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the α, β and γ Cyclodextrins
A thesis submitted for the partial fulfillment of the
M. Sc. (Drug Chemistry) Degree
By
Mr. BALTE ANUP SATISH
Under the guidance of
Prof. Shridhar P. Gejji
Department of Chemistry
University of Pune
Pune 411007
( June 2007 )
CERTIFICATE
This is certify that Mr. Balte.Anup Satish has completed the Project work entitled
“Theoretical studies on the encapsulation of Paracetamol in the α, β and γ
Cyclodextrins,”, under guidance of Prof. Shridhar P. Gejji for the fulfillment of the
Master’s Degree in Drug Chemistry during the academic year 200708, the report of
which submitted to the Department of Chemistry, Ahmednagar College, Ahmednagar.
  
Prof. Shridhar P. Gejji, Dr.V.V.KHANNA
Project Guide, Coordinator,
Department of Chemistry, Department of Drug Chemistry,
University of Pune. Ahmednagar College, Ahmednagar.
ACKNOWLEDGEMENT
It gives me immense pleasure to present my project and I take this opportunity to thank all those
who were of great help to me during my project work. I would like to express my sincere gratitude to
my guide, Prof. S. P. Gejji for his timetotime guidance, enthusiastic interest, support and constant
encouragement throughout the course. I profess my heart full gratitude to Dr. V.V.Khanna, Co
ordinator of Drug Chemistry, Ahmednagar College, Ahmednagar for giving me this great chance to
complete this project. I am also thankful to Dr.S.R.Thopate and S.V.Rohokale of Ahmednagar college.
My sincere thanks to Mr.Rahul Pinjare for his assistance in computations without whom I
would not be able to present this work. I would like to thank my coworker Mr. Thorat Sachin.M for
his constant support and cooperation in my work.
Finally, I would like to thank my parents who gave me constant moral support and
encouragement.
Balte .Anup.S
CONTENTS
CHAPTER 1: INTRODUTION
1.1 Preamble
1.2 Born – Oppenheimer approximations
1.3 Molecular Mechanics method
1.4 Schrodinger equation
1.5 Ab initio methods
1.6 Hartree –Fock Theory
1.7 semi – Empirical methods
CHAPTER 2:
2.1 Motivation
2.2 Cyclodextrin as Hosts
2.3 Paracetamol as guest
2.4 Methodology
2.5 Computational method
CHAPTER 3:
3.1 Results and Discussion
3.2 Conclusion
3.3 References
Chapter : 1
CHAPTER1
Introduction
1.1 Preamble
Modern computational chemistry has proven to be a useful tool in a variety of chemical problems and
have gained popularity to an extent such that the inherent empirical nature of chemistry seemed to be
lost in the recent years. These computational chemical methods find a variety of applications in
structure, spectroscopy and dynamics. These methods are classified as (a) Molecular mechanics
methods (b) ab initio methods (c) Semiempirical methods and (d) density functional methods. The
basis principles and the approximations underlying these theories are given in the following subsection.
1.2 Born – Oppenheimer approximation
In 1927, Born and Oppenheimer (BO) proposed an approximation
that led to a major leap towards a
practical solution to the Schrödinger equation. The Born–Oppenheimer approximation is based on the
notion that the nuclear and electronic motions take place at different time scales the latter being much
smaller than the former. Hence an electron in motion sees relatively static nuclei while a moving
nucleus feels averaged electronic motion. This enables one to separate the electronic and nuclear
Hamiltonians and the corresponding wavefunctions as well. The molecular wavefunction can then be
represented as a product of electronic and nuclear counterparts.
( ) ( ) ( ) } { Φ } };{ { Φ } };{ {
A nuc A i elec A i
R R r R r · Ψ
(1.1)
Here {r
i
} and {R
A
} are the positions of electrons and nuclei respectively. The eigenvalue equation for
the electronic case is then written as
( ) ( ) } { }; { E } { }; {
A i elec elec A i elec elec
R r R r H Φ · Φ
(1.2)
The electronic Hamiltonian depends explicitly on the electronic coordinates and parametrically on
nuclear coordinates. Since the chemical phenomena occur primarily due to various interactions
between electrons of the systems, explicit treatment of the electronic Hamiltonian generally suffices to
investigate chemical properties and reactions. However, probing the vibrational, rotational and
translational motions of molecules would further require an explicit treatment using the nuclear
Hamiltonian.
Simplified and convenient electronic Hamiltonian (excluding the internuclear repulsion) in atomic
units is as shown below.
∑∑ ∑∑ ∑
· > · · ·
−
+
−
− ∇ − ·
N
1 i
N
i j
j i
N
1 i
M
1 A A i
A
N
1 i
2
i elec
1 Z
2
1
r r R r
H
(1.3)
The first term is the electronic kinetic energy operator summed over the number of electrons ‘N’ while
the second term represents coulombic attraction between electrons {i} and M nuclei {A}, where {Z
A
}
are the nuclear charges. The last term attributes to the Coulombic repulsion between electrons. Once
the wavefunction Ψ is obtained by solving the Schrödinger equation, any experimental observable can
be computed as the expectation value of appropriate operator,
Ψ ΨΟ
. In the case of total electronic
energy, the operator is electronic Hamiltonian.
1.3 Molecular Mechanics Methods
The molecular mechanics (MM) methods treat molecules as classical objects made of hardsphere
atoms and springlike elastic bonds. The calculation of energies and properties involve empirical
parameters and employ classical equations of motion. A force constant obtained from existing
empirical data or from accurate ab initio treatment defines the behavior of bonds between specific pairs
of atoms. Similarly, several empirical parameters are used to arrive at the energy of the system as
contributions due to bonds, angles, torsions, van der Waal type interactions and electrostatic
interactions as shown below.
E
total
= E
l
+ E
θ
+ E
w
+ E
nb
(1.4)
where
E
l
= bond length energy
E
θ
= angle bond energy
E
w
= dihedral bond energy
E
nb
= non bonded energy
Contribution from bond stretching is given by Morse function
E
l
= ∑ D
e
[1 – exp { α (l – l
o
)}
2
(1.5)
where
D
e
= dissociation energy
α = force constant
l
o
= equilibrium bond length
In the simplest form of simple harmonic function is given as
E
l
= ∑ k
l
( l – l
o
)
2
(1.6)
where k
l
is mathematical parameter
Bond angle has been treated similar to bond length. Contribution of bond angle is given by
harmonic function.
E
θ
= ∑ k
θ
( θ – θ
o
)
2
(1.7)
where
θ
o
= equilibrium value
k
θ
= mathematical parameter.
The functional form if the dihedral angle is given in terms of Fourier series
E
ω
= ∑ V
n
(1 + s cosnω ) (1.8)
where
V
n
= is rotational barrier height
n = periodicity of rotation
Nonbonded interaction – Nonbonded interaction has two components.
van der Waal
Electrostatic
Functional form of van der Waal interaction is
E
vdw
= Σ∈[(r
m
/r)
12
–2(r
m
B/r)
6
] (1.9)
where
∈ = well depth
r
m
= minimum energy insulation distance
r
12
= short range repulsion
r
–6
= London dispersion attractive force
It is commonly called as 6 – 12 or Lennard – Jones potential.
For sterically crowded structures the equation 1.13 rewritten as
E
vdw
= A exp (Br)  Cr
6
(1.10)
The second component of nonbonded interaction is the electrostatic. In this case energy is calculated
using coulomb’s law.
E
el
= ∑ q
i
q
j
(1.11)
∑
,
`
.

−
,
`
.

·
10
ij
ij
12
ij
ij
hb
r
E
r
c
E
D
rij
where
D = Dielectric constant
r
ij
= distance between two charges
In some cases all the above terms constitute and describe the energy function but in many
situations, it is necessary to include the additional term like hydrogen bonding, planarity of isolated
unsaturated center.
The contribution of hydrogen bonding is
(1.12)
Planarity is maintained by a simple restraining force.
E
opl
=∑k
χ
. χ
2
(1.13)
where
k
χ
= mathematical parameter
χ = height above the plane formed by other 3 atoms
There are several sets of force fields (FF) that define these parameters for a given atom and
atompair. The MM method does not treat electrons explicitly and the FF implicitly includes the
electronic contributions. The MM method is an inexpensive computational method and hence can be
used to study chemical systems with several thousands of atoms. However, there is a compromise in
the accuracy of results from such calculations that are solely dependent on the FFs used. Reliable
energies can be only obtained by using extensive parameterization over a class of compounds. The
currently popular FFs include AMBER
,
OPLS, CHARMm, Dreiding, UFF etc. The FFs are obtained by
fitting the experimental or ab initio results and hence suffer from transferability to other systems.
Further, MM methods cannot be employed to investigate chemical problems where electronic effects
dominate.
1.4 Schrödinger equation
The eigenvalue equation proposed by Erwin Schrödinger is the basis of quantum chemistry. The time
independent Schrödinger equation can be expressed as
HΨ=EΨ
This is a second order linear equation homogeneous differential equation. H is the Hamiltonian
operator comprising of the nuclear and electronic kinetic energy operators and the potential energy
operators corresponding to the nuclearnuclear, nuclearelectron and electronelectron interactions. The
manyparticle wavefunction Ψ describes the system. Ψ is the mathematical function of the coordinates
of all electrons and nuclei constituting the molecule. The wavefunction should be wellbehaved i.e. it
should be continuous, single valued, finite, gradient of Ψ should be continuous and it should be square
integrable. E is the eigenvalue that is the energy of the system.
1.5 Ab initio methods
The goal of our calculations on a particular molecular system is to solve the nparticle time
independent Schrödinger equation. Manybody problems of this kind cannot be solved exactly. As a
simplification the independent particle model is introduced and thereby the problem reduces to solving
an nsingle particle equation. Thus an effective one electron Hamiltonian is applied to a set of single
particle wavefunctions, expanded in a suitable basis, and the total energy is minimized using variation
principle, which is precisely what is done in HartreeFock formulation. Other ab initio methods include
Configuration Interaction (CI), Multi configuration SelfConsistent Field (MCSCF), Coupled Cluster
(CC) etc.
1.6 HartreeFock Theory
The HartreeFock approximation forms the crux of computational and quantum chemistry. For defining
an electron completely, in addition to the spatial coordinates the spin of electron is also required. The
notion of electronic spin is introduced in the oneelectron wave function (orbital) by means of the spin
functions α(ω) and β(ω) that correspond to the up and down spin electrons respectively. This leads to
the spin orbitals, {
j
χ
} defined below.
) ( ) ( ψ ) ( χ
α
i 1 2i
ω α ·
−
r x
(1.14)
) ( ) ( ψ ) ( χ
β
i 2i
ω β · r x
(1.15)
where each electron is defined in terms of combined spatial and spin coordinates, x.
To satisfy the Pauli’s exclusion principle and the principle of antisymmetry, a Slater
determinant is used. An Nelectron wavefunction (Slater determinant) is given by
) x ( χ )... x ( χ ) x ( χ
. ... . .
) x ( χ )... x ( χ ) x ( χ
) x ( χ ... ) x ( χ ) x ( χ
N!
1
) x ,...., x , x ( Ψ
N N N j N i
2 N 2 j 2 i
1 N 1 j 1 i
N 2 1 HF
·
(1.16)
where ! N 1 is the normalization constant. The normalized Slater determinant can also be represented
in a shorter notation as
k j i N 2 1
χ ..... χ χ ) ....., , Ψ( · x x x
(1.17)
The expectation value for the total electronic energy of a system written in braket notation is given by
∑∑ ∑
<
+ · Ψ Ψ ·
a a b a
0
ab ab a h a H E
(1.18)
In the above equation, the first term corresponds to oneelectron integrals comprising of nuclear
electron attraction energy and kinetic energy of electrons. The second term is the electronelectron
repulsion integral. The indices a and b refer to occupied molecular orbitals (MOs).
Using braket notations introduced by Dirac the above one and twoelectron integrals can be
expressed as
∫
χ χ · ) ( ) ( ) ( d j i
1 j 1 1 1
*
i 1
x r h x x
(1.19)
∫
χ χ χ χ ·
−
) ( ) ( ) ( r ) ( ) ( d d kl ij
2 l 1 k 1
1
12 2
*
j 1
*
i 2 1
x x r x x x x
(1.20)
lk ij kl ij kl ij − ·
(1.21)
The essence of HF theory in its simplest form is in finding the best approximation to the ground sate of
a many electron system in the form of a Slater determinant, which minimizes energy of the system
given in Eq. (1.9). The minimization is carried out within the framework of variation principle i.e. the
expectation value of energy for a wellbehaved trial function, obeying appropriate boundary
conditions, is never lower than the corresponding energy obtained from an exact wavefunction.
0 0
0 0
0
trial trial
trial trial
E E
Ψ Ψ
Ψ Ψ
· ≥
Ψ Ψ
Ψ Ψ
·
H H
(1.22)
Here Ψ
trial
and Ψ
0
are the trial and exact wavefunctions respectively of the system while E is the
expectation value for Ψ
trial
and E
0
the corresponding exact HF energy. Thus the best possible estimate
for energy has been obtained by minimizing E with respect to the spin orbitals {χ
i
} with a constraint of
orthonormality
ab b a
δ · χ χ
(1.23)
Such a minimization leads to the HF equations:
) ( ) ( ) i (
i i
x x εχ · χ f . (1.24)
where f(i) is the effective oneelectron operator called the Fock operator and ε is its eigenvalue
(energies of spin orbitals). The success of HF method is in replacing the exact electronelectron
interaction by an effective electron repulsion potential υ
eff
, which is essentially a oneelectron operator.
The Fock operator is defined as
[ ]
∑
− + · υ + ·
a
a a
eff
) i ( ) i ( ) i ( ) i ( ) i ( ) i ( K J h h f
(1.25)
The first term is the oneelectron operator, called the coreHamiltonian and is a sum of kinetic energy
and nuclearelectron attraction energy operators, while J
a
and K
a
are the Coulomb and exchange
operators, respectively. The Coulomb operator gives the electronelectron repulsion energy and the
exchange operator provides lowering of energy due to correlation between electrons of same spin, an
artifact of the determinantal wavefunction. The operators J and K are defined by their operation on
oneelectron functions.
[ ] ) 1 ( ) 2 ( r ) 2 ( d ) 1 ( ) 1 (
b a
1
12
*
a 2 b a
χ χ χ · χ
∫
−
x J
(1.26)
[ ] ) 1 ( ) 2 ( r ) 2 ( d ) 1 ( ) 1 (
a b
1
12
*
a 2 b a
χ χ χ · χ
∫
−
x K
(1.27)
It may be seen that the operators, J and K, themselves are dependent on the eigenfunctions, the spin
orbitals {χ
i
}. Hence, the HF equation is termed as pseudoeigenvalue equation. In the matrix notation
it is written as
i i i
χ ε · χ f
(1.28)
Here, {ε
i
}, the eigenvalues of Fock operator and denote the energies of spin molecular orbitals.
Solving the equation results in a set of canonical spin orbitals that are delocalized and reflect the
molecular symmetry
For computational calculations, the MOs are expanded as linear combinations of suitable basis
functions. The equation
i i i
χ ε · χ f
takes the form of RoothaanHall equation, which is
ε SC FC ·
(1.29)
Moving from spin orbitals to MOs represented by basis functions, the elements of the Fock Matrix F
are given by
[ ]
∑
− + ·
2 / N
a
a a
) 1 ( ) 1 ( 2 ) 1 ( ) 1 ( K J h f
(1.30)
The coefficient matrix has the form shown below
,
`
.

·
kk 2 k 1 k
k 2 22 21
k 1 12 11
C C C
C C C
C C C
C
(1.31)
where k denotes the number of basis functions in the system. The overlap matrix S (between different
functions of the basis) has elements S
μν
defined by
1
3 *
r d ) 1 ( ) 1 ( S
∫
ν µ µν
φ φ ·
(1.32)
Since the RoothaanHall equation is also a set of pseudo eigenvalue equations, it needs to be solved
iteratively. Initially spin orbitals have been chosen using a proper basis set. Solving the HF equation
with the corresponding Fock matrix generates a new set of orbitals. The iterations are continued until
the orbitals are converged and the electronic energies in two successive iterations do not vary above a
predefined threshold, i.e. a selfconsistency in the field is achieved and hence this process is termed
selfconsistent (SCF) procedure.
1.8 SemiEmpirical Methods
Many semiempirical methods work within the framework of HF theory except that the laborious
integral evaluations involved in the HF theory are not solved rigorously. Instead, the two electron
integrals are obtained in terms of atomic parameters generated through fitting the results with
experimental data such as heats of formation, atomization energies etc. The PariserParrPople (PPP)
method is one such semiempirical method used for treating πelectron models. For solving the two
electron integrals generally the neglect of differential overlap (NDO) approximation is employed, using
different conditions to ignore orbital overlaps. The overlap (Eq. 1.33) and two electron (Eq. 1.34)
integrals within Zero Differential Overlap (ZDO) are given as
µν ν µ
δ φ φ = dv ) ( ) (
*
r r (1.33)
µν µν δ δ · λσ µν
νσ µλ
(1.34)
The NDO methods use extensive Parameterization. The core electrons are not treated explicitly;
instead a corecore repulsion function is used to represent them. The complete and intermediate
(CNDO
61
and INDO
62
) NDO methods and their variations were able to produce accurate orbitals and
properties like charge densities and dipole moments. The currently popular semiempirical methods
such as MNDO, AM1 and PM3 have minimal neglect of differential overlap and differ primarily in the
parameters used i.e. on the set of compounds used for fitting the parameters. In these models, the
differential overlap is ignored only if the orbitals are on neighboring atoms. They are very efficient
and the molecular geometries and properties produced by them are comparable with lowlevel ab initio
calculations.
Within MNDO framework, the Fock operator in the RoothaanHall equation becomes
∑ ∑ ∑ ∑
≠
+
]
]
]
− + ·
A on A B
core
P P H F
B on A on
)  ( )  (
2
1
)  (
ν λ σ
λσ µν µµ µµ
λσ µµ µν µν νν µµ
(1.35)
where
∑
≠
− ·
A B
B
core
V U H
µµ µµ µµ
∑ ∑ ∑
≠
+ − + ·
A B
core
P P P H F
B on A on
)  ( )  (
2
1
)  (
2
3
λ σ
λσ µν µν µν µν
λσ µµ νν µµ µν µν
(1.36)
where
∑
≠
− ·
A B
B
core
V H
µν µν
∑ ∑
− ·
B on
core
P H F
B on
)  (
2
1
λ σ
λσ µν µν
νλ µσ
(1.37)
where ) (
2
1
ν µ µν µν
β β + · S H
core
These RoothaanHall equations are solved selfconsistently.
In 1985, Dewar developed the Austin Model1 (AM1), which is a modified form of MNDO. Here, the
corecore term was modified using Gaussian functions, which were of both attractive and repulsive
type. In 1989, J. J. P. Stewart developed the Parameterization Method 3 (PM3), another modified
version of MNDO. Despite the use of more parameters, the accuracy level of AM1 and PM3 are almost
same.
A semiempirical method ‘PM5’  Parametric Model Number 5, has been employed in this study. It is a
simplified version of Hartree Fock theory that uses the empirical data to enhance the performance. It is
based on Neglect of Differential Diatomic Overlap (NDDO) wherein all the twoelectron integrals
involving twocenter charge distributions are neglected. A number of parameterization corrections are
made in these semiempirical methods using experimental data such as heat of atomization, atomic
mass of most abundant isotope, etc. PM5 is a reparameterization of PM3 and uses atomic as well as
diatomic parameters while PM3 uses only single atom parameter. PM5 is accurate enough to have
useful predictive powers and fast enough to be employed for large systems.
Chapter : 2
Chapter : 2
Defining the system:
The Cyclodextrins has a specific coupling of glucose monomers in cyclic manner giving a rigid
conical molecular structure with a hydrophilic exterior and hollow hydrophobic interior of a specific
volume. This internal cavity is capable of accommodating wide range of guest molecules including
polar as well as nonpolar aliphatic and aromatic compounds. The inside cavity of appropriate
dimension is conducive to binding to various guest molecules to form an inclusion complexes.
The paracetamol is a polar molecule. The width of molecule is 0.43nm and height is around
0.78nm. The molecule can be accommodated in all the three CDs. The complex of Paracetamol and
CDs is stable due to hydrogen bonding and hydrophobic interactions.
Motivation:
Paracetamol is widely studied as an analgesic & antipyretic drug. But they are not studied as a
guest molecule in a cyclodextrin cavity. In present work we are addressing the following questions.
1) How the guest (paracetamol) molecule orients itself in the cavity of α,β and γ cyclodextrins? 2)
Which types of interactions govern the encapsulation of guest in the cavity of CD? 3) How the
hydroxyl groups of CD and amide, hydroxyl group of Paracetamol interact to give stable inclusion
complex. 4) What are the binding energies of guest? 5) what are the energies associated with the
inclusion?
Cyclodextrins as Hosts
Cyclodextrins are the cyclic oligosaccharides made up of 6 or more α – D glucopyranose units
linked by 1→ 4 glycosidic linkages. These were firstly described by A .Villers in 1891.
There are mainly three types of cyclodextrines.
1) α cyclodextrines = made of six glucose molecules linked in ring.
2) β cyclodextrines = made of seven glucose molecules linked in ring.
3) γ cyclodextrines = made of eight glucose molecules linked in ring.
α, β, and γ cyclodextirnes
Cyclodextrin consist of 6,7,or 8 (α, β, and γ ) D – glucopyranose units connected by alpha (1 →
4) glycosidic linkages. The most stable threedimensional molecular configuration for these non –
reducing cyclic oligosaccharides takes the form of a toroid with the upper (larger) and lower (smaller)
opening of the toroid presenting secondary and primary hydroxyl groups respectively to solvent
environment. The interior of the toroid is hydrophobic as a result of the electron rich environment
provided in large part of the glycosidic oxygen atom.
Each glucose unit contain two secondary hydroxyl groups at C 2 and C 3 position and primary
hydroxyl group at C 6 position produces 18 to 24 sites for chemical modification and derivatisation.
Cyclodextines are synthesized from starch by easily available enzymes. Enzyme used is
cyclodextrin glucosytransferase (CGT ), along with α amylases. Starch is liquefied by heat treatment
or using α – amylase, then CGT is added for the enzymatic conversion. The product gives the mixture
of three main types of cyclic molecule.
Properties
1) Formation of host – guest inclusion compounds with lipophilic compounds.
2) Solubility:  soluble in water (low), DMF, DMSO, Pyridine.
3) Low toxicity.
4) Biodegradable.
Properties Alpha Beta Gamma
No. Of glucose units 6 7 8
Molecular wt 972 1135 1297
Solubility in water (g/cc) 14.5 1.85 23.2
pKa at 25°C 12.33 12.2 12.08
Inner diameter (nm) 0.45 – 0.57 0.62 – 0.78 0.79 – 0.95
Outer diameter (nm) 1.37 1.53 1.69
Height (nm) 7.9 7.9 7.9
Cavity volume 0.174 0.262 0.472
Crystal form Hexagonal plate Monoclinic
parallelogram
Quadratic prism
Complex formation is in stoichemtric ratio ( 1:1,1:2,2:1).complexation is Substrate unspecific.
Complexes with lower alcohols, amines or with compound contating heteroatom is easy. Complex
is stable in water solution. Compounds suitable for complexation are with low solubility and
boiling point < 250 ºC. Complexation improves molecules solubility and stability.
The ability of cyclodextrin to form inclusion complex with a guest molecule is a function of two key
factors:
1) Steric
Relative size of cyclodextrin to guest molecule molecule should be comparable.
If the guest is wrong size, it will not fit to cyclodextrin.
2) Thermodynamic interaction
There must be favorable net energetic driving force that pulls the guest into the cyclodextrin.
3) α cyclodextrin can from low molecular complex with aliphatic side chain, β will complex with
aromatic and heteorcycles, γ cyclodextrin can accommodate larger molecules such as macrocycles and
steroids.
Inclusion complexation with cyclodextrin is like a “hostguest interaction”. In this interaction
cyclodextrin act as host molecule and the drug molecule to be entrapped in host cavity act as guest
molecule. Comparing to other encapsulation methods, which involve entrapment of more than one
guest, cyclodextrin complexation involve entrapment of one molecule of guest in cyclodextrin cavity.
For formation of complex with cyclodextrin, variety of noncovalent forces like Vander wall forces,
hydrophobic interaction, and dipole movement are responsible. In majority of cases only a single guest
molecules is entrapped in the cavity. For High molecular weight molecules, more than one molecule of
cyclodextrins can bind to the guest.
Bonding in cyclodextrines
Cyclodextrins binds to guest molecule with bonding other than covalent bond. It is the interplay of
atomic (van der waals forces), thermodynamic (hydrogen bonding), and solvent (hydrophobic) forces
that count for the stable complexes, which may be formed with chemical substances in the apolar
environment of the cyclodextrin cavity. The complex exists in equilibrium dependent upon the
concentration of the cyclodextrin, the guest and water.
The bonding may break up with change in pH, temperature of solution, leading to cleavage of
hydrogen or ionic bonds between host and guest.
Cyclodextrin has vast applications in various fields.
Cyclodextrins can release the drug in the body (acts as a drug carrier). Cyclodextrin can be
employed for environment protection; they are used in food industry for preparation of cholesterol
free products.
They have ability to stabilize, the volatile or unstable compounds and the reduction of unwanted
taste and odour. It has strong ability to complex with fragrances i.e. used to eliminate bad smell. It
is used to solubilization of hydrophobic compounds. Separation of compound in the form of
complexes can also be done. Controlled release of compound (drugs, fragrances) is also possible.
Stabilization of reactive compounds.
In pharmaceuticals they are used to enhance the rate of dissociation of drug. More complete
and faster absorption after oral application is possible. Enhancement in drug absorption independently
of the acidity of the gastric juice. Reduced side effects. Reduce skin irritation and, muscular tissue
damage. Reduced kidney damage. The activity period of drug is increased.
Mechanism of drug capture by cyclodextrins
Cyclodextrins form a complex with drug rapidly because even the most lipophilic compounds are
solvated by water to some extent and these discrete hydrated molecular particles are better able to get
part of the hydrophilic hydroxyl group at the entrance of the cyclodextrin cavity.
Drug capture by cyclodextrin
The hydrating molecules of water can actively interact with the hydroxyl group on the rim of
cyclodextrin toroid or they may simply shield the hydrophobic drug molecule from being repelled by
the hydroxyl group.
Once, the part of the hydroxyl rim, the hydrating molecule of water is driven from the hydrophobic
cavity leaving the drug molecule to find its most stable resting place.
In the case of extremely water insoluble substances, the true equilibrium may not be achieved for hours
or days because molecular separation due to hydration occurs extremely slowly.
Dissociation is an equally rapid process, most often caused by the sudden increase in the number of
water molecules outside the cavity. Even though there may be an initial energy barrier to dissociation,
the concentration gradient created becomes excess and the chemical (drug) is displaced. It unable to
find relatively scare cyclodextrin molecule to reform the complex, the drug exists free in solution or
precipitates depending upon the amount of dilution and concentration of cyclodextrin.
Dissociation may also take place due to change in pH or temperature.

Paracetamol as guest
Paracetamol is a minor analgesic that is given orally for relief of mild to moderate pain. It also has
anti – pyretic effect and is commonly used in children for this action. It is also known as
Acetaminophen.
Fig:
paracetamol
Paracetamol consists of a benzene ring core, substituted by one hydroxyl group and the nitrogen
atom of an amide group in the Para (1,4) pattern. The amide group is acetamide (ethanamide). It is
extensively conjugated system, as the lone pair of the hydroxyl oxygen, the benzene pi cloud, the
nitrogen lone pair, the p – orbital on the carbonyl carbon and the lone pair on the carbonyl oxygen are
all conjugated.
Physical properties
1) Colour = White.
2) State = Solid, Crystalline.
3) Density = 1.263 g/ cc.
4) Melting point = 169 °C.
5) Solubility in water = 1.4 g/100ml at 20 °C.
6) Solubility in organic solvents = soluble in methanol, ethanol,dimethyl formamide, ethylene
dichloride. Insoluble in petroleum ether, pentane,benzene.
7) Mol.wt = 151.17 g/mol
8) Bioavailability = almost 100%.
9) Metabolism = 90 to 95 % Hepatic.
10) Halflife = 1 to 4 hours.
11)Excretion = Renal
Paracetamol is used to relive mild to moderate pain, including instances of tension, headache,
muscular aches, joint pain, general pain, and toothache. It is also used as an antipyretic that can reduce
fever. It is suitable to most people including the elder and young children because it has low side
effects.
The recommended adult dose of Paracetamol is two 500mg tablets with four hours between doses
and no more than eight tablets in 24 hours.There are no toxic effects even in prolonged or habitual use.
It does not accumulate in the body. But overdose affects the liver leading to hepatotoxicity.
While the precise mode of action of paracrtamol is unclear, it is thought that like Aspirin its effect
is due to inhibition of prostaglandin synthesis.Paracetamol inhibit the enzyme cyclooxygenase
responsible for the biosynthesis of prostaglandins. By reducing the synthesis of prostaglandin,
paracetamol produces analgesia by elevating the pain threshold and reduces fever by resetting the
hypothalamic heatregulating center of the brain.Paracetamol is thought to act almost exclusively on
the central nerves system with little peripheral effect. This explains why paracetamol even in higher
doses, has limited anti – inflammatory effect and is associated with fewer gastro intestinal side effects.
The plasma halflife of paracetamol ranges from 1 to 4 hours. It is distributed throughout most
fluids of the body and is metabolized primarily in the liver. Little unchanged drug is excreted in the
urine, but most metabolic products appears in the urine with in 24 hours. Compared with other minor
analgesics, such as aspirin, its onset of action is generally slower, since it is only absorbed once it has
left the stomach and entered the duodenum.
Features of Paracetamol
1) Its analgesic (pain relief) and antipyretic (fever relief) effects are comparable to those of
Aspirin.
2) There is virtually no group of people who should not take it.
3) An interaction with other treatments is not a problem.
4) At the recommended dosage there are no side effects.
5) It is suitable for small children and elders.
6) It can be taken by those sensitive to Aspirin.
7) It is well tolerated by patients with peptic ulcers.

Methodology:
CD complexes were optimized by employing the semi – empirical PM3 (parametric method 3)
Hamiltonian in the semi – empirical quantum chemical calculations. A parameterization scheme herein
is based on the known data of heats of formation. It may be remarked here that the PM3 method yields
good estimates of geometrical parameters of the stationary point geometries and relatively fast which
make it useful for longer molecular systems containing say 50 to few thousand atoms. GAUSSIAN 03
program were used for obtaining the stationary point geometries. The geometries thus derived were
confirmed to be local minima on the potential energy surface by calculating the vibrational frequencies.
Since no vibrational frequency turns out to be imaginary these are confirmed to be local minima. (one
imaginary frequency implies a transition state and more than one imaginary frequencies lead to saddle
point of order two or more on the potential energy surface.) A relative stabilization energies along with
the free energy change associated with the inclusion phenomenon are reported for all the conformers of
α,β and γ CDs.The results obtained using PM3 geometry optimization are reported in the following
chapter.
Computational Method
Structure drawing by Winmopac
Geometry optimization by PM3 method
Frequency and frontier orbital
calculations
Calculation of Stabilization energy of
conformers
Chapter : 3
Calculations
Stabilization energy of cyclodextrin complex with paracetamol is calculated as
1) ∆E = Ecomplex – ( Ecd + Eguest ) * 2625.5 kJ mol
–1
where, ∆E = stabilized energy.
Ecomplex = energy of complex.
Ecd = energy of host (cyclodextrin).
Eguest = energy of guest (paracetamol)
2) ∆Eref = E most stable complex – Ecomplex ) * 2625.5 kJ mol
–1
where, ∆Eref = energy of complex with reference to most stable complex11
Calculated energies of complexes are:
complex ∆E , kJ mol
–1
∆Eref , kJ mol
–1
No of H
bonding
No of HH
interactions
Alpha 1 –66.7 0.00 1 3
Alpha 2 –64.88 02.6 1 4
Alpha 3 –54.4 11.03 2 2
Alpha 4 –52.0 13.1 1 4
Alpha 5 –53.1 13.1 1 3
Alpha 6 –43.8 23.6 0 3
Alpha 7 –39.1 26.3 0 3
Alpha 8 –39.4 39.4 0 3
Beta 1 –84.4 0.00 1 2
Beta 2 –80.1 05.3 1 2
Beta 3 –70.1 15.8 1 3
Beta 4 –64.4 21.0 0 3
Beta 5 –63.72 21.5 2 2
Beta 6 –61.5 23.6 1 3
Beta 7 –61.1 26.3 2 2
Beta 8 –55.6 31.5 0 1
Beta 9 –49.5 36.8 0 2
Beta 10 –50.10 36.8 0 3
Beta 11 +820.3 905.7 2 3
complex ∆E , kJ mol
–1
∆Eref , kJ mol
–1
No of H
bonding
No of HH
interactions
Gamma 1 –104.5 0.00 0 2
Gamma 2 –97.1 07.9 1 2
Gamma 3 –95.8 07.9 1 1
Gamma 4 –91.8 13.1 1 1
Gamma 5 –91.5 13.5 0 1
Gamma 6 –88.7 15.8 1 3
Gamma 7 –84.5 18.4 3 3
Gamma 8 –82.0 21.0 0 1
Gamma 9 –82.0 21.0 1 2
Gamma 10 –35.2 68.3 0 2
Observation
1) The energy of the complex is less than the sum of energies of host (cyclodextrin) and guest
(paracetamol).
2) Complex of α cyclodextrin with paracetamol :
The most stable complex is of energy –66.7 kJ mol
–1
.The paracetamol molecule has width
around 0.44nm, and inner diameter of alpha cyclodextrin is about 0.57nm. So paracetamol has to fix
itself in guest straight up only. when methyl group is upward the hydrogen bonding may occur with
three hydrogen atoms thus leading to more stability, the nitrogen lone pair and carbonyl oxygen may
also interact with hydrogen of cyclodextrin. But if hydroxyl group is upward then hydrogen bonding
can occur only with one hydrogen and thus complex is not much stable. The Hydrogen – Hydrogen
interactions are much strong in α complex than the hydrogen bonding The extent of hydrogen bonding
is less than the H – H interactions.
3) Complex of β cyclodextrin with paracetamol:
The most stable complex is of energy –84.4 kJ mol
–1
.The inner diameter of beta cyclodextrin
is 0.78nm.Here the paracetamol molecule can be rotated and can also be kept slightly horizontal. The
interaction can occur with primary as well as secondary hydroxyl group of cyclodextrin,leading to
more stablilty. Thus the position of hydroxyl or methyl group do not affect stability of complex. The
extent of hydrogen bonding is greater in β complexes than H  H interactions.
3) Complex of γ cyclodextrin with paracetamol:
The most stable complex is of energy –104.5 kJ mol
–1
.The inner diameter of gamma
cyclodextrin is 0.95nm.Here the paracetamol molecule can be rotated freely. The paracetamol entirely
fits in to the of γ cyclodextrin, so the formation of hydrogen bonding and other interaction are easier
thus leading to most stable complex of paracetamol. The position of hydroxyl or methyl group do not
affect stability of complex. The of γ complex is stable due to balance of both H – bonding and H – H
interactions.
Conclusion
1) All the cyclodextrin i.e. ( α, β & γ ) forms stable inclusion complex with paracetamol.
2) The γ cyclodextrin forms most stable complex while α forms least stable complex.
3) The γ complexes are stable by 40 kJ mol
–1
energy than α and by 20 kJ mol
–1
energy than β.
4) The β complexes are stable by 20 kJ mol
–1
energy than α .
5) The cavity of cyclodextrin and number of possible hydrogen bonding and other interactions
determines the stability of the complex.
6) The hydroxyl group of cyclodextrins and hetero atoms in guest are responsible for hydrogen
bonding and complex stability.
7) The position of methyl or hydroxyl group affects the α complex stability and not of β & γ
complexes.
8) The Hydrogen bonding as well as Hydrogen – Hydrogen interactions strongly govern the
stability of complex.

References
Paracetamol Alpha cyclodextrin
Beta cyclodextrin Gamma cyclodextrin
Alpha 1, ∆E = – 66.7 kJ mol
–1
(∆E
rel
= 0 kJ mol
–1
) Alpha 2, ∆E = – 64.9 kJ mol
–1
(∆E
rel
= 02.6 kJ
mol
–1
)
Alpha 3, ∆E = – 54.4 kJ mol
–1
(∆E
rel
= 11.0 kJ mol
–1
) Alpha 4, ∆E = – 52.0 kJ mol
–1
(∆E
rel
= 13.1 kJ
mol
–1
)
Alpha 5, ∆E = – 53.1 kJ mol
–1
(∆E
rel
= 13.1 kJ mol
–1
) Alpha 6, ∆E = – 43.8 kJ mol
–1
(∆E
rel
= 23.6 kJ
mol
–1
)
Alpha 7, ∆E = – 39.1 kJ mol
–1
(∆E
rel
= 26.3 kJ mol
–1
) Alpha 8, ∆E = – 27.3 kJ mol
–1
(∆E
rel
= 39.4 kJ
mol
–1
)
Beta 1, ∆E = – 84.4 kJ mol
–1
(∆E
rel
= 0.0 kJ mol
–
1
)
Beta 2, ∆E = – 80.1 kJ mol
–1
(∆E
rel
= 05.3 kJ mol
–1
)
Beta 3, ∆E = – 70.1 kJ mol
–1
(∆E
rel
= 15.8 kJ mol
–
1
)
Beta 4, ∆E = – 64.4 kJ mol
–1
(∆E
rel
= 21.0 kJ mol
–1
)
Beta 5, ∆E = – 63.7 kJ mol
–1
(∆E
rel
= 21.5 kJ mol
–1
) Beta 6, ∆E = – 61.5 kJ mol
–1
(∆E
rel
= 23.6 kJ mol
–1
)
Beta 7, ∆E = – 61.1 kJ mol
–1
(∆E
rel
= 26.3 kJ mol
–1
) Beta 8, ∆E = – 55.6 kJ mol
–1
(∆E
rel
= 31.5 kJ mol
–1
)
Beta 9, ∆E = – 49.5 kJ mol
–1
(∆E
rel
= 36.8 kJ mol
–1
) Beta 10, ∆E = – 50.1 kJ mol
–1
(∆E
rel
= 36.8 kJ mol
–1
)
Beta 11, ∆E = +820.3 kJ mol
–1
(∆E
rel
= 905.7 kJ
mol
–1
)
Gamma 1, ∆E = – 104.5 kJ mol
–1
(∆E
rel
= 00.0 kJ
mol
–1
)
Gamma 2, ∆E = – 97.1 kJ mol
–1
(∆E
rel
= 07.9 kJ mol
–1
)
Gamma 3, ∆E = – 95.8 kJ mol
–1
(∆E
rel
= 07.9 kJ
mol
–1
)
Gamma 4, ∆E = – 91.8 kJ mol
–1
(∆E
rel
= 13.1 kJ mol
–1
)
Gamma 5, ∆E = – 91.5 kJ mol
–1
(∆E
rel
= 13.1 kJ
mol
–1
)
Gamma 6, ∆E = – 88.7 kJ mol
–1
(∆E
rel
= 15.8 kJ
mol
–1
)
Gamma 7 , ∆E = – 84.5 kJ mol
–1
(∆E
rel
= 18.4 kJ
mol
–1
)
Gamma 8, ∆E = – 82.0 kJ mol
–1
(∆E
rel
= 21.0 kJ
mol
–1
)
Gamma 9, ∆E = – 82.0 kJ mol
–1
(∆E
rel
= 21.0 kJ mol
–1
) Gamma 10, ∆E = – 35.2 kJ mol
–1
(∆E
rel
= 68.3 kJ mol
–1
)
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