of the most challenging problems in analytical chemistry, reflecting practical considerations important in many areas of science, particularly the pharmaceutical and agricultural industries.
For example, the pharmaceutically active site of many drugs is “chiral,” meaning that the active site is not identical to a mirror image of the site. However, many pharmaceutical formulations marketed today are racemic mixtures of the desired compound and its “mirror image.” One optical form (or enantiomer) of a racemic mixture may be medicinally useful, while the other optical form may be inert or even harmful, as has been reported to be the case for thalidomide.
Chiral drugs are now extensively evaluated prior to large scale manufacturing, both to examine their efficacy, and to minimize undesirable effects attributable to one enantiomer or to the interaction of enantiomers in a racemic mixture. The United States Food and Drug Administration has recently issued new regulations governing the marketing of chiral drugs.
Separating optical isomers often requires considerable time, effort, and expense, even when state-of-the-art chiral separation techniques are used. There is a continuing and growing need for improved chiral separation techniques.
Early chiral separation methods used naturally occurring chiral species in otherwise standard separation protocols. For example, natural chiral polymeric adsorbents such as cellulose, other polysaccharides, and wool were used as early as the 1920's. Later strategies used other proteins and naturally occurring chiral materials. These early strategies gave some degree of success. However, the poor mechanical and chromatographic properties of naturally occurring materials often complicated the separations. Although naturally occurring chiral materials continue to be used for chiral separations, efforts have increasingly turned to synthesizing chiral materials having better mechanical and chromatographic properties. D. Armstrong, “Optical Isomer Separation by Liquid Chromatography,” Anal. Chem., vol. 59, pp. 84A-91A (1987) gives a review of methods that have been used for chiral separations in liquid chromatography.
The two separation methods most often employed for chiral separations are high performance liquid chromatography and capillary electrophoresis, both of which have high efficiencies. High separation efficiencies are required for chiral separations because the difference in molar free energies of the interactions that discriminate between individual enantiomers is small, typically on the order of 100 calories per mole. The sum of the weighted time averages of these small interactions determines the overall enantioselectivity of a separation technique. High efficiencies are therefore important to improved chromatographic chiral separations. Separations on the order of 100,000 theoretical plates are readily achievable with capillary electrophoresis. Thus, small chiral selectivities can be magnified using capillary electrophoresis.
The so-called “three point rule” is a commonly used rule-of-thumb in many chiral recognition strategies. The “three point rule” recommends that there be a minimum of three simultaneous interactions between the chiral recognition medium and at least one of the enantiomers to be separated. In addition, at least one of the three interactions must be stereochemically dependent. The three interactions need not be attractive interactions, and may for example employ repulsion due to electrostatic or steric effects. For example, the “three point rule” was successfully used in 1971 in the design of a chiral stationary phase for the separation of the enantiomers of L-DOPA (L-dihydroxyphenylalanine). See R. J. Baczuk et al., “Liquid Chromatographic Resolution of Racemic &bgr;-3,4-Dihydroxyphenylalanine,” J. Chromatog., vol. 60, pp. 351-361 (1971).
Until recently, the most common type of synthetic chiral stationary phase used in high performance liquid chromatography (“HPLC”) was a Pirkle-type (Brush-type) phase. A Pirkle-type phase is based on the “three point rule,” and usually employs &pgr;-&pgr; interactions (electron donor-acceptor) and intermolecular hydrogen bonding in chiral recognition.
Another successful approach has used reversible complexes formed of metal ions and chiral complexing agents. This separation method is commonly called ligand-exchange-chromatography (“LEC”). LEC is usually explained by a model based on multicomponent complexes containing a central metal ion and two chelating chiral molecules. Enantiomers can be separated in LEC either by using chiral mobile phase additives, or by using a chiral stationary phase.
Host-guest enantioselective complexes, in either the mobile phase or the stationary phase, can also be used to separate individual enantiomers. Systems within this general category include those employing chiral crown ethers and cyclodextrins. Compared to crown ethers, cyclodextrins are relatively inexpensive, and are more readily derivatized. See E. Gassmann et al., “Electrokinetic Separation of Chiral Compounds,” Science, vol. 230, pp. 813-814 (1985); and R. Kuhn et al., “Chiral Separation by Capillary Electrophoresis,” Chromatographia, vol. 34, pp. 505-512 (1992). For example, D. Armstrong et al., “Enrichment of Enantiomers and Other Isomers with Aqueous Liquid Membranes Containing Cyclodextrin Carriers,” Anal. Chem., vol. 59, pp. 2237-2241 (1987) disclose the use of an aqueous liquid membrane employing cyclodextrin carriers to perform an enantiomeric enrichment.
Micelles
Surfactants, molecules having both hydrophilic and hydrophobic groups, associate with one another in polar solvents such as water to form dynamic aggregates known as “micelles.” A micelle typically takes roughly the shape of a sphere, a spheroid, an ellipsoid, or a rod, with the hydrophilic groups on the exterior and the hydrophobic groups on the interior. The hydrophobic interior provides, in effect, a hydrophobic liquid phase with solvation properties differing from those of the surrounding solvent. Micelles form when the concentration of the amphophilic molecules in solution is greater than a characteristic value known as the critical micelle concentration (“CMC”).
Micelles have been used for a variety of purposes, including micellar catalysis; micelle-substrate interactions; and analytical applications such as spectroscopic analyses, electrochemical measurements, and separations. For example, K. Taguchi et al., “Immobilized Bilayer Stationary Phases in Gas Chromatography,” J. Chem. Soc., Chem. Commun., pp. 364-365 (1986) disclose the use of an immobilized, stable, poly-ion complex containing vesicles for use in a gas chromatography column.
For a general discussion of micellar electrokinetic capillary chromatography, see S. Terabe et al., “Electrokinetic Chromatography with Micellar Solution and Open-Tubular Capillary,” Anal. Chem., vol. 57, pp. 834-841 (1985); and S. Terabe et al., “Electrokinetic Separations with Micellar Solutions and Open-Tubular Capillaries,” Anal. Chem., vol. 56, pp. 111-113 (1984).
Chiral Micelles
An important application of micelles is their use in chiral recognition and separation. Chiral surfactants have been used to form micelles having distinct chiral properties. The resulting chiral microenvironment has been shown to exhibit selective interactions with different enantiomers in solution. See, e.g., S. Terabe et al., “Chiral Separation by Electrokinetic Chromatography with Bile Salt Micelles,” J. Chromatog., vol. 480, pp. 403-411 (1989); S. Terabe et al., “Separation of Enantiomers by Capillary Electrophoretic Techniques,
Billiot Eugene J.
Shamsi Shahab A.
Thibodeaux Stefan J.
Warner Isiah M.
Board of Supervisors of Louisiana State University and Agricultu
Runnels John H.
Starsiak Jr. John S.
Warden Jill
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