Cyclodextrin
Encyclopedia
Cyclodextrins are a family of compounds made up of sugar molecules bound together in a ring (cyclic oligosaccharides).
Cyclodextrins are produced from starch
by means of enzymatic
conversion. They are used in food, pharmaceutical, and chemical industries, as well as agriculture and environmental engineering. Hydroxypropyl Beta Cyclodextrin (HPßCD) is the chief active compound found in Procter and Gamble's deodorizing product "Febreze
" under the brand name "Clenzaire".
Cyclodextrins are composed of 5 or more α-D-glucopyranoside units linked 1->4, as in amylose
(a fragment of starch
). The 5-membered macrocycle is not natural. Recently, the largest well-characterized cyclodextrin contains 32 1,4-anhydroglucopyranoside units, while as a poorly characterized mixture, even at least 150-membered cyclic oligosaccharides are also known. Typical cyclodextrins contain a number of glucose
monomers ranging from six to eight units in a ring, creating a cone shape. thus denoting:
was the leading researcher in this area, demonstrating that cyclodextrins formed stable aqueous complexes with many other chemicals. By the mid 1970s, each of the natural cyclodextrins had been structurally and chemically characterized and many more complexes had been studied. Since the 1970s, extensive work has been conducted by Szejtli and others exploring encapsulation by cyclodextrins and their derivatives for industrial and pharmacologic applications. Among the processes used for complexation, the kneading process seems to be one of the best.
In 2009, research from the lab of Drs. Michael S. Brown and Joseph L. Goldstein
, Nobel Prize winning scientists who pioneered the study of cholesterol metabolism, was published showing how cyclodextrin assists in moving cholesterol out of lysosomes in Niemann-Pick Type C disease
. Niemann Pick Type C disease is a lysosomal storage disease
causing progressive deterioration of the nervous system and dementia. It usually affects young children by interfering with their ability to metabolize cholesterol
at the cellular level. Numerous research studies have followed showing that Hydroxypropyl Beta Cyclodextrin (HPßCD) is not simply an agent to solubilize drugs but has powerful pharmacological properties. In April 2009, Investigational New Drug (IND) applications were approved by the U.S. Food and Drug Administration (FDA) in a one time clinical trial to treat identical twin girls suffering from Niemann-Pick Type C disease with intravenous infusions of Hydroxypropyl Beta Cyclodextrin (HPßCD).[14] On May 17, 2010, the FDA approved an orphan drug application for Hydroxypropyl Beta Cyclodextrin (Trappsol brand). On July 14, 2010, Children's Hospital & Research Center Oakland filed a second IND application with the FDA to deliver Hydroxypropyl Beta Cyclodextrin directly into the central nervous system of the twins to bypass the blood brain barrier. On September 23, 2010, the hospital announced that the FDA granted clearance of the intrathecal
application and will begin the world’s first HPßCD administration into the brain.
The formation of the inclusion compound
s greatly modifies the physical and chemical properties of the guest molecule, mostly in terms of water solubility. This is the reason why cyclodextrins have attracted much interest in many fields, especially pharmaceutical applications: because inclusion compounds of cyclodextrins with hydrophobic molecules are able to penetrate body tissues, these can be used to release biologically active compounds under specific conditions. In most cases the mechanism of controlled degradation of such complexes is based on pH
change of water solutions, leading to the cleavage of hydrogen or ionic bonds between the host and the guest molecules. Alternative means for the disruption of the complexes take advantage of heating or action of enzymes able to cleave α-1,4 linkages between glucose monomers.
(CGTase) is employed along with α-amylase
. First starch is liquified either by heat treatment or using α-amylase, then CGTase is added for the enzymatic conversion. CGTases can synthesize all forms of cyclodextrins, thus the product of the conversion results in a mixture of the three main types of cyclic molecules, in ratios that are strictly dependent on the enzyme used: each CGTase has its own characteristic α:β:γ synthesis ratio. Purification of the three types of cyclodextrins takes advantage of the different water solubility of the molecules: β-CD which is very poorly water soluble (18.5 g/l or 16.3mM) (at 25C???) can be easily retrieved through crystallization
while the more soluble α- and γ-CDs (145 and 232 g/l respectively) are usually purified by means of expensive and time consuming chromatography
techniques.
As an alternative a "complexing agent" can be added during the enzymatic conversion step: such agents (usually organic solvents like toluene
, acetone
or ethanol
) form a complex with the desired cyclodextrin which subsequently precipitates. The complex formation drives the conversion of starch towards the synthesis of the precipitated cyclodextrin, thus enriching its content in the final mixture of products.
Cyclodextrins are able to form host-guest complexes with hydrophobic molecules given the unique nature imparted by their structure. As a result, these molecules have found a number of applications in a wide range of fields.
Other than the above mentioned pharmaceutical applications for drug release, cyclodextrins can be employed in environmental protection: these molecules can effectively immobilise inside their rings toxic compounds, like trichloroethane
or heavy metals
, or can form complexes with stable substances, like trichlorfon (an organophosphorus
insecticide
) or sewage sludge, enhancing their decomposition.
In the food industry cyclodextrins are employed for the preparation of cholesterol
free products: the bulky and hydrophobic cholesterol molecule is easily lodged inside cyclodextrin rings that are then removed. Alpha-, beta-, and gamma-cyclodextrin are all generally recognized as safe
by the FDA.
Weight loss supplements are marketed from alpha-cyclodextrin which claim to bind to fat and be an alternative to other anti-obesity medications.
Other food applications further include the ability to stabilize volatile or unstable compounds and the reduction of unwanted tastes and odour. Alpha-cyclodextrin is used as emulsifier in food and cosmetic applications.
Reportedly cyclodextrins are used in alcohol powder
, a powder for mixing alcoholic drinks.
The strong ability of complexing fragrances can also be used for another purpose: first dry, solid cyclodextrin microparticles are exposed to a controlled contact with fumes of active compounds, then they are added to fabric or paper products. Such devices are capable of releasing fragrances during ironing or when heated by human body. Such a device commonly used is a typical 'dryer sheet'. The heat from a clothes dryer releases the fragrance into the clothing.
The ability of cyclodextrins to form complexes with hydrophobic molecules has led to their usage in supramolecular chemistry
. In particular they have been used to synthesize certain mechanically-interlocked molecular architectures, such as rotaxane
s and catenane
s, by reacting the ends of the threaded guest.
The application of cyclodextrin as supramolecular carrier is also possible in organometallic reactions. The mechanism of action probably takes place in the interfacial region. Wipff also demonstrated by computational study that the reaction occurs in the interfacial layer. The application of cyclodextrins as supramolecular carrier is possible in various organometallic catalysis.
β-cyclodextrins are used to produce HPLC
columns allowing chiral enantiomers separation.
from cultured cells. The methylated form MβCD was found to be more efficient than β-cyclodextrin. The water-soluble MβCD is known to form soluble inclusion complexes with cholesterol, thereby enhancing its solubility in aqueous solution. MβCD is employed for the preparation of cholesterol-free products: the bulky and hydrophobic cholesterol molecule is easily lodged inside cyclodextrin rings that are then removed. MβCD is also employed in research to disrupt lipid rafts by removing cholesterol from membranes.
Cyclodextrins are produced from starch
Starch
Starch or amylum is a carbohydrate consisting of a large number of glucose units joined together by glycosidic bonds. This polysaccharide is produced by all green plants as an energy store...
by means of enzymatic
Enzyme
Enzymes are proteins that catalyze chemical reactions. In enzymatic reactions, the molecules at the beginning of the process, called substrates, are converted into different molecules, called products. Almost all chemical reactions in a biological cell need enzymes in order to occur at rates...
conversion. They are used in food, pharmaceutical, and chemical industries, as well as agriculture and environmental engineering. Hydroxypropyl Beta Cyclodextrin (HPßCD) is the chief active compound found in Procter and Gamble's deodorizing product "Febreze
Febreze
Febreze is a brand of household odor eliminator manufactured by Procter & Gamble, sold in North America, Europe, Asia, Australia and New Zealand...
" under the brand name "Clenzaire".
Cyclodextrins are composed of 5 or more α-D-glucopyranoside units linked 1->4, as in amylose
Amylose
Amylose is a linear polymer made up of D-glucose units.This polysaccharide is one of the two components of starch, making up approximately 2-30% of the structure...
(a fragment of starch
Starch
Starch or amylum is a carbohydrate consisting of a large number of glucose units joined together by glycosidic bonds. This polysaccharide is produced by all green plants as an energy store...
). The 5-membered macrocycle is not natural. Recently, the largest well-characterized cyclodextrin contains 32 1,4-anhydroglucopyranoside units, while as a poorly characterized mixture, even at least 150-membered cyclic oligosaccharides are also known. Typical cyclodextrins contain a number of glucose
Glucose
Glucose is a simple sugar and an important carbohydrate in biology. Cells use it as the primary source of energy and a metabolic intermediate...
monomers ranging from six to eight units in a ring, creating a cone shape. thus denoting:
- α -cyclodextrin: six membered sugar ring molecule
- β -cyclodextrin: seven sugar ring molecule
- γ -cyclodextrin: eight sugar ring molecule
History of cyclodextrins
Cyclodextrins, as they are known today, were called "cellulosine" when first described by A. Villiers in 1891. Soon after, F. Schardinger identified the three naturally occurring cyclodextrins -α, -β, and -γ. These compounds were therefore referred to as "Schardinger sugars". For 25 years, between 1911 and 1935, Pringsheim in GermanyGermany
Germany , officially the Federal Republic of Germany , is a federal parliamentary republic in Europe. The country consists of 16 states while the capital and largest city is Berlin. Germany covers an area of 357,021 km2 and has a largely temperate seasonal climate...
was the leading researcher in this area, demonstrating that cyclodextrins formed stable aqueous complexes with many other chemicals. By the mid 1970s, each of the natural cyclodextrins had been structurally and chemically characterized and many more complexes had been studied. Since the 1970s, extensive work has been conducted by Szejtli and others exploring encapsulation by cyclodextrins and their derivatives for industrial and pharmacologic applications. Among the processes used for complexation, the kneading process seems to be one of the best.
In 2009, research from the lab of Drs. Michael S. Brown and Joseph L. Goldstein
Joseph L. Goldstein
Joseph L. Goldstein from Kingstree, South Carolina is a Nobel Prize winning biochemist and geneticist, and a pioneer in the study of cholesterol metabolism.-Biography:...
, Nobel Prize winning scientists who pioneered the study of cholesterol metabolism, was published showing how cyclodextrin assists in moving cholesterol out of lysosomes in Niemann-Pick Type C disease
Niemann-Pick disease, type C
Niemann-Pick type C is a lysosomal storage disease associated with mutations in NPC1 and NPC2 genes. Niemann-Pick Type C strikes an estimated 1:150,000 people...
. Niemann Pick Type C disease is a lysosomal storage disease
Lysosomal storage disease
Lysosomal storage diseases are a group of approximately 50 rare inherited metabolic disorders that result from defects in lysosomal function...
causing progressive deterioration of the nervous system and dementia. It usually affects young children by interfering with their ability to metabolize cholesterol
Cholesterol
Cholesterol is a complex isoprenoid. Specifically, it is a waxy steroid of fat that is produced in the liver or intestines. It is used to produce hormones and cell membranes and is transported in the blood plasma of all mammals. It is an essential structural component of mammalian cell membranes...
at the cellular level. Numerous research studies have followed showing that Hydroxypropyl Beta Cyclodextrin (HPßCD) is not simply an agent to solubilize drugs but has powerful pharmacological properties. In April 2009, Investigational New Drug (IND) applications were approved by the U.S. Food and Drug Administration (FDA) in a one time clinical trial to treat identical twin girls suffering from Niemann-Pick Type C disease with intravenous infusions of Hydroxypropyl Beta Cyclodextrin (HPßCD).[14] On May 17, 2010, the FDA approved an orphan drug application for Hydroxypropyl Beta Cyclodextrin (Trappsol brand). On July 14, 2010, Children's Hospital & Research Center Oakland filed a second IND application with the FDA to deliver Hydroxypropyl Beta Cyclodextrin directly into the central nervous system of the twins to bypass the blood brain barrier. On September 23, 2010, the hospital announced that the FDA granted clearance of the intrathecal
Intrathecal
Intrathecal is an adjective that refers to something introduced into or occurring in the space under the arachnoid membrane of the brain or spinal cord...
application and will begin the world’s first HPßCD administration into the brain.
Structure
Typical cyclodextrins are constituted by 6-8 glucopyranoside units, can be topologically represented as toroids with the larger and the smaller openings of the toroid exposing to the solvent secondary and primary hydroxyl groups respectively. Because of this arrangement, the interior of the toroids is not hydrophobic, but considerably less hydrophilic than the aqueous environment and thus able to host other hydrophobic molecules. In contrast, the exterior is sufficiently hydrophilic to impart cyclodextrins (or their complexes) water solubility.The formation of the inclusion compound
Inclusion compound
In host-guest chemistry an inclusion compound is a complex in which one chemical compound forms a cavity in which molecules of a second "guest" compound are located. The definition of inclusion compounds is very broad, extending to channels formed between molecules in a crystal lattice in which...
s greatly modifies the physical and chemical properties of the guest molecule, mostly in terms of water solubility. This is the reason why cyclodextrins have attracted much interest in many fields, especially pharmaceutical applications: because inclusion compounds of cyclodextrins with hydrophobic molecules are able to penetrate body tissues, these can be used to release biologically active compounds under specific conditions. In most cases the mechanism of controlled degradation of such complexes is based on pH
PH
In chemistry, pH is a measure of the acidity or basicity of an aqueous solution. Pure water is said to be neutral, with a pH close to 7.0 at . Solutions with a pH less than 7 are said to be acidic and solutions with a pH greater than 7 are basic or alkaline...
change of water solutions, leading to the cleavage of hydrogen or ionic bonds between the host and the guest molecules. Alternative means for the disruption of the complexes take advantage of heating or action of enzymes able to cleave α-1,4 linkages between glucose monomers.
Synthesis
The production of cyclodextrins is relatively simple and involves treatment of ordinary starch with a set of easily available enzymes. Commonly cyclodextrin glycosyltransferaseCyclodextrin glycosyltransferase
Cyclodextrin glycosyl transferase or CGTase for short is a bacterial enzyme belonging to the same family of the α-amylase specifically known as glycosyl-hydrolase family 13...
(CGTase) is employed along with α-amylase
Amylase
Amylase is an enzyme that catalyses the breakdown of starch into sugars. Amylase is present in human saliva, where it begins the chemical process of digestion. Food that contains much starch but little sugar, such as rice and potato, taste slightly sweet as they are chewed because amylase turns...
. First starch is liquified either by heat treatment or using α-amylase, then CGTase is added for the enzymatic conversion. CGTases can synthesize all forms of cyclodextrins, thus the product of the conversion results in a mixture of the three main types of cyclic molecules, in ratios that are strictly dependent on the enzyme used: each CGTase has its own characteristic α:β:γ synthesis ratio. Purification of the three types of cyclodextrins takes advantage of the different water solubility of the molecules: β-CD which is very poorly water soluble (18.5 g/l or 16.3mM) (at 25C???) can be easily retrieved through crystallization
Crystallization
Crystallization is the process of formation of solid crystals precipitating from a solution, melt or more rarely deposited directly from a gas. Crystallization is also a chemical solid–liquid separation technique, in which mass transfer of a solute from the liquid solution to a pure solid...
while the more soluble α- and γ-CDs (145 and 232 g/l respectively) are usually purified by means of expensive and time consuming chromatography
Chromatography
Chromatography is the collective term for a set of laboratory techniques for the separation of mixtures....
techniques.
As an alternative a "complexing agent" can be added during the enzymatic conversion step: such agents (usually organic solvents like toluene
Toluene
Toluene, formerly known as toluol, is a clear, water-insoluble liquid with the typical smell of paint thinners. It is a mono-substituted benzene derivative, i.e., one in which a single hydrogen atom from the benzene molecule has been replaced by a univalent group, in this case CH3.It is an aromatic...
, acetone
Acetone
Acetone is the organic compound with the formula 2CO, a colorless, mobile, flammable liquid, the simplest example of the ketones.Acetone is miscible with water and serves as an important solvent in its own right, typically as the solvent of choice for cleaning purposes in the laboratory...
or ethanol
Ethanol
Ethanol, also called ethyl alcohol, pure alcohol, grain alcohol, or drinking alcohol, is a volatile, flammable, colorless liquid. It is a psychoactive drug and one of the oldest recreational drugs. Best known as the type of alcohol found in alcoholic beverages, it is also used in thermometers, as a...
) form a complex with the desired cyclodextrin which subsequently precipitates. The complex formation drives the conversion of starch towards the synthesis of the precipitated cyclodextrin, thus enriching its content in the final mixture of products.
Uses
Other than the above mentioned pharmaceutical applications for drug release, cyclodextrins can be employed in environmental protection: these molecules can effectively immobilise inside their rings toxic compounds, like trichloroethane
Trichloroethane
Trichloroethane can refer to either of two isomeric chemical compounds:* 1,1,1-Trichloroethane * 1,1,2-Trichloroethane...
or heavy metals
Heavy metals
A heavy metal is a member of a loosely-defined subset of elements that exhibit metallic properties. It mainly includes the transition metals, some metalloids, lanthanides, and actinides. Many different definitions have been proposed—some based on density, some on atomic number or atomic weight,...
, or can form complexes with stable substances, like trichlorfon (an organophosphorus
Organophosphate
An organophosphate is the general name for esters of phosphoric acid. Phosphates are probably the most pervasive organophosphorus compounds. Many of the most important biochemicals are organophosphates, including DNA and RNA as well as many cofactors that are essential for life...
insecticide
Insecticide
An insecticide is a pesticide used against insects. They include ovicides and larvicides used against the eggs and larvae of insects respectively. Insecticides are used in agriculture, medicine, industry and the household. The use of insecticides is believed to be one of the major factors behind...
) or sewage sludge, enhancing their decomposition.
In the food industry cyclodextrins are employed for the preparation of cholesterol
Cholesterol
Cholesterol is a complex isoprenoid. Specifically, it is a waxy steroid of fat that is produced in the liver or intestines. It is used to produce hormones and cell membranes and is transported in the blood plasma of all mammals. It is an essential structural component of mammalian cell membranes...
free products: the bulky and hydrophobic cholesterol molecule is easily lodged inside cyclodextrin rings that are then removed. Alpha-, beta-, and gamma-cyclodextrin are all generally recognized as safe
Generally recognized as safe
Generally recognized as safe is an American Food and Drug Administration designation that a chemical or substance added to food is considered safe by experts, and so is exempted from the usual Federal Food, Drug, and Cosmetic Act food additive tolerance requirements.-History:On January 1, 1958,...
by the FDA.
Weight loss supplements are marketed from alpha-cyclodextrin which claim to bind to fat and be an alternative to other anti-obesity medications.
Other food applications further include the ability to stabilize volatile or unstable compounds and the reduction of unwanted tastes and odour. Alpha-cyclodextrin is used as emulsifier in food and cosmetic applications.
Reportedly cyclodextrins are used in alcohol powder
Alcohol powder
Alcohol powder is a powder that will produce an alcoholic drink when mixed with water.- Chemical properties :Little about the composition of the powder, as well as the process occurring when mixed with water, has been revealed in news sources....
, a powder for mixing alcoholic drinks.
The strong ability of complexing fragrances can also be used for another purpose: first dry, solid cyclodextrin microparticles are exposed to a controlled contact with fumes of active compounds, then they are added to fabric or paper products. Such devices are capable of releasing fragrances during ironing or when heated by human body. Such a device commonly used is a typical 'dryer sheet'. The heat from a clothes dryer releases the fragrance into the clothing.
The ability of cyclodextrins to form complexes with hydrophobic molecules has led to their usage in supramolecular chemistry
Supramolecular chemistry
Supramolecular chemistry refers to the area of chemistry beyond the molecules and focuses on the chemical systems made up of a discrete number of assembled molecular subunits or components...
. In particular they have been used to synthesize certain mechanically-interlocked molecular architectures, such as rotaxane
Rotaxane
A rotaxane is a mechanically-interlocked molecular architecture consisting of a "dumbbell shaped molecule" which is threaded through a "macrocycle" . The name is derived from the Latin for wheel and axle...
s and catenane
Catenane
A catenane is a mechanically-interlocked molecular architecture consisting of two or more interlocked macrocycles. The interlocked rings cannot be separated without breaking the covalent bonds of the macrocycles. Catenane is derived from the Latin catena meaning "chain"...
s, by reacting the ends of the threaded guest.
The application of cyclodextrin as supramolecular carrier is also possible in organometallic reactions. The mechanism of action probably takes place in the interfacial region. Wipff also demonstrated by computational study that the reaction occurs in the interfacial layer. The application of cyclodextrins as supramolecular carrier is possible in various organometallic catalysis.
β-cyclodextrins are used to produce HPLC
High-performance liquid chromatography
High-performance liquid chromatography , HPLC, is a chromatographic technique that can separate a mixture of compounds and is used in biochemistry and analytical chemistry to identify, quantify and purify the individual components of the mixture.HPLC typically utilizes different types of stationary...
columns allowing chiral enantiomers separation.
Methyl-beta-cyclodextrin
Both β-cyclodextrin and Methyl-β-cyclodextrin (MβCD) remove cholesterolCholesterol
Cholesterol is a complex isoprenoid. Specifically, it is a waxy steroid of fat that is produced in the liver or intestines. It is used to produce hormones and cell membranes and is transported in the blood plasma of all mammals. It is an essential structural component of mammalian cell membranes...
from cultured cells. The methylated form MβCD was found to be more efficient than β-cyclodextrin. The water-soluble MβCD is known to form soluble inclusion complexes with cholesterol, thereby enhancing its solubility in aqueous solution. MβCD is employed for the preparation of cholesterol-free products: the bulky and hydrophobic cholesterol molecule is easily lodged inside cyclodextrin rings that are then removed. MβCD is also employed in research to disrupt lipid rafts by removing cholesterol from membranes.
External links
- Cyclodextrin Database
- Addi and Cassi Hempel, identical twins with Niemann Pick Type C being treated with HPßCD cyclodextrin
- Information on Cyclodextrin, HIV/AIDS and Niemann Pick Type C
- OpenCDLig: a free Web application for host/guest complexes
- The European Cyclodextrin Society
- Cyclodextrin Technologies Development, Inc.