Investigation of inclusion complexes of sulfamerazine with α- And β-cyclodextrins: An experimental and theoretical study

Article abstract of DOI:10.1016/j.saa.2014.01.057

Inclusion complexation behavior and binding ability of sulfamerazine (SMRZ) with α- and β-cyclodextrins (α-CD and β-CD) were investigated. The formation of inclusion complexes are studied by UV-visible, fluorescence, time-resolved fluorescence, ¹

Full text of DOI:10.1016/j.saa.2014.01.057

Spectrochimica Acta Part A: Molecular and Biomolecular Spectroscopy 124 (2014) 441–450
Contents lists available at ScienceDirect
Spectrochimica Acta Part A: Molecular and
Biomolecular Spectroscopy
journal homepage: www.elsevier.com/locate/saa
Investigation of inclusion complexes of sulfamerazine
with
a- and b-cyclodextrins: An experimental and theoretical study
⇑
N. Rajendiran , T. Mohandoss, G. Venkatesh
Department of Chemistry, Annamalai University, Annamalai Nagar 608 002, Tamilnadu, India
h i g h l i g h t s
g r a p h i c a l a b s t r a c t
TEM photographs of SMRZ/b-CD inclusion complex.
ꢀ
ꢀ
Aniline part of SMRZ included into the
CD cavity.
Different types of inclusion
complexes are formed in both a-CD
and b-CD.
ꢀ
ꢀ
ꢀ
SMRZ exhibit biexponential decay in
water and triexponential decay in CD
solutions.
SMRZ form a nanochain like
agglomerated inclusion complexes
with a-CD and b-CD.
Intermolecular interactions present
in the SMRZ/CDs inclusion
complexes.
200 nm
a r t i c l e i n f o
a b s t r a c t
Article history:
Inclusion complexation behavior and binding ability of sulfamerazine (SMRZ) with
trins (a-CD and b-CD) were investigated. The formation of inclusion complexes are studied by UV–visible,
a- and b-cyclodex-
Received 16 November 2013
Received in revised form 30 December 2013
Accepted 8 January 2014
fluorescence, time-resolved fluorescence, 1H NMR, FT-IR, DSC, XRD, SEM, TEM and molecular modeling
methods. Both experimental and PM3 results indicated that the SMRZ is partially encapsulated in the
CD cavity. The different spectral shifts observed in both the CDs indicate that different types of inclusion
complexes are formed. Nanosecond time-resolved fluorescence studies demonstrated that SMRZ exhibit
biexponential decay in water and triexponential decay in CD solutions. The resonance of the aromatic
protons of SMRZ showed remarkably upfield shift in the complexes suggested that the aniline ring deeply
encapsulated in the CD cavity. The amino and amido stretching vibrations at 3483 cmꢁ1 and 3379 cmꢁ1
respectively are strongly affected in the inclusion complexes. DSC curves for the inclusion complexes
Available online 21 January 2014
Keywords:
Sulfamerazine
Cyclodextrins
Inclusion complexes
Nanomaterials
TEM
exhibited a broad endothermic effect from 106.4 °C, 123.8 °C and 234.5 6 °C for
a-CD and 118.2 °C and
Molecular modeling
231.4 °C for b-CD. TEM images of both inclusion complexes are forms a nanochain like agglomerated
structures with a width ranging from 40 nm to 100 nm. Thermodynamic parameters and binding affinity
of the inclusion complex formation were determined and discussed.
Ó 2014 Elsevier B.V. All rights reserved.
Introduction
such as antiangiogenic [1,2], antitumor [3], anti-inflammatory and
anti-analgestic [4]. Sulphonamides belong to the group of antibacte-
Sulfonamide is a generic name for derivatives of para-aminoben-
zene sulfonamide which possess enormous efficient bioactivities
rial drugs, which are used for human and animal therapy, to cure
infectious diseases of digestive and respiratory systems, affections
of the skin (in the form of ointments) and for prevention or therapy
of coccidiosis of small domestic animals [5,6]. Quality control of
sulphonamide formulations and their quick systematic monitoring
⇑
Corresponding author. Tel.: +91 94866 28800; fax: +91 4144238080.
E-mail address: drrajendiran@rediffmail.com (N. Rajendiran).
1386-1425/$ - see front matter Ó 2014 Elsevier B.V. All rights reserved.
http://dx.doi.org/10.1016/j.saa.2014.01.057

442
N. Rajendiran et al. / Spectrochimica Acta Part A: Molecular and Biomolecular Spectroscopy 124 (2014) 441–450
in body fluids are important analytical tasks. A number of articles
have been published concerning the determination of sulphona-
mides by different analytical methods. Sulfamerazine is one of the
well known and widely used sulfonamide antibacterial drugs to
treat bacterial disease in human and animals like cattle, sheep, pigs
and poultry [5,6]. Besides the broad spectrum of therapeutic appli-
cations, use of SMRZ drug has been limited by its poor aqueous sol-
ubility and dissolution rate. Therefore, it is essential to search a new
solubilizer with considerably improved efficacy and safety, in order
to deliver the drug at targeted site.
constant of SMRZ/CD complexes. In the present work, we prepared
solid inclusion complexes of the above SMRZ drug with -CD and
a
b-CD and it was characterized by UV–visible, fluorescence, life
time, FTIR, DSC, PXRD, 1H NMR, SEM and TEM and techniques.
Experimental
Reagents and methods
SMRZ,
a-CD, b-CD and solvents were purchased from Sigma–
Among the many different families of organic inorganic chemi-
cals being currently investigated because of their applications, sul-
fonamides and their N-derivatives are one of the outstanding
groups. Sulfonamides were the first effective chemotherapeutic
agents employed systematically for the prevention and cure of bac-
terial infections in humans. After the introduction of penicillin and
other antibiotics, the popularity of sulfonamides decreased. How-
ever, they are still considered useful in certain therapeutic fields,
especially in the case of ophthalmic infections as well as infections
in the urinary and gastrointestinal tract. Besides, sulfa drugs are
still today among the drugs of first election (together with
ampicillin and gentamycin) as chemotherapeutic agents in bacte-
rial infections by Escherichia coli in humans. The sulfanilamides
exert their antibacterial action by the competitive inhibition of
the enzyme dihydropterase synthetase towards the substrate
p-aminobenzoate.
Aldrich and used without further purification. The purity of the
compound was checked by similar fluorescence spectra when
excited with different wavelengths. All the experiments were car-
ried out using triply distilled water. The aqueous solutions were
prepared just before each measurement. The concentration of
stock solution of the drug was 2 ꢂ 10ꢁ3 M. The stock solution
(0.2 ml) was transferred into 10 ml volumetric flasks. To this,
varying concentration of CDs solution (range from 1.0 ꢂ 10ꢁ3
M
to 1.0 ꢂ 10ꢁ2 M) was added. The mixed solution was diluted to
10 ml with triply distilled water and shaken thoroughly. The final
concentration of SMRZ in all the flasks was 4 ꢂ 10ꢁ5 M. The exper-
iments were carried out at room temperature (303 K).
Preparation of inclusion complexes in solid state
a-CD/b-CD (0.9728/1.135 g) was dissolved in 40 ml distilled
Cyclodextrins (CDs) are well known for their capability to form
inclusion complexes with a diverse of molecules, in particular with
those having a hydrophobic character [7,8]. As a consequence of
this property, CDs have found substantial interest in supramolecu-
lar chemistry [9]. Cyclodextrins are extensively studied cyclic,
torus shaped, oligomer of amylose characterized by an inner cavity
size and number of glucose units present. These features make CDs
capable of hosting molecular guests via inclusion of the whole
guest, or part of it, into the void cavity and consequently form
supramolecular host–guest complexes [10,11]. Several forces are
known to be accountable for the formation of inclusion complexes
of CDs with suitable guest molecules i.e., hydrogen bondings, elec-
trostatic interactions, van der Waals forces, hydrophobic interac-
tions and dipole–dipole interactions [12,13]. Encapsulation of the
guest molecules in the host CDs cavities replicate the physico-
chemical properties of the guest molecules. For example, bioavail-
ability, solubility, stereo selectivity, catalytic activity, chemical and
physical stabilization [14–16].
In our previous studies, a sequence of sulfonamide derivatives
with b-CD was investigated through experimental [17,18] and
theoretical methods [19]. This study in aqueous solution clearly
demonstrated that the presence of intramolecular charge transfer
(ICT) or twisted intramolecular charge transfer (TICT) in the first
excited state as evidenced by the appearance of large Stokes
shifted longer wavelength (LW) emission [20]. The increased
emission intensity of LW with a considerable bathochromic shift
in CD solution has been attributed to the enhancing TICT in these
sulfanilamide molecules. Semiempirical calculations at PM3 level
of theory has been applied on the large molecular inclusion com-
plex systems [19]. This calculations suggested that the inclusion
complexation process was spontaneous and enthalpy driven pro-
cess in vacuum phase. Further the combination of experimental
and theoretical work leads to successful results in solving struc-
tural, energetic and dynamic problems [21,22].
water at 50 °C in a water bath. SMRZ (0.264 g) in 10 ml methanol
was slowly added to the CD solution with continuous agitation.
The molar ratio of SMRZ to CDs was 1:1. The vessel covered with
aluminum foil and stirred continuously for 24 h. Then the final
solution was refrigerated overnight at 5 °C. The precipitated
SMRZ/CDs complexes were recovered by filtration and washed
with small amount of methanol and water to remove uncomplexed
drug and CDs, respectively. This precipitate was dried in vacuum at
room temperature for two days and stored in an airtight bottle.
This powder samples were further analyzed by using FT-IR, 1H
NMR, DSC, XRD and SEM methods.
Instruments
Absorption and fluorescence spectral measurements were
carried out with Shimadzu (UV 1601 PC) UV–visible spectropho-
tometer and Shimadzu spectrofluorimeter (model RF-5301),
respectively. The fluorescence lifetime measurements were per-
formed using a picoseconds laser and single photon counting setup
from Jobin-Vyon IBH (Madras University, Chennai). One-dimen-
sional 1H NMR spectra for SMRZ and its CD inclusion complexes
were recorded on a Bruker AVANCE 500 MHz spectrometer (Ger-
many) using an inverse broadband (BBI) probe at room tempera-
ture. Samples were dissolved in DMSO-d6 (99.98%) and were
equilibrated for at least 1 h. FT-IR spectra of powder sample of
drug, both CDs and the inclusion complexes were measured from
4000 cmꢁ1 to 400 cmꢁ1 on JASCO FT/IR-5300 spectrometer by
using KBr pellets with 256 scans at a resolution of 4 cmꢁ1. Thermal
characteristics of solid inclusion complexes were measured using
Mettler Toledo DSC1 fitted with STRe software (Mettler Toledo,
Switzerland), temperature scanning range was from 25 to 260 °C
with a heating rate of 10 °C/min. XRD patterns were recorded with
a BRUKER D8 Advance diffractometer (Bruker AXS GmbH, Kar-
On continuation of our work, herein we report the self assembly
behavior of sulfamerazine (4-amino-N-[4-methyl-2-pyrimidinyl]
benzenesulfonamide, (SMRZ, Fig. 1) with a-CD and b-CD inclusion
complexes. We utilized absorption and fluorescence spectral tech-
niques to determine the inclusion stoichiometry and association
lsruhe, Germany) with Cu K
a radiation (k = 1.5406 Å), a voltage
of 40 kV and a 20 mA current. Scanning electron microscopy
(SEM) photographs were collected on a Hitachi S3400 N. The mor-
phology of SMP encapsulated CDs inclusion complexes was inves-
tigated by transmission electron microscopy (TEM) using a TECNAI

N. Rajendiran et al. / Spectrochimica Acta Part A: Molecular and Biomolecular Spectroscopy 124 (2014) 441–450
443
bioactive group
12.0564 Å
(a)
(b)
(c)
Fig. 1. Optimized structure of (a) SMRZ with the numbering system, (b)
a-CD and (c) b-CD obtained by PM3 level of theory. Colors of the atoms denotes: Blue ꢃ nitrogen,
yellow ꢃ sulphur, red ꢃ oxygen, white ꢃ hydrogen and grey ꢃ carbon of the molecules respectively. (For interpretation of the references to colour in this figure legend, the
reader is referred to the web version of this article.)
where Ecomp, ECD and ESMRZ represent the total energy of the opti-
mized most stable complex, the free optimized CDs and the free
optimized drug (SMRZ) molecule, respectively.
G2 microscope with accelerating voltage 200 kV. Carbon coated
copper TEM grid (200 mesh) was used for the TEM analysis.
Molecular modeling
Results and discussion
The theoretical calculations were carried out with Gaussian 03
software. Firstly, SMRZ,
a-CD and b-CD were built with Spartan
Absorption and fluorescence spectral studies
Fig. 2 shows the absorption spectra of SMRZ (2 ꢂ 10ꢁ5 M) in the
08 and the ground state geometry optimized in vacuum at PM3
level. And then the isolated guest and host molecules were re-
optimized at PM3 method with Gaussian 03. CD was fully
optimized by PM3 without any symmetry constraint. The glyco-
sidic oxygen atoms of CD were placed onto the XY plane and their
center was defined as the center of the coordination system. The
primary hydroxyl groups were placed pointing toward the positive
Z axis. The inclusion complexes were constructed from the PM3-
optimized CD and guest molecules. The longer dimension of the
SMRZ molecule was initially placed onto the Z axis. The position
of the guest was determined by the Z coordinate of one selected
atom of the guest. The inclusion process was simulated by putting
the guest in one end of CD and then letting it pass through the CD
cavity. Since the semiempirical PM3 method has been proved to be
a powerful tool in the conformational study of cyclodextrin inclu-
sion complexes and has high computational efficiency [23,24], it is
selected to study the inclusion process of CD with the sulfa drug in
this paper. The most stable complexes found by PM3 method without
absence and presence of
a-CD and b-CD concentrations at pH ꢃ6.5.
SMRZ itself has strong absorption in aqueous solution at ꢃ268.4
and 243.2 nm with a high molar absorption coefficient values (ꢃ
10ꢁ4 cmꢁ1). In the presence of
a-CD, there is no significant spectral
shift was observed but the absorbance was gradually increased.
Whereas, in b-CD, the absorption spectral maximum was red
shifted (about ꢃ5 nm) and the absorbance was decreased. The
above behavior indicates that both CDs forms different types of
the inclusion complexes with this drug molecule [25,26]. Further,
the presence of isosbestic point at ꢃ 290 nm, indicates that a
well-defined 1:1 inclusion complex is formed.
The effect of CDs on the fluorescence emission spectra of SMRZ
is more pronounced that the corresponding effect on the absorp-
tion spectra. The changes in the emission of SMRZ on addition of
a-CD/b-CD concentrations are shown in Fig. 3. SMRZ drug exhibits
dual fluorescence in aqueous solution when excited at ꢃ280 nm; a
strong fluorescence around ꢃ342 nm and a weak fluorescence
around ꢃ438 nm, respectively was observed. Among those bands,
the shorter wavelength fluorescence band can be assigned to the
normal emission (S1?S0), and the large Stokes shifted band can
imposing any symmetry constraint. The binding energy (DEbinding)
upon complexation between SMRZ and CDs is calculated for the
minimum energy structures according to the following equation.
D
Ebinding ¼ Ecomp ꢁ ðESMRZ þ ECDÞ

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N. Rajendiran et al. / Spectrochimica Acta Part A: Molecular and Biomolecular Spectroscopy 124 (2014) 441–450
0.80
0.40
0
480
0.77
Abs
320
If
260
(a)
0.75
7
1
0.73
200
0
15
12
10
[α-CD] × 10-3
0
8
4
5
[α-CD] x 10-3 M
M
240
7
1
(a)
0
290
380
200
290
405
520
Wavelength (nm)
Wavelength (nm)
1.00
0.50
600
300
0
0.76
Abs
600
(b)
If
0.72
300
0
1
7
7
0.68
0
12
0
4
8
[β-CD] x 10-3
M
15
10
[β-CD] × 10-3
5
M
1
(b)
0
200
275
350
405
520
290
Wavelength (nm)
Wavelength (nm)
Fig. 2. Absorption spectra of SMRZ in different a- and b-CD concentrations (M): (1)
0, (2) 0.001, (3) 0.002, (4) 0.004, (5) 0.006, (6) 0.008 and (7) 0.01. Insert Fig:
absorbance vs. CD concentration.
Fig. 3. Fluorescence spectra of SMRZ in different a- and b-CD concentrations (M):
(1) 0, (2) 0.001, (3) 0.002, (4) 0.004, (5) 0.006, (6) 0.008 and (7) 0.01. Insert Fig:
fluorescence intensity vs. CD concentration. Excitation wavelength ꢃ 275 mm.
be assigned to emission from the intramolecular charge transfer
(ICT) or twisted intramolecular charge transfer (TICT) state.
Fig. 3 shows the fluorescence spectra of SMRZ drug in aqueous
transfer (TICT)) is restricted which also causes an enhancement
of the SW band. Further, the geometrical restriction of the cavity
would restrict the free rotation of the pyimidine ring or aniline ring
solution as a function of a-CD and b-CD concentrations. The differ-
ent spectral shifts observed in both the CDs indicate that different
types of inclusion complexes are formed. In aqueous solution, the
shorter wavelength (SW, at 342 nm), fluorescence intensity of the
SMRZ was higher than that of longer wavelength (LW, at
in the
ing an enhancement of normal SW band.
Fig. 3 clearly indicates that in -CD solutions, the surrounding
a-CD cavity and thus hinders the formation of ICT state caus-
a
polarity of SO2NH- group does not change very much as there is
no hypsochromic shift of the most polar (ICT) state [17,18] but
the relative intensity (IICT/ILE) increases with the increase of b-CD
concentration. This may be possible if part of the aniline ring goes
inside the b-CD cavity. Further, if amino group present in the inte-
rior part of the b-CD cavity, a bathochromic shift or ICT emission
should be present in the b-CD medium. We found that in our ear-
lier results, with aqueous b-CD solution, hydrophobicity is the driv-
ing force for encapsulation of the molecule inside the cavity and
naturally the hydrophobic part like to go inside the deep core of
the nonpolar cavity and the polar group will be projected in the
hydrophilic part of the b-CD cavity [17–22].
The above results indicate that, part of SMRZ molecule is en-
trapped in non-polar cavity of the CD. Formation of the SMRZ
inclusion complex with b-CD cavity should result dual emission.
Since the size of SMRZ molecule is larger than CD cavity size, this
molecule is partially included into the CD cavities. Further, it is
noteworthy that, the LW emission intensity gradually increased
along with red shift by increasing the b-CD concentrations. Such
a spectral shift may correspond to an energy stabilization of the
emitting state and is characteristic for the fluorescence of an ICT
or TICT state. The LW emission from the SMRZ drug is originated
from the TICT state with twisting occurring at the amide SAN bond
between the aniline moiety (electron donor) and the SO2 moiety
(electron acceptor).
430 nm). Upon addition of
a-CD, the SW emission was gradually
increased whereas no significant enhancement observed in the
LW. In contrast in b-CD, the LW emission intensity was gradually
increased than that of SW.
The CD dependent emission spectra of SMRZ show that the LW
band is more sensitive in b-CD solution, whereas the SW band
shows a small enhancement with a regular hypsochromic shift
(Fig. 3). The SW intensity in b-CD medium is lower than LW inten-
sity and it is opposite in the a-CD solutions. With addition of b-CD
both SW and LW intensities are increases; however, the rate of
enhancement of the LW emission is greater than that for the SW
band. Further, with an increasing the b-CD concentrations, a regu-
lar red shift was observed in the LW band whereas blue shift was
observed in the SW band. This can be clearly observed in Fig. 3,
the LW intensity in 0.01 M b-CD solution is increased to 5 times
than the aqueous medium and the SW emission enhanced to
approximately 1.0 times. The enhancement of both LW and SW
bands of SMRZ drug in b-CD solutions may be explained as follows
[17,18].
The enhancement of the LW band in b-CD may be due to lower-
ing of solvent polarity at higher CD concentrations [17–22]. Inside
the b-CD cavity SMRZ molecule feels much less polar environment
and the main non-radiative path of the LW band (through intramo-
lecular charge transfer (ICT) or twisted intramolecular charge

N. Rajendiran et al. / Spectrochimica Acta Part A: Molecular and Biomolecular Spectroscopy 124 (2014) 441–450
445
We have already been reported whenever two aromatic rings
are separated by the groups like ASO2, ACH2, ACO, ANH, etc.,
can form a TICT state [27]. Thus it can be speculated that in the
present work the emission at 438 nm should originates from the
TICT state. This TICT state in SMRZ may be attributed to twisting
occur at the SO2ANH bond between the electron donor group (ani-
line ring) and the electron acceptor group (pyrimidine ring). Addi-
tion of various concentrations of CDs lead a considerable enhance
in the SMRZ emission intensity, especially for b-CD. Further, the
presence of b-CD produced a blue shift in the fluorescence band
at 342 nm, while a large red shift was observed in the TICT emis-
than that of
a-CD cavity; hence pyrimidine ring is not entrapped
in the -CD cavity. However, in b-CD, aniline ring is deeply encap-
a
sulated in the cavity; hence the TICT emission intensity is higher
than the SW intensity. Further, another question may arises why
SMRZ does exhibit weak TICT emission in polar and non-polar
solvents because of a weak dipole–dipole interaction between
RASO2ANHA group with solvent and fast back charge transfer.
These features support the idea that the TICT state in b-CD is
stabilized through complex formation between SMRZ with b-CD.
This confirms that the environment around the aniline group in
b-CD medium is different from the a-CD medium.
sion maximum from 438 to 452 nm. With increasing the
a
-CD con-
The stoichiometric ratios of the SMRZ/CDs complexes were
determined from the Benesi–Hildebrand (B–H) double reciprocal
plots [29]. The linearity of the plots of 1/(A ꢁ A0) of 1/(I ꢁ I0) versus
1/[CD], indicates the formation of 1:1 encapsulated complexes be-
tween the SMRZ drug and CDs (Fig. 4). Furthermore, a careful
investigation was performed for the determination of 1:2 stoichi-
ometries. The plot of 1/(A ꢁ A0) of 1/(I ꢁ I0) versus 1/[CD]2, give
an upward and/or downward curves. These non-linear plots ruled
out the possibility of 1:2 stoichiometry between SMRZ and CDs.
Thus, the linear plots can be used to determine the stability con-
stant (Ks) by simply dividing the intercepts by the slope values.
The calculated stability constant values for the inclusion com-
centrations, both the LE and TICT bands intensities enhanced at the
same wavelength. These results suggested that the inclusion com-
plexes were formed between the drug molecules and CDs [28].
We also found similar results in our earlier studies on other sul-
fa drugs (sulfadiazine and sulfamethoxazole) with b-CD [17,18].
The previous studies also suggesting that the encapsulation
process plays a crucial role in the enhancement of TICT emission.
The present results also supported by similar emission spectra
observed when SMRZ:CDs solution excited with different
wavelengths at 340 and 440 nm, respectively conform the
presence of TICT in this molecule.
plexes are SMRZ/
a
-CD; abs ꢃ179 Mꢁ1, flu ꢃ345 Mꢁ1 and SMRZ/
Prototropic reactions in CD medium
b-CD; abs ꢃ276 Mꢁ1, flu ꢃ469 Mꢁ1, respectively. The higher values
obtained for b-CD complex suggesting the larger cavity (diameter
of b-CD is 6.5 Å) make them further hydrophobic and flexible,
and therefore are capable to form the inclusion complexes more
efficiently.
To know the effect of CD on the prototropic equilibrium be-
tween neutral, monocation and dication on the pH dependent
changes (in the absorption and emission spectra) of the SMRZ drug
in aqueous solution containing CD were recorded. The absorption
and emission maxima of SMRZ molecule were studied in
6 ꢂ 10ꢁ3 M b-CD solutions in the pH range from 0.1 to 11. On com-
parison with aqueous medium, in b-CD solutions, the absorption
and emission maxima of this drug molecule neutral maximum
was red shifted (kabs ꢃ 268.4 and 243.2 nm to ꢃ272 and 246 nm
and kflu ꢃ 342 and 438 nm to ꢃ345 and 442 nm). The red shift ob-
served in the b-CD solutions compared to the aqueous solutions,
suggesting the SMRZ drug is encapsulated in the b-CD cavity.
Lifetime measurements
Time-resolved fluorescence decay is also carried out to substan-
tiate the inclusion complex formation of SMRZ with
a- and b-CD.
Fluorescence lifetime provides a sensitive parameter for exploring
the local environment around the guest molecule, and it is
sensitive to excited state interactions [30]. It is also offers the
understanding of interactions for the guest molecules with CD
nano-cavities [31]. In the absence of CDs, the fluorescence decay
curve for SMRZ was fitted to biexponential function with v2 values
of ꢃ1.1. This indicates that SMRZ has two lifetime components:
Possible inclusion complex
Considering the above discussions, the possible inclusion mech-
anism is proposed as follows: Naturally two different types of the
One maximum for the total fluorescence (
the other is the rest of the fluorescence (
s
1 = 3.824 0.2 ns) and
s2 = 0.983 0.1 ns). The
inclusion complex formation between SMRZ molecule with
a
-CD
first with a larger lifetime is assigned to LE emission and the other
to TICT state of guest molecule. It is noteworthy that the decay
time of the slow component is different to that of TICT emission
within experimental uncertainty. This indicates that a little equi-
librium between the locally excited (LE) state and the TICT state
is achieved in water in a rather short period. By the addition of
CDs, biexponential decay curve becomes triexponential. Three
and b-CD are possible: (i) aniline ring is captured in the CD cavity
and (ii) pyrimidine ring is captured in the CD cavity. Let us consider
the Type I arrangement, if aniline part is entrapped into the CD cav-
ity, blue shift should be noticed in the CD solutions. Further, if ami-
no group is entrapped into the CD cavity the dication maxima (i.e.,
protonation of amino group) [17,18] should be blue shifted in CD
than aqueous medium.
For type II encapsulation, the pyrimidine ring may included into
the CD cavity. If this Type of complex is formed, the neutral max-
ima of the SMRZ drug (protonation of tertiary nitrogen atom)
should be red shifted in CD than aqueous medium. The red shift
observed in pHꢃ7 (b-CD medium) indicates that, the pyrimidine
ring interact with the b-CD hydroxyl grouped, because it is well
known that CDs are good hydrogen donors [17–22].
lifetimes were obtained in the presence of both CDs (
3.964 ns, 2 = 1.082 ns and 3 = 0.562 ns; and b-CD: 1 = 4.553 ns,
2 = 2.551 ns and 3 = 1.122 ns). The lifetime values increased with
a-CD: s1 =
s
s
s
s
s
the addition of CD concentration than water due to the inclusion
complex formation between the drug and CDs. Thus, the increase
in fluorescence lifetime is a result of the significant interactions
between SMRZ and CD nanocavities. The efficient lifetime enhance-
ment is found to be higher with b-CD concentration suggests stronger
hydrophobic interaction between SMRZ and b-CD.
Further, in Type II complexes, both CD cavities will impose a
restriction about the free rotation of the CH3 group or pyrimidine
ring in its excited state. For this type, TICT emission should in-
crease in the CD solutions. The question may arise why very weak
1H NMR analysis
TICT emission is observed in
a
-CD, this is because even this com-
1H NMR spectroscopy can give effective evidence for the forma-
tion of inclusion complex, especially the interactions of guest mol-
ecule at specific site in the CD complexes [32–34]. In order to
demonstrate that whether or not the interaction between SMRZ
plex formation does not affect the free rotation of ASO2ANH2
group because, the aniline part of SMRZ is partially encapsulated
in the
a-CD cavity. Further the size of pyrimidine ring is greater

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N. Rajendiran et al. / Spectrochimica Acta Part A: Molecular and Biomolecular Spectroscopy 124 (2014) 441–450
200
0.048
(b)
(a)
100
0
0.036
0.024
1/(A-A0)
1/(I-I0)
SMRZ/α -CD
SMRZ/α-CD
-100
-200
0.012
0
0
200
400
600
800 100 120
0
200
400
600
800 100 120
1/[CD]
1/[CD]
200
0.048
(c)
(d)
100
0
0.036
0.024
1/(I-I0)
1/(A-A0)
-CD
SMRZ/α
SMRZ/α -CD
100
200
0.012
0
-
-
0
200
400
600
800 100 120
0
200
400
600
800 100 120
1/[CD] × 103
1/[CD] × 103
Fig. 4. Benesi–Hildebrand plot for the complexation of SMRZ with CDs. (a) Plot of 1/A ꢁ A0 vs. 1/[CD], (b) Plot of 1/I ꢁ I0 vs. 1/[CD], (c) Plot of 1/A ꢁ A0 vs. 1/[CD]2 and (d) Plot of
1/I ꢁ I0 vs. 1/[CD]2.
and CDs occurs through inclusion complex, 1H NMR spectra have
been recorded. 1H NMR spectrum of the SRMZ drug can be identi-
fied in Fig. S1, consistent with earlier observation [35]. The spectral
amine (CAN stretching), 1630 cmꢁ1 for secondary amine stretch-
ing, 1597 cmꢁ1 for C@C bending and 795–637 cmꢁ1 for CAH bend-
ing vibrations. The SO2 symmetric and asymmetric vibrations are
observed at 1153 cmꢁ1 and 1302 cmꢁ1, respectively. The charac-
teristic stretching vibrations for C@C 1607 and 1502 cmꢁ1 band
intensities are reduced and shifted in the solid inclusion complexes
(1597 cmꢁ1 and 1493 cmꢁ1) due to the encapsulation of phenyl
ring into the CD cavity. The symmetric and asymmetric vibrations
of SO2 group are shifted to 1157 cmꢁ1 and 1306 cmꢁ1 in the inclu-
sion complexes. However the band at 1246 cmꢁ1 (for CAN stretch-
ing) is diminished considerably. Further the amino and amido
stretching vibrations of SMRZ are covered by numerous AOH
stretching vibrations of CD. Even though, the broad AOH vibrations
of CD was perturbed by the presence of drug. These IR spectral
changes suggest that aromatic part along with SO2 group is proba-
bly encapsulated into the CD cavity and formed stable inclusion
complexes in solid state.
data for pure SMRZ and in the a-CD/b-CD inclusion complexes (in
parenthesis) in ppm are as follows: Ha ꢃ 11.125 (9.92/10.00);
Hb ꢃ 7.625 (8.40/8.43); Hc ꢃ 6.873 (7.69/7.58); Hd ꢃ 5.982 (6.54/
6.55); He ꢃ 8.300 (5.64/5.63); Hf ꢃ 6.555 (3.59/3.55) and
Hg ꢃ 2.491 (3.28–3.14/3.35–3.16). As can be seen from Fig. S1,
the chemical shift data for the inclusion complexes were different
from those of pure drug. The resonance of the aromatic protons of
SMRZ showed remarkably upfield shift (ꢁ0.25, ꢁ0.29) in the SMRZ/
CD complexes, which suggested that the resonance of Hb and Hc
protons are shielded considerably in the complex and thus the ani-
line ring should enter deeply into the cavity. However, a minor
shift was observed all other protons of the drug (Ha, He, Hf and
Hg) when the formation of inclusion complex, which clearly indi-
cated that the pyrimidine ring is not entrapped in the CD cavities.
Further the inclusion complexation with SMRZ had a significant
changes (upfield shift) on the resonance of H-30 and H-50 protons
of CD. It is noteworthy that the H-30 protons shifted 0.03–
0.06 ppm, while the H-50 protons shifted 0.01–0.03 ppm after guest
inclusion. Both H-30 and H-50 are located in the inner part of the CD,
and the H-30 protons are near at the wider rim side of the cavity
whereas H-50 protons are near at the narrow rim side. The 1H
NMR results revealed that SMRZ enter into the CD cavity form
the wider side.
DSC analysis
The DSC profiles of pure components (SMRZ,
a-CD and b-CD)
and corresponding encapsulated complexes within the tempera-
ture range from 25 to 260 °C are displayed in Fig. 5. The thermal
curve of SMRZ was typical of a crystalline anhydrous substance
with a sharp fusion endotherm at 236.8 °C, corresponding to the
melting point of the SMRZ drug. The DSC curves exhibited a broad
endothermic peak range from 60 to 150 °C which attains a maxi-
mum at 128.6 °C for b-CD and three endothermic peak around at
FT-IR analysis
79.2 °C, 109.1 °C, 137.5 °C for
a-CD attributed to crystal water
FT-IR is a useful analytical tool to verify the formation of
inclusion complex in solid state. The basis of information gained
from FT-IR spectroscopy is the band shift and change in their inten-
sity observed on the solid inclusion complexes [36]. The FT-IR
losses from CD nano-cavity [37]. The DSC curves for the inclusion
complexes exhibited
123.8 °C, 234.5 6 °C for
a
a
broad endothermic peak at 106.4 °C,
-CD and 118.2 °C, 231.4 °C for b-CD. Com-
paring with the DSC curves of pure drug and CDs, the inclusion
complex samples (in 1:1 mol ratio) clearly showed the displace-
ment of the endothermic peaks due to loss of water into lower
temperature. Further, the complete disappearance of the charac-
teristic endothermic peak of SMRZ in the inclusion complexes
spectra of
a-CD, b-CD, SMRZ and solid complexes are shown in
Fig. S2. In Fig. S2c, the characteristic bands of SMRZ are observed
at 3483 cmꢁ1 and 3379 cmꢁ1 for amido stretching and amino
stretching vibrations respectively, 1246 cmꢁ1 for primary aromatic

N. Rajendiran et al. / Spectrochimica Acta Part A: Molecular and Biomolecular Spectroscopy 124 (2014) 441–450
447
2
Transmission electron microscopy (TEM)
(e)
TEM was engaged to investigate the morphology aggregates of
the inclusion complex of SMRZ. TEM images of SMRZ/ -CD and
SMRZ/b-CD nanomaterials are shown in Fig. 7. It could be found
that nanochain like agglomerated structures formed in both
SMRZ/a-CD and SMRZ/b-CD complexes with a width ranging from
40 nm to 100 nm. The nanochain agglomerated structured formed
from the replication of the cylindrical shape of polyrotaxane struc-
ture of SMRZ/a-CD and SMRZ/b-CD complexes. The vesicle or
spherical particles have strong agreement between the center
0
-2
-4
-6
a
(d)
(c)
(b)
and margin in SMRZ/b-CD complex nanomaterial (Fig. 7b),
(a)
40
whereas, it is a distinctive typical vesicular structure SMRZ/a-CD
(Fig. 7a). For convenience, the general composition of the SMRZ/
CD inclusion complex is represented by (SMRZ)m/(CD)n in which
the guest:host ratio is m:n (1:1). The self assembly of CDs with
SMRZ is the key factor for the typical nanochain-like agglomerates
(Fig. 7). The nanochain-like agglomerate structure that SMRZ/CD
inclusion nanomaterials are fixed in head–head or head–tail ap-
proach and nanovesicles may be related to the weaker supramolec-
ular interaction, van der Waals force, hydrogen bond between
-8
-10
60
100 120 140 160
180
200 220 240 260
80
Temperature (oC)
Fig. 5. DSC thermograms of (a)
SMRZ/b-CD inclusion complexes in 1:1 M ratio (25–260 °C at 10 °C/min).
a-CD, (b) b-CD, (c) SMRZ, (d) SMRZ/a-CD and (e)
neighbouring complex (SMRZ/a-CD and SMRZ/b-CD) and even
the weaker assembly between the inclusion complexes of SMRZ
with CDs.
indicating a strong interaction of the drug with CD nano-cavities
and the stable encapsulated complexes are formed between SMRZ
and CDs.
Molecular modeling studies
XPRD analysis
Semi-empirical quantum mechanics calculations using PM3
method were performed in order to gain information about the
structural characteristics and thermodynamic magnitudes for the
1:1 inclusion complexes between SMRZ and CDs. The optimized
Further confirmation for the formation of encapsulated com-
plexes between SMRZ and CDs was provided by X-ray powder dif-
fraction pattern (XPRD). The diffraction patterns for SMRZ/
and SMRZ/b-CD inclusion complexes are demonstrated in Fig. S3
along with pure SMRZ, -CD and b-CD molecules. The XPRD pat-
a-CD
geometries of SMRZ/a-CD and SMRZ/b-CD inclusion complexes
with lowest binding energies are presented in Fig. 8. According
to this calculation, there is no possibility for complete encapsula-
tion of SMRZ molecule (long axis ꢃ 12.0564 Å) within the cavity
of CDs with a height of 7.9 Å. Therefore, either the part of the phe-
nyl rings or any one of the aromatic ring can only included into the
cavity. The PM3 results indicates that, (i) the aniline part of SMRZ
is fully encapsulated into the CD nano-cavity, (ii) the pyrimidine
ring having methyl substituent present outside of the cavity and
(iii) the drug molecule prefers to enter the CD cavity from its wider
side rather than the narrower side.
a
tern of SMRZ (Fig. S3a) shows intense peaks at 2h values of
12.28, 14.56, 17.02, 24.21, 30.86 and 32.45, indicates the higher de-
gree of crystallinity of drug. The diffractograms of just mixed sam-
ples showed peaks characteristics of pure components (SMRZ and
CDs), indicating simple superimposition of the drug and CDs. In
contrast, the encapsulation systems in the solid form presented a
quite different diffraction patterns to that of physical mixture,
where the broader peaks with lower intensities were obtained. In
addition, it can be observed the disappearance of characteristic
peaks of SMRZ in the inclusion complexes suggesting that the crys-
tallinity of the drug was further reduced to a greater degree. These
phenomena are an indication of the existence of molecular interac-
tions between the drug and CDs, resulting in an amorphous state.
All of the XPRD results were in well concord with those obtained
by DSC to confirm the encapsulation of SMRZ with CDs in the solid
state.
To investigate the thermodynamics of the encapsulation pro-
cess, thermodynamic parameters of complexes SMRZ/a-CD and
SMRZ/b-CD calculated by PM3 method are summarized in Table 1.
From this table, we can see that the formation energy of b-CD com-
plex (ꢁ1491.60 kcal molꢁ1) is lower than that of
a-CD complex
(ꢁ1272.28 kcal molꢁ1) and the binding energy of SMRZ/b-CD com-
plex is 9.19 kcal molꢁ1 lower than that of SMRZ/
a
-CD. This sug-
-CD
complex. In addition, we can also see that the enthalpy change
H) and entropy change ( S) of both CDs complexes with SMRZ
gests that SMRZ/b-CD complex is more stable than SMRZ/
a
Scanning electron microscopy (SEM)
(D
D
are negative, suggesting that the formation of the encapsulated
complex is an enthalpy-driven process in vacuum phase and the
encapsulation processes are thermodynamically favor in nature.
SEM, which is reliable technique for studying the structural as-
pects of materials and it was employed to investigate the micro-
structures of the inclusion complexes in solid state. The surface
The experimentally determined free energy change (DG) values
morphology of SMRZ,
are presented in Fig. 6. Images of SMRZ sample shows well-defined
bar shape and a mean size of 5–10 m. Pure -CD consisted of
rombhic shaped crystals whereas b-CD sample had platted shaped
crystals. However, the morphology of the inclusion complexes
a
-CD, b-CD and the inclusion complexes
of the inclusion complexes from the stability constant are as fol-
lows: SMRZ/
a
-CD ꢄ abs ꢃ ꢁ3.12 kcal molꢁ1, flu ꢃ ꢁ3.52 kcal molꢁ1
l
a
and SMRZ/b-CD; abs ꢃ ꢁ3.38 kcal molꢁ1, flu ꢃ ꢁ3.70 kcal molꢁ1
.
As can be seen from the above data, the negative values for free en-
ergy change of these complexes means that the encapsulation pro-
cess is a spontaneous and thermodynamically favored in the
experimental temperature range (303 K). In comparison to that of
(Fig. 6c and e) is quite different in shape and size. SMRZ/a-CD
exhibited cylindrically shaped particles and irregularly shaped
crystals were observed for SMRZ/b-CD solids. This difference is
an indicative of the formation of the inclusion complexes of SMRZ
experimental
b-CD complex by PM3 calculations. Positive
served for the SMRZ/ -CD complex indicating that the formation of
D
G values, similar negative magnitude obtained for
D
G magnitude was ob-
with
a
-CD and b-CD.
a

448
N. Rajendiran et al. / Spectrochimica Acta Part A: Molecular and Biomolecular Spectroscopy 124 (2014) 441–450
(a)
μm
5
5 μm
5 μm
(b)
(c)
(e)
(d)
5 μm
5μm
Fig. 6. SEM photographs of (a) SMRZ, (b)
a
-CD, (c) SMRZ/
a-CD, (d) b-CD (e) SMRZ/b-CD nano-encapsulated complexes.
(b)
(a)
200 nm
0.5 μm
Fig. 7. TEM photographs of (a) SMRZ/
a
-CD complex and (b) SMRZ/b-CD complex.
a
-CD encapsulated complex is a non-spontaneous process in vac-
system, which are identified in the structure of optimized com-
plexes. According to Fig. 8, IHB plays an important role in the for-
mation of encapsulated complexes between CDs and SMRZ. The
ASO2ANHA group, tertiary nitrogen in pyrimidine ring and
ANH2 groups of SMRZ are participated in the formation of such
intermolecular interactions. Here, the IHB with a dHꢅ ꢅ ꢅO or dHꢅ ꢅ ꢅN
distances and angles at H atom in these H-bonding ranges from
1.826 to 2.986 Å and from 107.4° to 142.8° respectively, which just
fall in the reported data (>3.0 Å and <90°). However, it can be ob-
served from Fig. 8 that the H-bonding with a minimum distance
uum phase. This deviation can be explained by the solvent effect.
It should be considered that in the entropy of system at aqueous
medium, the release of water molecules from the CD cavity due
to the insertion of guest and the conformational changes of CD mol-
ecule, which occur during the course of molecular encapsulation.
This factor is not considered in the PM3 calculations, since the cal-
culations were made in gas phase.
The stabilization of inclusion complex is supported essentially
by the intramolecular hydrogen bonding (IHB) in the host–guest

N. Rajendiran et al. / Spectrochimica Acta Part A: Molecular and Biomolecular Spectroscopy 124 (2014) 441–450
449
Upper view
Side view
(a)
1.876 Å
1.840 Å
2.784 Å
(b)
1.826 Å
2.966 Å
2.986 Å
Fig. 8. Upper and side view of the optimized structures for the most stable 1:1 encapsulated complexes of SMRZ with (a) a-CD and (b) b-CD obtained by PM3 method. Colors
of the atoms denotes: Blue ꢃ nitrogen, yellow ꢃ sulphur, pale red ꢃ oxygen, white ꢃ hydrogen and grey ꢃ carbon of the molecules respectively. (For interpretation of the
references to colour in this figure legend, the reader is referred to the web version of this article.)
Table 1
Energetic features, thermodynamic parameters, HOMO–LUMO energy calculations and physical properties for SMRZ and its inclusion complexes with
PM3 method.
a- and b-CD obtained by
Properties
SMRZ
a-CD
b-CD
SMRZ/a-CD
SMRZ/b-CD
EHF (kcal molꢁ1
D
)
ꢁ14.09
ꢁ1247.62
ꢁ570.84
ꢁ676.37
0.353
ꢁ1457.75
ꢁ1272.28
ꢁ10.57
ꢁ442.25
ꢁ8.36
ꢁ567.45
12.12
ꢁ1491.60
ꢁ19.76
ꢁ548.27
ꢁ17.67
ꢁ548.27
ꢁ0.33
0.485
ꢁ0.058
ꢁ8.88
ꢁ0.83
ꢁ8.05
9.08
E° (kcal molꢁ1
)
H° (kcal molꢁ1
)
136.95
96.80
0.134
ꢁ667.55
ꢁ789.52
0.409
D
H° (kcal molꢁ1
)
G° (kcal molꢁ1
D
)
G° (kcal molꢁ1
)
S° (kcal/mol-Kelvin)
S° (kcal/mol-Kelvin)
0.419
D
ꢁ0.068
ꢁ8.86
ꢁ0.82
ꢁ8.04
7.56
EHOMO (eV)
ELUMO (eV)
EHOMO–LUMO (eV)
Dipole (D)
ꢁ9.18
ꢁ0.77
ꢁ8.41
5.12
ꢁ10.37
1.26
ꢁ10.35
1.23
ꢁ11.63
ꢁ11.58
11.34
12.29
D
l
g
S
D
ꢁ8.90
ꢁ4.84
4.02
ꢁ8.33
ꢁ4.85
4.02
ꢁ4.97
4.20
0.23
ꢁ4.55
5.81
0.17
ꢁ4.56
5.79
0.17
0.24
0.24
x
2.94
140.06
1.78
635.08
1.79
740.57
2.91
777.48
2.92
883.25
Zero point vibrational energy (kcal molꢁ1
)
D
D
H° = H°complex ꢁ H°SMRZ ꢁ H°CD
S° = S°complex ꢁ S°SMRZ ꢁ S°CD
;
D
G° = G°complex ꢁ G°SMRZ ꢁ G°CD
.
.
between guest and host in SMRZ/b-CD complex. This may explains
why the binding energy of b-CD complex is more in comparison to
that of SMRZ/a-CD.
The HOMO and LUMO orbital isosurfaces of SMRZ obtained by
PM3 method are shown in Fig. S4. The electronic absorption corre-
sponds to the transition from the ground state to the first excited

450
N. Rajendiran et al. / Spectrochimica Acta Part A: Molecular and Biomolecular Spectroscopy 124 (2014) 441–450
singlet state and it principally described by an electron excitation
from the highest occupied molecular orbital (HOMO) to the lowest
unoccupied molecular orbital (LUMO). The HOMO is mainly lo-
cated on the pyrimidine ring and ANHA group. In contrast, LUMO
is delocalized over the whole of CAC bond of benzene ring, CAS
bond and ANH2 group. Moreover, these two orbital significantly
overlapped at the SO2ANH group of SMRZ. Therefore the
HOMO ? LUMO transition implies an electron density transfer to
CAC bond of benzene ring and ANH2 group from the pyrimidine
ring. In addition, the HOMO–LUMO energy gap values for SMRZ
and its encapsulated complexes with CDs are given in Table 1.
The energy gap reflects the chemical stability of substance and
chemicals with larger energy gap values tend to have higher stabil-
ity. The results reported in Table 1 demonstrated that the more
negative energy gap values indicated the encapsulated complexes
are thermodynamically more stable. Thus similar results of energy
gap for both complexes suggested that there will be a analogous
electronic structure of the drug molecule during the molecular
encapsulation and binding. But unexpectedly, the absorption and
emission experimental results in aqueous solution showed the var-
iation in the electronic structure of the guest molecule.
The bond distances (Å), bond angles and the most interesting
dihedral angles (°) of SMRZ molecule before and after encapsula-
tion are listed in Table S1. Table S1 clearly shows that the
PM3 structural parameters of SMRZ were slightly altered in the
encapsulated complexes. The alteration was significant in dihedral
angles, which suggested that the drug adopted a specific conforma-
tion to form a stable complex. As mentioned earlier we also noticed
the conformational changes of CD molecules that occur due to the
guest encapsulation. It was found that the cavity of CD transfer into
an oval shaped cavity. These results revealed that atoms present in
CD cavity play a significant role in binding the SMRZ.
of Hyderabad for his kind help and UGC Networking Resource Cen-
tre, School of Chemistry, University of Hyderabad for providing
facilities. The authors also thank to Dr. P. Ramamurthy, Director,
National centre for ultrafast processes, Madras University for
allowing the fluorescence lifetime measurements for this work.
Appendix A. Supplementary material
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.saa.2014.01.057.
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a-CD and b-CD were
investigated by experimental and molecular modeling methods.
The spectral and PM3 results indicates that, (i) The different spec-
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inclusion complexes are formed, (ii) SMRZ is partially encapsulated
into the CD nano-cavities, (iii) aniline ring deeply present in the b-
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-CD and
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This work is supported by the Council of Scientific and Indus-
trial Research [No. 01(2549)/12/EMR-II] and University Grants
Commission [No. F-351-98/2012 (SR)], New Delhi, India. We are
grateful to Dr. R. Chandrasekar, School of Chemistry, University
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