Cyclodextrins and

their Applications
By
Geethika (2012B2PS619G)
Sai Kulkarni (2012B2A4640G)
Priyanka Bedarkar (2012B2A7586G)

Cyclodextrins
Cyclic oligosaccharides
Cage molecules with a
stable hydrophobic cavity
that can trap or encapsulate
other molecules
Used in food,
pharmaceutical, drug
deliveryand chemical
industries, agriculture and
environmental engineering.

Important Periods in
Cyclodextrin History
Discovery: 18911911
The Period of Doubt: 19111935
Reaching Maturity: 19351950
Exploration: 19501970
The Period of Application: From 1970 until
Now

Discovery (1891-1911)

1.

2.

.
1.

2.

Antoine Villiers
During experiments on the degradation and reduction of
carbohydrates under the action of ferments, Villiers noted
the formation of unwanted crystals with particular
properties; he named it cellulosine.
Under certain conditions, potato starch can ferment to
mainly yield dextrins

Franz Schardinger
Isolated pure fractions: obtained a maximum yield of 30%
crystalline dextrins from starch.
First researcher to describe the fundamental properties of
these dextrins, therefore known as the Founding Father of
cyclodextrin chemistry.

The Period Of Doubt:

19111935

1.

2.

structure of the dextrins had not yet been

established
Hans Pringsheim
depolymerized the Schardinger dextrins into
polyamyloses and studied the relationship between
these polyamyloses and the amylose and
amylopectin molecules
Discovered in 1930 that crystalline dextrins and their
acetate derivatives tended to form complexes with
various organic compounds

Paul Karrer

1.

rst to propose that dextrins are composed of

maltose units only joined by (14) glucosidic
linkages
However, just like Schardinger and Pringsheim,
Karrer failed to elucidate the cyclic structure of the
dextrins

2.

Reaching Maturity: 19351950

1.

2.

3.

4.

Karl Johann Freudenberg

In 1935, he described a method for the
synthesis of Schardinger dextrins with high
purity and, using a cryoscopic method for the
determination of molecular weights, reported
(erroneously) the number of glucose units
that the CDs contained: ve for -dextrin and
six for -dextrin
observed that enzymatic hydrolysis gave no
trace of a sugar unit other than D-glucose,
and methylation studies failed to reveal the
presence of any D-glucose units.
suggested, for the rst time, the
hydrophobicity of the inner surface of the
dextrin and noted how dextrins had the ability
to accept molecular inclusions in their cavity
Prepared pure -dextrins and discovered dextrins.


1.

2.

3.

4.

Dexter French
hypothesized that the cryoscopic method used by
Freudenberg was inappropriate to determine the
molecular weights because the dextrins were of
comparatively high molecular weight and were very
dicult to free from low molecular weight impurities
determined the molecular weights of - and -dextrins
and discovered the exact number of glucose units per
dextrin, that is, six and seven, respectively
showed that Schardinger dextrins were cyclic
oligosaccharides
In the late 1950s, French and co-workers had established
the molecular weight, the exact chemical structure, the
dimensions, and the types of bonding in the three
cycloamyloses

Exploration: 19501970

1.

2.

Friedrich Cramer
showed that the main value of CDs resided in their ring
structure and their consequent ability to include guest
molecules inside their internal cavity
showed that not only can CDs be used as accelerating
agents but also as an asymmetric agent.

Friedrich Cramer

Benito Casu

Myron Bender

Benito Casu

1.

Showed that 1H NMR and infrared spectroscopy were

powerful methods to study the conformations of CDs
IR and NMR spectra showed that the C1H bond was
equatorial and C1O axial, also conrming the C1 chair
conformation of the glucopyranose units.
Casu also showed the existence of intermolecular hydrogen
bonds contributing to the stabilization of the helical
structures

2.

3.

. Myron
1.

2.

Lee Bender

initiated the era of biomimetic chemistry (including articial

enzymes, molecular recognition, and bioinsipired reactivity),
works of Bender made the creation of articial enzymes possible

The Period Of Application:

From 1970 Until Now

1.

2.

1970s
Pharmaceutical applications: enhancing the solubility of drugs, and nonionic
surfactants
Creation of articial enzymes using CDs

1980s

1.

chromatographic applications and many industrial applications discovered

numerous fundamental studies were done on CDs

2.

1990s

1.

synthesis of new supramolecular molecules and materials such as interlocked

molecules (catenanes, rotaxanes), scaolds and templates to self-assemble
supramolecular architectures, and also in biomimetism.

Pharmaceutical Applications of
Cyclodextrins
1.Drug solubilization
2.Drug stabilization
-Sai Kulkarni

Solubility of cyclodextrins

Solubility of beta cyclodextrin in water is very low

1.85(g/100ml)
High crystal lattice energy
Intramolecular hydrogen bond
Solubility can be increased by replacing H atom of
secondary hydroxyl groups by substitution (alkylation,
esterication etc.)

Driving forces for drug-CD

complex formation :
1.

2.

3.
4.
5.

6.

Release of enthalpy rich water molecule from CD

cavity
Van der Waals interaction(negative H and
negative S)
Hydrogen bonding
Hydrophobic interactions(Large positive S)
Release of ring strain in CD molecule(specially in
case of -cyclodextrin)
Changes in solvent surface tensions

Orstan, A.; Ross, J. B. A. J. Phys. Chem. 1987, 91, 2735-2745 .

Method for enhancing

complexation :

Formation of ternanry complex with

cyclodextin molecule, drug molecule and third
component.(water soluble polymers , hydroxy
acids or salts with basic drugs)
Addition of hydroxy acids enhances formation
of super complexes and salts
Water soluble polymers increases stability
constant

Higuchi, T.; Connors, K. A. In Advances in Analytical Chemistry

and Instrumentation; Reilly, C. N., Ed.; Wiley-Interscience: New
York, 1965; Vol. 4, pp 117-212

Drug Solubilization :
1.
2.
3.

Aqueous solubility of pure drug

Molar substitution on cyclodextrin molecule
Charge on cyclodextrins

Loftsson, T.; Brewster, M. E.; Derendorf, H.; Bodor, N. Pharm.Ztg. Wiss.

1991, 4/136, 5-10.

Cyclodextrin-based
multivalent glycodisplays

Cyclodextrin-based multivalent glycodisplays: covalent and supramolecular

conjugates to assess carbohydrateprotein interactions A lvaro Martnez,a
Carmen Ortiz Mellet*a and Jose M. Garc a Fernandez*b Chem. Soc. Rev.,

What are multivalent CDs?

Multivalent CDs can be considered as hybrid

ligandhost molecules bearing two
orthogonal recognition domains, namely
the glycoligand display
.
.
.
.

Articial glycoprotein conjugates

Glycopeptides
Saccharide thin layers
Saccharide nano-particles

the hydrophobic cavity

Lectins
Lectinsare a type of protein that can bind
to cell membranes.
They are sugar-binding and become the
glyco portion of glycoconjugates on the
membranes.
Lectinsoer a way for molecules to stick
together without getting the immune
system involved, which can influence cellcell interaction.

Why glycoclusters form?

Saccharides displayed on the surfaces of

cells have been related to a variety of
dierent biological activities, including cellcell adhesion, protein recognition, pathogen
infection, and cancer metastasis.
Saccharide-protein interactions, however,
are usually too weak to be used as drugs
and biomaterials.
Interestingly, it is well known that
saccharide-protein interactions can be
amplied by multivalency, otherwise known
as the cluster glycoside eect

Self-Inclusion into CD
Acting as switch

Many of the multivalent sugar constructs

succeed in emulating the increase in
binding anity towards specic protein
receptors encountered in natural systems.
Yet, only a few of them can fully mimic the
switching between the on and o
states and the regulation of the binding
intensity after an external stimulus
characteristic of carbohydrateprotein
binding-mediated processes.

cavity. Installing this segment in the

bridge connecting the bCD core to a
glycodendritic branch, containing either
one or two copies of the branched
trisaccharide 3,6-di-O-(a-Dmannopyranosyl)-a- D-mannopyranose
(Man-tri), led to formation of the
corresponding intramolecular complex, in
which the external sugars were not
accessible to Con A lectin recognition
processes. The addition of a guest
molecule having strong anity towards
the bCD cavity, e.g. an adamantane
derivative, disrupted self-inclusion and
activated lectin binding capabilities. Full
reversibility of the process was proven by
addition of an a,a0-trehalose-based host
(cyclotrehalan) that behaved as an
adamantane scavenger, restoring the
initial state. The involvement of
selnclusion as the key step was
supported by spectroscopic evidence as
well as by molecular dynamics
simulations.

Primary face-anchored jellyfishtype glycoclusters

Selective replacement of the primary hydroxyl groups in

cyclodextrins by halogen (I, Br) represents the most
ecient strategy to access homogeneously per-(C-6)functionalized CD derivatives.
The reproducibility and high yield of these transformations
have provided an excellent model system to test the
suitability of dierent methodologies towards glycocluster
synthesis, which are itemized hereinafter.
Moreover, in the resulting jellysh-type arrangement
the wider secondary rim of the CD platform remains open
for the entrance of suitable guests to the internal cavity,
potentially retaining the capacity for drug encapsulation
and delivery.

Eventually, the incorporation

of coating sugars on CD
platform resulted in additional
interactions with an included
guest following an induced-t
process that, at its turn, may
preorganize the glycotopes for
lectin recognition.
This accounts for the
unexpected high association
constants of the amidolactitolderived bGal conjugate
towards both the anticancer
drugs doxorubicin (DXR) and
PNA lectin

Guest-induced mechanism for

preorganization of bGal ligands in
jellyfish-like heptavalent bCD
conjugates proposed by Hattori
and co-workers

Why glycoclusters form?

The above pioneering work already evidenced

three important general features of primary
face-anchored multivalent CDglycoclusters
that make them attractive candidates for sitespecic drug delivery, namely
high water solubility,
an improved binding anity towards
complementary lectins
encapsulation capabilities that are retained for
guests entering the CD cavity through the
secondary rim.