CA1321192C - Inclusion complexes of cyclodextrins by agglomeration - Google Patents
Inclusion complexes of cyclodextrins by agglomerationInfo
- Publication number
- CA1321192C CA1321192C CA000564609A CA564609A CA1321192C CA 1321192 C CA1321192 C CA 1321192C CA 000564609 A CA000564609 A CA 000564609A CA 564609 A CA564609 A CA 564609A CA 1321192 C CA1321192 C CA 1321192C
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- Prior art keywords
- guest
- agglomerates
- liquid
- water
- cyclodextrin
- Prior art date
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Classifications
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- B—PERFORMING OPERATIONS; TRANSPORTING
- B82—NANOTECHNOLOGY
- B82Y—SPECIFIC USES OR APPLICATIONS OF NANOSTRUCTURES; MEASUREMENT OR ANALYSIS OF NANOSTRUCTURES; MANUFACTURE OR TREATMENT OF NANOSTRUCTURES
- B82Y5/00—Nanobiotechnology or nanomedicine, e.g. protein engineering or drug delivery
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
- A61K47/69—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit
- A61K47/6949—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit inclusion complexes, e.g. clathrates, cavitates or fullerenes
- A61K47/6951—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit inclusion complexes, e.g. clathrates, cavitates or fullerenes using cyclodextrin
Abstract
TITLE
INCLUSION COMPLEXES OF CYCLODEXTRINS
BY AGGLOMERATION
INVENTORS
Abdul Majid John A. Ripmeester ABSTRACT OF THE DISCLOSURE
A combined process is described in which inclusion complexes are formed from guest molecules and cyclodextrins during agglomeration of the cyclodextrins. Sufficient agi-tation in the presence of a small amount of water results in complex formation and bonding into strong agglomerates.
The agglomerates are strong and stable and useful inter alia in foods (the guest molecules are flavors), pharma-ceuticals (the guest molecules are drugs) and agriculture (the guest molecules are various agrochemicals).
INCLUSION COMPLEXES OF CYCLODEXTRINS
BY AGGLOMERATION
INVENTORS
Abdul Majid John A. Ripmeester ABSTRACT OF THE DISCLOSURE
A combined process is described in which inclusion complexes are formed from guest molecules and cyclodextrins during agglomeration of the cyclodextrins. Sufficient agi-tation in the presence of a small amount of water results in complex formation and bonding into strong agglomerates.
The agglomerates are strong and stable and useful inter alia in foods (the guest molecules are flavors), pharma-ceuticals (the guest molecules are drugs) and agriculture (the guest molecules are various agrochemicals).
Description
1~21192 This invention is concerned with the formation of agglomerates of cyclodextrin inclusion complexes directly from guest molecule materials and cyclodextrins. The re-sulting agglomerates have been found to be strong, stable and easily handled.
Cyclodextrins, discovered about one century ago, are emerging as a new group of industrial materials. The ability to include a variety of guest molecules into their hydrophobic cavity, without the formation of any covalent bond, is their most important property. Among the natural cyclodextrins, ~-cyclodextrin is widely used because of its unique cavity size (internal diameter about 6.5 ~), and the ease with which it can be obtained on a large scale.
The guest inclusion function of cyclodextrins has been adopted for pharmaceuticals, foods, cosmetics, toiletries, agrochemicals, and other industrial uses.
Many basic studies on cyclodextrins have been published, covering artificial enzymes, catalysts, photocontrolled reactions, isomer separation or selective production, and molecular electronics.
Some of the advantages and uses of cyclodextrin guest complexation include:
(1) Stabilization, controlled release and storage as stable powders of gaseous, volatile, and sublimable guest substances, e.g. pesticides.
Cyclodextrins, discovered about one century ago, are emerging as a new group of industrial materials. The ability to include a variety of guest molecules into their hydrophobic cavity, without the formation of any covalent bond, is their most important property. Among the natural cyclodextrins, ~-cyclodextrin is widely used because of its unique cavity size (internal diameter about 6.5 ~), and the ease with which it can be obtained on a large scale.
The guest inclusion function of cyclodextrins has been adopted for pharmaceuticals, foods, cosmetics, toiletries, agrochemicals, and other industrial uses.
Many basic studies on cyclodextrins have been published, covering artificial enzymes, catalysts, photocontrolled reactions, isomer separation or selective production, and molecular electronics.
Some of the advantages and uses of cyclodextrin guest complexation include:
(1) Stabilization, controlled release and storage as stable powders of gaseous, volatile, and sublimable guest substances, e.g. pesticides.
(2) Improvement of physical and chemical stability of labile cornpounds e.g. these guest compounds are protected . :. : .
13211~2 from oxidation by air; the rates of decomposition, dispro-portionation, polymerization, autocatalytic reactions, etc.
are considerably decreased and sensitivity to light is reduced.
13211~2 from oxidation by air; the rates of decomposition, dispro-portionation, polymerization, autocatalytic reactions, etc.
are considerably decreased and sensitivity to light is reduced.
(3) In the formulation of drugs, liquid guest compounds can be transformed into a solid form which is suitable for tablet-manufacturing. Usually bad tastes or smells can be masked, and incompatible compounds can be mixed when one of the components is protected by inclusion complex formation.
(4) The bioavailability of poorly soluble drugs can be enhanced. The solubility in water, as well as the rate of dissolution of poorly soluble substances can be increased.
Following oral administration of poorly water soluble drugs, higher blood levels can be achieved if they are complexed with cyclodextrins.
Following oral administration of poorly water soluble drugs, higher blood levels can be achieved if they are complexed with cyclodextrins.
(5) A very promising method for the stabilization of food flavors and fragrances is their complexation with cyclo-dextrins, which has already been realized on an industrial scale.
(6) Unpleasant tastes and odors can be removed by cyclo-dextrin complexation. Thus, cyclodextrin complexation have been used for reducing the bitterness of orange and grapefruit juice, animal and plant protein hydrolysates, mushroom extracts, certain stereoisomers, and propylene glycol. It can lighten specific smells of mutton, fish meat, yeast extracts, soybean milk, fish meal, lecithin, and old grains.
'.. ~1' '' ''~,. ' ' "~' :' " ' ' ~ ~ '. ' ' "~ `' 1321~
- (7) Separation, concentration and fractionation of speci-fic substances. Separations of xylene isomers and ethyl-benzenes, trimethylbenzenes, isomeric alkylphenols, alkyl-toluene isomers, straight and branched chain hydrocarbons have been reported. Resolution of various enantiomers employing cyclodextrin complexation has also been reported.
Various known methods used for the formation of cyclodextrin complexes include: Xneading, freeze drying, spray drying, mixed pulverization and crystallization from saturated solution. However, most of these methods are time consuming and laborious.
We have found that inclusion complexes with ~, or y cyclodextrins can be conveniently made in more advan-tageous form using agglomeration techniques. The advantages of this method and product include:
(1) It is more simple and quick than known methods.
(2) Complexation and agglomeration occur simultaneously thus eliminating an extra step for pelletiz2tion after complex formation.
(3~ When the guest molecule is liquid, cyclodextrins can be dispersed in the liquid guest molecule phase, thus eliminating the need for a solvent.
(4) Agglomerates can be easily separated from the bulk liquid phase, e.g. by screening.
(5) The size of agglomerates can be controlled at will.
(6) The resulting agglomerates or pellets are strongly bonded by residual water remaining after drying and are very stable.
1321~92 Summary of the Invention This invention includes a process for preparing inclusion complexes of guest: molecules and cyclodextrins, in agglomerate form, comprising:
(a) contacting the cyclodextrin in solid form with a selected guest molecule material in the presence of a small amount of water sufficient to serve as agglomeration binding liquid, to form a mixture, (b) agitating the mixture sufficiently to cause inter-penetration of the components and inclusion complex forma-tion to occur, (c) continuing agitation until agglomerates form, and (d) recovering agglomerates of the inclusion complexes.
When the guest molecule material is a water-immiscible liquid, sufficient may be used to form a con-tinuous liquid phase, and the agglomeration follows spher-ical agglomeration techniques (see A.F. Sirianni et al, Can. J. Chem. Engin. 1969, 47, 166-170). If the guest molecule is too viscous, an operative lower viscosity can be achieved by the addition of a water-immiscible solvent, e.g. hexane and diethylether.
When the guest material is solid, the steps in-clude intimate solid-solid mixing and wet pelletization operations. In this case the guest material preferably is present in approximately the stoichiometric amount to form the desired inclusion complex. A stage of severe agitation has been found necessary to form the inclusion ` . !
'`' . " ,,`. '. ~ .
`' ` ' ` ' complex (with mild agitation the complex did not form).
Any final wet pelletization procedure may be used to form the final agglomerates.
The amount of water added normally will be with-in about 10 to about 100% by wt. based on the cyclodextrin,preferably about 25-50%. Added water has been found neces-sary for formation of the complex and for agglomeration.
Excess liquid guest phase, after removal of the agglomerates, can be recycled to step (a).
The starting cyclodextrin can be any of the alpha, beta or gamma forms known in the art. Normally the form of cyclodextrin is used which has a cavity size matched to the size of the guest molecule. The match need not be exact. Usually the cyclodextrin will contain some water of hydration: additional water as outlined above is essential both for inclusion complex and for agglomerate formation.
Many different guest materials which will form the inclusion complexes may be used. Examples of guest liquids include citral, citronellal, limonene, peppermint oil, lemon oil, benzaldehyde, allethrins, and pyrethroids.
Examples of guest solids include salicylic acid, cinnari-zine, chloropicrin, and phenacetin. Tetrahydrocannabinol is a viscous liquid (see Example 5).
The resulting agglomerates are easily separated, recoveredr handled and utilized. Not all of the added water is removed on drying: it appears some residual water . ,': ' , - : :
1321~92 is binding the cyclodextrin particles together. Under appropriate conditions the agglomerates are readily dis-persed, dissolved or otherwise incorporated or applied.
The size of the agglomerates can be varied by controlling the amount of water added and to a lesser degree the agitation. Increasing the amount of water tends to increase the agglomerate size. Increasing the agitation tends to decrease the agglomerate size.
When the guest materials are water-soluble solids, wet pelletization techniques including a severe agitation, may be used to form the agglomerates.
The following examples will serve to illustrate the invention. Examples 1-3 involve liquid guest com-pounds and for these small scale tests the general proce-dure was as follows:
About 0.2-0.5 gms of hydrated ~-cyclodextrin was dispersed in 2-5 ml of liquid guest compound in 250 ml glass jar. A small amount of water (50-500 microliter) was added to this suspension. The jar was sealed tightly using a polyethylene gasket. The contents were agitated on a Spex (TM) mixer for 5-15 minutes when agglomerates of ~-cyclodextrin complex with the guest molecules were formed. This mixer gave a severe agitation in a 3-dimen-sional path to the jar contents. These agglomerates ranged in size from less than 0.1 mm to greater than 1 cm.
Agglomerates were separated from excess guest compound either by decantation or by screening. Agglomerates were ~, .:
. . : ~ , , - ~ .;, .
,, : -: ~", 1321~92 further dried by pressing against tissue papers. Complete drying or the agglomerates was not found to be necessary because the solid state CP/MAS, ~ 3C NMR spectroscopy used for analytical characterization of the complexes only detects the complexed guest molecules. However, if com-plete removal of free guest compound from the agglomerates is necessary well established routine procedures such as spray drying, freeze drying and vacuum drying could be used.
Analytical Procedure: ~-cyclodextrin complexes were char-acterized using solid state 1 3C NMR spectrometry. Spectra were obtained at 45.28 MHz on a Bruker CXP 180 NMR spec-trometer using the cross polarization (CP) technique with magic angle spinning (MAS). A contact time of 2 ms and repetition times of 2-4 S were selected. The magic angle spinning speeds were 3.0-4.0 KHz.
Example 1 0.5 g of hydrated ~-cyclodextrin was dispersed in 5 g of citral in a 250 ml glass jar. 100 microliters of water was-added to this suspension and the contents agitated on a Spex (TM) mixer for 10 minutes. This result-ed in the formation of micro-agglomerates of about 1 mm size. Excess citral was removed by decantation and agglo-merates dried by pressing against tissue paper.
The CP/MAS, ~ 3 C NMR spectrum of these agglome-rates was compared with the spectrum of hydrated ~-cyclo-dextrin. A comparison of the two spectra clearly showed ,': , : .. - ...
. . : . , , , ,:: -significant broadening of the carbon resonances oE the ~-cyclodextrin. This broadening is because of the displace-ment of water molecules in the host cavity by the citral molecules, indicating the formation of an inclusion com-plex. The guest molecule's resonances observed in the solid state complex were readily assigned due to their close resemblance to those observed in solution. It is interesting to note that the intensity of the C-5 signal of the cis isomer of citral was low compared with the C-5 signal of the corresponding trans isomer. Since, the starting guest material had almost equal proportions of both cis and trans isomers, this suggested selective complexa-tion of the trans isomer compared with the cis isomer.
This is consistent with published reports for the selec-tive inclusion of a particular isomer of various guest materials. Inclusion complex formation has been employed in the separation of isomers.
~xample 2 0.~5 g of hydrated ~-cyclodextrin was dispersed in 5 g of citronellal in a glass jar. 100 microliters of water was added to this suspension and the contents agitated on a Spex (TM) mixer for 5 minutes. This gave 0.5-2 mm size agglomerates that were dried as described in Example 1.
The verification of the inclusion complex forma-tiGn was obtained by comparing the CP/MAS-I 3C NMR spectrum of these agglomerates with the hydrated ~-cyclodextrin .
, : -1321~9~ `
spectrum and the fact that all carbons from citronellal could be accounted for.
Ex,ample 3 0.5 g of hydrated ~-cyclodextrin was dispersed in 7 g of limonene. 100 microliters of water was added to this suspension and the contents agitated on a Spex (TM) mixer for 10 minutes. Microagglomerates of about 1 mm size were obtained that were dried as described in Example 1.
The formation of ~-cyclodextrin-limonene complex was confirmed from the CP/MAS-I 3C NMR spectrum of the ag-glomerates.
Wet pelletization has been carried out with three solid guest molecules to form the inclusion complex as agglomerates. One procedure is given in Example 4.
Example 4 0.3-0.4 millimoles of the hydrated ~-cyclodextrin and 0.5-0.8 millimoles of solid guest molecule were ground together in an agate pestle and mortar in the presence of 50-500 microliters tpreferably 100-300 microliters) of water. The resulting paste was transferred to a 100 ml Teflon tTM) jar with a screw type cap and a rubber ring for a tight seal. After sealing the jar tightly the con-tents were agitated on a Spex (TM) mixer for 5-15 minutes when agglomerates of ~-cyclodextrin complex with the guest molecules were formed. These agglomerates ranged in size from <0.1 mm to >0.2 mm. These complexes were character-ized using solid state ~ 3C NMR spectroscopy as described g .. :: . . -132~2 previously. Examples of solid guest molecules for which ~-cyclodextrin complexes were prepared using this proce-dure include~ salicylic acid, cinnarizine and phenacetin.
It is possible to form the complex and agglo-merate using viscous liquid guest molecule material and cyclodextrin by dissolving the guest material in a water-immiscible sol~ent, adding the cyclodextrin and water and agitating as a slurry. Example 5 is typical.
Example 5 Tetrahydrocannabinol (THC) was obtained as a solution in ethanol. The ethanol was evaporated and 0.1 g of THC was dissolved in 15 ml of hexane. B-cyclodextrin hydrate 0.2 g and 50 microliters of water were dispersed in the hexane solution, and the mixture agitated in a Spex (TM) mixer for 5-10 minutes. The resulting agglomerates were separated and dried. The dried agglomerates were free of hexane. Inclusion complex formation was confirmed as in Example 1.
Where the guest molecules are gaseous, it is possible to disperse the cyclodextrin particle in a water-immiscible liquid, add the water required for inclusion complex formation and agglomeration, and dissolve a stoi-chiometric: excess of the gaseous guest molecules in the liquid phase before agitation. On appropriate agitation, agglomerates of the inclusion complexes will form. Examples include gaseous aromas or deodorizers.
. .
~ . . ; ::
'.. ~1' '' ''~,. ' ' "~' :' " ' ' ~ ~ '. ' ' "~ `' 1321~
- (7) Separation, concentration and fractionation of speci-fic substances. Separations of xylene isomers and ethyl-benzenes, trimethylbenzenes, isomeric alkylphenols, alkyl-toluene isomers, straight and branched chain hydrocarbons have been reported. Resolution of various enantiomers employing cyclodextrin complexation has also been reported.
Various known methods used for the formation of cyclodextrin complexes include: Xneading, freeze drying, spray drying, mixed pulverization and crystallization from saturated solution. However, most of these methods are time consuming and laborious.
We have found that inclusion complexes with ~, or y cyclodextrins can be conveniently made in more advan-tageous form using agglomeration techniques. The advantages of this method and product include:
(1) It is more simple and quick than known methods.
(2) Complexation and agglomeration occur simultaneously thus eliminating an extra step for pelletiz2tion after complex formation.
(3~ When the guest molecule is liquid, cyclodextrins can be dispersed in the liquid guest molecule phase, thus eliminating the need for a solvent.
(4) Agglomerates can be easily separated from the bulk liquid phase, e.g. by screening.
(5) The size of agglomerates can be controlled at will.
(6) The resulting agglomerates or pellets are strongly bonded by residual water remaining after drying and are very stable.
1321~92 Summary of the Invention This invention includes a process for preparing inclusion complexes of guest: molecules and cyclodextrins, in agglomerate form, comprising:
(a) contacting the cyclodextrin in solid form with a selected guest molecule material in the presence of a small amount of water sufficient to serve as agglomeration binding liquid, to form a mixture, (b) agitating the mixture sufficiently to cause inter-penetration of the components and inclusion complex forma-tion to occur, (c) continuing agitation until agglomerates form, and (d) recovering agglomerates of the inclusion complexes.
When the guest molecule material is a water-immiscible liquid, sufficient may be used to form a con-tinuous liquid phase, and the agglomeration follows spher-ical agglomeration techniques (see A.F. Sirianni et al, Can. J. Chem. Engin. 1969, 47, 166-170). If the guest molecule is too viscous, an operative lower viscosity can be achieved by the addition of a water-immiscible solvent, e.g. hexane and diethylether.
When the guest material is solid, the steps in-clude intimate solid-solid mixing and wet pelletization operations. In this case the guest material preferably is present in approximately the stoichiometric amount to form the desired inclusion complex. A stage of severe agitation has been found necessary to form the inclusion ` . !
'`' . " ,,`. '. ~ .
`' ` ' ` ' complex (with mild agitation the complex did not form).
Any final wet pelletization procedure may be used to form the final agglomerates.
The amount of water added normally will be with-in about 10 to about 100% by wt. based on the cyclodextrin,preferably about 25-50%. Added water has been found neces-sary for formation of the complex and for agglomeration.
Excess liquid guest phase, after removal of the agglomerates, can be recycled to step (a).
The starting cyclodextrin can be any of the alpha, beta or gamma forms known in the art. Normally the form of cyclodextrin is used which has a cavity size matched to the size of the guest molecule. The match need not be exact. Usually the cyclodextrin will contain some water of hydration: additional water as outlined above is essential both for inclusion complex and for agglomerate formation.
Many different guest materials which will form the inclusion complexes may be used. Examples of guest liquids include citral, citronellal, limonene, peppermint oil, lemon oil, benzaldehyde, allethrins, and pyrethroids.
Examples of guest solids include salicylic acid, cinnari-zine, chloropicrin, and phenacetin. Tetrahydrocannabinol is a viscous liquid (see Example 5).
The resulting agglomerates are easily separated, recoveredr handled and utilized. Not all of the added water is removed on drying: it appears some residual water . ,': ' , - : :
1321~92 is binding the cyclodextrin particles together. Under appropriate conditions the agglomerates are readily dis-persed, dissolved or otherwise incorporated or applied.
The size of the agglomerates can be varied by controlling the amount of water added and to a lesser degree the agitation. Increasing the amount of water tends to increase the agglomerate size. Increasing the agitation tends to decrease the agglomerate size.
When the guest materials are water-soluble solids, wet pelletization techniques including a severe agitation, may be used to form the agglomerates.
The following examples will serve to illustrate the invention. Examples 1-3 involve liquid guest com-pounds and for these small scale tests the general proce-dure was as follows:
About 0.2-0.5 gms of hydrated ~-cyclodextrin was dispersed in 2-5 ml of liquid guest compound in 250 ml glass jar. A small amount of water (50-500 microliter) was added to this suspension. The jar was sealed tightly using a polyethylene gasket. The contents were agitated on a Spex (TM) mixer for 5-15 minutes when agglomerates of ~-cyclodextrin complex with the guest molecules were formed. This mixer gave a severe agitation in a 3-dimen-sional path to the jar contents. These agglomerates ranged in size from less than 0.1 mm to greater than 1 cm.
Agglomerates were separated from excess guest compound either by decantation or by screening. Agglomerates were ~, .:
. . : ~ , , - ~ .;, .
,, : -: ~", 1321~92 further dried by pressing against tissue papers. Complete drying or the agglomerates was not found to be necessary because the solid state CP/MAS, ~ 3C NMR spectroscopy used for analytical characterization of the complexes only detects the complexed guest molecules. However, if com-plete removal of free guest compound from the agglomerates is necessary well established routine procedures such as spray drying, freeze drying and vacuum drying could be used.
Analytical Procedure: ~-cyclodextrin complexes were char-acterized using solid state 1 3C NMR spectrometry. Spectra were obtained at 45.28 MHz on a Bruker CXP 180 NMR spec-trometer using the cross polarization (CP) technique with magic angle spinning (MAS). A contact time of 2 ms and repetition times of 2-4 S were selected. The magic angle spinning speeds were 3.0-4.0 KHz.
Example 1 0.5 g of hydrated ~-cyclodextrin was dispersed in 5 g of citral in a 250 ml glass jar. 100 microliters of water was-added to this suspension and the contents agitated on a Spex (TM) mixer for 10 minutes. This result-ed in the formation of micro-agglomerates of about 1 mm size. Excess citral was removed by decantation and agglo-merates dried by pressing against tissue paper.
The CP/MAS, ~ 3 C NMR spectrum of these agglome-rates was compared with the spectrum of hydrated ~-cyclo-dextrin. A comparison of the two spectra clearly showed ,': , : .. - ...
. . : . , , , ,:: -significant broadening of the carbon resonances oE the ~-cyclodextrin. This broadening is because of the displace-ment of water molecules in the host cavity by the citral molecules, indicating the formation of an inclusion com-plex. The guest molecule's resonances observed in the solid state complex were readily assigned due to their close resemblance to those observed in solution. It is interesting to note that the intensity of the C-5 signal of the cis isomer of citral was low compared with the C-5 signal of the corresponding trans isomer. Since, the starting guest material had almost equal proportions of both cis and trans isomers, this suggested selective complexa-tion of the trans isomer compared with the cis isomer.
This is consistent with published reports for the selec-tive inclusion of a particular isomer of various guest materials. Inclusion complex formation has been employed in the separation of isomers.
~xample 2 0.~5 g of hydrated ~-cyclodextrin was dispersed in 5 g of citronellal in a glass jar. 100 microliters of water was added to this suspension and the contents agitated on a Spex (TM) mixer for 5 minutes. This gave 0.5-2 mm size agglomerates that were dried as described in Example 1.
The verification of the inclusion complex forma-tiGn was obtained by comparing the CP/MAS-I 3C NMR spectrum of these agglomerates with the hydrated ~-cyclodextrin .
, : -1321~9~ `
spectrum and the fact that all carbons from citronellal could be accounted for.
Ex,ample 3 0.5 g of hydrated ~-cyclodextrin was dispersed in 7 g of limonene. 100 microliters of water was added to this suspension and the contents agitated on a Spex (TM) mixer for 10 minutes. Microagglomerates of about 1 mm size were obtained that were dried as described in Example 1.
The formation of ~-cyclodextrin-limonene complex was confirmed from the CP/MAS-I 3C NMR spectrum of the ag-glomerates.
Wet pelletization has been carried out with three solid guest molecules to form the inclusion complex as agglomerates. One procedure is given in Example 4.
Example 4 0.3-0.4 millimoles of the hydrated ~-cyclodextrin and 0.5-0.8 millimoles of solid guest molecule were ground together in an agate pestle and mortar in the presence of 50-500 microliters tpreferably 100-300 microliters) of water. The resulting paste was transferred to a 100 ml Teflon tTM) jar with a screw type cap and a rubber ring for a tight seal. After sealing the jar tightly the con-tents were agitated on a Spex (TM) mixer for 5-15 minutes when agglomerates of ~-cyclodextrin complex with the guest molecules were formed. These agglomerates ranged in size from <0.1 mm to >0.2 mm. These complexes were character-ized using solid state ~ 3C NMR spectroscopy as described g .. :: . . -132~2 previously. Examples of solid guest molecules for which ~-cyclodextrin complexes were prepared using this proce-dure include~ salicylic acid, cinnarizine and phenacetin.
It is possible to form the complex and agglo-merate using viscous liquid guest molecule material and cyclodextrin by dissolving the guest material in a water-immiscible sol~ent, adding the cyclodextrin and water and agitating as a slurry. Example 5 is typical.
Example 5 Tetrahydrocannabinol (THC) was obtained as a solution in ethanol. The ethanol was evaporated and 0.1 g of THC was dissolved in 15 ml of hexane. B-cyclodextrin hydrate 0.2 g and 50 microliters of water were dispersed in the hexane solution, and the mixture agitated in a Spex (TM) mixer for 5-10 minutes. The resulting agglomerates were separated and dried. The dried agglomerates were free of hexane. Inclusion complex formation was confirmed as in Example 1.
Where the guest molecules are gaseous, it is possible to disperse the cyclodextrin particle in a water-immiscible liquid, add the water required for inclusion complex formation and agglomeration, and dissolve a stoi-chiometric: excess of the gaseous guest molecules in the liquid phase before agitation. On appropriate agitation, agglomerates of the inclusion complexes will form. Examples include gaseous aromas or deodorizers.
. .
~ . . ; ::
Claims (12)
1. A process for preparing inclusion complexes of guest molecules and cyclodextrins, in agglomerate form, comprising:
a) contacting the cyclodextrin in solid form with a selected guest molecule material in the presence of a small amount of water sufficient to serve as agglo-meration binding liquid, to form a mixture, b) agitating the mixture sufficiently to cause interpenetration of the components and inclusion complex formation to occur, c) continuing agitation until agglomerates form, and d) recovering agglomerates of the inclusion complexes.
a) contacting the cyclodextrin in solid form with a selected guest molecule material in the presence of a small amount of water sufficient to serve as agglo-meration binding liquid, to form a mixture, b) agitating the mixture sufficiently to cause interpenetration of the components and inclusion complex formation to occur, c) continuing agitation until agglomerates form, and d) recovering agglomerates of the inclusion complexes.
2. The process of claim 1 in which the guest material is liquid and sufficient is used to form a continous liquid phase.
3. The process of claim 1 in which the guest material is solid and the steps include intimate solid solid mixing and wet pelletization.
4. The process of claim 3 in which the guest material is present in approximately the stoichiometric amount to form the desired complex.
5. The process of claims 1, 2 or 3 in which the amount of water is from about 10 to about 100% by wt.
based on the cyclodextrin.
CLAIMS (cont.)
based on the cyclodextrin.
CLAIMS (cont.)
6. The process of claim 2 wherein after removal of the agglomerates, the excess liquid guest phase is recycled.
7. The process of claims 1, 2 or 3 in which the recovered agglomerates are dried to remove unbound water and any excess liquid guest material.
8. The process of claims 1, 2 or 3 in which the starting cyclodextrin comprises a hydrated beta-cyclo-dextrin.
9. The process of claim 2 in which the liquid guest material is selected from flavours, perfumes, agrochemicals, and drugs.
10. The process of claim 3 in which the solid guest material is selected from pharmaceuticals.
11. The process of claim 1 in which the guest material is gaseous, a water-immiscible liquid is pre-sent and an excess of the gaseous guest molecules are dissolved in the liquid phase in step (a).
12. Agglomerates of guest inclusion complexes of cyclodextrins formed by substantially concurrent complex formation and agglomeration, and containing bound water.
Priority Applications (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CA000564609A CA1321192C (en) | 1988-04-20 | 1988-04-20 | Inclusion complexes of cyclodextrins by agglomeration |
| US07/337,969 US5070081A (en) | 1988-04-20 | 1989-04-14 | Inclusion complexes of cyclodextrins by agglomeration |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CA000564609A CA1321192C (en) | 1988-04-20 | 1988-04-20 | Inclusion complexes of cyclodextrins by agglomeration |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1321192C true CA1321192C (en) | 1993-08-10 |
Family
ID=4137875
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA000564609A Expired - Fee Related CA1321192C (en) | 1988-04-20 | 1988-04-20 | Inclusion complexes of cyclodextrins by agglomeration |
Country Status (2)
| Country | Link |
|---|---|
| US (1) | US5070081A (en) |
| CA (1) | CA1321192C (en) |
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| TW282399B (en) * | 1990-05-25 | 1996-08-01 | Takeda Pharm Industry Co Ltd | |
| US5321014A (en) * | 1991-06-28 | 1994-06-14 | The United States Of America As Represented By The Department Of Health And Human Services | Molecular encapsulation and delivery of alkenes alkynes and long chain alkanes, to living mammalian cells |
| AT400674B (en) * | 1991-07-24 | 1996-02-26 | Biochemie Gmbh | PHARMACEUTICAL PLEUROMUTILIN PREPARATION |
| US5300280A (en) * | 1992-02-14 | 1994-04-05 | Mallinckrodt Medical, Inc. | Stabilized radiopharmaceutical kits |
| GB9211573D0 (en) * | 1992-05-30 | 1992-07-15 | Kodak Ltd | Compounds capable of forming inclusion complexes |
| US5472954A (en) * | 1992-07-14 | 1995-12-05 | Cyclops H.F. | Cyclodextrin complexation |
| US5403828A (en) * | 1992-08-13 | 1995-04-04 | American Maize-Products Company | Purification of cyclodextrin complexes |
| US5474718A (en) * | 1993-02-08 | 1995-12-12 | Eastman; James E. | Starch hydrolysates as sequesterers |
| EP0777415A4 (en) * | 1994-07-11 | 1999-06-16 | David W Pate | Anandamide analogue compositions and method of treating intraocular hypertention using same |
| US5631297A (en) * | 1994-07-11 | 1997-05-20 | Pate; David W. | Anandamides useful for the treatment of intraocular hypertension, ophthalmic compositions containing the same and methods of use of the same |
| JP2000509374A (en) | 1996-04-19 | 2000-07-25 | アルファ セラピュティック コーポレイション | Method for virus inactivation of lyophilized blood proteins |
| JP3940209B2 (en) * | 1996-11-14 | 2007-07-04 | 株式会社資生堂 | Solubilized cosmetics |
| SE520645C2 (en) * | 1996-11-15 | 2003-08-05 | Interhealth Ab | Therapeutic and cosmetic compositions, their use and method of preparation thereof |
| WO2000015049A1 (en) * | 1998-09-17 | 2000-03-23 | The Nutrasweet Company | THE USE OF CYCLODEXTRIN TO STABILIZE N-[N- (3,3-DIMETHYLBUTYL) -1-α- ASPARTYL] -L-PHENYLALANINE 1-METHYL ESTER |
| US6555139B2 (en) | 1999-06-28 | 2003-04-29 | Wockhardt Europe Limited | Preparation of micron-size pharmaceutical particles by microfluidization |
| US6056941A (en) * | 1999-07-28 | 2000-05-02 | Bracco Research Usa | Kit for the preparation of technetium TC 99m teboroxime myocardial perfusion agent |
| US6287603B1 (en) * | 1999-09-16 | 2001-09-11 | Nestec S.A. | Cyclodextrin flavor delivery systems |
| WO2001097814A1 (en) * | 2000-06-22 | 2001-12-27 | Ceramoptec Industries, Inc. | Photosensitizers with ligand targeting properties for tumor therapy |
| US6444619B1 (en) * | 2000-09-28 | 2002-09-03 | Rohm And Haas Company | Delivery system for cyclopropenes |
| US20020146409A1 (en) * | 2001-01-30 | 2002-10-10 | Herring Steven W. | Methods for stabilizing lyophilized blood proteins |
| US20030028014A1 (en) * | 2001-04-26 | 2003-02-06 | Chris Sikorski | Agglomerated modified cyclodextrin and process for making same |
| FI113340B (en) * | 2002-02-20 | 2004-04-15 | Tomi Jaervinen | New complexes of natural cyclodextrin |
| PT2260871E (en) | 2004-04-01 | 2013-08-01 | Pf Medicament | Inclusion complexes comprising piroxicam, a cyclodextrin and arginine |
| US7838044B2 (en) * | 2004-12-21 | 2010-11-23 | Purecircle Sdn Bhd | Extraction, separation and modification of sweet glycosides from the Stevia rebaudiana plant |
| EP2027136A4 (en) * | 2006-06-13 | 2011-08-03 | Cargill Inc | Large-particle cyclodextrin inclusion complexes and methods of preparing same |
| US20110009362A1 (en) * | 2008-02-27 | 2011-01-13 | Dr. Reddy's Laboratories Ltd. | Solubility-enhanced forms of aprepitant and pharmaceutical compositions thereof |
| CA2692211C (en) | 2009-12-14 | 2011-09-13 | Cellresin Technologies, Llc | Maturation or ripening inhibitor release from polymer, fiber, film, sheet or packaging |
| CN102232949A (en) * | 2010-04-27 | 2011-11-09 | 孙远 | Drug dissolution increasing composition and preparation method thereof |
| US10182567B2 (en) | 2011-03-27 | 2019-01-22 | Cellresin Technologies, Llc | Cyclodextrin compositions, articles, and methods |
| SI2690951T1 (en) | 2011-03-27 | 2016-02-29 | Cellresin Technologies, Llc | Cyclodextrin compositions, articles, and methods |
| EP2906603B1 (en) * | 2012-10-10 | 2017-08-16 | The University of Queensland | Encapsulation of gases within cyclodextrins |
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| BR112018016066A2 (en) | 2016-02-04 | 2019-01-02 | Czap Res And Development Llc | delivery vehicle, method for treating a gastrointestinal disorder, use of the delivery vehicle, method for formulating a delivery vehicle, pharmaceutical formulation, method for formulating acetaminophen, meal replacement, inclusion complex, method for treating a patient, method for modulating the microbiome |
| US10058531B1 (en) | 2017-06-01 | 2018-08-28 | Spartak LLC | Dosage delivery film |
| MX2020007483A (en) * | 2018-01-13 | 2020-11-12 | Pure Green Pharmaceuticals Inc | Transformation of cannabinol and terpene oils into water soluble dry powders for solid form sublingual delivery. |
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| JPS5813541A (en) * | 1981-07-16 | 1983-01-26 | Kureha Chem Ind Co Ltd | Cyclodextrin clathrate compound of eicosapentaenoic acid or docosahexaenoic acid |
| JPS6081166A (en) * | 1983-10-11 | 1985-05-09 | Fujisawa Pharmaceut Co Ltd | Beta-cyclodextrin clathrate compound of 2-nitroxymethyl-6- chloropyridine and production thereof |
| US4675395A (en) * | 1984-03-14 | 1987-06-23 | Seiwa Technological Laboratories Limited | Cyclodextrin inclusion compound and process for its preparation |
| JPS61152765A (en) * | 1984-12-27 | 1986-07-11 | Nippon Ekishiyou Kk | Synthetic resin product including compound clathrated with cyclodextrin |
| GB8613688D0 (en) * | 1986-06-05 | 1986-07-09 | Euro Celtique Sa | Pharmaceutical composition |
| US4904773A (en) * | 1987-03-09 | 1990-02-27 | Allelix Inc. | Process for extracting methylxanthines from aqueous solutions containing same |
| US4916161A (en) * | 1988-10-25 | 1990-04-10 | Bristol-Myers Squibb | Taste-masking pharmaceutical agents |
-
1988
- 1988-04-20 CA CA000564609A patent/CA1321192C/en not_active Expired - Fee Related
-
1989
- 1989-04-14 US US07/337,969 patent/US5070081A/en not_active Expired - Fee Related
Also Published As
| Publication number | Publication date |
|---|---|
| US5070081A (en) | 1991-12-03 |
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