Journal of Carbohydrate Chemistry

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A systematic review on the significant roles

of cyclodextrins in the construction of
supramolecular systems and their potential usage
in various fields

R. Periasamy

To cite this article: R. Periasamy (2020): A systematic review on the significant roles of
cyclodextrins in the construction of supramolecular systems and their potential usage in various
fields, Journal of Carbohydrate Chemistry, DOI: 10.1080/07328303.2020.1792919

To link to this article: https://doi.org/10.1080/07328303.2020.1792919

Published online: 07 Aug 2020.

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JOURNAL OF CARBOHYDRATE CHEMISTRY
https://doi.org/10.1080/07328303.2020.1792919

A systematic review on the significant roles of

cyclodextrins in the construction of supramolecular
systems and their potential usage in various fields
R. Periasamy
Department of Chemistry, Annamalai University, Annamalainagar, India

ABSTRACT ARTICLE HISTORY

Cyclodextrins (CDs) are oligosaccharides consisting of cyclic Received 16 April 2020
a(1,4)-linked glucopyranose subunits. They have cage-like Accepted 3 July 2020
three-dimensional structures. CDs have many applications due
KEYWORDS
to their ability to form inclusion complexes. This review has
Application; cyclodextrin;
addressed the historical background of CD discovery and inclusion complex;
highlighted the chemical and physical properties of cyclodex- supramolecular chemistry
trins. In addition, the paper has also discussed the roles of
CDs in supramolecular chemistry, the mechanisms involved in
their formation of inclusion complexes, the techniques
involved in characterizing inclusion complexes, and the appli-
cations of CDs in various fields.

Introduction
Supramolecular chemistry is a growing discipline, which studies supra-
molecular phenomena in between the traditional fields of chemistry,
including organic, inorganic, and physical chemistry. It is also heavily influ-
enced by other natural sciences, such as biology, physics, and material sci-
ences including engineering. Fischer coined the “lock and key” principle,
which is used to explain the fundamental concept of supramolecular chem-
istry.[1] The discovery of molecular bindings via intermolecular interactions
led to the term supramolecule.[2] The relationship between supramolecular
chemistry and other disciplines of science was defined by Lehn, who has
also suggested the term “Supramolecular Science.”[3]
Supramolecular chemistry concentrates on the interactions between mol-
ecules rather than within the molecules. Therefore, it concentrates on the
intermolecular bonds instead of covalent bonds,[4] and supramolecular
chemistry is often defined as “the chemistry of the non-covalent bond” or

CONTACT R. Periasamy rps1400000@gmail.com Department of Chemistry, Annamalai University,

Annamalainagar 608002, Cuddalore district, Tamilnadu, India.
ß 2020 Taylor & Francis Group, LLC
2 R. PERIASAMY

Figure 1. Schematic representation of supramolecular interactions.

Figure 2. From molecular chemistry to supramolecular chemistry.

“the chemistry beyond the molecules.” The intermolecular interactions

include (Figure 1) van der Waals interaction, hydrogen bonding, hydropho-
bic effect, the interaction between p–p bonds and ions, and dipole–dipole
interactions. Supramolecules are defined as “self-assembly of molecules via
molecular recognition leading to the formation of aggregates and also a col-
lection of non-bonded molecules.” Self-organization is considered as
ordered self-assembly leading to the formation of aggregates to a greater
degree of complexity. Their formation may result in the display of property
and function not having in individual molecular components.
Supramolecular chemistry is the base for most of the biochemical processes
of life. Figure 2 outlines the relationships between molecular and supra-
molecular chemistries.[5] Some of the hosts involved in supramolecular
interactions include cyclodextrins (CDs), calixarenes, crown ethers, macro-
cyclic polyamines, etc.

Host–guest chemistry
Host–guest chemistry is a subdivision of supramolecular chemistry, and it
can explain the different type of processes occurring in various research
fields, such as biological, analytical, organometallic and organic chemistry,
and involving molecules and ions with different properties, structures and
 JOURNAL OF CARBOHYDRATE CHEMISTRY 3

dimensions. In host–guest chemistry, a supramolecular complex is formed

between two or more ions or molecules that are held together in a unique
structural relationship through intermolecular forces like ion-pairing,
hydrogen bonding, van der Waals forces and/or hydrophobic interac-
tions.[6,7] As a result, a molecule (host) binds another molecule (guest) to
produce a “host–guest” complex, and the interactions between the host and
guest are non-covalent.[8] The host is normally a large molecule or an
aggregate such as a synthetic cyclic compound or an enzyme having a cav-
ity or hole of suitable size. The guest molecule is included in the cavity of
the host molecule and the host acts as the building blocks for big func-
tional architectures.[9] The host is called “the molecular entity having con-
vergent binding site” and the guest is called “the molecular entity
possessing divergent binding sites.” In general, host–guest interactions are
achieved via the formation of multiple non-covalent bonds between a host
and a guest. The geometrical requirements are essential to fit the definition
of host–guest chemistry.[10] Several types of macrocyclic ligands have been
prepared that possess structures of enhancing complexity, which includes
cryptands, cavitands, calixarenes, carcerands, cyclophanes, and so on.[10]
CDs are another type of very important host.[11]

Cyclodextrins
CDs were first discovered by a French scientist A. Villiers in 1891.[12] He
isolated a tiny amount of a crystalline substance from a culture of Bacillus
amylobacter, grown in a starch medium. Villiers named this product as
“Cellulosine” as it resembles cellulose. Then, an Australian microbiologist
F. Schardinger laid down the foundation of CD chemistry. In 1903,
Schardinger prepared two crystalline products, dextrin A and B, which
were elucidated with respect to their lacking of reducing power. However,
the bacterial strain producing these products from starch was not main-
tained.[13] One new organism which produced acetone and ethanol from
sugar and starch-containing plant materials was separated by Schardinger
in 1904.[14] In 1911, Schardinger explained that this strain called “Bacillus
macerans” also produced remarkable amounts (25–30%) of crystalline dex-
trins from starch.[15] Schardinger gave names for these crystalline products
as crystallized dextrin “a” and crystallized dextrin “b.” In the consecutive
years, CDs were named as “Schardinger dextrins” in his honor.
After Schardinger, Pringsheim[16] had played a major role in CD
research. He discovered the complexing ability of CDs. In 1935,
Freudenberg and his coworkers elucidated the chemical structure of CDs
and also discovered gamma-CD.[17] CDs, also called cycloamyloses, cyclo-
glycopyranoses, or Schardinger dextrins, are cyclic oligosaccharides with
4 R. PERIASAMY

Figure 3. The structures of CDs.

glucose units linked by a-1,4 glucosidic bonds.[18,19] Later, French proved

the existence of epsilon and delta CDs.[18] Thoma and Stewart found fur-
ther homologs of CDs containing 11 and 12 glucopyranose units.[20]

Physico-chemical properties of CDs

Since the discovery of CDs, these compounds have attracted significant
interest.[18] With respect to their chemical properties, especially their bio-
chemical behavior, CDs are very different from starch although they are
related.[18,21] CDs show resistance to hydrolysis by regular starch-splitting
enzymes (e.g., beta-amylase) because CDs are macrocyclic oligosaccharides
(Figure 3) without a free reducing end for beta-amylase to attack. CDs are
also stable to alpha-type amylases.[22]
The three major and most common CDs are (i) a-CD which is consist-
ing of six glucose units, (ii) b-CD which is consisting of seven glucose
units, and (iii) c-CD which is consisting of eight glucose units. The struc-
tures of CDs are shown in Figure 3. With an increased number of glucose
units in CDs, the dimension of the cavity also increases. The important
physical properties of CDs are listed in Table 1.[19,23]
The CD rings have a truncated cone shape (Figure 3) in order to accom-
modate the sterically demanding secondary hydroxyl groups at the C2- and
C3-positions. The cavity inside CDs is relatively hydrophobic in nature
when compared to outside due to the hydroxyl groups at the rims. As a
result, CDs are water-soluble, although to variable extents. The solubility of
b-CD in water is only 1.85 g/100 mL at 25
C,[24] while that of a-CD and
c-CD is 14.5 and 23.2 g/100 mL, respectively. These differences are due to
 JOURNAL OF CARBOHYDRATE CHEMISTRY 5

Table 1. Some important physical properties of CDs.

Property a-Cyclodextrin b-Cyclodextrin c-Cyclodextrin
No. of glucopyranose units 6 7 8
M.wt (g/mol) 972 1135 1297
Solubility in water at 25
C (%w/v) 14.5 1.85 23.2
Outer diameter (A˚) 14.6 15.4 17.5
Cavity diameter (A˚) 4.7–5.3 6.0–6.5 7.5–8.3
Height of torus (A˚) 7.8 7.8 7.8
Cavity volume (A˚) 174 262 427

the formation of internal hydrogen bonds. The ring size of a CD is respon-

sible for hydrogen bond strength. The C2-OH group of every pyranose
ring forms a hydrogen bond with the C3-OH group in the next ring. In
b-CD, this will create a completed “Sphere” of hydrogen bonds, which con-
fer a rather rigid structure to the molecule and lower the number of avail-
able hydrogen bonds for the solvent, leading to the low water solubility
compared to the other two CDs. In a-CD, a distortion of one of the pyra-
nose rings inhibits the creation of a completed sphere and only four of six
possible hydrogen bonds are created. c-CD has a more flexible structure
due to its size and is therefore the most water-soluble of the three.[11]
CDs are thermally stable (up to at least 200
C). They are also relatively
stable under basic conditions (pH up to 14) but only moderately stable in
acidic solutions (pH > 3). CDs can be hydrolyzed under strongly
acidic conditions.

Formation of CD inclusion complexes

The term “inclusion complex” was introduced by Schlenk in 1950 to
describe a major and interesting property of CDs, that is, their ability to
form inclusion complexes with many compounds.[25–29] From X-ray struc-
tural analysis, it is observed that the primary hydroxyl groups at C6 of CDs
are located on the edge of the narrower end of the cone and the secondary
hydroxyl groups at C2 and C3 are located on the wider edge. The apolar
hydrogen atoms on C3, C5, and C6 and ether-like oxygen atoms are placed
in the inside of the torus-like molecules. Thus, the molecules have a hydro-
philic outside and are soluble in water, while its apolar cavity provides a
hydrophobic matrix to form a microheterogeneous environment.[30,31]
Hence, CDs can form inclusion complexes with various hydrophobic guest
molecules, and guest molecules are encapsulated by one, two, or more
CDs. Normally, the formation of the inclusion complex is a dimensional fit
between the guest molecule and the host cavity.[32] The hydrophobic cavity
of CDs gives a microenvironment, in which appropriately sized non-polar
guest molecules can enter to form complexes.[33] Covalent bonds are not
formed or broken during the formation of inclusion complexes.[34] The
main driving force for forming inclusion complexes is the release of water
6 R. PERIASAMY

molecules from the CD cavity. Hydrophobic guest molecules that replace

the water molecules and attain apolar–apolar interactions inside CDs can
decrease the ring strain of CDs, resulting in more stable states with lower
energy.[11] The most suitable guest molecules for molecular encapsulation
in CDs include straight-chain or branched aliphatic alcohols, aldehydes,
ketones, and fatty acids, as well as other organic acids, gases, and aromatic
compounds.[35]

Techniques used to generate CD-complexes

The special molecular geometry of CDs enables a variety of guest com-
pounds to be accommodated in the inner hydrophobic cavity to form
inclusion complexes.[36] This can protect the guest molecule and thus
reduce the rate of its oxidation, hydrolysis, racemization, steric rearrange-
ment, enzymatic decomposition, and so on.[37] Due to the different
molecular dimensions of CDs, they show molecular selectivity. a-CD can
form complexes with low molecular weight molecules, whereas b-CD com-
plexes with heterocyclics and aromatics and c-CD can accommodate lager
molecules such as macrocycles and steroids. Complexes can be formed in a
solution or in the crystalline state. Water is the main solvent of choice for
inclusion complexation but complexation can also be achieved in a co-solv-
ent system and in the presence of any non-aqueous solvents.[38] Normally,
guest/CD complexes have a 1:1 molar ratio, but the molar ratio can be
higher or lower, which depends on the CD and the size of the guest mol-
ecule. Several techniques have been used to generate CD-complexes, which
include co-precipitation, kneading, sealing, dry mixing, slurry complex-
ation, spray drying, neutralization, solvent evaporation, and freeze-drying.

Kneading method
This process is similar to the wet granulation process and needs conven-
tional kneaders (e.g., high and low shear mixers).[39] The guest-CD inclu-
sion complex is prepared in the lab by wetting the physical mixture in a
mortar with water of minimal volume and kneading thoroughly with a pes-
tle-mortar to make a paste. It is then dried under vacuum at room tem-
perature, sieved through suitable sieves, and then stored in a desiccator
until further evaluation.[38,40–42]

Co-precipitation method
The co-precipitation method is the most widely used in the laboratory.
Sapkal et al.[43] prepared inclusion complexes of guest molecules of poor
aqueous solubility with b-CD by this method. First, the guest molecule is
 JOURNAL OF CARBOHYDRATE CHEMISTRY 7

dissolved in a minimal quantity of an organic solvent like acetone or

methanol, and the solution is added drop-wise into the b-CD solution in a
minimal quantity of water that is stirred at 75
C. Stirring is maintained at
75
C for 1 h. The mixture is then gradually cooled to room temperature
while stirring. The precipitates formed are filtered, dried, and then stored
at 25
± 2.0
C with a relative humidity of 40–50%. Sometimes the pre-
cipitate is washed with a small amount of water or a water-miscible solvent
such as methanol, acetone, or ethyl alcohol.[44–45] When an organic solvent
is used for precipitation, it may interfere with complexation; as a result, in
some cases, the co-precipitation method is less attractive than the kneading
method. One more disadvantage of the co-precipitation method lies in the
difficult scale-up.[46–47] However, this method often yields highly pure and
crystalline inclusion complexes.[39]

Dry mixing method

In this method, guests are simply added to CDs, which are mixed together
to result in complexation. Parlati et al. prepared solid complexes with
modified dry mixing methods by putting the reactants together in a 2:1
molar ratio for 3 d,[48] but the duration of mixing vary depending on the
guest.[38] This method gives a good result with oil or liquid guests. Its
advantage is that no water is added unless a washing step is needed. Its
main disadvantages are the risk of caking on scale-up, insufficient mixing
which leads to incomplete complexation, and prolonged mixing time.

Sealing method
Solid guest-CD complexes are formed by grinding a fixed amount of phys-
ical mixtures of guests and CDs, keeping the mixtures at a temperature
ranging from 60 to 90
C after being sealed in a glass container. Wang
et al.[49] prepared a paeonol-b-CD inclusion complex by a simple quick
“sealed-control temperature method.” The formed complex was confirmed
by Powder XRD diffraction and infrared (IR) spectrometry. This study also
proved that inclusion complex formation was affected by the crystallinity of
b–CD, heating time, and heating temperature.

Slurry complexation
In the slurry complexation method, the CD is suspended in water at up to
45% w/w concentration and is stirred in a reactor while the gust is added.
CD forms complexes in solution with the guest and the complex precipi-
tates. Usually, ambient temperature is required for slurry complexation. For
some guests, mild heat may be applied to increase the rate of complexation,
8 R. PERIASAMY

but care should be taken as too much heat can destabilize the com-
plex.[38,44] The time taken for complexation is determined by the character-
istics of the guest and the r.p.m. of stirring.[49] The complex is collected in
the same way as with the co-precipitation method. An advantage of the
slurry complexation method is about the size of the reactor and reduction
in the amount of water required.[38]

Neutralization method
Solid complexes of ionizable guests can be prepared by neutralization
method, where the guest is dissolved in a basic (for acidic guests) or acidic
(for basic guests) aqueous CD solution. The solubility of the guest molecule
is reduced by adjustment of pH to force the complex out of solution.
Terfenadine has somewhat low bioavailability after oral administration
because of its limited solubility in water. Choi et al.[50] prepared a terfena-
dine-b-CD (1:2) inclusion complex by this method to increase its antihista-
minic activity. The formation constant of this inclusion complex was
higher at low pH, but the formation ratio was 1:2 irrespective of pH. They
finally concluded that the inclusion complex increased the antihistaminic
activity of terfenadine due to enhanced dissolution and solubility.

Spray drying method

In this method, the CD is dissolved in a solution alkalinized with 25% aq
ammonia (final pH 9.5). Then, it was mixed with a guest solution dissolved
in 96% ethyl alcohol and then sonicated. Finally, the solution is
spray-dried.[51]

Freeze-drying (lyophylization) method

In this method, the guest and CD are mixed in a little amount of buffer
solution. When this solution is kneaded, it gives a homogeneous suspension
which is then freeze-dried. The complexes are pulverized and sieved
through suitable sieves. This method is industrially applicable to heat-labile
guests. When a large quantity of water is used and excessive CD is required
due to the low solubility of a hydrophobic guest in aqueous solution, the
process can be time-consuming.[52]

Solvent evaporation method

In the solvent evaporation method, organic solvents are used, and residual
solvents need to be removed. Osadebe et al.[53] prepared a solid dispersion
(SD) of piroxicam and b-CD by the solvent evaporation method. First,
 JOURNAL OF CARBOHYDRATE CHEMISTRY 9

piroxicam and b-CD are dissolved in a common solvent like methanol and
stirred at 28
C for 24 h to prepare the inclusion complex with a 1:1 or 1:2
molar ratio. Then, the mixture is concentrated, filtered, and dried under
vacuum at 25
C for 24 h to get the inclusion complex.

Technologies used to study CD-complexes

Mechanism of complex formation
The unique structure of CDs determines that they can host hydrophobic
guests inside their cavities. The key condition for this to occur is that the
size of the guest must fit into the internal dimension of the host cavity.[32]
Generally, water plays a crucial role in the inclusion complex formation
process. In water, the complex is formed as a result of the positive interac-
tions between the hydrophobic cavity and the apolar guest molecule as
shown in Figure 4. In the process, enthalpy and entropy changes also play
a vital role.[54]
Host-CD inclusion complexes can be formed either in solution or in a
crystalline state, and water is normally the choice as a solvent. In aqueous
solutions, the cavity of CDs is originally occupied by energetically unfavor-
able water molecules (polar–apolar interaction). Hydrophobic guest mole-
cules of the proper sizes can enter the cavity and replace the water
molecules to reduce the CD ring strain, lower the energy, and stabilize the
system to form inclusion complex through guest-CD apolar–apolar interac-
tions.[11] The binding of the guest to the host is not fixed but dynamic
equilibrium. The host–guest binding strength depends on the host–guest fit
and the local interactions between the surface atoms. Thus, the driving
forces responsible for inclusion complex formation are van der Waals
interactions,[55] hydrophobic interactions, hydrogen bond formation,[56]
dipole-induced dipole interactions,[57] charge transfer,[58] release of water
molecules “at high-enthalpy” in the CD cavity,[12] and release of solvent
molecules in the CD cavity with a gain in entropy.

Figure 4. Mechanism for CDs to form inclusion complexes in water.

10 R. PERIASAMY

Characterization of inclusion complex

Inclusion complexes are characterized by a number of spectrometric meth-
ods. UV spectroscopy is commonly used to determine the binding or sta-
bility constants and thermodynamic parameters of interactions between
CDs and guests in aqueous solution,[59] as complexation induces a change
in the UV absorption spectrum of guest molecules. When complexation
takes place, the chromophore of the guest molecule is transferred from an
aqueous medium to the CD non-polar environment. The reason for the
above changes is the perturbation of the electronic energy levels of the
guest caused either by direct interaction with CD or by the displacement of
solvating water molecules or by the combined effect of both.[60]
Bathochromic or hypsochromic shift, increase or decrease in the absorption
intensity without any change in the kmax value, is taken as evidence for the
inclusion complex formation and the hydrogen bondings are being consid-
ered as the force behind this result. As hydrogen bonding reduces the
energy of “n” orbitals, blue shift (hypsochromic shift) will be observed, and
the breaking of hydrogen bonds existing in the compound can lead to a
red shift (bathochromic shift).[61–62] It was also reported that when benzene
was complexed with b-CD the absorption intensity was increased.[59]
Circular dichroism is also used to examine the formation of inclusion
complexes of CDs in aqueous solution.[63] When an achiral guest is encap-
sulated inside the CD cavity, new circular dichroism bands are induced for
the optically inactive guest. Chiral guest molecules give changes in circular
dichroism spectra in the inclusion complex formation with CDs as well.[63]

Determination of the stoichiometry of inclusion complexation

Job’s method is the first one used to determine the stoichiometry of inclu-
sion complexes. It is also called the continuous variation method.[64] The
experiment is carried out using stock solutions of equimolecular concentra-
tions of H and G. Here “H” represents CD (i.e., the host molecule) and
“G” represents the guest molecule. The experiment samples are prepared
by mixing different volumes of H and G solutions, but the total concentra-
tion of [H] þ [G] remains constant and also the molar fraction XG of the
guest, where XG ¼ [G]t/([G]tþ [b-CD]), is in the range of 0–1. The differ-
ence of the experimentally noted property, DP, in the presence of the host
with respect to the value for the free guest is plotted vs XG or XH. The
value of XG for which the plot shows the maximum deviation is the stoichi-
ometry of the inclusion complex (e.g., XG ¼ 0.5 for 1:1 or 2:2 G:H com-
plexes; XH ¼ 0.33 for 1:2 G:H complexes). In most of the cases, DP
represents the deviation of the absorbance of the guest, DA, by addition of
the host.[65] Other properties are correlated with the concentration of the
 JOURNAL OF CARBOHYDRATE CHEMISTRY 11

Figure 5. Typical Job’s plots for 1:1 and 1:2 complexes.

complex, like the change in the NMR chemical shifts (Dd). The enthalpy
changes (DH) can also be used.[66] Two types of Job’s plots for 1:1 and 1:2
inclusion complexes are shown in Figure 5. It is clear that a maximum
deviation of XH ¼ 0.5 is obtained for the 1:1 complex, and a maximum of
XH  0.37 is reached for the 1:2 complex.
Literature data give many examples for the application of Job’s
method.[67–68] Further development of Job’s method was derived by Landy
et al.[69] to determine the stoichiometry of CD inclusion complexes, which
is named as Competitive Continuous Variation Plot. This approach couples
Job’s method with competitive experiments and spectral displacements,
known in the study of biopolymer–ligand interactions. The basic purpose
was to record the changes of a given experimental property and to make a
Job plot when a competitor ligand, for which the features of the inclusion
complex was already determined, is introduced into the system. This
method is recommended for the experiments in which either the low solu-
bility prevents the regular experimental determinations or the spectral
properties of the guest molecule are not in the range of experimental
accessibility.
IR spectroscopy is also useful to determine the interactions between CDs
and the guest molecules in a solid state. When a part of the guest molecule
is included in the CD cavity, normally changes occur in the CD bands,
while the bands of the included part of guest molecules are easily masked
by CD bands. Recently, thermal analysis is another method used to deter-
mine the inclusion complex. It is noted that the decomposition of the guest
after complexed with CD occurs above the original decomposition
12 R. PERIASAMY

temperature of the free guest.[60] However, in some cases, there are no

melting or decomposition peaks observed for the guest molecule on the
thermogram obtained with DSC or DTA during the inclusion complex for-
mation.[62,70] There are also other methods used to detect or characterize
the inclusion complexes, such as fluorescence spectroscopy,[60] powder X-
ray diffraction,[61,62,70] scanning electron microscope (SEM),[71–72] atomic
force microscope (AFM),[73–74] etc.

Applications of CD inclusion complexes

When a free guest molecule is individually complexed with a CD molecule
or derivative, the guest molecule is known to be micro-encapsulated from a
microscopical point of view. This causes changes in the physical and chem-
ical properties of the guest. As a result, CD complexation is used in many
fields.[75] Listed below are some of the properties of a guest molecule that
may be affected by CD complexation.

 Stabilization toward lights or oxygen.

 Changes in chemical reactivity.
 Fixation of volatile ingredients.
 Increase in water solubility.
 Protection against degradation by microorganisms.
 Masking the bad taste and smell.
 Masking the pigments or color.
 Changes in catalytic activity.

Application in textile industry

Since CDs can encapsulate various dyes, they are able to act as retarding
agents in the dyeing process. Furthermore, there are many other variables
such as temperature, pH, the addition of electrolytes, and the addition of dif-
ferent auxiliaries that can be adjusted to change the final finishing process to
obtain the desired properties in the finished goods. Auxiliary products are
also used in the wet finishing process. The leveling agent is one of the auxil-
iary products, which can produce uniform level dyeing by slowing down the
dye exhaustion process or by dispersing the dyes in a uniform way to the
fiber. There are two groups of leveling agents, one having affinity to dyes
and the other having affinity to fibers. Agents having an affinity to dyes
form a complex with the dyes and slow down the dyeing exhaustion process.
This complex acts with a slower rate when compared to free dyes. When the
temperature is raised, the dye is released from the complex and is fixed to
the fiber. Applications of CDs as leveling agents have been analyzed in the
 JOURNAL OF CARBOHYDRATE CHEMISTRY 13

dyeing process of cellulose fibers with direct dyes in an exhaust method,[76]

where b-CD has been tried as a dye complexing material. b-CD used as a
dye retarding agent in the dyeing process of PAN fibers with cationic dyes
were tested.[77] Some of the azo disperse dyes forming inclusion complexes
with a-, b- and c-CDs are also reported.[78] Level dyeing was attained when
microfiber PP6 and PA66 were used in the presence of CD.[79,80]
The quantity of aromatic organic pollutants like aniline formaldehyde, phe-
nol, and others from dyeing plant wastewater is minimized by applying CD
immobilized on water-insoluble organic supports. The modern concept to
modify the textile substrates depends on the permanent fixation of the supra-
molecular CD complex on the material surface and gives new functionality to
the fabrics.[81,82]

Application in pharmaceutical industry

The applications and benefits of CD complexation in the pharmaceutical
industry have been covered by several reviewers,[83–86] which will not be
discussed in detail here. In general, the significant benefits of CD complex-
ation are the enhancement of bioavailability,[87] stabilization,[88] taste or
odor masking,[89] reducing irritation,[90] and material handling.[91,92]
CDs are also used to decelerate or accelerate certain reactions, for
example, competitive inhibition and catalyst-substrate formation. If an ester
group of the guest drug molecule is located close to the secondary hydroxyl
groups in the CD cavity, hydrolysis of the ester group can be accelerated.
On the other hand, the hydrolysis is decelerated when the ester group is
encapsulated inside the CD cavity. The acid-catalyzed hydrolysis of glyco-
side bonds in digoxin is decelerated by the addition of CD.[87] CD-induced
drug stability enhancement may also be the result of inhibiting drug inter-
action with vehicles and due to the hindrance of drug bioconversion at the
absorption site.[84]
Taste is the vital parameters ruling patient compliance, and oral adminis-
tration of bitter drugs with an allowable degree of palatability is the main
issue to observe. Hence, the products should be masked suitably, particu-
larly for pediatric patients.[93] CD complexation suppressed the bitter taste
of drugs like oxyphenonium bromide. It was reported that the free drug
molecule only is responsible for bitter taste regardless of nature and the
concentration of CD.[84]

Application in food industry

CDs are used in food processing with various objectives: (i) to stabilize fla-
vors, fragrances, vitamins, and required oils against degradation, (ii) to
14 R. PERIASAMY

protect lipophilic food components which are sensitive to heat, light or

oxygen, (iii) to convert the liquid food ingredient into solid powders, (iv)
to suppress unpleasant odor or taste, (v) to dissolve vitamins and change
food color, (vi) to maintain quality of food during storage by improving
the packaging technology, and (vii) to manage the release of certain food
ingredients and to eliminate the undesirable component.
The effective method to stabilize the flavor in a food item and to protect
against evaporation and heat is the encapsulation of that flavor components
into the cyclodextrin cavity.[94–96] When b-CD is mixed with molten butter,
cholesterol present in butter forms inclusion complexes but not triglycer-
ides. Therefore, it is quite easy to remove cholesterol:b-CD complex from
butter. Over 90% of cholesterol can be removed in a single step.[97]

Application in cosmetics, personal care, and toiletry industry

Cosmetic components are generally insoluble in water, but these compo-
nents can form inclusion complexes with CD to have improved water solu-
bility. In most personal care and cosmetics products, triclosan is used as a
disinfectant and topical antiseptic. It is soluble in organic solvents and par-
tially soluble in basic solutions, but nearly insoluble in water. The CD-tri-
closan complex is completely soluble in water and gives a clear solution.
CDs are also used in deodorant sticks and can form complex perspir-
ation malodors.[98]
Perfuming cosmetic products are a significant part of consumer require-
ments. The important functions of fragrance materials are to give a pleas-
ant odor and masking the unpleasant smell of the product. The amount of
fragrance agents present in the product is decreased quickly during storage
due to their volatility and poor stability. In the cosmetic field, CDs are
used (i) to convert the liquid or oily guests to solid powders, (ii) to increase
the water solubility of lipophilic guest molecules, (iii) to release the guest
with control, (iv) to minimize or prevent skin irritation, (v) to increase the
physical and chemical stability of guest molecules by avoiding oxidation,
hydrolysis, evaporation, and decomposition, (vi) to prevent the interactions
between the different formulation ingredients, (vii) to increase or decrease
the rate of absorption of various compounds into the skin, (viii) to elimin-
ate or reduce bad odors, and (ix) to stabilize emulsions and suspensions.[99]

Application in biotechnologies
One of the applications of CDs in biotechnologies is found in the enzyme-
catalyzed transformation of hydrophobic components in aqueous solutions.
CDs can increase the solubility of complex components in an aqueous
 JOURNAL OF CARBOHYDRATE CHEMISTRY 15

medium and decrease their toxicity without changing the microbial cells or
enzymes. Thus, enzyme-catalyzed conversion of hydrophobic components
is intensified and the yield of product-inhibited fermentation is improved.
As a result, the products are isolated more simply and economically from
reaction mixtures.[94] One step microbial transformation process by
“Lactobacillus bulgaricus” was found by Kumar et al.[28] to produce testos-
terone from cholesterol, while cholesterol was biotransformed in the pres-
ence of CD in fermentation media. Prabhu et al. reported an increased rate
of production of benzyl penicillin when both 6-aminopenicillanic acid and
phenylacetic acid were complexed with b-methyl-CD and c-CD, respect-
ively, which was condensed in the presence of catalyst penicillin acy-
lase.[100] Fern
andez et al.[101] produced modified Bovine pancreatic trypsin
with 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide as the coupling agent
in the presence of a mono-6-amino-6-deoxy derivative of CD. They noticed
that the specific esterolytic activity and the affinity of trypsin were
improved by CD residues. CD-spironolactone complexes were prepared
and the effect of pH value on CD-catalyzed deacetylation of spironolactone
in presence of modified-b-CDs was studied to find an increased rate of
deacetylation of spironolactone.[102] Schwartz and Bar found that CD
increased the degradation of p-toluic acid and toluene by “Pseudomonas
putida.” Normally, the toxic effect of liquid toluene is more to “P. putida”
and this toxicity is removed when toluene was complexed with crystalline
b-CD. Degradation of toluene vapors was increased in the presence of
b-CD, to reduce the molecular toxicity and facilitate the absorption of the
gaseous component.[103]

Application in chemical industry

In the chemical industry, CDs and their derivatives have been used as cata-
lysts for improving the selectivity of reactions, as reaction inhibitors, and
separating agents to purify products in industrial scales.[104–105] CDs are
useful as separating agents because of their ability to form inclusion com-
plexes with smaller hydrophobic guest molecules. Most of the CDs and
their derivatives are completely soluble in water, so they are used as solu-
bilizers in an aqueous medium for lipophilic compounds for different types
of separations.[34] CDs are also used as chiral selectors for the separation of
enantiomer and as additives to improve the separation of cyclic com-
pounds. Wang and Ren found that there is an interaction between CD and
thymine which has a small ring, thus they examined the potential to
improve the separation of pyrimidines and purines using b-CD.[106] CDs
have also been used to separate enantiomers by HPLC or gas
16 R. PERIASAMY

chromatography (GC). CDs can act as selective agents to modify the spec-
tra in circular dichroism and as chiral shift agents in NMR studies.[38]

Recent trends in applied supramolecular chemistry

Supramolecular polymer
Since its conception by Leh,[107] supramolecular chemistry has a major
impact on the whole field of chemistry, particularly polymer chemistry,
because of supermolecular properties to form high level and complex self-
assembled macromolecules.[108] The major types of supramolecular interac-
tions utilized in polymer sciences are metal complexation,[109] hydrogen
bonding,[110] and inclusion complexes.[111] Common hosts for inclusion
complexes in aqueous solution are cucurbiturils,[112] calixanes,[113] pillar-
aenes,[114] and CDs.[115] Currently, CDs and functionalized CDs are more
readily available due to their industrial production on a large scale.
Moreover, CDs are biocompatible and biodegradable and already utilized
in a real-world application. As a result, the combination of CD host/guest
chemistry and synthetic macromolecules has opened a plethora of possibil-
ities and more importantly higher levels of molecular complexity as shown
in Figure 6. Taking dynamic hierarchical materials formation as the guiding
principle, the host or guest functional building blocks can be considered as
the primary structure that needs to be initially in place. On the next hier-
archical level, supramolecular complexes formed via the utilization of
macromolecular host and guest functionalized building blocks can be
viewed as secondary structures. The formation of even higher-order self-
assemblies/aggregates on the basis of secondary macromolecular structures
represent the tertiary structure.

Figure 6. Increasing levels of complexity via the combination of CD host/guest chemistry and
macromolecular design.
 JOURNAL OF CARBOHYDRATE CHEMISTRY 17

Rotaxanes, catenanes, daisy chains

Rotaxane is a mechanically interlocked molecular architecture consisting of
a “dumbbell-shaped molecule” that is threaded through a “macrocycle”
(Figure 7). The two components are kinetically trapped as the ends of the
dumbbell (called stoppers) are larger than the internal diameter of the ring.
This prevents dissociation (unthreading) of the two components since it
would require significant distortion of the covalent bonds. Nowadays, stud-
ies on these interlocked compounds are steadily increasing as they allow
one to construct highly sophisticated functional molecular devices.[116]
Threading the axis through the ring is a necessary step for rotaxane synthe-
sis. The host–guest interaction between axis and ring often leads to high
rotaxane yield.
Encapsulation of guest molecules is a prerequisite for rotaxane synthesis.
Thus, this property of CD is very useful for rotaxane synthesis. CD rotax-
anes are prepared by two different approaches: (a) threading approach and
(b) dipping approach. In the synthesis of CD rotaxanes 1a and 1b
(Figure 8), after a bola-amphiphile was complexed with methylated b-CD,
stoppers were installed onto the terminal amino groups of bola-amphiphile
via reaction with 2,4,6-trinitrobenzenesulfonic acid in aqueous solution to
provide the corresponding CD rotaxanes in 42–48% yields.[117]
Polymeric inclusion compounds are formed by self-organization of mul-
tiple host–guest complexes and then attachment of stoppers. This leads to a
special type of poly rotaxanes called daisy chain polyrotaxane (Figure 9).
In the preparation of CD catenanes, the template direction plan follows
the same principle as that for CD rotaxane synthesis.[118] Macrocyclization
of a guest molecule that is at least partly incorporated inside a CD cavity is
favorable on steric grounds. On the other hand, since no third component,

Figure 7. Mechanically interlocked molecular architecture of Rotaxane.

18 R. PERIASAMY

Figure 8. CD rotaxanes 1a and 1b.[117]

Figure 9. Rotaxanes and daisy chain inclusion compounds with end group E. (a) cyclic mono-
mer ([1]-rotaxane); (b) cyclic dimer ([2]-rotaxane); (c) cyclic trimer ([3]-rotaxane); (d) daisy chain
polyrotaxane.[117]

such as a blocking group, is needed in the process of forming CD cate-

nanes, one might expect catenation to proceed smoothly in comparison to
the formation of analogous[2]-rotaxanes.
CDs are hydrophilic, non-toxic, and biodegradable. Hence, CD polyro-
taxanes are useful in various fields, such as drug delivery systems, implants,
sensor devices, contrasting agents,[119] and fluorescent probes.[120] CD poly-
rotaxanes have also been combined with genes, enzymes, and antibodies to
control their biological functions.
 JOURNAL OF CARBOHYDRATE CHEMISTRY 19

Recent development in CD applications to various other fields

Removal of organic micropollutants from water
Activated carbon is normally used as an adsorbent to remove organic pol-
lutants in water. However, it has deficiencies like long pollutant up-taking
time and poor ability to remove hydrophilic micro-pollutants. Also, high
temperature (500–600
C) is required to regenerate activated carbon, while
the regenerated carbon has reduced performance. When b-CD is cross-
linked with rigid aromatic groups, it provides mesoporous b-CD polymers
with high surface area, which can rapidly sequester various organic micro-
pollutants with an adsorption rate constant 15–200 times greater than that
of activated carbon.[121–123] Moreover, the polymer can be regenerated
many times by a washing procedure without losing its performance.

b-CD-citrox for reduction of COVID-19 spread

COVID-19 infection caused by Coronavirus SARS-CoV-2 starting from
December 2019 has become a serious threat to the global economy and
health.[124] It spreads from person to person by inhalation of small droplets
produced from sneezing and coughing or by contact with nasal, oral, and
ocular mucous membranes.[125] SARS-CoV-2 may also be spread directly
or indirectly by saliva. Some mouth rinses presently available in the market
contain ingredients that can lower SARS-CoV-2 load. However,
Chlorhexidine as a common component in mouth rinse does not have the
efficiency to kill SARS-CoV-2 virus. When b-CD is combined with flavo-
noids like Citrox and used as mouth rinses and/or applied nasally, the
treatment can reduce the viral load of saliva and nasopharyngeal micro-
biota.[126] This may help control COVID-19 infection.

CDs in the treatment of viral infections

Infections caused by enveloped viruses like coronavirus and influenza virus
are mediated through viral binding to cellular receptors and fusion of the
viral envelope with the host cell membrane. It is evidenced that cholesterol
existing in the microdomains of the cell membrane and the viral envelope
is required for viruses to enter host cells. CDs can sequester cholesterol
from viral particles, thereby causing lipid rapt disruption and structural
deformation of viral envelops[127] to make them less infectious. Methylated
b-CD was demonstrated to reduce coronavirus and influenza A virus infec-
tions through depletion of chelosterol.[128,129]
20 R. PERIASAMY

CDs in control of biofouling and gene therapy

Recently, several studies have demonstrated the potential of CD-based poly-
mers to passively resist biofouling without overt cytotoxicity.[130] CDs have
also been extensively studied for gene therapy, such as usage in DNA and
RNA delivery systems to improve gene editing, replacement, and modula-
tions within the cell.[131]

b-CD for nasal drug delivery

CDs are not popular excipients for nasal or pulmonary drug delivery yet,
but this will change soon with the availability of an FDA- and
EMA-approved new product from Lilly, named Baqsimi.[132] Baqsimi is a
glucagon nasal powder containing b-CD as an inactive ingredient. As a
hyperglycemic agent, it is used in emergency situations to treat severe
hypoglycemic reactions in insulin users with diabetes mellitus. Currently,
emergency treatment for severe hypoglycemia is intramuscular glucagon
injection. According to EMA, Baqsimi contains 3 mg of glucagon, and the
remaining is b-CD and dedecylphosphocholine. b-CD can enhance the
solubility, stability, and bioavailability of glucagon.
The recent approval of Baqsimi is important since before it there was
only one CD-containing intranasal formulation on the market, Aerodiol
from Servier. Aerodiol contained Estradiol and randomly methylated b-CD
(RAMEB). This nasal spray was launched in Ireland for the menopausal
syndrome, but it is not on the market anymore.

Conclusions
The capability of CDs to form inclusion complexes with different types of
guest molecules via full or partial encapsulation within the cavity is a
unique property. When a guest molecule forms inclusion complex with
CD, the chemical and physical properties of the guest molecule are signifi-
cantly modified. This makes cyclodextrin very useful in many fields such as
food, pharmaceutical and agricultural industries, etc. Since CDs are non-
toxic, they can be used for oral administration. The latest studies have
proved that CDs form both non-inclusion and inclusion complexes and
that these complexes coexist in an aqueous medium. It has also been
proved that CD form aggregates in aqueous medium and the aggregates
can act as solubilizers in a micelle-like fashion. Recent studies also demon-
strated many other potential applications of CDs. Therefore, studies on
CDs and their application will be increasing rapidly in the forthcom-
ing years.
 JOURNAL OF CARBOHYDRATE CHEMISTRY 21

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