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CAS NUMBER: 128446-35-5
EC NUMBER: 420-920-1
MOLECULAR FORMULA: (C6H9O5)7(C3H7O)
MOLECULAR WEIGHT: 1541.6
2-Hydroxypropyl-β-cyclodextrin is the most widely used modified cyclodextrin.
2-Hydroxypropyl-β-cyclodextrin has shown to change the physicochemical properties of lipophilic compounds when co-administered.
2-Hydroxypropyl-β-cyclodextrin functions by forming an inclusion complex with 2-Hydroxypropyl-β-cyclodextrin being administered for easier diffusion across biological membranes.
The popularity of 2-Hydroxypropyl-β-cyclodextrin can be attributed to its large 7 glucose unit cavity size.
Some advantageous effects are reduction of negative effects, increased aqueous solubility and increased stability.
The effects of 2-Hydroxypropyl-β-cyclodextrin have been observed to be dose dependent with both advantageous and disadvantageous results occurring at sporadic concentrations.
2-Hydroxypropyl-β-cyclodextrin may also increase the antimicrobial effectiveness of chemical agents by increasing their release rate.
2-Hydroxypropyl-β-cyclodextrin is also known as Hydroxypropyl-beta-cyclodextrin, (2-Hydroxypropyl)-beta-cyclodextrin, 2-hydroxypropyl ethers β-cyclodextrin, and HP-β-CD.
2-Hydroxypropyl-β-cyclodextrin are cyclic oligosaccharides consisting of 6, 7, or 8 glucopyranose units, usually referred to as α-, β-, or γ-cyclodextrins, respectively.
These compounds have rigid doughnut-shaped structures making them natural complexing agents.
The unique structures of these compounds owe their stability to intramolecular hydrogen bonding between the C2- and C3-hydroxyl groups of neighboring glucopyranose units.
The molecule takes on the shape of a torus with the C2- and C3-hydroxyls located around the larger opening and the more reactive C6-hydroxyl aligned around the smaller opening.
The arrangement of C6-hydroxyls opposite the hydrogen bonded C2- and C3-hydroxyls forces the oxygen bonds into close proximity within the cavity, leading to an electron rich, hydrophobic interior.
The size of this hydrophobic cavity is a function of the number of glucopyranose units forming the cyclodextrin.
The solubility of natural cyclodextrins is very poor.
In the late 1960′s, it was discovered that chemical substitutions at the 2, 3, and 6 hydroxyl sites would greatly increase solubility.
Most chemically modified cyclodextrins are able to achieve a 50% (w/v) concentration in water.
Cavity size is the major determinant as to which cyclodextrin is used in complexation.
The cavity diameter of
2-Hydroxypropyl-β-cyclodextrin or β-glucopyranose unit compounds is well-suited for use with molecules the size of hormones, vitamins and many compounds frequently used in tissue and cell culture applications.
For this reason, ß-cyclodextrin is most commonly used as a complexing agent.
Cyclodextrins are a family of cyclic oligosaccharides, consisting of a macrocyclic ring of glucose subunits joined by α-1,4 glycosidic bonds.
Cyclodextrins are produced from starch by enzymatic conversion.
They are used in food, pharmaceutical, drug delivery, and chemical industries, as well as agriculture and environmental engineering.
Cyclodextrins are composed of 5 or more α-D-glucopyranoside units linked 1->4, as in amylose (a fragment of starch).
The largest cyclodextrin contains 32 1,4-anhydroglucopyranoside units, while as a poorly characterized mixture, at least 150-membered cyclic oligosaccharides are also known.
2-Hydroxypropyl-beta-Cyclodextrin are non-toxic solubilizers.
The solubility of drugs increases linearly with the concentration of 2-Hydroxypropyl-b-cyclodextrin in aqueous buffer.
The formation of drug/cyclodextrin complexes is a rapidly reversible reaction and complexes exist both in solution and crystalline states. Solutions of many such complexes may be lyophilized to produce freely soluble powders which may be compressed into tablets.
Bio-effects are only slightly affected by cyclodextrin complexation. Cells in serum supplemented medium can be grown in up to 1-2%.
2-hydroxypropyl-g-cyclodextrin with its 8 glucose units, has a slightly larger cavity and can accomodate larger substrates than the beta form.
2-Hydroxypropyl-β-cyclodextrin, due to its excellent biocompatibility, has been widely used in drug delivery systems, environmental remediation, food additives, and pharmacotherapy.
2-Hydroxypropyl-β-cyclodextrin can readily cross the BBB and target nerve cells.
The excretion in faeces and expired air was minimal.
Plasma levels of unchanged HP-β-CD declined rapidly and showed a bi-phasic decline after single intravenous and oral dosing in healthy volunteers.
The utility of a 45%w/v HP-β-CD aqueous dosing vehicle in preclinical studies is very common.
This vehicle is useful with poorly aqueous drugs.
Hydroxypropyl beta cyclodextrin (HPβCD) is comprised of seven sugar molecules bound together in a ring (cyclic oligosaccharide).
The ring-shaped, three-dimensional structure has a hydrophobic cavity in its center, which is capable of trapping cholesterol and lipids.
2-Hydroxypropyl-β-cyclodextrin has been used extensively as an excipient in the food, deodorant, and drug industry for the past century, and it is generally recognized as safe (GRAS).
As an active ingredient, HPβCD entraps and removes intracellular cholesterol and lipids that can cause injury to the kidneys and other organs, including the brain and liver.
Hydroxypropyl-β-cyclodextrin (HPCD), a highly water-soluble derivative, was synthesized by the substitution of the hydroxyl groups in the glucopyranose units of β-cyclodextrin (β-CD) with hydroxypropyl groups to improve its solubility in aqueous solution and its biocompatibility. β-CD has only limited water solubility (∼1.8 g/mL at ambient temperature), whereas HPCD showed high water solubility and also dissolved in solvents such as methanol, ethanol, DMF, and DMSO.
To investigate their feasibility for transdermal delivery applications, HPCD inclusion complexes containing several lipophilic guest molecules (retinol, tocopherol, and genistein) were prepared through complex formation by taking advantage of the special molecular structure of HPCD, which has a hydrophobic interior cavity and a hydrophilic exterior.
The molar inclusion efficiency of guest molecules within HPCD was ca. 8-12 % when the feed molar ratio of guest molecules to CD was.
The inclusion efficiency was influenced by the feed molar ratio and by the type of guest molecule.
The stabilities of the inclusion complexes were investigated with respect to the temperature, pH, and solvent.
HPCD complexes exhibited enhanced stability in comparison with those of the parent β-CD.
From an in vitro skin permeation study using a Frantz diffusion cells, ca. 70-90 % permeation of guest molecules was observed within 7 days.
USES:
2-Hydroxypropyl-β-cyclodextrin (HBC) is a widely used modified cyclodextrin, the lipophilic cavity formed by 7 glucose units.
Drug solubility in water is greatly enhanced by complexing with 2-Hydroxypropyl-β-cyclodextrin.
The ability of cyclodextrins to hold guest compounds has been harnessed in many ways.
The food industry has capitalized on this property to entrap various ingredients, masking or preserving flavors in food products.
As food additives, the natural α-, β-, and γ- cyclodextrins have the Generally Recognized as Safe (GRAS) label by the U.S. Food and Drug Administration (FDA; Notices 000155, 000074, 000046, respectively), subject to certain percent composition limits.
The 2-Hydroxypropyl-β-cyclodextrin do not cross the intestinal barrier in significant amounts and are fermented by gut bacteria or excreted whole; γ-cyclodextrins are metabolized by mammalian α-amylases into linear oligosaccharides.
Consequently, cyclodextrins in food or otherwise consumed orally do not usually enter the circulation in significant amounts (Frijlink et al., 1990), and thus are generally safe.
Pharmaceutical applications primarily involve the use of cyclodextrins to increase the stability and solubility of drug compounds, but the ability to form inclusion complexes has also been exploited in scavenging applications where injected cyclodextrins can bind to active compounds and end their action on target systems.
As constituents of drug formulations, several modified and unmodified cyclodextrins are in the FDA’s Inactive Ingredient Database, suggesting that they are relatively inert up to certain dosages. Safety is greatly increased by hydroxypropyl and sulfobutylether substitution, which has allowed so-modified cyclodextrins to be administered parenterally at high doses to experimental animals with little morbidity and mortality and few obvious side effects (Gould and Scott, 2005).
High dosing due to the relative safety of the substituted versions has opened the door to cyclodextrins being used for their own drug effects, rather than just for the actions of guest compounds.
New medical applications have arisen from the insight that uncomplexed cyclodextrins—those with an empty central cavity—can extract and shuttle membrane lipids.
Therapeutic applications include treatments for atherosclerosis, Alzheimer’s disease, Parkinson’s disease, infectious disease, and lipid storage disorders (Dass and Jessup, 2000; Graham et al., 2003; Yao et al., 2012; Ottinger et al., 2014; Oliveri and Vecchio, 2016; Zimmer et al., 2016).
A recent report generated considerable excitement, showing that 2-hydroxypropyl-β-cyclodextrin reversed atherosclerosis and limited the formation of new sclerotic plaques in mice, even when the mice were fed a cholesterol-rich diet (Zimmer et al., 2016).
The affordability and (reported) safety of 2-Hydroxypropyl-β-cyclodextrin makes it attractive compared to other treatments for cardiovascular disease, especially for patients who are sensitive to statins or cannot maintain a low-fat, low-cholesterol diet.
Similar dosing has been used successfully to treat a mouse model of Alzheimer’s disease (Yao et al., 2012), further increasing the clinical interest in HPβCD.
However, the true surge in attention given 2-Hydroxypropyl-β-cyclodextrin has been driven by its ability to normalize lipid homeostasis and prolong survival in animal models of NPC.
2-Hydroxypropyl-β-cyclodextrin can be used as selective estrogen receptor modulator for the prevention of osteoporosis
-solubilizer
-embedding agent
-stabilizer
-masking agent
APPLICATIONS:
2-Hydroxypropyl-β-cyclodextrin are ingredients in more than 30 different approved medicines.
With a hydrophobic interior and hydrophilic exterior, cyclodextrins form complexes with hydrophobic compounds.
2-Hydroxypropyl-β-cyclodextrins are all generally recognized as safe by the U.S. FDA.
They have been applied for delivery of a variety of drugs, including hydrocortisone, prostaglandin, nitroglycerin, itraconazol, chloramphenicol.
2-Hydroxypropyl-β-cyclodextrin confers solubility and stability to these drugs.
The 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 loss 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.
2-Hydroxypropyl-β-cyclodextrin were also shown to enhance mucosal penetration of drugs.
2-Hydroxypropyl-β-cyclodextrin bind fragrances.
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.
They are the main ingredient in Febreze which claims that the β-cyclodextrins "trap" odor causing compounds, thereby reducing the odor.
2-Hydroxypropyl-β-cyclodextrin are also used to produce alcohol powder by encapsulating ethanol.
The powder produces an alcoholic beverage when mixed with water.
Hydroxypropyl-β-cyclodextrin in aqueous solution because of the complex between HBC and the drug.
This guest-host type complex is formed between the drug and the non-polar cavity in the HBC that results in enhanced solubility.
Solutions may be lyophilized to produce freely soluble powders.
-medicine
-food
-cosmetics
PHARMACEUTICAL APPLICATION:
2-Hydroxypropyl-β-cyclodextrin has been widely investigated in pharmaceutics and has principally been used as a solubilizer for hydrophobic molecules in oral liquids,oral solids, parenterals, pressurized metered dose inhalers, dry powder inhalers, and topical formulations.
2-Hydroxypropyl-β-cyclodextrin has also been shown to act as a stabilizer during processing and storage of formulations.
2-Hydroxypropyl-β-cyclodextrin inclusion complexes have been reported to show mechanical properties distinct from the pure materials.
The reported advantage of hydroxypropyl betadex over unsubstituted b-cyclodextrin is its greater water solubility.
PROPERTIES:
-Appearance: white powder,sweet,indodorous nontoxic
-Assay: ≥99%
-Theaveragesubstitution: perfect
-Moisturecontent: ≤2.0%
-ResidueonIgnition: ≤2.0%
-Heavymetal(Pb): ≤0.0025%
-AS: ≤0.0002%
-Thetotalnumberofgerm: ≤1000
-Thetotalnumberofmould: ≤100
-Physical State: Solid
-Solubility: Soluble in water (100 mM).
-Storage: Store at room temperature
-Melting Point: 305° C
-Optical Activity: α20D +139, c = 1 in water
CHEMICAL PROPERTIES:
White to slightly yellow powder.
2-Hydroxypropyl-β-cyclodextrin occurs as a white or almost white, amorphous or crystalline powder.
PRODUCTION METHOD:
2-Hydroxypropyl-β-cyclodextrin is prepared by the treatment of an alkaline solution of b-cyclodextrin with propylene oxide.
The substitution pattern can be influenced by varying the pH.
Formation of O-6 and O-2 substituted products is favored by high and low alkali concentration, respectively.
The mixture of products produced may be refined by preparative chromatography.
STRUCTURE:
2-Hydroxypropyl-β-cyclodextrins are ring-shaped oligosaccharides formed in nature by the digestion of cellulose by bacteria.
2-Hydroxypropyl-β-cyclodextrins are composed of varying numbers of glucose units held together by α-1, 4 glycosidic bonds.
The naturally occurring varieties contain at least six glucose units, with the most common having six, seven, or eight (so called, α-, β-, and γ- cyclodextrins, respectively). Cyclodextrins with more than eight glucose members are less common in nature and less well characterized, and compounds with five glucose units are only synthetic.
Bountiful research has been poured into α-, β-, and γ- cyclodextrins and their properties are well characterized.
The ring these molecules form (is often depicted as a cup-shaped toroid (Figure 1B).
The outside of the cup is hydrophilic, and the inside is more hydrophobic.
Thus, these chemicals are water soluble with the ability to contain hydrophobic guest molecules within them, singly or as dimers.
The resulting increase in solubility and stability of the guest compounds is the predominant basis for the vast medical, industrial and scientific uses of cyclodextrins. Much effort has been expended on improving and tailoring this characteristic by chemical substitution of the hydrogen in the hydroxyl groups, which form the mouths of the toroidal openings, extending from the glucose units.
Some common substitutions at these sites are methyl, hydroxylpropyl and sulfobutylether groups.
Adding these groups occurs with different efficiencies and results in different sets of impurities along with the intended reaction product.
2-Hydroxypropyl-β-cyclodextrin is chemically difficult to achieve substitution of all possible sites, so a reaction process results in a “degree of substitution”, often expressed as the average number of substituted groups present per molecule or per glucose unit.
Different processes produce varied degrees of substitution, and this can have advantages, since both the nature of the substituent group and the degree of substitution influence the performance of the cyclodextrin in ways that can be useful.
2-Hydroxypropyl-β-cyclodextrin are constituted by 6-8 glucopyranoside units.
2-Hydroxypropyl-β-cyclodextrins are linked by 1,4 glycosidic bonds.
2-Hydroxypropyl-β-cyclodextrin have toroidal shapes, 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.
They are not soluble in typical organic solvents.
SYNTHESIS:
2-Hydroxypropyl-β-cyclodextrins are prepared by enzymatic treatment of starch.
Commonly cyclodextrin glycosyltransferase (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.
2-Hydroxypropyl-β-cyclodextrins produce mixtures 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 2-Hydroxypropyl-β-cyclodextrins takes advantage of the different water solubility of the molecules: β-CD which is 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. 2-Hydroxypropyl-β-cyclodextrin uses dedicated enzymes, that can produce alpha-, beta- or gamma-cyclodextrin specifically. 2-Hydroxypropyl-β-cyclodextrin is very valuable especially for the food industry, as only alpha- and gamma-cyclodextrin can be consumed without a daily intake limit.
SAFETY:
2-Hydroxypropyl-β-cyclodextrins are of wide interest in part because they are nontoxic.
The LD50 (oral, rats) is on the order of grams per kilogram.
Nevertheless, attempts to use β-Cyclodextrin for the prevention of atherosclerosis, age-related lipofuscin accumulation and obesity encounter an obstacle in the form of damage to the auditory nerve
and nephrotoxic effect.
HANDLING:
Wherever possible, you should prepare and use solutions on the same day.
However, if you need to make up stock solutions in advance, we recommend that you store the solution as aliquots in tightly sealed vials at -20°C.
Generally, these will be useable for up to one month.
Before use, and prior to opening the vial we recommend that you allow your product to equilibrate to room temperature for at least 1 hour.
STORAGE:
2-Hydroxypropyl-β-cyclodextrin should be sealed and shaded to be stored in a dry, cool, well ventilated place.
