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Cyclodextrins An Overview
Matthias ArenskötterFlorence Folmer
Chris Llewellyn Aurélie PardoFrank ReineckeGrazia Trebbi
Gent 2001
1. Introduction
2. Microbial Production
3. Purification And Fractionation
4. Properties
5. Applications
Cyclodextrins - An Overview
Introduction• Cyclodextrins (CDs) are torus shaped cyclic
oligomers consisting of 6 (),7 () or 8 (-CD) glucose units with -1,4-linkages with a hydrophobic cavity and a hydrophilic exterior
O
CH2OH
OOH
OHO
O
O
CH2OH
O
OH
OH
O
CH2OH
OH
OH
O
CH2OH
OH
OH O
O
CH2OH
O
OH
OH
O
CH2OH
OH
OH
IntroductionHistory:
• 1891 Discovery, Villiers
• 1903 Descriptions of properties, Shardinger
• 1939 Tilden and Hudson were able to show that the conversion of starch to CD was due to the action of an enzyme, CD Glycosyl-Transferase (CGTase), which was secreted into the culture medium.
Introduction• 1957 Complexation ability of CDs widely
accepted; Cramer, French
• 1981 First International Symposium on CDs, Szejtli
• 1987 Total synthesis, Ogawa
• 1994 Total synthesis of cyclo[D-Glcp(1->4)]5
Introduction• Today CDs are only synthesized either by
fermentation or enzymatically.
• Many CGTases from different microorganisms are known, cloned, sequenced, characterized and used for production of CDs.
IntroductionApplications:
• Because of their unique properties CDs allow „packaging on a molecular level“ of various molecules which is applied in pharmaceutics, food and flavours etc...
• Used in chromatographic columns CDs can separate stereoisomers.
• Derivatives of CDs can even be used to mimic enzymes.
1. Introduction
2. Microbial Production
3. Purification And Fractionation
4. Properties
5. Applications
Cyclodextrins - An Overview
Microbial Production• CGTases are produced by many different
bacterial species of the genus Bacillus but also by Flavobacterium sp., Klebsiella pneumoniae and Micrococcus sp.
• Genes have been cloned and recombinantly expressed in Escherichia coli and other organisms, including for example Solanum tuberosum (Potato).
• The CGTase acts on linear starch and transfers a part of the chain (F) to its own non-reducing end (A) as indicated in this model:
Microbial Production
CGTaseA
BC
D
E F G H
starch
A
BC
D
E F G H
-CD
1. Introduction
2. Microbial Production
3. Purification And Fractionation
4. Properties
5. Applications
Cyclodextrins - An Overview
• Enzymatic synthesized CDs are selectively precipitated by organic solvents.
Purification and Fractionation
precipitating agent yield (%)-CD 1-decanol 40-CD toluene 50-60-CD cyclohexadec-8-en-1-ol 40-50
1. Introduction
2. Microbial Production
3. Purification And Fractionation
4. Properties
5. Applications
Cyclodextrins - An Overview
PropertiesImportant Properties:• CDs have hydrophobic cavities of different sizes enabling
the complexation of hydrophic guest molecules.• These complexes represent a solution for insolubility.• They have neither a reducing nor a non-reducing end-group.
PropertiesStability:
• CDs are not decomposed by hot aqueous alkali and rather resistant to acid hydrolysis.
• CDs are resistant to -amylases (except microbial enzymes) and they are completely resistant to yeast-fermentation and -amylases.
Properties
Properties
Molecular weight 972 1135 1297Glucose monomers 6 7 8Internal cavity diameter(angstroms)
4.7-5.3 6.0–6.6 7.5–8.3
Water solubility(g/100mL: 25 deg. C)
14.2 1.85 23.2
Melting range (deg. C) 255-260 255-265 240-245Water of crystallization 10.2 13-15 8-18Water molecules in cavity 6 11 17Cavity volume (ml/mol) 174 262 472Price (US$/g pharma-grade) 1.0 0.025 0.8
1. Introduction
2. Microbial Production
3. Purification And Fractionation
4. Properties
5. Applications
Cyclodextrins - An Overview
ApplicationsPharmaceutical industry:• Treatment of inflammation or throat infection (with iodine)• Coronary dilatation (with nitroglycerin)• Anti-ulcerate (with benexate)• Vectors for vitamins or hormones• Reduction of side-effects and increase in efficiency of anti-cancer drugs
ApplicationsPharmaceutical
industry:
SolidComplex
Dissolution (kd)
Dissolved Complex
Adsorption (ka)
(kc)
CyclodextrinCompeting
Agent
Competing Agent-Cycloddextrin Complex
(ki)
Drug
Drug
Biomembrane
Systemic Circulation
ApplicationsCosmetics & Hygiene:• Long-lasting perfume release• Deodoriser (with peppermint oil, i.e.)• Removal of dryness wrinkles (with seaweed compounds, Vitamin A & E)• Anti-cellulitis compound• Shampoo industry• Teeth cleaning, anti-plaque compound• Antibacterial in refrigerators
ApplicationsFood industry:
• Emulsion stabiliser
• Taste-masking
• Long-lasting flavouring
• Removal of cholesterol from milk, butter, eggs, a.o.
ApplicationsPaint industry:• Increase in compatibility of paint ingredients• Increase in stability of the paint• Increase in the range of colours and in the quality of
dyes
ApplicationsEnvironmental protection:
• Reduction in oxidiser requirements in paper production
• Environmentally friendly oil-spill clean-up
• Treatment of tree-wounds (with auxin)
• Mobilisation of toxins without leaving toxic residues behind (innovative technique)
ApplicationsEnvironmental protection:• Removal or detoxification of waste material, esp.
aromatic pollutants• Use in agriculture to increase the stability and the
efficiency of herbicides, insecticides, repellents,…
ApplicationsChemical and biochemical applications:• Reaction catalyst in adhesives• Use in chromatography (separation of stereoisomers)• Increase in speed of diagnostic test reaction
ApplicationsChemical and biochemical applications:• Enzyme mimicry
Dimer of -cyclodextrin linked on primary side by a metal-binding-group as catalyst of hydrolysis of a phosphate diester
O2N
O
NO2
O
NN
S S
La
O
O
O
P
O
3+
Summary• When Cyclodextrins were discovered they were just a chemical
curiosity but today a lot of applications are known.
• Due to intensive studies and advances in production procedures prices continue to decrease making CDs attractive for many applications.
• To date more than 3300 European Patents are registered indicating great industrial interest.
Group Members• Matthias Arenskötter, Westfälische Wilhelms-
Universität Münster, Germany
• Florence Folmer, University of Wales Bangor, UK
• Chris Llewellyn, University of Wales Swansea, UK
• Aurélie Pardo, Institue Nationale Polytechnique de Toulouse, France
• Frank Reinecke , Westfälische Wilhelms-Universität Münster, Germany
• Grazia Trebbi, Universita´ di Bologna, Italy
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