A Review On Cyclodextrin Encapsulation of Essential Oils and Volatiles

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A review on cyclodextrin encapsulation of

essential oils and volatiles
ARTICLE in FLAVOUR AND FRAGRANCE JOURNAL SEPTEMBER 2010
Impact Factor: 1.76 DOI: 10.1002/ffj.2019
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Helena Marques
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Review
Received: 14 February 2010;
Revised: 30 June 2010;
Accepted: 2 July 2010;
Published online in Wiley Online Library
(wileyonlinelibrary.com) DOI 10.1002/j.2019
A review on cyclodextrin encapsulation of

essential oils and volatiles
Helena Ma Cabral Marques*
ABSTRACT: Cyclodextrins (CyDs) are cyclic carbohydrates derived from starch. The parent CyDs contain six, seven and eight
glucopyranose units and are referred as a-, b- and g-CyD, respectively. The most important property of the CyDs is the ability
to establish specic interactions molecular encapsulation with various types of molecules through the formation of noncovalently bonded entities, either in the solid phase or in aqueous solution. These nano-encapsulating agents may form
inclusion complexes with essential oils and volatiles, or their components, in order to improve their characteristics, such as
transformation of liquid compounds into crystalline form; masking unpleasant smells and tastes of some compounds; improving the physical and/or chemical stability; and stabilizing volatile compounds by reducing or eliminating any losses through
evaporation. Complexation has been used to avoid the destruction of certain avours by processing or, on storage, allowing
the use of minor amounts of avours. The guest molecule is released in the warm moisture of the mouth. Examples are spices,
essential oils of vegetable origin and plant avours, chamomile oil and extract, eucalyptus oil, fennel oil, lemon oil, onion and
garlic oil, camphor, menthol, thymol, etc. There are several methods for the preparation of inclusion complexes; kneading,
co-precipitation, freeze-drying and spray-drying the most commonly used. Evidence for a guest inclusion into the apolar CyD
cavity may be proved by various analytical techniques, including NMR spectroscopy, UVvisible absorption spectroscopy,
optical rotatory dispersion and circular dichroism, uorescence, infrared/FT-IR spectroscopy, thermo-analysis, TLC, mass spectromety, and powder X-ray diractometry. Copyright 2010 John Wiley & Sons, Ltd.
Keywords: cyclodextrins; inclusion complexes; encapsulation of essential oils and volatiles
Introduction/Historical Background,
Structure and Properties of
the Cyclodextrins
Flavour Fragr. J. 2010, 25, 313326
* Correspondence to: Helena Ma Cabral Marques, Faculdade de Farmcia da

Universidade de Lisboa, i-Med.UL, Research Institute for Medicines and Pharmaceutical Sciences, Av. Prof. Gama Pinto, 1649-003 Lisbon, Portugal. E-mail:
hcmarques@.ul.pt
This article is part of the Special Issue of Flavour and Fragrance Journal
entitled, Aromatic Plants, Spices and Volatiles in Food and Beverages, edited
by Ana Cristina Figueiredo and M. Graa Miguel
Copyright 2010 John Wiley & Sons, Ltd.
313
Cyclodextrins (CyDs) were rst isolated in 1891 by Villiers[1] as

degradation products of starch from a medium of Bacillus amylobacter which he called cellulosine because of its similarity to
cellulose.[1] It was Schardinger,[2,3] however, who did much of the
characterization of CyDs and determined that they were cyclic
oligosaccharides. For this reason CyDs were also termed
Schardinger dextrins.
Pure CyDs (which are cyclic, water-soluble, non-reducing, macrocycle carbohydrate polymers) were prepared by Freudenberg
and co-workers,[4,5] who reported that CyDs are constructed from
a-(1-4)-linked D-glucopyranose units, in a ring formation.[69] CyD
chemistry was discussed in detail by Bender and Komiyama[10]
and Saenger et al.[11]
Loftsson and Duchne[12] list some books, book chapters and
reviews that may be useful for further reading on CyDs. A book on
the chemistry, analytical methods and applications of CyDs and
their complexes was recently edited by Dodziuk[13] oering comprehensive and up-to-date information on this eld.
The most common of these naturally occurring, ring-shaped
molecules are the a- (alpha), b- (beta) and g- (gamma) CyDs
formed by six, seven and eight glucose units (Fig. 1), respectively,
and which enclose cavities of approximately 0.6, 0.8 and 1.0 nm
in diameter.[14,15] Because of their sugar backbone, these CyDs are
also known as cycloamyloses: hexa- (C6A), hepta- (C7A) and octaamylose (C8A)[15] or cyclohexa-, -hepta-, -octaglucan and a-, band g-amylosan (French, 1957).[16]
CyDs with fewer than six glucopyranose residues do not exist,

probably for steric reasons.[17] Larger CyDs have already been
identied; d- (delta) and e- (epsilon) by French in 1957,[16] z- (zeta)
and h- (eta) CyDs containing 11 and 12 glucopyranose units,
respectively, by Thoma and Stewart in 1965[18] and, more recently,
the q- (theta) composed of 13 glucopyranose units;[19] however,
their yields are extremely small, and their complexing properties
are not as good as natural CyDs.[20] A review article was published
by Larsen[21] summarizing the studies relating to large CyDs. The
existence of large CyDs, cyclic a-D-(14) glucans with a degree of
polymerization higher than 8, has been proven and a number of
4-a-glucanotransferases have been shown to be able to produce
large CyDs consisting of up to several hundred glycosyl units,
from both amylose and amylopectin. Large CyDs with a degree of
polymerization up to 31 have been isolated to purity by using
elaborate purication schemes. CyDs with a degree of polymerization up to 17 units enabled studies of their structural and
complex forming properties.
The large CyDs represent an interesting class of molecule
within the eld of macrocyclic and supramolecular chemistry and
may be a key to increased understanding of the process of inclusion complex formation.[22,23]
View this article online at wileyonlinelibrary.com
Approved for dietary supplement
ADI, acceptable daily intake; EU, European Union; FDA, US Food and Drug Administration; FSANZ, Food Standards Australia New Zealand; GRAS, generally regarded as safe;
WHO/FAO, World Health Organization/Food & Agriculture Organization of the United Nations.
The Mercosur States are Argentina, Brazil, Paraguay, Uruguay and Venezuela.
a
GRAS in a wide range of intended use in food.
b
GRAS as a avour protectant.
Novel food, 2003

Food approved
Novel food, led January 2010

Natural product
Follow FDA approvals with an import licence
Carrier for food additives (<1 g kg-1)
Natural product
ADI = not specied 1999 and 2000

GRASa, September 2000
ADI = 5 mg kg day , January 1995
GRASb, October 2001
WHO/FAO
USA
Canada
EU
Japan
Mexico
Mercosur States
FSANZ
Korea
Phillipines
Thailand
Taiwan
ADI = not specied June 2001 and June 2004

GRASa, January 2004
Filed for novel food status, July 2006
Novel food, approved 2008
Natural product
Food approved
Novel food, January 2004
Food approved
-1
a-CyD
Country or organization
Table 1. Food approval status of CyDs (adapted from Winterhalter[26])
314
These starch derivatives are non-toxic ingredients, are not

absorbed in the upper gastrointestinal tract, and are completely
metabolized by the colon microora. Besides this, a-, b- and
g-CyDs enjoy generally regarded as safe GRAS status (US FDA) for
use as additives in food products, as avour carriers and protectants.[24,25] The food approval status of CyDs[26] in several countries and regions of the world is summarized in Table 1.
According to Mintels Global New Products Database (GNPD),
since 2001 there have been 265 food products containing CyDs
listed (more than 30% in beverages).[27]
Molecular encapsulation on CyDs derivatives (alkylated and
CyD polymers) has received much attention, in attempts to
design better carriers; thus, methylated, ethylated, hydroxypropylated, hydroxyethylated, ethylated, acetylated, sulfoethyl, sulfopropyl, sulfobutyl-CyDs, etc. and polymeric b-CyDs have been
employed in the rational design of water-soluble or insoluble
carrier systems.
The biosynthesis and properties of the CyDs were rst discussed in detail by French,[16] French et al.[28] and Cramer and
Hettler.[29]
CyDs are produced from starch and related a-1,4-glucans via
enzymatic conversion degradation and cyclization using CyD
glycosyltransferase (CGTase) and, partly, a-amylases. Dierent
types of starch can be used as substrate, but corn starch and
potato starch are the most commonly used for CyD production.
Maize starch and wheat starch are used but they contain a higher
percentage of amylose, which gives lower yields of CyD than
amylopectin.[30]
CGTase is produced by dierent types of microorganisms,
such as strains of Bacillus sp. (B. amylobacter, B. macerans, B. circulans, B. subtilis, B. megaterium, alkalophilic Bacillus sp.), Klebsiella (K. pneumoniae, K. oxytoca), Thermoanaerobacter sp.,
Clostridium sp., etc.[31,32]
The biotechnological advances after the 1970s led to great
improvements in the production of CyDs. The use of genetic engineering has made possible the isolation of dierent types of CyD
glucosyl transferases (CGTases) that are both more active and
more specic towards the production of predominantly a-, b- or
g-CyDs than previous production methodologies. Genetically
b-CyD
Figure 1. The chemical structure of cyclodextrins: n = 1, 2 and 3 corresponds to a-CyDs, b-CyDs and g-CyDs, respectively
-1
g-CyD
H. Marques
Flavour Fragr. J. 2010, 25, 313326
Cyclodextrin encapsulation of oils and volatiles
Flavour Fragr. J. 2010, 25, 313326
Figure 2.
The toroidal structure of b-cyclodextrin
In order to improve the aqueous solubility of this material, the

structure of b-CyD has been modied via alkylation and hydroxyalkylation.[38,39] The OH groups on C-2, C-3 and C-6 are available as
points of structural modication without danger of eliminating
the central void.[40] The OH groups on C-6 are the most reactive
whereas the hydroxyls at C-3 are much less reactive than those at
C-2. Consequently, by various molecular manipulations, CyDs can
be transformed into derivatives having dierent physicochemical
properties.[41] It is possible to create cylinders that vary in their
length or have lids attached or tails coming out. They can be
readily cross-linked to form CyD polymers. A useful general
review of chemical methods for modifying CyDs is that given by
Croft and Bartsch[42] and Khan et al.[43]
CyDs have no well-dened melting point and start to decompose at temperatures above 270C, and at 300C a sharp endothermic process is detected by dierential scanning calorimetry,
which indicates that the melting is accompanied by decomposition. Generally, their solubility in water is increased at higher
temperatures, but the opposite happens with dimethyl (DM)-bCyD.
Other important physicochemical characteristics are outlined
in Table 2.[37] It is noteworthy that there are slight dierences in
the reported central cavity and outer periphery diameters of the
CyDs.
The Formation of CyclodextrinGuest

Molecule Inclusion Complexes
An inclusion compound is a unique form of chemical complex in
which one molecule is enclosed (encased, clatherated, included)
within another molecule or aggregation of molecules. Inclusion
compounds were rst observed by Mylius in 1886[14] as unusual
complexations occurring between hydroquinone and several
volatile compounds. He proposed that the two components
were interacting in the absence of ordinary chemical bonds and
suggested that one molecule was enclosing the other. The
essential criterion is simply that the enclosed molecule, or
guest, be of a suitable size and shape (i.e. the best possible
lling of space) to t into a cavity within a solid structure formed
by host molecules.[44,45]
315
engineering CGTases, together with other technological and

process innovations, has made highly puried a-, b- and g-CyDs
available as food and pharmaceutical excipients. Nowadays, they
are industrially produced, with an annual b-CyD production of
about 10 000 tons and the present price of food grade b-CD is
very reasonable, i.e. less than 5 US$ per kg.[12,24]
Much eort has been made to improve the production, recovery and purication of CyDs. The production of CyDs by CGTase is
an important industrial process, and it has been studied and
reviewed by many authors. Singhal et al.[33] have reviewed the
industrial production, processing and utilization of sago palmderived products such as modied starches and CyDs. Li et al.[34]
have reviewed the enzymatic production, unique properties, and
applications of g-CyD as well as its dierence with a- and b-CyDs.
As all known wild-type CGTases produce a mixture of a-, b-, and
g-CyDs, the obtaining of a CGTase predominantly producing
g-CyDs is also discussed.
The composition of the CyD products obtained by a CGTase
synthesis reaction is determined primarily by the type of the
enzyme employed and can be manipulated by addition of complexing agents or organic solvents to the reaction mixture.
CGTases catalyse transglycosylation reactions, which include
cyclization, coupling and disproportionation reactions, as well as
a hydrolysis reaction.[35] In this study, a novel system was set up in
which CGTase was anchored on the surface of Saccharomyces
cerevisiae and utilized as an immobilized enzyme, which enables
its reuse.
Szerman et al.[30] optimized the conditions to produce CyD with
CGTase from Bacillus circulans DF 9R using experimental designs.
They developed a simple and economic method to partially
purify and concentrate the CGTase from cultural broth, and to
produce CyD in two successive steps using the same cassava
starch as both enzyme adsorbent and substrate.
More economic processes for g-CyD and especially a-CyD production have been developed using improved CGTases and
downstream processing. New purication steps, e.g. anity
adsorption, may reduce the use of complexing agents.[31]
Vassileva et al.[36] studied four systems for a continuous CGTase
production by Bacillus circulans ATCC 21783, which produces
mainly b-CyD. An ideal combination of CGTase, raw material,
reaction conditions, etc. is crucial for achieving an economic production process.[31]
CyDs are shown to have a toroidal, hollow, truncated cone
structure (Fig. 2), where the secondary hydroxyl groups on the
C-2 and C-3 atoms are located on the wider side of the torus,
while the primary hydroxyl groups on the C-6 are positioned on
the opposite side of the torus (the narrower) and are directed
away from the cavity, except if H-bonded to include guest molecules forming inclusion complexes. The CH groups comprising
H-1, H-2 and H-4 are located on the exterior of the molecule,
while the polar sugar hydroxy groups are oriented to the cone
exterior, and consequently the external faces of CyDs are hydrophilic. This distribution of polar groups provides for the aqueous
solubility of these materials. The interior of the torus oers an
environment of much lower polarity than is present in water so it
can be considered as a hydrophobic cavity, which is lined by two
rings of CH groups (H-3 and H-5) and by a ring of glucosidic
oxygen-bridge atoms, ether oxygens (O-4 and O-5); H-6 forms
the narrower rim of the truncated cone. The result of this
amphipathic property is that CyDs can form soluble, reversible
inclusion complexes with water-insoluble compounds, resulting
in compound solubilization.[37]
H. Marques
Table 2. Some important characteristics of CyDs[37]

Characteristic
a-CyD
No. of glucose units

6
Molecular weight (Da)
972
No. of water molecules in cavity
6
Water solubility at 25C (%w/v)
14.5
Half-life in 1 M HCl at 60C (h)
6.2
Melting onset (C)
275
Diameter of central cavity (nm)
0.50.6
Diameter of outer periphery (nm) 1.41.5
Height of the torus (nm)
0.8
b-CyD
g-CyD
7
1135
11
1.85
5.4
280
0.60.8
1.51.6
0.8
8
1297
17
23.2
3.0
275
0.81.0
1.71.8
0.8
316
The stereochemistry and, possibly, the polarity of both the host

and the guest molecules determine whether inclusion can occur.
The main binding contribution between CyD and its partners is
the geometrical tting, so complexation occurs in a stereospecic fashion.[46] The spatial requirements for the formation of a
CyD inclusion compound in part mimic the lock and key mechanism of enzyme catalysis which occurs if the substrate or guest
molecule is orientated properly with respect to the active centres
of the host.[29] It is also possible to use the CyD ring to include or
hold a molecule partially, blocking some reactive sites on the
guest but exposing others.
The resulting close t of the two components produces a combination of signicant strength due to the total dispersion forces,
and possibly, highly orientated dipoles for stability, etc. between
the interacting components, as this type of spatial complex formation does not occur by means of ionic, covalent or coordinate
covalent bonds (the usual concept of chemical complexation).[47]
The general title for this class of complexes, inclusion compounds (einschlussverbindung), was rst used by Schlenk in 1949.
Besides the general terms (occlusion and adducts), other terms
that have been used to describe these complexes are molecular
compounds, cryptates[7,14] and clathrates.[44] The term clathrate,
derived from the Latin clathratus, meaningenclosed or protected
by cross bars of a grating,[44] has been used to describe the cagelike structure of the hydroquinone inclusion compounds.
CyDs may be considered nano-encapsulating agents and the
complex formation is equivalent to molecular encapsulation, as
the guest molecules are isolated from each other and are dispersed on a molecular level in an oligosaccharide matrix.
The formation of inclusion complexes comprises several steps,
as illustrated in Fig. 3. In general, the smaller the guest molecule,
the greater is its complexing activity, as long as interactions
occur between the included guest molecule and the host cavity.
Likewise, the degree of activity for the large molecules is dependent on the presence of a suitable group or ring capable of
entering the cavity (one or two benzene rings or even larger
ones carrying an aromatic moiety, a side chain or other groups of
comparable size), only some lipophilic part of the molecule has
to t into the lipophilic CyD cavity and not the entire molecule.
Compounds with the lowest water solubility generally show the
greatest % increase in solubility as a function of the concentration of CyD.[49] Little or no eect was observed when hydrophilic
and water soluble molecules were tested, e.g. propranolol and
triuorothymidine.[50]
When the guests have a similar molecular dimension, the more
hydrophobic molecule or residue has the higher anity for the
CyD cavity in aqueous solution, because the cavity provides a
microheterogeneous hydrophobic matrix in such polar solvents;

the cavity is more hydrophobic than water.[6,51,52] In fact, Heredia
et al.[53] and Cox et al.[54] claimed that the polarity of the internal
cavity of b-CyD is similar to that of ethanol. Among the natural
CyDs available, b-CyD appears to be the most useful complexing
agent due to its size and availability.
Molecular encapsulation (entrapment) by CyDs often advantageously modies various physicochemical properties of the
encapsulated molecules such as aqueous solubility and stability.
It is also simpler and cheaper than most other methods of
encapsulation.
The structure of crystalline CyD complexes is not always identical to that of the complexes in solution. In the dissolved state all or
part of the guest molecule is located within the CyD cavity and the
whole complex is surrounded by a multilayer hydrate shell. In the
crystalline state, however, guest molecules are located not only
inside the CyD cavity but also between the CyD rings as crystallattice inclusions and may form non-inclusion complexes.[55]
Some of the CyD molecules include only water molecules, consequently they are incorporated into the crystal lattice as water
complexes. Therefore, the crystalline complexes are practically
never of strictly stoichiometric composition; however, they are
stable even if the ring cavities are only partially saturated by
apolar guest molecules. Because covalent bonds do not form
between the components, the complexes are easily dissociated
under physiological conditions.[14,20] In the solid state, the crystallinity of the inclusion compound will signicantly aect many
physicochemical and mechanical properties such as chemical
stability, dissolution rate, mixing, ow, and compression
characteristics.
As CyDs possess the capacity to associate through the whole
spectrum of weak intermolecular forces, several are almost certainly involved in determining the net stability of any complex
and the very wide ability of CyDs to incorporate molecules of
quite dierent chemical types. It is dicult to draw a denite
conclusion for the binding force, particularly in the case of drug
molecules having complex structures. However, a variety of intermolecular forces, such as a hydrophobic eect, van der Waals and
London dispersion forces, hydrogen bonding, release of highenergy water, relief of conformational strain and others, may
operate during inclusion compound formation, although the
relative contribution of each factor is dierent depending on the
guest employed.[47]
Several factors may inuence inclusion complex formation,
such as type of CyD, cavity size, pH and ionization state, temperature and method of preparation.[56]
Evaluation of Inclusion Complexation:

Stability Constants, Molar Ratios and
Loading of the Complex
The extent of complexation in an aqueous medium, i.e. the stability of the complex formed, is characterized by the stability (or
equilibrium) constant, KS, of the complex:
KS =
kr
[ complex ]
=
kd [ CyD][guest ]
(1)
where kr (M-1 s-1) is the recombination rate constant and kd (s-1) is

the dissociation rate constant. The greater the magnitude of this
ratio the greater is the stability of the complex.
Flavour Fragr. J. 2010, 25, 313326
Figure 3. The formation of an inclusion complex between a drug and a CyD. 1. Displacement of
polar water molecules from the apolar CyD cavity. 2. An increasing number of hydrogen is bonds
formed as the displaced water returns to the pool. 3. Reduction of the replusive interactions between
the hydrophobic guest molecule and the aqueous environment. 4. Increase in hydrophobic interactions as the guest inserts itself into the apolar CyD cavity. (Adapted from information on the ISP
Website[48])
solubility. BS-type response denotes complexes of limited solubility and a BI-type curve indicates the formation of insoluble complexes. A-type curves are subdivided into AL-type (linear
increases of drug solubility as a function of CyD concentration),
AP-type (positively deviating isotherms) and AN-type (negatively
deviating isotherms) subtypes.
KS may be obtained from the linear portion of the phase solubility diagrams[57] by the equation:
KS =
Figure 4. Phase solubility proles and classication of complexes

according to Higuchi and Connors.[57] S0 is the intrinsic solubility of the
substrate (the dissolved guest/drug) in the aqueous complexation
medium when no ligand (cyclodextrin) is present
Flavour Fragr. J. 2010, 25, 313326
(2)
where S0 is the intrinsic solubility of the substrate on the medium.

Several methods have been reported for the determination of KS
besides phase solubility studies: potentiometry, conductometry,
polarography, microcalorimetry, circular dichroism, NMR, ORD,
UVvisible spectrophotometry, HPLC[37] and TLC.[58]
Usually, complexes with stability constants from about 100 to
5000 M-1, seem to be suitable for practical applications. Very
labile complexes result in premature release of the guest (due to
the weak interaction, i.e. insignicant improvement in solubility)
and very stable complexes result in a retarded or an incomplete
release of the guest and consequently absorption is hindered;
using this concept, modied release, especially slow release
control, may be reached for drugs[37] and fragrances.[59]
However, in some cases, even with small KS values, complexation conferred better physicochemical, pharmaco-technical and
biopharmaceutical properties of drugs and/or other molecules.
The molar ratio of host to guest molecules is usually 1:1 for
inclusion complexes formed in solution, except for complexes
with long-chain or bifunctional guest molecules (e.g. guest molecules having two aromatic rings on opposite sides of a small
central molecule segment). As the majority of avour components are mono- and sesquiterpenoids and phenylpropane
derivatives of an average molecular weight of 120160, a 1:1
complex formation is observed.[60] But there are reports of complexes exhibiting other host : guest molar ratios, such as
b-CyD : allyl isothiocyanate (1:2)[61] and b-CyD:(-)-a-bisabolol
(2:1).[62]
317
In solution, the fundamental parameters for inclusion compound formation (e.g. stability constant, stoichiometry and thermodynamic parameters) can be accurately obtained and the
equilibrium of Equation 1 can be controlled in order to move in
the desired direction, by changing the environmental conditions
such as concentration, temperature, pH, polarity of the solvent,
addition of a competitive molecule, or by choosing the most
suitable CyD or its derivative.
Higuchi and Connors[57] have established a classication of the
complexes from the phase solubility proles (Fig. 4) obtained
from the interaction between the guest and the host when in
solution. Thus, in a simplied and summarized view, A-type
curves indicate the formation of soluble inclusion complexes.
B-type suggests the formation of inclusion complexes with poor
slope
S0 (1 slope )
H. Marques
Table 3. Flavour content in b-CD complexes[64]

Flavour material
Flavour load of complex (%)
Anise oil
Basil oil
Laurel leaf oil
Benzaldehyde
Carawayoil
Carrot oil
Celery oil
Cinnamon oil
Coriander oil
Dill oil
Smoke oil
Garlic oil
Lemon oil
Marjoram oil
Mustard oil
Onion oil
Orange oil
Mint oil
Raspberry oil
Sage oil
Sweet cumin oil
Tarragon oil
Thyme oil
Vanilla
9.00
10.72
10.80
8.70
10.50
8.82
10.00
8.76
7.72
6.92
12.20
10.20
8.75
8.00
10.92
10.20
9.20
9.70
8.66
8.20
10.00
10.23
9.60
6.20
Carrier et al.[63] in an exhaustive examination study involving

dierent CyDs and several drugs suggest some guidelines in
order to improve their bioavailability by means of an increase on
their solubility. They stated the following considerations in order
to obtain the best outcome: the utilization of pre-formed complexes rather than physical mixtures, guest hydrophobicity (log
P > 2.5), low guest solubility (typically < 1 mg ml-1), moderate
binding constant (< 5000 M-1), low dose ( < 100 mg), and low
CyD : drug ratio (2:1).
The avour/aromatizing responsible substances normally
consist of several components. Therefore, it is important that all
these components should be incorporated into the complex
without altering its composition. The most hydrophobic guest
molecule will be complexed rst when several potential guest
molecules are present in solution. A list of avourb-CyD complexes loading is shown in Table 3.[64]
Applications of Cyclodextrin-assisted
Molecular Encapsulation
Applications in the Food and Beverage Industries
318
CyDs as multifunctional food ingredients can be utilized mainly

as carriers for molecular encapsulation improving the stability of
sensitive ingredients (e.g. avours, aromatizing agents and
other), both in the physical and chemical sense leading to
extended product shelf-life. Accelerated and long-term storage
stability of CyD-entrapped food ingredients surpassed that of the
traditionally formulated ones. The basic objectives of CyD encapsulation are as follows: to reduce the volatility or ammability of
liquids, to make liquids behave like solids, separate reactive
materials from one another, reduce material toxicity, provide

environmental protection to sensitive compounds, alter surface
properties of the materials, control the release of materials, and
to mask the bitter taste of certain compounds, among
others.[12,47,6467] CyD itself is a promising new sweetener.
Enhancement of avour by CyDs has been also claimed for alcoholic beverages such as whisky and beer.[64]
Thus, CyDs as molecular encapsulating agents have very specic interaction with many molecules and may form inclusion
complexes with essential oils and volatiles present in foods and
beverages, in order to improve their characteristics oering the
following desirable eects/advantages.
Technological advantages. Technological advantages include
typically stable and standardizable compositions, simple dosing
and handling of dry powders, with the consequent reductions of
packing and storage costs, leading to more economical technological processes and manpower savings. Technological advantages of the use of CyDs in foods and beverages and their
processing technologies are also manifested in improved
sensory, nutritional and performance properties. Lindner et al.[67]
compared natural spices with their equivalent avourb-CD complexes. For this, they used foods and sausages prepared according to conventional recipes; however, they substituted one or
more spices by the corresponding avourb-CD complexes.
Spices needed to season dierent foods could be reduced
keeping equivalent taste by replacement with avourb-CD complexes. Thus, the amount of garlic could be decreased 20-fold on
garlic sauce and that of dill decreased 150-fold on dill sauce. The
amount of onion and mustard could be decreased 55 and 66
times on spiced ewe cheese, respectively, but the caraway could
be decreased only to half. The amount of caraway could be
reduced to half on thick brown soup and the marjoram to about
one-sixth on meat pies with marjoram.[67]
Additionally, compounds can be mixed and formulated
together if one of them is protected by inclusion complex formation avoiding undesirable incompatibilities.
Transformation of liquid compounds. The transformation
of liquid compounds into crystalline form can render such materials suitable for the manufacture of powders, granules and
even tablets, e.g. seed oil of Carthamus tinctorius (saower),
squalene[68,69] and essential oils.[70] Also, the transformation of
greasy, oily or liquid, coee aroma concentrates into a microcrystalline stable inclusion complex may have practical importance
as an additive to enhance the sensory properties and quality of
instant coee products.[71] The elimination or reduction of hygroscopicity and of microbiological contaminations is also possible
by complex formation.
Modication of tastes and odours. CyDs may be useful for the
modication and/or elimination of bitter and disgusting tastes
and odours of foods and beverages. Masking, reduction or elimination of undesired or unpleasant smell (odours) and/or taste of
some compounds, such as thymol and carvacrol, ginseng extract,
and other functional foods and spices has been proved.[60,72,73]
At lower temperatures and at higher CyD concentration,
unpleasant tastes and odours can be masked or covered by CyD
complexation. Bitter, astringent components of foods (e.g. soya),
beverages (e.g. naringin in citrus fruit juice, or chlorogenic acid
and polyphenols in coee) can also be complexed and their taste
reduced or completely eliminated.[73]
Flavour Fragr. J. 2010, 25, 313326

A randomized panel was asked to evaluate the reduction in
odour intensity of garlic oil with dierent CyDs; both a- and
b-CyDs were successful.[74]
Reduction of the smell and taste of thymol, carvacrol and
g-terpinene,[75] as well as ginseng extract, and other functional
foods and spices has been proved.[44,72] Milk casein hydrolysate is
a readily digestible protein source but its bitter taste limits its
uses. By adding 10% b-CyD to the protein hydrolysate the bitter
taste can be eliminated. On the other hand the bitter taste of
grapefruit or mandarin juices decreased substantially when 0.3%
b-CyD was added prior to a heat treatment of canned juices. The
bitter substances naringin and limonin form stable inclusion
complexes with b-CyD resulting in the reduction of free bitter
substances in solutions.[60,73]
CyDs have eciently reduced the bitter taste of some plant
extracts such as guava tea extract, gingko extract and gymnema
extract in the order g-CyD >> b-CyD >> a-CyD.[26,74]
Flavour Fragr. J. 2010, 25, 313326
319
Improvement of chemical stability. To limit aroma degradation or loss during processing and storage, it is benecial to
encapsulate volatile ingredients prior to use in foods and beverages.[67] CyDs lead to an improvement of the molecular stability, such as physical stability by the retardation of the crystal
growth and chemical stability by the deceleration or even suppression of chemical reactivity, such as volatility, photodegradation, dehydration, hydrolysis, sublimation, oxidation, thermal
decomposition, stereochemical transformations and isomerization.[47] Examples are spices, essential oils of vegetable origin
and plant avours, chamomile oil and extract, eucalyptus oil,
fennel oil, lemon oil, onion and garlic oil, camphor, menthol,
thymol, citral, etc.
The formation of an inclusion complex may have an accelerative (catalytic) or decelerative (inhibitory) eect on the reactivity
of the guest molecule (acceleration factors ranging from
0.3 to 300), depending on the nature of the reaction and the
orientation of the guest within the CyD cavity.[76,77] Compounds in
which the active centres are included in the torus of the CyD are
expected to exhibit a decelerating eect; compounds which are
only partially included leaving the active centre out of the cavity
undergo acceleration. This unique catalytic (positive and negative) feature has been used as a model for enzymesubstrate
interactions,[78] to enhance stereoselectivity of chemical reactions,[79] and to improve the molecular stability of the guests.
Volatile compounds can be stabilized by complex formation
reducing or eliminating any losses through evaporation. The
reduction of volatility can be demonstrated by a rise in the
boiling point of solutions, or in the sublimation for solids.[80]
Complexation has been used to avoid the destruction of certain
avours, colours or vitamins associated with certain ingredients
by processing or on storage. The guest (e.g. oil) may be released
in the warm moisture of the mouth.
Generally, most avour components are highly volatile and
chemically unstable in the presence of air, light, moisture and
heat. Natural and synthetic coee avours or other food avours
(anethol, anis oil, citral, citronellal, linalool, menthol, sage oil, cinnamon oil, jasmin oil, bergamott oil, orange oil, lemon oil, lime oil,
onion oil, garlic oil, mustard oil, marjoram oil, other monoterpenes such as thymol and geraniol, etc.) are stabilized with CyDs
to avoid the loss of avours during storage of the product or
as a result of exposure to light or oxygen; upon contact with
water the complex-bound avour substances were released
immediately.[60,66,71,81,82]
These inclusion complexes have a good reputation for their

high stability exhibited when they are heated during industrial
food processing and they are stable and last for a longer period
than liquid essence or the components themselves. For example,
many aromatizing substances are sensitive to some kind of radiation; e.g. citral (a component responsible for fresh citrus odour)
cyclizes under UV irradiation, suering, like other cyclic monoterpenes, signicant taste modications. This kind of alteration is
prevented by complexation with b-CyD and this protective eect
is more marked on materials in the solid state than in aqueous
solutions, where a fraction of the guest species is released from
the complex.[64]
In order to minimize the evaporative avour loss and to
improve avour stability, with b-CyD, starch and its derivatives,
four dierent types of synthetic avours, namely benzaldehyde,
dimethyl trisulde, 2-mercaptopropionic acid and benzothiazole,
model volatile avour mixture containing components typical of
roasted chicken avour, were selected. The suitability of starches
for retaining volatile meat avour encapsulation was proved
eective.[83]
b-Farnesene, as the most volatile component of chamomile
owers, could be partially protected from volatilization during
freeze-drying. The extent of the protection depended on the
applied mass of b-CyD.[84] Carvone and limonene, constituents of
caraway essential oil, were complexed with b-CyD. The b-CyD
inclusion complex seemed to protect volatile substances from
evaporation more eciently during storage whereas microcapsules with modied starches as wall material were more heat
tolerant.[85]
The use of volatile plant compounds in postharvest potato
storage is an ancient concept. D-Carvone, or (4S)-(+)-carvone, a
monoterpene present in the essential oil of caraway seeds
(Carum carvi L.), acts as a sprouting inhibitor agent for potato
tubers in storage. However, this compound is extremely volatile
and therefore unstable. Inclusion of carvone into b-CyD reduces
volatility and improves stability, thus, the inclusion compound
carvoneb-CyD indicates that these systems satisfy the basic
requirements for use in sprout suppression in Solanum tuberosum
L. tubers.[86]
Tobacco avours can be sprayed or dusted onto the dried
leaves (because they are lost during processing and storage due
to their volatility). b-CyD complexes will remain unchanged in the
tobacco mix until liberated by ignition.[87]
Carvacrol, thymol and eugenol (components of essential oils of
vegetable origin) are oxidized, decomposed or evaporated when
exposed to the air, light or heat. If prepared as b-CyD inclusion
complexes they are stabilized as CyDs and greatly reduce volatility, oxidation and heat-decomposition.[88]
The colour preservation of fruit juice during processing and
storage was proved by Lopez-Nicolas et al.[25] CyDs have been
successfully used as anti-browning agents in dierent fruit juices
including the prevention of enzymatic browning in peach juice,
as browning inhibitors.
Thus, CyD complexation has been largely used in the food
industry to stabilize components, avoiding the destruction of
certain avours, colours or vitamins associated with certain ingredients (e.g. onion and garlic oil) by processing or on storage. The
guest (oil) is released in the warm moisture of the mouth.[87]
Lemon oil shows greatly enhanced thermal stability towards oxidation of the b-CyD inclusion complexation.[89] Thus, CyDs
improve the shelf-life of food products by protecting against
light-, air- and heat-induced decomposition.
H. Marques
Increase in the solubility, dissolution and release
rates. Complexation can result in increased wettability and/or
marked reduction in crystal size.[47] Also a marked increase in
solubility occurs in the guest molecules in water, when inclusion
complexes of b-CyD and the essential oils carvacrol, thymol and
eugenol were prepared by the SC-CO2 technique.[88]
Smart food packaging. Szente and Szejtli[60] reported special
applications of CyDs in foods and CyD-containing food packaging materials. CyDs or CyD-complexed antimicrobial agents
incorporated into food packaging plastic lms eectively reduce
the loss of the aroma substances and improve the microbiological preservation during storage. Various CyD complexes can be
utilized in foods as antiseptic or conserving agents; 0.1% iodine
b-CyD inhibits putrefaction for 2 months at 20C in sh paste or in
frozen sea-food products.[60]
Preparation of CyD- and sugar-containing edible lm has been
also described: CyD-complexed benzoic acid and its esters are
known, broadening the selection of smartfood packaging materials with preserving power.[60]
Complexes of a- and b-CyDs with allyl isothiocyanate, a major
avour component of mustard essential oil, has been evaluated
as a slow-release additive in polylactide-co-polycaprolactone
(PLA-PCL) biopolymer lm packaging. Encapsulation of that
naturally derived preservative has shown to be suitable for long
shelf-life storage packaging of cheeses.[90,91]
Gaseous 1-methylcyclopropene (1-MCP) is an inhibitor of ethylene perception that is being used extensively for apples and
ornamental products. However, food packaging materials that
release 1-MCP at a predictable rate into the package headspace
might be useful for application in inhibiting the deleterious
eects of ethylene in postharvest packaging and storage of some
horticultural products. A 1-MCPa-CyD complex was incorporated into several common packaging lms by heat-pressing
(dry-blend, lamination) and solution-casting methods. Pressing
1-MCPCyD containing lms above 100C reduced the amount of
1-MCP remaining in the lm.[92]
Applications in Industries Other than Food and Beverages
As a result of molecular complexation phenomena CyDs are
widely used in many industrial products and technologies. The
negligible cytotoxic eects of CyDs are an important attribute in
applications such as drug carriers, food and avours, cosmetics,
personal care and toiletries, packaging, textiles, agriculture, separation processes, environment protection, fermentation and
catalysis.
Cyclodextrins in the cosmetics industry. CyD complex formation has been used in the cosmetic industry to:
320
avoid the destruction of certain avours, colours or vitamins

associated with certain ingredients by processing or on storage
increase the water solubility of lipophilic materials
convert liquid or oily materials to powder form
increase the physical and chemical stability of guest molecules
by protecting against decomposition, oxidation, hydrolysis or
loss by evaporation
provide controlled release of active ingredients
reduce or prevent skin irritation
prevent interactions between various formulation ingredients
increase or decrease the absorption of various compounds into
skin
stabilize emulsions and suspensions

reduce or eliminate undesired odours
The essential functions of fragrance materials are to provide a
pleasant odour, to mask the base smell of the product, and to
give the product an identity. However, since fragrance materials
are poorly water-soluble or insoluble compounds and usually
exist in a liquid state, the perfuming process may be dicult.[59]
Surfactants used as solubilizing agents lead to dierent problems, such as causing cloudiness and turbidity in the transparent
formulations, skin irritation and sensitization to light. Furthermore, the amount of fragrance materials in the product rapidly
decreases during storage because of their volatility and poor stability. CyD complexation of fragrance materials increases their
solubility and reduces or prevents their evaporation. The interaction of the guest with CyDs produces a higher energy barrier
to overcome volatilization, thus producing long-lasting
fragrances.[59]
Numanolu et al.[59] proved that it was possible to (a) increase
the stability (decreased volatility) and water solubility of fragrance materials (linalool and benzyl acetate), (b) provide controlled release of these compounds, and (c) convert these
substances from liquid to powder form by preparing their inclusion complexes with b-CyDs and 2-HPbCyD. The stability of these
compounds in gel formulations can be increased by complex
formation. As a result, it can be concluded that CyDs (especially
2-HPbCyD) are very suitable cosmetic delivery systems for fragrance materials. Procter & Gamble has a great number of
patents in the eld of cosmetic and toiletries using CyDs.
Cyclodextrins in the pharmaceutical industry. In the pharmaceutical industry, CyDs can be used to:
suppress volatility
transform liquid compounds into crystalline form
mask the unpleasant smell and taste of some drugs
avoid undesirable incompatibilities
increase bioavailability
increase stability of a drug in the presence of light, heat and
oxidizing conditions
Thus, the shelf-life of drugs as well as organoleptic properties,

such as palatability of active ingredients in dosage forms, can be
increased. This will enable the production and re-introduction of
numerous active substances that, owing to stability, compatibility or absorption problems, are presently not in use. The increase
in the solubility, dissolution, release rates and bioavailability, the
modication of pharmacokinetics, the modication of the disposition of drugs, sustained release of drugs and targeted therapy
are also some achievements that might be possible with
CyDs.[47,56]
However, with regard to the potential application of CyDs in
drug delivery, it is noteworthy that complexation can signicantly increase oral bioavailability only for Class II drugs (i.e. those
with poor solubility and high permeability, according to the
Biopharmaceutical Classication System).[19,93,94]
Molecular encapsulation of drugs with CyD derivatives has
received much attention for sustained drug release. Among these
derivatives, in attempts to design better drug carriers, alkylated
CyDs and CyD polymers have been prepared and have recently
gained acceptance in pharmaceutical applications. Methylated,
ethylated, hydroxypropylated, hydroxyethylated, ethylated,
Flavour Fragr. J. 2010, 25, 313326

acetylated, sulfoethyl, sulfopropyl, sulfobutyl-CyDs, etc. and polymeric b-CyDs are being employed in the rational design of watersoluble or insoluble drug carrier systems as needed and
according to the aims. Hydrophilic CyD derivatives are particularly useful for improving the solubility and/or dissolution rate of
poorly water-soluble drugs by means of inclusion complex formation. Hydrophobic CyD derivatives may be more useful for
controlling the release rate of water-soluble drugs. The more
stable a complex, the slower the initial release and consequently
the longer is the time required for complete drug release.
The release of a drug from a vehicle is well known to be inuenced by various factors including drugvehicle interactions,
solubility, partition coecient, and particle size of drug in the
vehicle. Various release rates of drug can be obtained and controlled by combining hydrophilic and hydrophobic b-CyD complexes in appropriately dierent mixing ratios which may oer
a more suitable preparation for modied-release dosage
forms.[95,96]
Worldwide there are several commercial pharmaceuticals with
CyD-based formulations: a-CyD (oral, parenteral), b-CyD (oral,
sublingual, rectal, topical), methylated-b-CyD (ocular, nasal,
topical), hydroxypropylated-g-CyD (ocular), hydroxypropylatedb-CyD (oral, parenteral, ocular, rectal), sulfobutylether-b-CyD
(parenteral).[19,24,97,98]
Modication of the pharmacokinetics and the disposition of
drugs, as well as targeted therapy, may be brought about by
increasing the duration of action, avoiding the rst-pass eect
and decreasing the lag time in oral applications. Thus, poor and
unpredictable bioavailability, narrow therapeutic indices and
undesirable side eects of some drugs can be improved upon
CyD complex formation.
The increased drug ecacy and potency (i.e. reduction of the
dose required for optimum therapeutic activity), caused by CyDincreased drug solubility, may reduce drug toxicity by making the
drug eective at lower doses. CyD entrapment of drugs at the
molecular level prevents their direct contact with biological
membranes and thus reduces their side eects (by decreasing
drug entry into the cells of non-targeted tissues) and local irritation with no drastic loss of therapeutic benet.
In conclusion, due to their unique architecture and chelating
properties, CyDs are becoming important biotechnological
options in biocatalysis, in the encapsulation and controlled
release of molecules, and in many other pharmaceutical
applications.
Preparation of the Solid Complex
Flavour Fragr. J. 2010, 25, 313326
The Kneading Method

The guest compound, liquid or dissolved, is added to a slurry of
CyD and kneaded thoroughly (in a mortar) to obtain a paste
which is then dried. The solid thus obtained is washed with a
small amount of solvent such as ether or ethanol to remove the
adsorbed free guest component from the inclusion compound
and dried under vacuum. This method is particularly useful for
poorly water-soluble guests, since the guest dissolves slowly with
the formation of inclusion compounds.[99] With some molecules
reproducibility is poor and therefore it is unsuitable for largescale preparation.[75] This method gives a very good yield of inclusion formation.[100] An example is complex formation with
camomile essential oils.[62]
The Co-precipitation Method, Not Based on Phase Solubility
The guest is dissolved in diethyl ether, chloroform, benzene, etc,
and the appropriate amount of CyD dissolved in water is added
with agitation. On cooling crystallization occurs. The crystals are
washed with diethyl ether or another organic solvent and then
dried at 50C to yield a powdered sample.[6,101]
The method is useful for substances that are not water-soluble
but it results in poor yields since the organic solvents used as the
precipitant may competitively inhibit the inclusion.[6,52,102]
The Co-precipitation Method, Based on Phase Solubility
In this method the solid inclusion compound is isolated from the
saturated aqueous solution. The amounts of host and guest to be
mixed in water are estimated from the descending curvature of
BS-type phase-solubility diagrams,[57] i.e. where there is no more
undissolved guest and the CyD is still within its solubility limit.
These components are added to water and shaken until solubility
equilibrium is reached, or they are dissolved in hot water and
cooled slowly. The inclusion compound precipitates as a
microcrystalline powder and is separated by ltration and
dried.[52,101,103,104]
This method is not applicable to a system with an A-type phase
solubility diagram[57] because of the formation of a soluble inclusion compound. It is also unsuitable for large-scale preparations
as large quantities of water are used and it is time consuming[6,52,105,106] giving a low yield with some drugs.[103]
Heating in a Sealed Container
Nakai et al.[107] reported a method of heating the active compound (benzoic acid) and the host molecule (a- or g-CyD) in a
sealed container. A physical mixture was sealed in a container
after adsorbing a denite amount of water vapour, and then
heated to a temperature ranging from 43C to 142C. A crystalline
inclusion compound was produced when the container was
heated to over 70C. This method was also used under nitrogen
gas pressure; but the pressurized samples had a higher combination ratio than non-pressure samples. This method might be used
for thermostable volatiles, as guest molecules in the gaseous
state are better included into the CyD cavity.
321
There are several methods for obtaining CyDguest complexes

depending on the properties of the compound included and on
the nature of the CyD chosen. The physicochemical properties of
CyDs, including their ability to form complexes, may be greatly
aected by the type, number and position of the substituents on
the parent CyD molecule. The method of preparation can aect
the eectiveness of the complex.[56,99]
Complex formation is an enthalpy-driven process involving
expulsion of enthalpy-rich water molecules. Chemical modication of CyDs with charged substituents may lower complexation
by providing a hydrogen bonding source for the water molecules
that decreases the energy dierence between the included water
molecules and bulk of the solution. The presence of bulky, highly
charged, and hydrated sulfonate groups near the CyD cavity
entrance inhibits the approach of hydrophobic molecules. On the
other hand, increasing the distance between the charged substituents on the CyD torus by spacer groups reduces the steric
interference and raises the CyD binding potential, the eect is
also sensitive to the substrate structure.[47,56]
H. Marques
GasLiquid Method
Passing a vapour through a CyD solution hot or cold will
complex many solvents or other chemicals present. The complex
can either be separated by ltration or the volatiles recovered by
steam distillation.[87]
General Comments Regarding Methods of Preparation
Freeze-drying or Lyophilization
The guest molecule is dissolved in water using ammonia if necessary (for bringing slightly soluble, weakly acidic compounds
into aqueous solution), and then the CyD is dissolved with stirring
in the required proportion. The mixed solution is freeze-dried and
then washed with diethyl ether and the residue dried under
vacuum.[52,102,108,109] In certain circumstances the last two steps can
be omitted.[110112]
This method is more suitable for water soluble guests, since
CyDs and guests should be dissolved in water before drying, or
for thermolabile drugs.[6] It produces a powdered sample in a very
good yield of inclusion formation and it is possible to scale up the
procedure.[100,102]
Spray-drying
Amounts of guest molecule and CyD are dissolved in deionized
water. Small quantities of solvent (ammonium hydroxide or
ethanol or other co-solvents) may be used in order to obtain
limpid solutions before drying. Once the solutions are transparent, they are atomized into a drying chamber with a spray nozzle.
The spray-dryer is operated under the most appropriate conditions (e.g. inlet temperature, sample feeding speed) to the system
in use.[108,113,114] This method is only used for thermostable molecules as temperatures of 5070C are used.
The preparation method most often used for a complex consists

of stirring or shaking the aqueous solution (cold or warm, neutral
or acidic) of CyD together with the guest molecule or its solution.
After equilibrium has been attained, water is eliminated by
freeze-drying, spray-drying, or by any other convenient method.
However, most frequently, the microcrystalline product is separated by ltration.[99]
When added in small amounts, water-soluble polymers or ion
pairing agents enhance the CyD solubilizing eect by increasing
the apparent complex stability constant.[117] Certain additives
may compete with the guests for CyD cavities and thus decrease
the apparent complex stability constant, e.g. additives with positive and negative hydrotropic eect.[56]
The inclusion compound prepared by any of the above
methods should be analysed for its composition (e.g. guest : host
ratio and water content) because the stoichiometry sometimes
varies depending on the preparation conditions, particularly for
preparations on an industrial scale.[99]
Commercial availability[118122] and price as well as the regulatory status are some important considerations for CyD selection
in industry.
Evidence for Complex Formation

In order to conrm the formation of complexes, the interaction
between a guest molecule and CyD can be studied by a number
of methods.[99]
Supercritical Fluid Technology
322
Supercritical (SC) uid technology is a unique concept

that exploits the solvent properties of SC uids above their
critical temperature and pressure conditions. Near the critical
point, SC uids possess liquid-like densities and gas-like transport properties.[108]
This technology is an interesting approach in order to prepare
guestCyD solid complexes with fewer processing steps, avoiding the use of dangerous ammonium hydroxide and other solvents. Thus, residual solvent removal is not necessary.
CO2 is the solvent of choice for many reasons. It is (a) inert and
non-corrosive, (b) non-ammable and non-explosive, (c) abundant and inexpensive, (d) non-toxic, and (e) has desirable physical
properties such as low Critical temperature (Tc; 31C) and low
Critical pressure (Pc; 73.8 bar), low viscosity, low surface tension,
and high diusivity. But it has limitations in its ability to dissolve
many guests because it is a non-polar solvent. The addition of
small amounts of co-solvents such as ethanol, also known as
entrainers, can have dramatic eects on its solvent power.
A mixture of CO2 and ethanol (2.5%) is previously prepared in a
stainless steel cylinder. The high-pressure cell is charged with a
mixture of guest and CyD and immersed in a thermostated silicone bath (62C) and is internally stirred using an ecient stirring
device. The mixture in the cylinder is pumped into the system by
means of a liquid pump up to the desired pressure (e.g. 160 bar).
The system is slowly vented in a continuous mode. The powder
obtained is washed with fresh high-pressure CO2 to remove the
ethanol before depressurizing.
The use of SC uid CO2 as a processing medium for CyD

complex formation is discussed in the literature.[108,115] b-CyD
inclusion complexes with carvacrol, thymol and eugenol, and
also citral avours were prepared by the SC-CO2 technique[88,116]
and also b-farnesene and matricine.[84]
Nuclear Magnetic Resonance Spectroscopy

The most direct evidence for the inclusion of a guest into the
apolar CyD cavity in solution has been obtained by nuclear magnetic resonance (NMR) spectroscopy which reveals guestCyD
interactions. This technique has been employed since the 1970s
to CyDs complex formation[51,123] describing a 1H-NMR method for
examining the mode of interaction of b-CyD with a variety of
aromatic substrates. If a guest molecule is incorporated into
the CyD cavity, the hydrogen atoms located in the interior of the
cavity (C-3-H and C-5-H) will be considerably shielded by the
guest molecule and show a signicant upeld shift,[123,124]
whereas the hydrogen atoms on the outer surface (C-2-H, C-4-H
and C-6-H) will be unaected or show only a marginal upeld
shift.[20] Those of the drug display a corresponding downeld
shift.
This technique has been used to detect the CyD inclusion of
numerous substrates: salbutamol,[111] benzene derivatives,[125] azo
dyes,[126,127] carvacrol, thymol and eugenol (components of essential oils of vegetable origin),[88] and fragrance materials (linalool
and benzyl acetate).[59]
From 13C-NMR spectra (which may be obtained in aqueous
solutions) it can be determined which atoms of the guest molecule are involved in stabilizing the complex and also how they
are oriented. Some guests to which this technique has been
applied are azo dyes.[126,127] The more intense the interaction
Flavour Fragr. J. 2010, 25, 313326

between the guest molecule and the wall of CyD cavity, the
higher are the shifts of the carbon atoms involved.
The application of 13C-NMR techniques for the analysis of solid
samples is measurable by means of the cross-polarization magicangle spinning technique with high-power proton decoupling.
Such spectroscopy can give insights concerning the dynamic
properties of the inclusion compound in the solid state, whereas
X-ray diraction studies can provide only static details.[52,128,129]
Visible and Ultraviolet Spectroscopy
Sometimes complex formation with CyD alters the original visible
or ultraviolet (UV) absorption spectrum of the guest; usually a
bathochromic shift and/or band broadening occurs. The shift of
the UV absorption maximum on complex formation may be
explained by a partial shielding of the excitable electrons in the
CyD cavity.[130] High electron density inside the CyD cavity
mobilizes the electrons of the entrapped guest molecule.[20]
This phenomenon has been observed in literature for
8-anilinonaphthalene-1-sulfonate,[131]
naphthalene[132]
and
naproxen.[108]
Optical Methods
Further useful methods for the investigation of complex formation are optical rotatory dispersion (ORD) and circular dichroism
(CD). Complexes from chiral but non-absorbing CyDs and an
achiral but light-absorbing molecule must be both chiral and
light-absorbing.[20,130] This interaction results in new peaks in the
CD spectra of CyDs[102] and distinct features of the ORD spectra
known as Cotton eects. In ORD the rotation of polarized light is
measured as a function of wavelength whereas in CD it is the
molecular ellipticity (the dierence between the molecular
extinction coecients of a compound measured with both left
and right circularly polarized light). According to the symmetry
rule, the sign of the induced Cotton eect is determined by the
conguration of the chiral centre and its position relative to the
excited chromophore.[20,130] However, these eects can be attributed partially to the optical activity of the guest molecule
induced by inclusion complex formation[133] and partially to conformational changes of the CyD cavity.[134] According to Bergeron
et al.[135] and Bergeron and McPhie,[136] the observed changes in
optical rotation are mainly due to the induced optical activity of
the guest molecule. CD spectra can give conclusive proof of
complex formation in aqueous solution, a Cotton eect only
being observed when the guest molecule is really included in the
CyD cavity.[20,129,130] Accordingly, observed changes in absorption
spectra aord insucient evidence for complex formation; they
may only indicate the formation of association complexes. The
stereostructure of the guest molecule determines both the intensity and sign of the bands in the CD spectrum. If the electric
dipole moment coincides with the axis of CyD (i.e. axial inclusion)
a positive Cotton eect is observed and if they are perpendicular
to each other (i.e. equatorial inclusion), a negative Cotton eect
occurs.[133] CyDfragrance materials (linalool and benzyl acetate)
inclusion complexation was conrmed using CD spectroscopy.[59]
Fluorescence Spectroscopy
Flavour Fragr. J. 2010, 25, 313326
Phase Solubility
Organic compounds, which are sparingly soluble in water, frequently display an increased aqueous solubility in the presence
of CyDs. This is due to the formation of a water soluble complex
between the guest molecule and the dissolved CyD. Complexation lowers the thermodynamic activity of the dissolved molecule. Consequently, more guest dissolves until its activity, which
is in chemical equilibrium with the complex, becomes equal to
the thermodynamic activity of the pure undissolved molecules.
Estimation of the complex-forming ability of CyDs by the phase
solubility method is conducted according to the procedure
described by Cohen and Lach[140] or Higuchi and Connors,[57]
and has been applied to large range of compounds. Some
examples are salbutamol,[110] camomile essential oil and pure
a-bisabolol.[62]
The existence of an inclusion complex in aqueous solution
does not guarantee the existence of the same complex in the
crystalline state. Therefore, after separating the powder-like
product it must be determined whether it is an inclusion complex
or only a simple mixture of the guest and host molecules.[20]
Infrared Spectroscopy
Certain types of complex formation may be demonstrated by
infrared spectroscopy including the Fourier transform IR (FT-IR)
spectra. Bands due to the included part of the guest molecule are
generally shifted or their intensities altered, but since the mass of
the guest molecule does not exceed 515% of the mass of the
complex, these alterations are usually obscured by the spectrum
of the host. Owing to similar reasons, no useful results can be
obtained in the far IR region. However, in certain cases spectroscopic changes indicating complex formation can be observed;
carbonyl stretching bands that appear between 1650 cm-1 and
1700 cm-1 are shifted in the inclusion complex.[141] For example,
the carbonyl stretching bands (about 1700 cm-1) of
p-hydroxybenzoic acid esters are shifted 40 cm-1 to a higher
wavenumber in the inclusion compound, since the intermolecular hydrogen bonding of the guests is disrupted and they are
then mono-molecularly dispersed in the host cavity. Similar shifts
were observed for benzoic and p-hydroxybenzoic acids,
p-acetoxydiphenyl.[107,125] The FT-IR drug spectrum KBr discs in the
4000500 cm-1 region presents a band at about 1730 cm-1 due to
carbonyl stretching.[108] FT-IR proved to be suitable for the identication of carvone and limonene, volatile constituents of
caraway essential oil.[85] Rodriguez-Tenreiro et al.[142] have studied
the interaction between CyDs and carbopol by this method.
Dierential Scanning Calorimetry
CyD complex formation can also be observed by dierential scanning calorimetry (DSC), as an endothermic peak can be observed
for the molecule (at the temperature of its melting point or
boiling point) and for the physical mixture but will be absent for
the complex.[129151] Evidence of complex formation has been
obtained using DSC for limonene and carvone[85] and nonvolatiles, salbutamol[110] and naproxen.[108] The interaction
between CyDs and carbopol has been studied by DSC.[142]
323
Since the uorescent properties of many molecules are highly

dependent on environment, uorescence is a potentially useful
method for determining complexation geometry.[137,138] For
example, uorescence intensity increases considerably (10-fold)
if CyD is added to an aqueous solution of 1-anilinonaphthalene8-sulfonate. Complex formation results in a higher uorescence
quantum yield, and the emission maximum is shifted towards
shorter wavelengths.[139]
H. Marques
Vacuum Methods
The simplest way of detecting complex formation with subliming
materials is to subject the material in the supposedly complexed
state to vacuum sublimation or vacuum drying. The material not
bound in the complex sublimates easily, but the included material does not leave the complex below the degradation temperature (about 200C) of CyD. Szejtli[141] reports the volatility of the
included molecule may be several orders of magnitude lower
than the free molecule. This method is suitable if the guest molecule is a liquid and the boiling point is not too high, such as
essential oils and volatiles.[62]
X-ray Diraction
Powder X-ray diractometry is a simple and useful method for
the detection of CyD inclusion compounds in powder or microcrystalline states. The diraction pattern of the inclusion compound is clearly distinct from the superposition of each
component if a true inclusion compound exists.[52,112] In the case
of liquid guest molecules (e.g. oils and volatiles) X-ray powder
diraction is the most useful method for the detection of inclusion complex formation. Since the liquid guest molecules
produce no diraction patterns at all and if the diractogram
diers from that of uncomplexed CyD, then the formation of a
crystal lattice of a new type, i.e. the fact of complex formation,
can be established.[20,141] In the case of crystalline guest molecules
the X-ray powder diraction pattern suggests complex formation
only if some of the bands characteristic of isolated b-CyD are
missing or if other characteristic reection bands appear that
originally were missing from the X-ray diagrams of both the CyD
and the guest molecule.[20]
This method has been useful for chamomile oil and other
essential oils[143] such as thymol and Lippia sidoides Cham essential oil extract.[144]
Chromatography
324
Thin-layer chromatography may also be useful for the verication

of complex formation, since this process alters the RF values considerably. They are usually greatly reduced, provided that the
complex is suciently stable in the solvent mixture used. The RF
value obtained with a physical mixture is between the RF of the
pure guest molecule and that of the complex,[141] e.g. warfarin.[145]
Another approach is the use of TLC on cellulose developed
with aqueous CyDs eluents for the study of the complexation of
various avonoids with CyDs and CyD derivatives.[95] The results
indicated that the avonoids examined did not complex readily
with a-CyD or with succinylated a-CyD. However, avonoids do
complex with b-CyD, succinylated b-CyD, succinylated g-CyD, and
a-, b- and g-CyD polymers. With g-CyD elongated trails were
obtained, suggesting that the formation kinetics are slower.
Head-space gas chromatography is a specic method used for
volatile compounds; complex formation can be proved by the
reduction of the volatility of the compounds under complex
form.[146149]
In the thermo-analytical system (TAS) the sample is heated in a
sealed glass tube equipped with a capillary outlet. The products
in the vapour or gaseous state, leave through the capillary tube
then condense directly onto a thin-layer chromatographic plate.
On shifting the plate gradually, volatile products liberated at different temperatures are deposited at dierent sites along the
start line of the plate. Upon developing the plate the number and
type of components volatilized at dierent temperatures can be

determined. In the case of volatile materials this method is useful
for establishing the formation of a complex and investigating its
stability.[102,141]
Mass Spectrometry
Mass-spectrometric (MS) investigations have shown that the
characteristic peaks of a drug with a boiling point below the
decomposition temperature of the CyD when complexed appear
only with the degradation products of the CyD.[141] Liquid chromatography (LC)/MS was used to show that in the presence of
DM-b-CyD and after photo-irradiation of protriptyline, the
epoxide formation was suppressed.[150]
Monitoring the products of the thermal fragmentation of
parent CyD and the included molecule(s), applying the thermogravimetry (TG)-MS combined technique provides evidence for
inclusion complex formation. b-CyD inclusion complexes of
thymol and Lippia sidoides Cham essential oil extract have been
prepared and investigated using conventional and combined
(TG-MS) thermoanalytical techniques and the formation of an
inclusion complex was proved.[144]
Other Thermal Methods
Dierential thermal analysis (DTA) is very similar to DSC. It can be
appreciated that due to the sensitivity of the technique, any
change in the crystalline state of a material will be detected. This
lends itself very readily to the detection of inclusion complexes,
and it has been shown that vitamin D3 forms an inclusion
complex with b-CyD,[102] and thymol and Lippia sidoides Cham
essential oil extract form an inclusion complex with b-CyD.[144]
Sztatisz et al.[151] showed that thermal gravimetric analysis
(TGA) and evolved gas analysis (also called thermal evolution
analysis (TEA)) are the most suitable for analysing HBr and volatile
oilb-CyD complexes, respectively. Uekama et al.[152] used TGA
and showed that the volatility of various cinnamic acid derivatives was lowered by the formation of b-CyD inclusion complexes. Szente et al. [143] and Stadler-Szke et al.[153] used TEA to
show b-CyDmenthol (and other essential oils) and PGI2Me
complex formation, respectively. Lippia sidoides Cham essential
oil extract (thymol, carvacol, p-cimene, cis-cariophyllene,
g-terpinene, mircene and other terpens) b-CyD complexes are
other examples.[144]
Conclusions
Encapsulation is a method of protecting food ingredients that are
sensitive to temperature, oxidation, moisture, microorganisms,
etc. The use of CyDs in foods and beverages has increased signicantly in the last few years, as they are highly recommended for
applications in food processing and as food additives.
Essential oils and volatile compounds can be encapsulated in
CyDs in order to improve water solubility, avoid oxygen-, light- or
heat-induced degradation and loss during processing and
storage, and to stabilize fragrances, avours and essential oils
against unwanted changes. Moreover, the use of CyDavour
inclusion complexes allows the use of very small amounts of
avours. On the other hand, CyDs can also be used for deodorizing and removing undesirable components such as o-avours
or bitter components present in the foods and beverages in their
natural forms, suppressing unpleasant odours or tastes. CyDs
Flavour Fragr. J. 2010, 25, 313326

may also be used to achieve controlled release of certain food
and beverage constituents. The food ingredient is released at the
desired site and time at a desired rate by a change in temperature, moisture or pH.
Another interesting application of CyDs is their incorporation
in the food packaging materials as antiseptic or preserving
agents.
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A Review On Cyclodextrin Encapsulation of Essential Oils and Volatiles

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A review on cyclodextrin encapsulation of

Available from: Helena Marques

Revised: 30 June 2010;

Accepted: 2 July 2010;

Published online in Wiley Online Library

(wileyonlinelibrary.com) DOI 10.1002/j.2019

A review on cyclodextrin encapsulation of

Flavour Fragr. J. 2010, 25, 313326

* Correspondence to: Helena Ma Cabral Marques, Faculdade de Farmcia da

Copyright 2010 John Wiley & Sons, Ltd.

Cyclodextrins (CyDs) were rst isolated in 1891 by Villiers[1] as

CyDs with fewer than six glucopyranose residues do not exist,

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Copyright 2010 John Wiley & Sons, Ltd.

Approved for dietary supplement

Novel food, 2003

Novel food, led January 2010

Approved for dietary supplement

ADI = not specied 1999 and 2000

ADI = not specied June 2001 and June 2004

Table 1. Food approval status of CyDs (adapted from Winterhalter[26])

These starch derivatives are non-toxic ingredients, are not

Flavour Fragr. J. 2010, 25, 313326

Cyclodextrin encapsulation of oils and volatiles

Flavour Fragr. J. 2010, 25, 313326

The toroidal structure of b-cyclodextrin

In order to improve the aqueous solubility of this material, the

The Formation of CyclodextrinGuest

Copyright 2010 John Wiley & Sons, Ltd.

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engineering CGTases, together with other technological and

Table 2. Some important characteristics of CyDs[37]

No. of glucose units

The stereochemistry and, possibly, the polarity of both the host

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microheterogeneous hydrophobic matrix in such polar solvents;

Evaluation of Inclusion Complexation:

where kr (M-1 s-1) is the recombination rate constant and kd (s-1) is

Copyright 2010 John Wiley & Sons, Ltd.

Flavour Fragr. J. 2010, 25, 313326

Cyclodextrin encapsulation of oils and volatiles

Figure 4. Phase solubility proles and classication of complexes

Flavour Fragr. J. 2010, 25, 313326

where S0 is the intrinsic solubility of the substrate on the medium.

Copyright 2010 John Wiley & Sons, Ltd.

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Table 3. Flavour content in b-CD complexes[64]

Flavour load of complex (%)

Carrier et al.[63] in an exhaustive examination study involving

CyDs as multifunctional food ingredients can be utilized mainly

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materials from one another, reduce material toxicity, provide

Copyright 2010 John Wiley & Sons, Ltd.

Flavour Fragr. J. 2010, 25, 313326

Cyclodextrin encapsulation of oils and volatiles

Flavour Fragr. J. 2010, 25, 313326

Copyright 2010 John Wiley & Sons, Ltd.

View this article online at wileyonlinelibrary.com

These inclusion complexes have a good reputation for their

avoid the destruction of certain avours, colours or vitamins

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stabilize emulsions and suspensions