Cyclodextrins and their uses: a review

doi:10.1016/S0032-9592(03)00258-9

Process Biochemistry

Volume 39, Issue 9, 31 May 2004, Pages 1033-1046

https://doi.org/10.1016/S0032-9592(03)00258-9 Get rights and content

Abstract

Cyclodextrins are a family of cyclic oligosaccharides composed of α-(1,4) linked glucopyranose subunits. Cyclodextrins are useful molecular chelating agents. They possess a cage-like supramolecular structure, which is the same as the structures formed from cryptands, calixarenes, cyclophanes, spherands and crown ethers. These compounds having supramolecular structures carry out chemical reactions that involve intramolecular interactions where covalent bonds are not formed between interacting molecules, ions or radicals. The majority of all these reactions are of ‘host–guest’ type. Compared to all the supramolecular hosts mentioned above, cyclodextrins are most important. Because of their inclusion complex forming capability, the properties of the materials with which they complex can be modified significantly. As a result of molecular complexation phenomena CDs are widely used in many industrial products, technologies and analytical methods. The negligible cytotoxic effects of CDs are an important attribute in applications such as rug carrier, food and flavours, cosmetics, packing, textiles, separation processes, environment protection, fermentation and catalysis.

Section snippets

History

Cyclodextrins are cyclic oligosaccharides consisting of six α-cyclodextrin, seven β-cyclodextrin, eight γ-cyclodextrin or more glucopyranose units linked by α-(1,4) bonds (Fig. 1). They are also known as cycloamyloses, cyclomaltoses and Schardinger dextrins [1], [2]. They are produced as a result of intramolecular transglycosylation reaction from degradation of starch by cyclodextrin glucanotransferase (CGTase) enzyme [3].

They were first discovered in 1891 [1], when in addition to reducing

Properties

Cyclodextrins are of three types: α-cyclodextrin, β-cyclodextrin and γ-cyclodextrin, referred to as first generation or parent cyclodextrins. α-, β- and γ-cyclodextrins are composed of six, seven and eight α-(1,4)-linked glycosyl units, respectively [15]. β-Cyclodextrin is the most accessible, the lowest-priced and generally the most useful. The main properties of those cyclodextrins are given in Table 1.

Studies of cyclodextrins in solution are supported by a large number of crystal structure

Conclusions

Many types of encapsulation are available which coat a fine particle of an active core with an outer shell. Encapsulation also can occur on a molecular level. This can be accomplished using a category of carbohydrates called CDs, encapsulates made with these molecules may possibly hold the key for many future encapsulated formulation solutions.

The ability of cyclodextrins to form inclusion complexes with many guest molecules by taking up a whole molecule, or some part of it, into the cavity

References (83)

S.D. Eastburn et al.
Applications of modified cyclodextrins
Biotechnol. Adv.
(1994)
H. Matsuda et al.
Cyclodextrins in transdermal and rectal delivery
Adv. Drug Deliv. Rev.
(1999)
X. Lu et al.
Chiral separation of amino acids derivatized with fluoresceine-5-isothiocyanate by capillary electrophoresis and laser-induced fluorescence detection using mixed selectors of beta-cyclodextrin and sodium taurocholate
J. Chromatogr. A
(2002)
R. Kumar et al.
Biotransformation of cholesterol using Lactobacillus bulgaricus in glucose controlledbioreactor
Bioresour Technol.
(2001)
T. Irie et al.
Pharmaceutical applications of cyclodextrins. III. Toxicological issues and safety evaluation
J. Pharm. Sci.
(1997)
L. Szente et al.
Spontaneous opalescence of aqueous γ-cyclodextrin solutions: complex formation or self-aggregation
J. Pharm. Sci.
(1998)
T. Loftsson et al.
Pharmaceutical applications of cyclodextrins: 1. Drug solubilisation and stabilization
J. Pharm. Sci.
(1996)
E. Schneiderman et al.
Cyclodextrins: a versatile tool in separation science
J. Chromatogr. B
(2000)
G. Schmid
Cyclodextrin glucanotransferse production: yield enhancement by overexpression of cloned genes
Trends Biotechnol.
(1989)
M.A. Hussain et al.
Complexation of moricizine with nicotinamide and evaluation of the complexation constants by various methods
J. Pharm. Sci.
(1993)

M. Másson et al.

Stabilisation of drugs through complexation with non-ionic and ionic cyclodextrins

Int. J. Pharm.

(1998)

K.A. Connors

Population characteristics of cyclodextrin complex stabilities in aqueous solution

J. Pharm. Sci.

(1995)

T. Loftsson et al.

Pharmaceutical applications of cyclodextrins. 1. Drug solubilization and stabilization

J. Pharm. Sci.

(1996)

T. Loftsson et al.

Cyclodextrin complexation of NSAIDS: physicochemical characteristics

Eur. J. Pharm. Sci.

(1993)

J. Pitha et al.

Effects of ethanol on formation of inclusion complexes of hydroxypropylcyclodextrins with testosterone or with methyl organe

Int. J. Pharm.

(1992)

T. Loftsson et al.

Effect of cyclodextrins and polymers on triclosan availability and substantivity in toothpastes in vivo

J. Pharm. Sci.

(1999)

T. Kristmundsdóttir et al.

Formulation and clinical evaluation of a hydrocortisone solution for treatment of oral disease

Int. J. Pharm.

(1996)

T. Irie et al.

Cyclodextrins in peptide and protein delivery

Adv. Drug Deliv. Rev.

(1999)

B. Ekberg et al.

The synthesis of an active derivative of cyclomalto hexose for the hydrolysis of esters and the formation of amide bonds

Carbohydr. Res.

(1989)

T. Morozumi et al.

Selective synthesis using cyclodextrins as catalyst. 6. Cyclodextrin modification for para-selective hydroxymethylation and hydroxyetheylation of phenol

J. Mol. Catal.

(1991)

A. Kamal et al.

Enantioselective hydrolysis of aryloxypopionic esters by bovine serum albumin: enhancement in selectivity by β-CD

Tetrahedron: Asymmetry

(1991)

L. Bardi et al.

Hydrocarbon degradation by a soil microbial population with beta-cyclodextrin as surfactant to enhance bioavailability

Enzyme Microb. Technol.

(2000)

A. Villiers

Compt Rendu

(1891)

J. Szetjli

Introduction and general overview of cyclodextrin chemistry

Chem. Rev.

(1998)

V.J. Stella et al.

Cyclodextrins: their future in drug formulation and delivery

Pharm. Res.

(1997)

Mabuchi N, Ngoa M. Controlled release powdered flavour preparations and confectioneries containing preparations....

Buschmann HJ, Schollmeyer E. Applications of cyclodextrins in cosmetic products: a review. J Cosmet Sci...

Hirose T, Yamamoto Y. Hinokitol containing cyclo-olefin polymer compositions and their molding with excellent...

R.A. Hedges

Industrial applications of cyclodextrins

Chem. Rev.

(1998)

C. Baudin et al.

Inclusion of organic pollutants in cyclodextrin and derivatives

Int. J. Environ. Anal. Chem.

(2000)

R. Koukiekolo et al.

Mechanism of porcine pancreatic alpha-amylase inhibition of amylose and maltopentaose hydrolysis by alpha-, beta- and gamma-cyclodextrins

Eur. J. Biochem.

(2001)

J. Szetjli

Downstream processing using cyclodextrins

TIBTRCH

(1989)

C.R. Dass et al.

Cyclodextrins and liposomes as potential drugs for the reversal of atherosclerosis

J. Pharm. Pharmacol.

(2000)

Nash RA. Cyclodextrins. In: Wade A, Weller PJ, editors. Handbook of pharmaceutical excipients. London: Pharm. Press &...

D.O. Thompson

Cyclodextrins-enabling excipients: their present and future use in pharmaceuticals

Crit. Rev. Ther. Drug Carrier Syst.

(1997)

A.M. Totterman et al.

Intestinal safety of water-soluble β-cyclodextrins in paediatric oral solutions of spironolactone: effects on human intestinal epithelial Caco-2 cells

J. Pharm. Pharmacol.

(1997)

S. Muñoz-Botella et al.

Cyclodetrin properties and applications of inclusion complex formation

Ars. Pharm.

(1995)

Fujishima N, Kusaka K, Umino T, Urushinata T, Terumi K. Flour based foods containing highly branched cyclodextrins....

R. Bhardwaj et al.

Approaches to reducing toxicity of parenteral anticancer drug formulations using cyclo-dextrins

J. Pharm. Sci. Technol.

(2000)

Holland L, Rizzi G, Malton P. Cosmetic compositions comprising cyclic oligosaccharides and fragrance. PCT Int Appl WO...

M. Lezcano et al.

Complexation of several benzimidazole-type fungicides with alpha and beta-cyclodextrins

J. Agric. Food Chem.

(2002)

Cited by (2940)

Cyclodextrins: Establishing building blocks for AI-driven drug design by determining affinity constants in silico
2024, Computational and Structural Biotechnology Journal
Cyclodextrins (CDs) are cyclic carbohydrate polymers that hold significant promise for drug delivery and industrial applications. Their effectiveness depends on their ability to encapsulate target molecules with strong affinity and specificity, but quantifying affinities in these systems accurately is challenging for a variety of reasons. Computational methods represent an exceptional complement to in vitro assays because they can be employed for existing and hypothetical molecules, providing high resolution structures in addition to a mechanistic, dynamic, kinetic, and thermodynamic characterization. Here, we employ potential of mean force (PMF) calculations obtained from guided metadynamics simulations to characterize the 1:1 inclusion complexes between four different modified βCDs, with different type, number, and location of substitutions, and two sterol molecules (cholesterol and 7-ketocholesterol). Our methods, validated for reproducibility through four independent repeated simulations per system and different post processing techniques, offer new insights into the formation and stability of CD-sterol inclusion complexes. A systematic distinct orientation preference where the sterol tail projects from the CD's larger face and significant impacts of CD substitutions on binding are observed. Notably, sampling only the CD cavity's wide face during simulations yielded comparable binding energies to full-cavity sampling, but in less time and with reduced statistical uncertainty, suggesting a more efficient approach. Bridging computational methods with complex molecular interactions, our research enables predictive CD designs for diverse applications. Moreover, the high reproducibility, sensitivity, and cost-effectiveness of the studied methods pave the way for extensive studies of massive CD-ligand combinations, enabling AI algorithm training and automated molecular design.
Gas-phase solvent-free complexation of phenolic acids in cyclodextrins: A mass spectrometric study
2024, Carbohydrate Polymers
Phenolic acids are phytochemicals commonly existing in plants that are also beneficial to the human body after consumption. As additives in the food industry, phenolic acids typically need stabilization by encapsulation. We have been studying cyclodextrins as potential encapsulating agents, elucidating the structure and energetics of the complexes they form with phenolic acids. To highlight the role of the solvent in these interactions and to investigate the possible component ratios available to these complexes, we first carried out gas-phase studies monitored through mass spectrometry that allowed us to work in solvent-free conditions. In addition to detecting the products of these complexation equilibria qualitatively, we were also able to find conditions to quantitative determine the relative binding affinities associated with these processes. As well as on the unusual complex stoichiometry observed in the gas phase for a series of phenolic acids with α-CD, β-CD, and γ-CD. We propose an explanation of these uncommon stoichiometries through solvation effects involving the cyclodextrin host as the solvating species. We also report on the observed trends in the measured relative affinities of these interactions.
Unraveling the molecular dynamics of sugammadex-rocuronium complexation: A blueprint for cyclodextrin drug design
2024, Carbohydrate Polymers
Sugammadex, marketed as Bridion™, is an approved cyclodextrin (CD) based drug for the reversal of neuromuscular blockade in adults undergoing surgery. Sugammadex forms an inclusion complex with the neuromuscular blocking agent (NMBA) rocuronium, allowing rapid reversal of muscle paralysis. In silico methods have been developed for studying CD inclusion complexes, aimed at accurately predicting their structural, energetic, dynamic, and kinetic properties, as well as binding constants. Here, a computational study aimed at characterizing the sugammadex-rocuronium system from the perspective of docking calculations, free molecular dynamics (MD) simulations, and biased metadynamics simulations with potential of mean force (PMF) calculations is presented. The aim is to provide detailed information about this system, as well as to use it as a model system for validation of the methods. This method predicts results in line with experimental evidence for both the optimal structure and the quantitative value for the binding constant. Interestingly, there is a less profound preference for the orientation than might be assumed based on electrostatic interactions, suggesting that both orientations may exist in solution. These results show that this technology can efficiently analyze CD inclusion complexes and could be used to facilitate the development and optimization of novel applications for CDs.
Effect of pH on Ellagic acid and its complexation with gamma-cyclodextrins
2024, Journal of Molecular Structure
In food chemistry, the determination of the Ellagic acid (EA) from a food sample by Cyclodextrins (CDs) based nanosensor is a cheap, rapid, and sensitive method. EA acts as a ligand of CDs encapsulation. This study describes the effect of pH on EA and EA-γ-CD complex formation with the aid of spectroscopic and emission decay measurement. From this study, it was observed that pH of the medium has a high effect on the photophysical properties of EA and EA-γ-CD complexes. Due to larger cavity size, γ-CD forms a 1:1 stoichiometric complex with EA. Based on our results, it can be concluded that the stability of the complex between EA and γ-CD enhanced in an acidic medium. From the binding energy calculation by DFT method, it was observed that the encapsulation of EA in the cavity of γ-CD from the front side is more favorable compared to the back side to form EA-γ-CD complex. Such investigation should provide new information that will make it possible to improve the quality and safety of food. This study will be helpful in the use of γ-CD as a biosensor for EA determination.
Fabrication of novel covalently-coupled graphene oxide-per-6-amino-β-cyclodextrin composite with abundant active oxygen- and nitrogen-containing sites for azo dyes removal
2024, Journal of Environmental Chemical Engineering
The presence of diverse pollutants in wastewater highlights critical opportunities and urgent needs to develop effective strategies and technologies for their removal. In the present study, a novel composite of per-6-amino-β-cyclodextrin (PACD) covalently modified graphene oxide (GO) was fabricated by a facile one-step procedure. The morphologies, composition and bonding modes of GO-PACD composite were investigated by Fourier transform infrared spectroscopy (FTIR), scanning electron microscopy (SEM), thermalgravimetric analysis (TGA), X-ray photoelectron spectroscopy (XPS) and specific surface analysis by the Brunauer-Emmett-Teller (BET) method. The prepared GO-PACD composite was used as an efficient adsorbent for the removal of azo dyes (alizarin yellow R) from colored wastewater. The maximum adsorption capacity of GO-PACD was 130.92 mg g⁻¹ at 298 K. The influencing factors such as contact time, solution pH, initial dye concentration and temperature were investigated and optimized by a batch adsorption experiment. Adsorption kinetics, isotherms and thermodynamics were also investigated to reveal the possible adsorbent-adsorbate mechanisms. GO-PACD composite could be regenerated by a facile acid-soaking process. The results showed that the GO-PACD composite exhibited high stability and excellent reusability during 10 cycles of consecutive loading and regeneration. In summary, the developed GO-PACD composite is highly-efficient, regenerable, stable and facile-to-synthesize, making it be a potential candidate for azo dyes removal by adsorption.
A volumetric, ultraacoustical study and computational study of molecular interactions in 4-aminoantipyrine-aqueous-β-cyclodextrin solutions
2024, Chemical Physics Impact
Present work reports experimental densities and corresponding apparent and standard partial molar volumes, ultrasonic velocities and isentropic, apparent and standard partial molar compressibilities of 4-Aminoantipyrine-aqueous-β-cyclodextrin (0.000 mol∙kg⁻¹, 0.001 mol∙kg⁻¹, 0.005 mol∙kg⁻¹, 0.010 mol∙kg⁻¹and 0.015 mol∙kg⁻¹) solutions at different temperatures. Transfer properties like transfer volumes and compressions were calculated. The refractive indices of these systems were also measured. The computational properties such as solvation energy (ΔE_Sol), relative stabilization energy (ΔE_Rel), complexation energy (ΔE_Comp) and change in volume (ΔV) were computed using DFT. The results from volumetric and acoustical studies have been evaluated in terms of molecular interactions and their existence confirmed from experimental and computational studies. The values of transfer volumes and compressibilities indicate the hydrophilic-hydrophilic interactions between polar groups of 4-Aminoantipyrine and hydroxyl groups of β-cyclodextrin dominating over hydrophobic-hydrophobic interactions between the phenyl group of 4-Aminoantipyrine and hydrophobic interior of β-cyclodextrin.

View all citing articles on Scopus

View full text

ReviewCyclodextrins and their uses: a review

Abstract

Section snippets

History

Properties

Conclusions

Biotechnol. Adv.

Adv. Drug Deliv. Rev.

J. Chromatogr. A

Bioresour Technol.

J. Pharm. Sci.

J. Pharm. Sci.

J. Pharm. Sci.

J. Chromatogr. B

Trends Biotechnol.

J. Pharm. Sci.

Int. J. Pharm.

J. Pharm. Sci.

J. Pharm. Sci.

Eur. J. Pharm. Sci.

Int. J. Pharm.

J. Pharm. Sci.

Int. J. Pharm.

Adv. Drug Deliv. Rev.

Carbohydr. Res.

J. Mol. Catal.

Tetrahedron: Asymmetry

Enzyme Microb. Technol.

Compt Rendu

Introduction and general overview of cyclodextrin chemistry

Chem. Rev.

Cyclodextrins: their future in drug formulation and delivery

Pharm. Res.

Industrial applications of cyclodextrins

Chem. Rev.

Inclusion of organic pollutants in cyclodextrin and derivatives

Int. J. Environ. Anal. Chem.

Mechanism of porcine pancreatic alpha-amylase inhibition of amylose and maltopentaose hydrolysis by alpha-, beta- and gamma-cyclodextrins

Eur. J. Biochem.

Downstream processing using cyclodextrins

TIBTRCH

Cyclodextrins and liposomes as potential drugs for the reversal of atherosclerosis

J. Pharm. Pharmacol.

Cyclodextrins-enabling excipients: their present and future use in pharmaceuticals

Crit. Rev. Ther. Drug Carrier Syst.

Intestinal safety of water-soluble β-cyclodextrins in paediatric oral solutions of spironolactone: effects on human intestinal epithelial Caco-2 cells

J. Pharm. Pharmacol.

Cyclodetrin properties and applications of inclusion complex formation

Ars. Pharm.

Approaches to reducing toxicity of parenteral anticancer drug formulations using cyclo-dextrins

J. Pharm. Sci. Technol.

Complexation of several benzimidazole-type fungicides with alpha and beta-cyclodextrins

J. Agric. Food Chem.

Review
Cyclodextrins and their uses: a review