WO1992002283A1

WO1992002283A1 - Chiral separation media

Info

Publication number: WO1992002283A1
Application number: PCT/US1990/005123
Authority: WO
Inventors: Daniel W. Armstrong
Original assignee: Advanced Separation Technologies Inc.
Priority date: 1990-08-08
Filing date: 1990-09-11
Publication date: 1992-02-20
Also published as: EP0494967A1; EP0494967A4; JPH04506218A; JPH0720890B2

Abstract

The media is an ether derivative of cyclodextrin such as a permethylated hydroxy ether of cyclodextrin or a dialkyl trifluoroacetyl ether derivative of cyclodextrin and is used in capillary gas chromatographic columns. Particular benefit is obtained using the ether derivative of cyclodextrin in a fused silica capillary.

Description

CHIRAL SEPARATION MEDIA

This application is a continuation-iri-part

of application Serial No. 406,141 filed September 12, 1989.

This invention relates to a composition used

for separation of optical isomers or chiral compounds, as well as other isomeric and non-isomeric compounds, by means of gas chromatography and, more particularly, to the separation of enantiomers by capillary gas

chromatography. The composition used is a media

of an ether derivative of a cyclodextrin such as

a permethylated hydroxy or a dialkyl trifluoroacetyl ether of cyclodextrin.

The configuration of a chiral molecule is

generally what determines its biological and

pharmaceutical activity and effectiveness. One

of the enantiomers of the chiral molecule may be

active and the other may be inactive or even toxic.

It is therefore essential to be able to separate

the different enantiomers from each other to obtain

an isolated enantiomer in pure form. The isolated

enantiomers are used in the pharmaceutical, pesticide and/or herbicide industries, among others. A conventional way to separate enantiomers is by gas chromatography using a chiral stationary phase. Chiral stationary phases can rapidly and reversibly form diastereomeric association complexes with chiral analytes. Successful chiral stationary phases for wall-coated capillary tubes should have some characteristic properties. They need to be highly viscous even at elevated temperatures and have the proper surface tension to wet the capillary wall completely. They should be able to form rapid and reversible diastereomeric associate complexes with the chiral analytes via various interactions such as hydrogen bonding, dispersion, dipole-dipole and steric interactions to give reasonable chiral selectivity. Other desirable properties include high temperature stability, no racemization at

elevated temperatures and low levels of bleeding.

Most of the early work on chiral stationary phases for gas chromatography used amino acids, peptides, and various derivatives thereof. Some efforts have been made to use other naturally occurring chiral molecules as chiral stationary phases such as tartaric acid, malic acid, mandelic acid and

chrysanthemic acid. Despite a large amount of

work in this area, the only resulting widely available and commercially viable chiral stationary phase

for gas chromatography has been Chirasil-Val from

Macherey-Nagel of the Federal Republic of Germany

which consists of a siloxane copolymer to which

L-valine-tert-butylamide was coupled.

There are a number of limitations to these

early amino acid based gas chromatography chiral

stationary phases. First, they do not seem to

be widely applicable. Most of the reported separations were of racemic amino acid derivatives. Just as

significant was the fact that, using these early

chiral separation phases, the high column temperature needed for gas chromatography often results in

racemization, decomposition and bleeding of the

chiral stationary phase. Even the moderately successful

Chirasil-Val is not recommended to be used at temperatures much above 200°C. Also, the enantioselectivity

of the chiral stationary phase decreases significantly at the higher temperatures needed for gas chromatography.

Previously there have been a number of efforts

to use alpha- and beta-cyclodextrin as gas chromatography stationary phases. It was apparent from the early

gas chromatography and more recent liquid chromatography work that cyclodextrins had potential as gas chromatographic stationary phases. Unfortunately, the cyclodextrin gas chromatography stationary phases were not as successful as the liquid chromatography bonded

stationary phases. Although interesting selectivities, mainly for achiral solutes, were obtained, the

efficiency and reproducibility were less than desirable. Cyclodextrins are crystalline solids and had to

be dissolved or suspended in another solvent prior to coating the separation column. The fact that

native cyclodextrins and their simple derivatives

(dimethyl, acetyl, etc.) are crystalline solids

with high melting or decomposition points, makes

them difficult to use directly as gas chromatography stationary phase coatings. Recently, there have

been reports on derivatized cyclodextrins that

are liquids or lower melting point amorphous solids and therefore can be used directly as stationary

phase coatings. All of these previous compounds

are lipophilic derivatives of cyclodextrin (such

as perpentyl-beta-cyclodextrin).

Cyclodextrins (also called "Schardinger dextrins") are known to be cyclic oligosaccharides composed

of glucose residues bonded together by alpha 1,4

bonds. The six, seven and eight membered rings

are called alpha-, beta-, and gamma-cyclodextrin, respectively. The cyclodextrins have different chemical and physical properties from the linear

oligosaccharides derived from starch in that they

are non-reducing dextrins and the ring structure

is widely used as a host for the inclusion of various compounds, usually organic compounds for the food, pharmaceutical, and chemical fields.

As is also well-known, cyclodextrins are produced from starch of any selected plant variety such

as corn, potato, waxy maize and the like which

may be modified, or unmodified starch derived from cereal or tuber origin and the amylose or amylopectin fractions thereof. The selected starch in aqueous slurry at selected concentrations up to about 35%

by weight solids is usually liquefied as by gelatinization or treatment with a liquefying enzyme such as bacterial alpha-amylase enzyme and then subjected to treatment with a transglycosylase (CGT) enzyme to form the

cyclodextrins.

The amount of the individual alpha-, betaand gamma-cyclodextrins produced by treating the

starch with the CGT enzyme will vary depending

on the selected starch, selected CGT enzyme and

processing conditions. The parameters to select

for the CGT enzyme conversion for the desired result in the amount of each individual cyclodextrin to

be produced is conventional and well-described

in the literature. Conventionally, the DE of the liquefied starch is maintained below about 20 DE, the starch solids concentration is below about 35% by weight, the

pH for conversion may be about 4.5 to 8.5 at a

selected temperature from ambient up to about 75°C for a selected period of time, typically from about

10 hours up to seven days and more. The amount

of CGT enzyme used for conversion is conventional

and well-known in the art.

It has now been discovered that ether derivatives of cyclodextrin such as permethylated hydroxy ethers of cyclodextrin and dialkyl trifluoroacetyl ethers

of cyclodextrin can be used to separate a wide

variety of optical isomers. The optical isomers

resolved include chiral alcohols, diols, polyols,

amines, amino alcohols, halohydrocarbons, ketones,

lactones, alpha-halocarboxylic acid esters, carbohydrates, epoxides, glycidyl analogues, haloephihydrins,

nicotine compounds, pyrans, furans, bicyclic and

heterocyclic compounds and other miscellaneous

compounds.

The permethylated hydroxy ether of cyclodextrin is hydrophilic and relatively polar compared to

previous cyclodextrin derivatives used as chiral

stationary phases. The dialkyl trifluoroacetyl derivative is of intermediate polarity. Both of

these ether derivatives of cyclodextrin have better coating properties on fused silica capillaries

than the hydrophobic cyclodextrin derivatives.

The more hydrophilic permethylated hydroxy ether

of cyclodextrin and the dialkyl trifluoroacetyl

derivatives have different selectivities for the

enantiomers as compared to the hydrophobic cyclodextrin derivatives. Also, they can be used at higher

temperatures than Chirasil-Val without racemization.

With respect to the ether derivative of cyclodextrin which is a permethylated hydroxy cyclodextrin,

the degree of substitution (DS) of the hydroxy

ether groups for the hydroxyl groups on the underivatized cyclodextrin molecule is from about 10% to about

75% of the available hydroxyl groups on the cyclodextrin. For example, for alpha-cyclodextrin the DS for

the hydroxy ether groups is about 2 to about 12;

for beta-cyclodextrin, about 2 to about 14; and

for gamma-cyclodextrin, about 2 to about 16. More preferably, the DS is about 25% to about 60% of

the available sites and more preferred is about

40%. It is important that the degree of substitution of the cyclodextrin hydroxy groups by the ether

side chains be random and non-uniform. The DS of the methyl groups for the remaining hydroxyl groups on the cyclodextrin and the hydroxyl groups on the ether side chains of the cyclodextrin is greater than about 90% and more preferably above about 95%. Ideally, all of the available hydroxyl sites on the hydroxy ether of cyclodextrin are

methylated; although this is sometimes difficult

to achieve.

The permethylated hydroxy ether of cyclodextrin is made in a conventional manner starting from

either individual cyclodextrin or mixtures of the

alpha-, beta- and/or gamma-cyclodextrins. However, it is preferred to use only a single cyclodextrin, i.e. either alpha-, beta-, or gamma-cyclodextrin.

The separation and/or purification of the alpha-,

beta-, and gamma-cyclodextrin may be done before,

after, or at any stage of the derivatization process.

The procedure for making the hydroxy ether of cyclodextrin and the subsequent step of methylating are accomplished in a conventional manner. The order of reaction

for forming the permethylated hydroxy ether cyclodextrin derivative is first to make the hydroxy ether and

then to methylate it.

In order to etherify the underivatized cyclodextrin, the cyclodextrin is suitably reacted with an epoxide. Suitable epoxides include ethylene oxide, propylene oxide, butylene oxide, amylene oxide, glycidol

(hydroxypropylene oxide), butadiene oxide, glycidyl methyl ether, glycidyl isopropyl ether, alkyl glycidyl ether, styrene oxide, and t-butyl glycidyl ether.

Preferably, the epoxide is selected from the group consisting of propylene oxide, glycidyl methyl

ether, glycidyl isopropyl ether, alkyl glycidyl

ether, t-butyl glycidyl ether and styrene oxide.

Good results have been obtained with an epoxide

selected from the group consisting of propylene

oxide, glycidyl methyl ether and glycidyl isopropyl ether.

As is known, the reaction of cyclodextrin

with the above noted epoxides produces an ether

of cyclodextrin with two hydroxy groups on adjacent carbon atoms on the side chains. Such hydroxy

ethers of cyclodextrin are sometimes referred to as dihyύroxyalkyl ethers of cyclodextrin.

The preferred permethylated ether derivatives of cyclodextrin for use in the present invention

include hydroxy propylated cyclodextrin, hydroxy propylated methyl ether cyclodextrin, hydroxy propylated isopropyl ether cyclodextrin, hydroxy propylated

vinyl ether cyclodextrin, hydroxy propylated t-butyl ether cyclodextrin, and hydroxy ethylated phenyl

cyclodextrin. Good results have been obtained

with hydroxy propylated cyclodextrin, hydroxy propylated methyl ether cyclodextrin and hydroxy propylated

isopropyl ether cyclodextrin.

With respect to the ether derivative of cyclodextrin which is a dialkyl trifluoroacetyl cyclodextrin,

the degree of substitution (DS) of the alkyl groups

for the hydrogens of the hydroxyl groups on the

underivatized cyclodextrin molecule to form the

etherified derivative is from about 20% to about

80% of the available hydrogens on the cyclodextrin.

For example, for alpha-cyclodextrin the DS for

the alkyl groups is about 1 to about 15; for beta-cyclodextrin, about 1 to about 16; and for gamma-cyclodextrin,

about 1 to about 18. More preferably, the DS is

about 40% to about 70% of the available sites and

more preferred is about 65%. Generally, the alkyl

groups will substitute for the hydrogens on the

2 and 6 carbons. It is important that the degree

of substitution of the cyclodextrin hydroxy groups

by the ether side chains be random and non-uniform.

The DS of the trifluoroacetyl group for the

hydrogen of the remaining available hydroxyl group

on the cyclodextrin is greater than about 90% and

more preferably above about 95%. The dialkyl trifluoroacetyl ether of cyclodextrin is made in a conventional manner starting from

either individual cyclodextrin or mixtures of the alpha-, beta- and/or gamma-cyclodextrins. However, it is preferred to use only a single cyclodextrin, i.e. either alpha-, beta-, or gamma-cyclodextrin.

The separation and/or purification of the alpha-, beta-, and gamma-cyclodextrin may be done before, after, or at any stage of the derivatization process. The procedure for making the ether of cyclodextrin and the subsequent step of esterifying are accomplished in a conventional manner. The order of reaction

for forming the cyclodextrin derivative is first

to make the ether derivative and then to esterify

it.

In order to form the dialkylated ether derivative of cyclodextrin, the cyclodextrin is first suitably reacted with an alkyl halide to form an ether derivative. Suitable alkyl halides include chlorinated, brominated, iodiated or fluorinated alkanes such as methane,

ethane, propane, butane, pentane or hexane. The

alkanes may be straight-chained or branched. Preferably, the alkyl halide is selected from the group consisting of n-propyl bromide, n-propyl chloride, n-butyl

chloride, n-butyl bromide, n-pentyl bromide and n-pentyl chloride. Best results have been obtained with n-pentyl bromide.

Suitably, in order to esterify the ether derivative of cyclodextrin, fluorinated anhydrides are used. It is more preferred to use fluorinated anhydrides such as trifluoroacetic anhydride, trifluorobutanoic anhydride, or trifluoropropanoic anhydride. It is most preferred to use

trifluoroacetic anhydride.

The preferred dialkyl trifluoroacetic ether derivatives of cyclodextrin for use in the present invention include dipentyl trifluoroacetic ether cyclodextrin, dipentyl trifluoroacetic ether cyclodextrin, dipentyl trifluorobutanoic ether cyclodextrin and dipentyl trifluoropropanoic ether cyclodextrin.

The gas chromatography is performed in a conventional manner.

It is preferred to use fused silica capillaries when performing the gas chromatography operation. Fused silica capillaries are much more flexible, practical and easier to handle than conventional glass capillaries.

The ether derivatives of cyclodextrin of the present invention are liquids at room temperature and can be used to coat undeactivated fused silica capillaries. They are nonvolatile and are thermally stable at temperatures up to about 300°C in the absence of oxygen.

The gas chromatography can also be performed by administering the ether derivative of cyclodextrin of the present invention to a packed column by

means of a carrier such as polysiloxane or polyethylene glycol. The admixture of the ether derivative

of cyclodextrin of the present invention with the carrier and the administration of this admixture to the column is performed in a conventional manner.

The solid support in the packed column may

be any suitable support such as diatomaceous earth. Teflon powder, or fine glass beads. The selection of the type, size and shape of the solid support depends on the molecules being isolated and the

flow rate desired. The determination of which

solid support to use is conventional and well-known to those of skill in the art.

Although it is less common, enantioselective reversals also can occur among like-derivatized

alpha-, beta-, and gamma-cyclodextrins. Reversals in elution order have been observed between alphaand beta-cyclodextrin and between beta- and gammacyclodextrin. Further details and advantages of the present invention may be more fully understood by reference to the following examples.

EXAMPLE 1

This example illustrates making a permethylated hydroxypropylated ether derivative of cyclodextrin of the present invention.

The permethyl hydroxypropyl ether derivative of cyclodextrin were made in two steps. First, propylene oxide, sodium hydride and the desired cyclodextrin (either alpha-, beta-, or gamma-) were dissolved in dimethyl sulfoxide (DMSO) at

60°C and allowed to react for one hour with stirring. After cooling to room temperature for 15 hours, the mixture was further cooled in an ice bath.

Excess methyl iodide was added dropwise. After

24 hours the reaction was complete.

EXAMPLE 2

This example illustrates the making of the dialkyl trifluoroacetyl ether derivative of

cyclodextrin of the present invention. The alkane used herein is pentane.

3.0 g of dried cyclodextrin and excess 1-bromopentane were added to 30 ml dimethyl sulfoxide (DMSO). The reaction was carried out at 60°C for 6 hours. Water was then added to the reaction mixture and a waxy precipitate was obtained. The raw product was dissolved in chloroform (CHCl₃) and the solution was washed with water. CHCl₃ was removed under vacuum and the product was used for the next reaction without further purification.

The above material and an excess of

trifluoroacetic anhydride were added to 30 ml

tetrahydrofuran (THF). The mixture was boiled for 2 hours, then poured over ice to precipitate the product. The precipitate was washed with cold water and dissolved in CHCl₃. The CHCl₃ solution was extracted three times with 5% aqueous sodium bicarbonate (NaHCO₃) and three times with water.

The CHCl₃ layer was collected and dried with

anhydrous sodium sulfate (Na₂SO₄). CHCl₃ was

allowed to evaporate in a vacuum desiccator and the final viscous liquid was dried in a vacuum overnight to form the final product of dipentyl trifluoroacetyl ether cyclodextrin derivative.

EXAMPLE 3

This example illustrates separating optical isomers using the media made in Example 1 above.

The optical isomers were derivatized in order to decrease their volatility for better resolution in the gas chromatograph process. Fused silica capillary tubes (0.25 mm ID)

were obtained from Alltech or Supelco. The capillaries were coated with the cyclodextrin derivatives of the present invention via the static method.

Untreated 10 m capillary columns were placed in a water bath at 36°C. A 0.2% w/v ether solution of the cyclodextrin derivative of the present invention filled the capillary. One end of the capillary

was sealed and the other connected to a vacuum

line. It took about 4 hours to coat a 10 m column.

The column efficiency was tested at 100°C by using n-hydrocarbons (C11 and C12) as test solutes.

Only columns that produced ≥ 3600 plates per column meter were used.

Racemic mixtures of amines and alcohols to

be resolved were derivatized with trifluoroacetic anhydride, acetic anhydride or chloroacetic anhydride. Other compounds containing hydroxyl and/or amine functionalities were also derivitized. All chemicals were obtained from Aldrich Chemical Co., Sigma

Chemical Co., or Fluka Chemical Co. In each case, approximately 1.0 mg of the racemic analyte was

dissolved in 0.5 ml of methylene chloride and 200 μl of the desired anhydride added. After reacting for about 5-30 minutes, dry nitrogen was bubbled through the solution to remove excess reagent,

The solution residue was dissolved in 0.5 ml of ether or methanol for chromatographic analysis.

Racemic mixtures of sugars to be resolved were trifluoroacetylated by the above procedure except that tetrahydrofuran was used as the solvent.

Also, because this reaction was somewhat slower and the trifluoroacetic anhydride was volatile, three additional aliquots of trifluoroacetic anhydride were added at seven minute intervals.

Both Hewlett Packard (5710A) and Varian (3700) gas chromatographs were used for all separations.

Split injection and flame ionization detection

were utilized. The injection and detector port temperatures were 200°C and nitrogen was used as the carrier gas. Gas velocity was about 10-15

cm/sec. A split ratio of 100/1 was used for all the columns and at all of the column temperatures.

The injection volume was 0.5 μl.

Referring to the following tables, the separation factor, α, is a measure of the separation between the eluted peaks. The greater the separation between the peaks, the greater is α. Mathematically, α is defined as the ratio of the corrected retention times of the two peaks being compared (i.e.,

where t' = corrected retention time, t = uncorrected time and t₀ = retention time of an unretained compound. Traditionally, the longest retained peak time,

t₂, is put in the numerator so that ot will be greater than 1. An α-value of 1 means that there is no separation (the peaks co-elute).

Tables IA, IB and IC illustrate the separation results using permethylated hydroxypropyl ether

cyclodextrin (PHCD) as the ether derivative of

cyclodextrin. Tables IA, IB and IC show the results using alpha-, beta-, and gamma-cyclodextrin,

respectively. The permethylated hydroxypropyl

ether cyclodextrin was made in accordance with

Example 1 above.

EXAMPLE 4

This example illustrates separating nonderivatized optical isomers using the media of permethylated hydroxypropyl ether derivative of cyclodextrin as made in Example 1 above.

The capillary tubes, the gas chromatographs and the determination of α were as set forth in Example 3 above.

Tables IIa, IIb and IIc illustrate the results using alpha-, beta-, and gamma-cyclodextrin, respectively.

-33

EXAMPLE 5

This Example illustrates separating enantiomers using the media of dipentyl trifluoroacetyl ether

derivative of cyclodextrin as made in Example 2

above .

Table III illustrates the separation results

using the dipentyl trifluoroacetyl ether cyclodextrin

(DP-TFA-CD) as the ether derivative of cyclodextrin.

The capacity factor of the first eluted enantiomer, k, is determined as follows:

where k' = retention time of the eluted solute; and

k" = retention time of an unretained compound.

The column in the Table for "Stationary Phase" indicates which cyclodextrin was used for the ether

derivative. "A" indicates that the ether derivative was dipentyl trifluoroacetyl alpha cyclodextrin;

"B" that it was dipentyl trifluoroacetyl beta cyclodextrin; and "G" that it was dipentyl trifluoroacetyl ether

gamma cyclodextrin.

The capillary tubes, the gas chromatographs

and the determination of α were as set forth in

Example 3 above.

EXAMPLE 6

This Example illustrates retention and selectivity results of homologous racemic amines, diols, and α-halocarboxylic acid esters using the media of dipentyl trifluoroacetyl ether cyclodextrin as

made in Example 2 above. These results are set

forth in the following Table IV.

The capillary tubes, the gas chromatographs and the determination of α were as set forth in

Example 3 above.

The capacity factor and the indication of

the base cyclodextrin used were as set forth in

Example 4 above.

EXAMPLE 7

A test was made to determine if the stereochemistry of the ether side chain has any effect on separation.

Three different media were prepared,

permethyl-(S)-hydroxypropyl-beta-cyclodextrin;

permethyl-(R)-hydroxypropyl-beta cyclodextrin; and permethyl-(racemic)-hydroxypropyl-beta-cyclodextrin.

Three identical columns were coated with these materials and a series of tests were run. Each

of the three columns produced essentially identical separations.

It will be understood that it is intended

to cover all changes and modifications of the preferred embodiments herein chosen for the purpose of illustration which do not constitute a departure from the spirit and scope of the invention.

Claims

What is claimed is:

1. A composition for separation of optical

isomers in a gas chromatographic column, said composition being an ether derivative of cyclodextrin .

2. The composition of claim 1 wherein the

ether derivative of cyclodextrin is a permethylated hydroxy ether of cyclodextrin having about 10%

to about 75% of the hydroxyl groups of the cyclodextrin substituted with hydroxy ether side chains and

substantially all of the hydroxyl groups of the

hydroxy ether of cyclodextrin substituted with

methyl groups.

3. The composition of claim 1 wherein the

cyclodextrin is beta-cyclodextrin.

4. The composition of claim 1 wherein the

cyclodextrin is gamma-cyclodextrin.

5. The composition of claim 1 wherein the

cyclodextrin is alpha-cyclodextrin.

6. The composition of claim 1 wherein the

hydroxy ether of cyclodextrin is selected from

the group consisting of hydroxy propylated cyclodextrin, hydroxy propylated methyl ether cyclodextrin, hydroxy propylated isopropyl ether cyclodextrin, hydroxy propylated vinyl ether cyclodextrin, hydroxy propylated t-butyl ether cyclodextrin, and hydroxy ethylated phenyl cyclodextrin.

7. The composition of claim 1 wherein the ether derivative of cyclodextrin is a dialkyl trifluoro ester ether of cyclodextrin having about 20% to about 80% of the hydrogens of the hydroxyl groups of the cyclodextrin substituted with alkyl side

chains and at least about 90% of the hydrogens

of the remaining hydroxyl groups of the alkylated ether of cyclodextrin substituted with a fluorinated ester group.

8. The composition of claim 7 wherein the

fluorinated ester group is selected from the group consisting of trifluorinated acetyl, trifluorinated butyryl, and trifluorinated propanoic.

9. The composition of claim 8 wherein the

alkyl group is pentane.

10. The composition of claim 8 wherein the cyclodextrin is gamma-cyclodextrin.

11. The composition of claim 8 wherein the cyclodextrin is beta-cyclodextrin.

12. The composition of claim 8 wherein the cyclodextrin is alpha-cyclodextrin.

13. A composition made by the process comprising: a) etherifying a cyclodextrin with an epoxide to form an hydroxy ether of cyclodextrin having between about 10% and about 75% of

the hydroxyl groups on the cyclodextrin substituted by the epoxide; and

b) permethylating substantially all of the hydroxyl groups on the hydroxy ether of cyclodextrin.

14. The composition of claim 13 wherein the cyclodextrin is selcted from the group consisting of alpha-, beta-, and gamma-cyclodextrin.

15. The composition of claim 13 wherein the epoxide is selected from the group consisting of ethylene oxide, propylene oxide, butylene oxide, amylene oxide, glycidol (hydroxypropylene oxide), butadiene oxide, glycidyl methyl ether, glycidyl isopropyl ether, alkyl glycidyl ether, styrene

oxide, and t-butyl glycidyl ether.

16. A composition made by the process comprising: a) etherifying a cyclodextrin with an alkyl halide to form an ether of cyclodextrin having between 20% and about 80% of the hydrogens of the hydroxyl groups of the cyclodextrin

substituted by the alkyl of the alkyl halide; and b) esterifying at least about 90% of

the hydrogens of the remaining hydroxyl groups of the ether derivative of cyclodextrin.

17. The composition of claim 16 wherein the cyclodextrin is selected from the group consisting of alpha-cyclodextrin, beta-cyclodextrin, and gammacyclodextrin.

18. The composition of claim 16 wherein the alkyl halide is selected from the group consisting of propyl bromide, propyl chloride, butyl chloride, butyl bromide, pentyl bromide and pentyl chloride.

19. The composition of claim 16 wherein the esterification agent is fluorinated and is selected from the group consisting of trifluoroacetic anhydride, trifluorobutanoic anhydride, and trifluoropropanoic anhydride.

20. A method for separation of compounds

by means of gas chromatography comprising:

a) passing a mixture of compounds having different structure through a column having an ether derivative of cyclodextrin; and b) eluting separated individual compounds from said column.

21. The method of claim 20 wherein the ether derivative of cyclodextrin is a permethylated hydroxy ether of cyclodextrin having about 10% to about

75% of the hydroxyl groups of the cyclodextrin

substituted with hydroxy ether side chains and

substantially all of the hydroxyl groups of the

hydroxy ether of cyclodextrin substituted with

methyl groups.

22. The method of claim 21 wherein the cyclodextrin is selected from the group consisting of alpha-cyclodextrin, beta-cyclodextrin, and gamma-cyclodextrin.

23. The method of claim 21 wherein the hydroxy

ether of cyclodextrin is selected from the group

consisting of hydroxy propylated cyclodextrin,

hydroxy propylated methyl ether cyclodextrin, hydroxy propylated isopropyl ether cyclodextrin, hydroxy

propylated vinyl ether cyclodextrin, hydroxy propylated t-butyl ether cyclodextrin, and hydroxy ethylated

phenyl cyclodextrin.

24. The method of claim 20 wherein the ether

derivative of cyclodextrin is a dialkyl trifluoro

ester ether of cyclodextrin having about 20% to

about 80% of the hydrogens of the hydroxyl groups

of the cyclodextrin substituted with alkyl side

chains and at least about 90% of the hydrogens

of the remaining hydroxyl groups of the alkylated

ether of cyclodextrin substituted with a fluorinated

ester group.

25. The method of claim 24 wherein the dialkyl

trifluoroester ether of cyclodextrin is selected

from the group consisting of dipentyl trifluorinated acetic ether of cyclodextrin, dipentyl trifluorinated butanoic ether of cyclodextrin,

and dipentyl trifluorinated propanoic ether of

cyclodextrin.

26. The method of claim 24 wherein the cyclodextrin is selected from the group consisting of alpha-cyclodextrin, beta-cyclodextrin, and gamma-cyclodextrin.

27. The method of claim 20 wherein the ether

derivative cyclodextrin is administered into the

column by means of a carrier.

28. The method of claim 27 wherein the carrier

is polyethylene glycol or polysiloxane.

29. The method of claim 20 wherein the column

is a fused silica capillary and the ether derivative

of cyclodextrin is applied as a stationary phase

coating on the capillary.