Spectral, thermal, and molecular modeling studies on the encapsulation of selected sulfonamide drugs in β-cyclodextrin nano-cavity

Article abstract of DOI:10.1016/j.saa.2014.04.136

In the present work the inclusion complexation of three sulfonamide (SA) drugs, namely sulfisoxazole (SSX), sulfamethizole (SMZ), and Sulfamethazine (STM) with β-cyclodextrin (β-CD) has been investigated using UV-Vis spectroscopy, DSC, ¹H NMR spectroscopy, and molecular modeling methods. The binding constant (K_b) of SA:β-CD inclusion complexation was determined via applying the modified form of Benesi-Hildebrand equation employing the changes in absorbance at ^λmax. Obtained results revealed that SA drugs form 1:1 inclusion complex with β-CD with K_b of 650, 1532, 714 M^-1 at 25 °C for SSX, SMZ, and STM, respectively. The UV-Vis absorption spectra displayed solvatochromic behavior of bathochromic shift with decreasing solvent polarity that in turn is good agreement with their behavior in the presence of β-CD in terms of environment polarity dependency. The inclusion complex formation between β-CD and tested SA drugs in liquid and solid states was confirmed by ¹H NMR and DSC, respectively. Using semi-empirical quantum chemistry methods at PM3 theoretical level, inclusion complexes' structures as well as energetic and thermodynamic parameters of encapsulation were elucidated. Obtained results revealed that the encapsulation is favorably energetic and enthalpic in nature with the inclusion of the aniline moiety through the wide rim side of β-CD nano-cavity. Further, molecular modeling revealed that β-CD encapsulation of SA drugs reduced their (E_HOMO - E _LUMO) gap.

Full text of DOI:10.1016/j.saa.2014.04.136

Spectrochimica Acta Part A: Molecular and Biomolecular Spectroscopy 131 (2014) 424–431
Contents lists available at ScienceDirect
Spectrochimica Acta Part A: Molecular and
Biomolecular Spectroscopy
journal homepage: www.elsevier.com/locate/saa
Spectral, thermal, and molecular modeling studies on the encapsulation
of selected sulfonamide drugs in b-cyclodextrin nano-cavity
b
Abdulilah Dawoud Bani-Yaseen a, , Abeer Mo’ala
⇑
a Department of Chemistry & Earth Sciences, College of Arts & Science, Qatar University, P.O. Box 2713, Doha, Qatar
b Department of Chemistry, Faculty of Science, Taibah University, Al-Madinah Al-Munawarah, Saudi Arabia
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
ꢀ
ꢀ
ꢀ
ꢀ
Sulfonamide (SA) drugs SMZ, STM and
SSX form 1:1 inclusion complexes
with b-CD.
Absorption spectra of SA drugs
exhibited b-CD encapsulation and
medium polarity dependency.
1H NMR spectroscopy confirmed
formation of SA:b-CD inclusion
complex in liquid state.
Molecular modeling revealed b-CD
encapsulation of SA drugs abridged
their (EHOMO ꢁ ELUMO) gap.
a r t i c l e i n f o
a b s t r a c t
Article history:
In the present work the inclusion complexation of three sulfonamide (SA) drugs, namely sulfisoxazole
(SSX), sulfamethizole (SMZ), and Sulfamethazine (STM) with b-cyclodextrin (b-CD) has been investigated
using UV–Vis spectroscopy, DSC, 1H NMR spectroscopy, and molecular modeling methods. The binding
constant (Kb) of SA:b-CD inclusion complexation was determined via applying the modified form of Bene-
si–Hildebrand equation employing the changes in absorbance at kmax. Obtained results revealed that SA
drugs form 1:1 inclusion complex with b-CD with Kb of 650, 1532, 714 Mꢁ1 at 25 °C for SSX, SMZ, and
STM, respectively. The UV–Vis absorption spectra displayed solvatochromic behavior of bathochromic
shift with decreasing solvent polarity that in turn is good agreement with their behavior in the presence
of b-CD in terms of environment polarity dependency. The inclusion complex formation between b-CD
and tested SA drugs in liquid and solid states was confirmed by 1H NMR and DSC, respectively. Using
semi-empirical quantum chemistry methods at PM3 theoretical level, inclusion complexes’ structures
as well as energetic and thermodynamic parameters of encapsulation were elucidated. Obtained results
revealed that the encapsulation is favorably energetic and enthalpic in nature with the inclusion of the
aniline moiety through the wide rim side of b-CD nano-cavity. Further, molecular modeling revealed that
b-CD encapsulation of SA drugs reduced their (EHOMO ꢁ ELUMO) gap.
Received 28 January 2014
Received in revised form 13 March 2014
Accepted 14 April 2014
Available online 30 April 2014
Keywords:
b-Cyclodextrin
Inclusion complex
Sulfonamides
Absorption spectroscopy
Environment polarity
Molecular modeling
Ó 2014 Elsevier B.V. All rights reserved.
Introduction
actions are of the host–guest type. Host–guest interactions include
a complementary stereoelectronic order of binding sites in host
Supramolecular interactions exhibit promising applicability in
various industrial and biomedical fields, where most of these inter-
and guest. Studies involving supramolecular host–guest complexes
are a fast advancing research domain in chemistry, where encapsu-
lation of a guest molecule inside the macrocyclic cavity of a host
takes place [1–5]. Interestingly, cyclodextrins (CDs) family is
considered as one of the most popular potential hosts for several
⇑
Corresponding author. Tel.: +97474018575.
E-mail address: abdulilah.baniyaseen@qu.edu.qa (A.D. Bani-Yaseen).
http://dx.doi.org/10.1016/j.saa.2014.04.136
1386-1425/Ó 2014 Elsevier B.V. All rights reserved.

A.D. Bani-Yaseen, A. Mo’ala / Spectrochimica Acta Part A: Molecular and Biomolecular Spectroscopy 131 (2014) 424–431
425
reasons; this includes that they can be produced from ecologically
friendly technologies, potentially considered semi natural products
that are formed from starch via simple enzymatic conversion, they
are relatively financially affordable for most industrial purposes,
they are safe for human consumption and can be used as compo-
nents of medicines, cosmetics, or foods, and more importantly
properties of complex material can be adjusted considerably
through their inclusion complexes. CDs composed of cone-shaped
4-amino-N-(5-methyl-1,3,4-thiadiazol-2-yl)-benzenesulfonamide.
The chemical structures of the selected drugs are shown in Fig. 1.
The inclusion complexes were prepared in aqueous solutions and
solid states and then characterized using UV–Vis and NMR spec-
troscopy, and DSC Thermal analysis, respectively. Moreover,
molecular modeling investigations were conducted as well.
Experimental
cyclic oligosaccharides consisting of an
anose units in their C1 chair conformation. The most common
types of CDs are , b, and which are composed of 6, 7, and 8 glu-
a-(1,4) linkage of glucopyr-
Materials
a
c
copyranose units, respectively, which have the same depth for
b-CD was purchased from Acros Organics. Sulfisoxazole,
sulfamethizole, sulfamethazine sodium, and methanol were sup-
plied by Sigma–Aldrich. Deionized water was used for the prepara-
tion of all solutions. All materials were used without further
purification.
their cavities of ꢂ0.78 nm, whereas their inner cavity diameters
are ꢂ0.57, 0.78, and 0.95 nm, for
a, b, and c respectively [1]. In gen-
eral, these compounds have a characteristic feature of possessing
hydrophobic internal cavity and hydrophilic external surface that
facilitates their solubilization in water [1].
The characteristics properties of CDs facilitate their ability to
form host–guest inclusion complexes with a wide range of suitably
sized guest molecules. In these types of complexes, the guest mol-
ecule is held inside the cavity of the CD molecule. Penetration of
the guest molecule into the cavity can be fully or only partially
[1]. CDs interaction with different types of guest molecules via
inclusion complex formation have found many applications in var-
ious fields; this includes drug carrier [6–8], cosmetics [9], environ-
ment and agricultural protection [10–12], textile industry [13],
catalysis [14–16], chromatography and separation sciences
[17–21], pharmaceutics [22–27], and many other applications. The
inclusion complexes of drugs with CDs have been widely studied
in recent years because of their pharmaceutical interest. CDs can
be considered as a model for proteins and enzymes due to their
interaction with many drugs in a manner similar to that of proteins
and enzymes. In general, the driving forces for forming CD:guest
inclusion complexes have been suggested to be van der Waals
forces, hydrogen bonds, hydrophobic interactions, and the release
of ‘‘high-energy water’’ molecules from the cavity of CDs. Through
configuring of drug–CD complex, no covalent bonds are formed or
broken which stresses the physical rather than the chemical nature
of the procedure. Hence, the encapsulation process of drug mole-
cules by CDs induces significant changes in the properties of a
guest drug molecule [22–30].
Apparatus
Absorption spectra were recorded on Jasco UV–Vis spectropho-
tometer (USA) double-beam spectrophotometer (range 1999–
190 nm) with scan speed of 200 nm minꢁ1 using 1.0 cm quartz cell.
Thermal behavior were examined using DSC 910S Differential
Scanning Calorimeter (TA instrument) equipped with vented alu-
minum pans. Thermograms of ꢂ5 mg samples were obtained by
scanning within a temperature range of 15–250 °C at a scanning
rate of 10 °C/min. The 1H NMR spectra were recorded for all
Sulfa drugs, or sulfonamide drugs (SA), are a class of family of
synthetic drugs used pharmacologically as antimicrobial agents to
treat or prevent many kinds of bacterial inflammations in humans
and animals. Other uses are as hypoglycemics, antitumor, antiviral
drugs, diuretics, antithyroid agents, and some other biological
activities [31]. In general, their structures are characterized by
the presence of SA groups and distinct six- or five-member het-
erocyclic rings. SAs are not readily biodegradable and have many
serious side effects that can cause illnesses in humans, like imbal-
ances in the central nervous system, which in turn requires
comprehension of their various properties, such as their pharma-
cokinetics, pharmacodynamics in humans and animals, and their
physicochemical behavior in different environments. [31–33].
Importantly, although CDs are widely used to form inclusion com-
plexes with different types of drugs for different purposes, there is
still a necessity for investigating such interaction with unstudied
drugs or even deepening and promoting our understanding for
existing ones, this includes the subject of this work, namely
sulfonamide-based drugs [34–35]. In view of this, the main objec-
tive of the present study is to prepare and physically characterize
the inclusion complexes of selected SA drugs with b-CD. The
model drugs used in this study are sulfisoxazole (SSX), or
(4-amino-N-(3,4-dimethyl-1,2-oxazol-5-yl) benzene sulfonamide),
Sulfamethazine (STM), or Sulfadimidine (2-(p-Aminobenzene sul-
fonamido)-4,6-dimethylpyrimidine), and sulfamethizole (SMZ), or
⁄
Fig. 1. Chemical structures of SA drugs; atoms labeled with for computational
purposes.

426
A.D. Bani-Yaseen, A. Mo’ala / Spectrochimica Acta Part A: Molecular and Biomolecular Spectroscopy 131 (2014) 424–431
samples dissolved in D2O on a Bruker AVANCE 400 MHz, where
chemical shifts were relative to the DOH signal at 4.78 ppm.
form of the Benesi–Hildebrand equation that implies a 1:1 inclu-
sion complex was used to calculate the formation constant [36]:
1
1
1
1
¼
þ
ð1Þ
Procedure
D
A
D
e
½guestꢄT
K
bD
e
½guestꢄT ½b-CDꢄT
where
D
A denotes the change in absorbance (
D
A = A ꢁ A0) at kmax in
Stock solution for each drug with
a concentration of
ꢂ 8 ꢃ 10ꢁ4 M was prepared in methanol. Diluted solution of drug
with a concentration 2.6 ꢃ 10ꢁ5 M was prepared by withdrawing
an appropriate volume of drug stock solution, then evaporating
the methanol under relatively low pressure, followed by re-
dissolving the drug residues in appropriate volumes of the solvent
of interest. Inclusion complexes in buffer-free aqueous solutions
were prepared using a diluted solution of the drug prepared in
deionized water with b-CD of a concentration of 10 mM. Quench-
ing experiment was conducted by transferring 2 ml of the drug
diluted solution (2.6 ꢃ 10ꢁ5 M) into a quartz cuvette, then appro-
priate volumes of the inclusion complexes aqueous solutions were
added sequentially to give a series of solutions of the same drug
concentration and different CD concentrations in the range of
0.5–10 mM. Inclusion complex in the solid state was prepared by
mixing the same molar ratio of drug and b-CD in 2 ml of water.
The solution was stirred overnight to dry, and then the solid pre-
cipitate was collected.
the presence of b-CD, (A), and absence of b-CD, (A0); [b-CD]T is the
total concentration of added b-CD,
De is the difference in molar
absorption coefficients for the complex and uncomplexed
compound; [guest]T is the total concentration of drug, and Kb is
the binding constant. Further, Kb has been determined as well as
by a non-linear fit of Benesi–Hildebrand equation implying a 1:1
inclusion complex:
K
bD
e
½guestꢄT½b-CDꢄT
D
A ¼
ð2Þ
1 þ Kb½b-CDꢄT
The effects of b-CD on the UV–Vis absorption spectra of SMZ are
illustrated in Fig. 2 (For simplicity purposes, only results obtained
for SMZ are shown; results of STM and SSX are provided in the
Molecular modeling studies
All molecular modeling and calculations were conducted using
the Gaussian 09 (G09) software package. Semi-empirical quantum
chemistry methods at PM3 theoretical level were utilized for con-
ducting all computational calculations and geometry optimization.
Geometry optimization of the inclusion complex was conducted
via setting the coordinate system as follows: the center of the gly-
cosidic oxygen atoms of b-CD is situated at the origin of the Carte-
sian coordinates, while the tertiary inertial axis and secondary
inertial axis were set at the z-axis and y-axis, respectively; the
guest molecule was coincident with the z-axis toward the wider
rim of the b-CD cavity and manually placed inside the b-CD cavity
⁄
with centering a reference atom (labeled with in Fig. 1) at the
origin of the Cartesian coordinates. Geometry optimization was
followed by conducting frequency calculations for avoiding any
imaginary frequency. Calculations were conducted based on vac-
uum phase without considering the solvation effect.
Fig. 2. Absorption spectra of 2.6 ꢃ 10ꢁ5 M of SMZ in the presence of growing
concentration of b-CD (mM): (a) 0; (b) 0.5; (c) 0.9; (d) 1.3; (e) 1.7; (f) 2.3; (g) 2.9; (h)
3.3; (i) 3.8; (j) 4.1 and (k) 10.
Results and discussion
UV–Vis spectroscopic studies
It is well known that through the inclusion of the guest mole-
cule inside the CD cavity, its spectral characteristics can experience
notable changes. UV–Vis spectrophotometric studies of the inter-
actions of host with guest molecule facilitate determining the sta-
bility constants of the inclusion complexes via employing the
spectral changes associated with the formation of the inclusion
complexes. The solvation shell of the molecule is partially or
completely replaced by the CD molecule, leading to new solute-
environment interactions. In most studied cases, when the CD is
added to an aqueous solution of an organic or inorganic material,
notable changes in the position and intensity of the absorption
spectra can be observed. However, the gradual change in the absor-
bance with the addition of b-CD was attributed to the improved
dissolution of the drug molecules representing the formation of
drug:b-CD inclusion complexes. The changes in the absorbance
intensity of SA drugs molecules upon forming an inclusion com-
plex with b-CD were measured to calculate the Kb. For all data
points an average of three measurements was employed. A linear
Fig. 3. Normalized absorption spectra of SMZ in different solvents.

A.D. Bani-Yaseen, A. Mo’ala / Spectrochimica Acta Part A: Molecular and Biomolecular Spectroscopy 131 (2014) 424–431
427
Table 1
Supplementary data). As can be noticed, the absorption spectra of
SMZ, as well as for the other drugs, showed a decrease in the absor-
bance and also a change in the position of the kmax to longer wave-
lengths (ꢂ2–3 nm shift), i.e. bathochromic effect. This change in the
position of kmax can be attributed to the fact that the drug molecules
were transferred from aqueous phase (polar environments) to the
b-CD cavity (less polar environment). For investigating this phenome-
non further, i.e. the effect of medium polarity on the absorption
spectra of SA drugs, the absorption spectra of all drugs were mea-
sured in solvents of different polarity, as illustrated in Fig. 3. As
can be noticed, a bathochromic shift can be observed in all absorp-
tion spectra of the selected drugs with decreasing solvent polarity.
This behavior is consistent with the results obtained from the effect
of b-CD in terms of the fact that the absorption spectra of the tested
drugs exhibit maxima that are environment polarity dependent.
As the changes in the absorption spectra confirm the formation
of inclusion complex between these drugs with b-CD, Kb for the
formation of inclusion complexes has been identified by analyzing
the changes in the absorbance as a function of the b-CD concentra-
tion. In order to determine the stoichiometry of the inclusion
Calculated binding constant (Kb) values with correlation coefficients (R) of the
inclusion complex.
Drug
Linear relation
Nonlinear relation
Kb (Mꢁ1
)
R
Kb (Mꢁ1
)
R
SSX-b-CD
SMZ-b-CD
STM-b-CD
650
1532
714
0.991
0.993
0.993
682
1430
245
0.984
0.996
0.986
Fig. 5. Benesi–Hildebrand plot of 1/D
A versus 1/[b-CD]2 for the tested complexes.
complex, the correlation between the drug absorbance and b-CD
concentration was analyzed using Benesi–Hildebrand relation
[23,36,37]. The linear form of the Benesi–Hildebrand relation pro-
vided in Eq. (1) was applied against all obtained absorbance data.
As illustrated in Fig. 4A, the plot of 1/DA versus 1/[b-CD] yielded
a linear correlation. Calculating Kb of the inclusion complex was
performed through the slope/intercept ratio of the linear plots.
Obtained values with the corresponding correlation coefficients
(R) are compiled in Table 1. The results obtained from Fig. 4B
revealed that the linear from of Benesi–Hildebrand relation applied
on the three drugs of interest can be expressed as:
1
0:0299
Kb½B-CDꢄT
¼ ꢁ19:441 ꢁ
¼ ꢁ21:665 ꢁ
¼ ꢁ11:148 ꢁ
ðSSXÞ
ðSMZÞ
ðSTMÞ
ð3Þ
ð4Þ
ð5Þ
D
A
1
0:0141
Kb½B-CDꢄT
D
A
1
0:1562
Kb½B-CDꢄT
D
A
On the other hand, applying the nonlinear form of the Benesi–
Hildebrand relation (Eq. (2)) was applied as well. As illustrated in
Fig. 4B, the plot of A versus [b-CD] yielded a nonlinear relationship
D
with R as compiled in Table 1. It can be noted that applying both
forms of Benesi–Hildebrand relation yielded approximately similar
values of Kb for the tested drugs. Furthermore, it is noteworthy
mentioning that the calculated Kb for these drugs are comparable
with reported values of Kb for the inclusion complexation of b-CD
with various guest molecules that share high structural resem-
blances with the sulfonamide drugs examined in this work [34,35].
Interestingly, the results obtained from the linear and nonlinear
forms of Benesi–Hildebrand relation indicate that for all three
Fig. 4. Benesi–Hildebrand plot of (A) 1/DA versus 1/[b-CD] and (B) DA versus [b-CD]
for the tested complexes.

428
A.D. Bani-Yaseen, A. Mo’ala / Spectrochimica Acta Part A: Molecular and Biomolecular Spectroscopy 131 (2014) 424–431
Table 2
linear form of the Benesi–Hildebrand relation with 1/[b-CD]
replaced by 1/[b-CD]2 in Eq. (1) was employed:
1H chemical shift (d/ppm) of SA drugs before and after forming inclusion complexes
with b-CD (D2O, 400 MHz).
1
1
1
1
d (ppm)
¼
þ
ð6Þ
2
D
A
D
e
½guestꢄT
K
bD
e
½guestꢄT
½b-CDꢄT
H-a*
H-b*
7.500
7.510
ꢁ0.010
7.605
7.600
0.005
7.600
7.605
H-c*
1.571
1.650
ꢁ0.071
2.400
H-d*
2.000
2.080
ꢁ0.080
–
SSX
SSX-b-CD
6.775
6.675
0.100
6.705
6.700
0.005
6.660
6.650
0.010
Plotting 1/D
A versus 1/[b-CD]2 yielded nonlinear correlation
confirming that 1:2 inclusion complex is much less probable to
be formed as shown in Fig. 5.
D
d
SMZ
SMZ-b-CD
2.450
–
–
D
d
ꢁ0.050
Thermal characterization
STM
STM-b-CD
2.025
6.350
6.377
ꢁ0.027
2.050
ꢁ0.025
Thermal analysis, DSC in particular, is one of the most fre-
quently applied tools that can be used for characterizing solid-state
interactions between drugs and CDs. When guest molecules are
included into b-CD cavities, their boiling, melting, or sublimating
points usually disappeared or shifted to different temperatures.
DSC thermograms for pure STM, physical mixture and inclusion
complexes of STM-b-CD are shown in Fig. S5. Thermograms were
analyzed qualitatively through examining both the peak tempera-
tures and endothermic transition curves. As can be noticed from
Fig. S5, STM exhibits sharp endothermic peak at approximately
D
d
ꢁ0.005
D
*
d = d(SA) ꢁ d(SA-b-CD).
Letters indicate the protons as labeled in Figs. 7, S5 and S6.
inclusion systems the stoichiometric ratio for the inclusion com-
plexes is 1:1, i.e. one drug molecule included in the cavity of one
b-CD molecule. To further confirm that these drugs form an 1:1
inclusion complex with b-CD and not 1:2 stoichiometric ratio, a
Fig. 6. 1H NMR of SMZ-b-CD system.
Fig. 7. Schematic for the coordinate system used for the inclusion complexation of different parts of SMZ molecule inside the b-CD cavity A and B correspond to inclusion of -
Aniline and -L groups through the wide rim of b-CD, respectively.

A.D. Bani-Yaseen, A. Mo’ala / Spectrochimica Acta Part A: Molecular and Biomolecular Spectroscopy 131 (2014) 424–431
429
Fig. 8. Side and top views of SMZ-b-CD for Aniline (A) and L (B) groups’ inclusion.
140 °C that is characteristic meting point of crystalline anhydrous
STM, whereas a broad endothermic peak was observed for b-CD
that is attributed to the presence of trapped water molecules inside
the cavity. On the other hand, the physical mixture was examined
for comparison purposes, where its profile exhibits two endother-
mic bands at approximately 140 and 125 °C that correspond to
STM and b-CD in the solid state, respectively. Interestingly, the
DSC thermogram of STM-b-CD exhibits a disappearance of STM
endothermic peak at ꢂ140 °C and a notable shift in the position
of the b-CD peak toward lower temperature with relatively
reduced temperature. The obtained results for STM:b-CD system
is an evidence for the formation of inclusion complex in the solid
state, which are interestingly consistent with DSC thermograms
reported for other SA drugs [35].
1H NMR studies
1H NMR spectroscopy is a powerful technique and is particu-
larly useful as it provides direct and detailed evidence and infor-
mation on the dynamics of the system and on the individual
nuclei which are involved in forming the inclusion complex [38].
The formation of inclusion complexes generally is associated with
notable change of the chemical environment of guest molecules
with a subsequent effect on the chemical shift values of both host
and guest protons. All spectra were collected using D2O as a sol-
vent for minimizing any potential solvent effect during the inclu-
sion complexation process. 1H NMR spectra were collected for all
tested drugs in the form of free drug and b-CD, and SA:b-CD inclu-
sion complex. Obtained 1H NMR spectral data in terms of chemical
Table 3
Thermodynamic and energetic properties of the inclusion complexes formation of
b-CD with SA drugs.
Properties
SSX
SMZ
STM
Aniline
L
Aniline
L
Aniline
L
Ebinding (kcal/mol) ꢁ15.694 ꢁ12.655 ꢁ10.849 ꢁ5.390 ꢁ10.135 ꢁ12.808
D
D
D
H (kcal/mol)
G (kcal/mol)
S (kcal/mol K)
ꢁ15.554 ꢁ12.706 ꢁ10.210 ꢁ4.645 ꢁ10.245 ꢁ12.465
0.658 2.974 3.817 7.187 6.232 3.219
ꢁ0.001 ꢁ0.053 ꢁ0.047 ꢁ0.040 ꢁ0.055 ꢁ0.053
Table 4
Calculated HOMO–LUMO energy for SA drugs and their inclusion complexes with b-CD.
Orbital
SSX
SMZ
STM
Free drug
Aniline-inclusion
L-inclusion
Free drug
Aniline-inclusion
L-inclusion
Free drug
Aniline-inclusion
L-inclusion
HOMO (eV)
LUMO (eV)
D
ꢁ0.332
ꢁ0.036
ꢁ0.296
ꢁ0.341
ꢁ0.045
ꢁ0.295
ꢁ0.347
ꢁ0.047
ꢁ0.300
ꢁ0.340
ꢁ0.042
ꢁ0.299
ꢁ0.346
ꢁ0.056
ꢁ0.290
ꢁ0.337
ꢁ0.052
ꢁ0.285
ꢁ0.338
ꢁ0.025
ꢁ0.314
ꢁ0.346
ꢁ0.038
ꢁ0.308
ꢁ0.336
ꢁ0.029
ꢁ0.307
E* (eV)
*
D
E = EHOMO ꢁ ELUMO
.

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A.D. Bani-Yaseen, A. Mo’ala / Spectrochimica Acta Part A: Molecular and Biomolecular Spectroscopy 131 (2014) 424–431
shift observed for SA:b-CD systems are compiled in Table 2. Fig. 6
display the 1H NMR spectra for SMZ system. 1H NMR spectra of SSX
and STM systems are displayed in Figs. S6 and S7, respectively. As
can be noticed from Table 2, all tested drugs experienced chemical
shift changes in the range of approximately 0.005–0.100 ppm. Such
change can be probably associated with changes in the local polar-
ity around the drugs molecules as well as the confinement of the
drug molecules inside the nano-cavity of b-CD. Hence, these results
confirm the formation of SA:b-CD inclusion complexes in the liquid
state. Obtained results are in good agreements with reported
results of other sulfa drugs [34,35]. However, the change in chem-
ical shift was observed for all proton types of the two substituents,
namely aniline and ligand, either as upfield or/and downfield
change. This in turn promotes the possibilities for forming the
inclusion complex SA:b-CD via either confining the aniline or the
ligand inside the b-CD cavity with fair preferences for the inclusion
of the aniline moiety; a result that is in high agreement with those
obtained from the computational investigations.
Energetic (Ebinding) and thermodynamic parameters, namely
DH,
D
G, and S, accompanying the formation of 1:1 inclusion complex
D
between the tested drugs molecules and b-CD were calculated at
298.15 K and 1.0 atm. All parameters were calculated via applying
the following equation:
D
Ecomplexation ¼ Edrug:b-CD ꢁ ðEfree drug þ Efreeb-CD
Þ
ð7Þ
where Ecomplexation corresponds to the energetic or thermodynamic
parameter of the inclusion complexation process, whereas Edrug:b-CD
,
Efree and Edrug:b-CD represents the same parameter for
,
drug
drug-b-CD inclusion complex, free drug, and free b-CD, respectively.
Obtained results considering all energetic and thermodynamic
parameters for all possible orientations, namely aniline and ligand
inclusions, of the inclusion complexes of the tested drugs with
b-CD are compiled in Table 2.
The results in Table 2 indicate that the complexation energies
are negative, which in turn implies that the inclusion processes of
the tested drugs with b-CD are thermodynamically favorable. The
lowest values for Ebinding represent the most stable complex that
can be formed between drug and b-CD. Top and side views for the
computationally optimized structures of SMZ-b-CD are displayed
in Fig. 8. Optimized structures for the other two drugs are provided
in Figs. S8 and S9. Frequency calculation conducted revealed no
imaginary frequency for any of the optimized geometries for all
tested drugs. It can be observed that the approaches of the aniline
groups for each of the three drugs from the wide rim of b-CD yielded
approximately complete inclusion inside the b-CD cavity, whereas
the L groups for each of the three drugs yielded an incomplete inclu-
sion inside b-CD cavity, which on the other hand varies depending
on the size and type of the ligand. The calculated Ebinding for the
SA:b-CD systems are lower than that of the free b-CD indicating sta-
bilization after forming the inclusion complexes. Moreover, the cal-
culated Ebinding for the tested drugs indicates that orientation of the
aniline group inside the cavity of b-CD is fairly favored over ligand
Computational studies
The focal benefit of performing computational studies is provid-
ing insights regarding the inclusion process that can support the
experimental results. The calculations for the three drugs were
performed based on their tendency to form 1:1 inclusion com-
plexes. In order to supply comprehensive computational analysis,
two main approaches were considered with inclusion through
the wide rim of b-CD cavity. In particular, two parts of the tested
drug molecules were permitted to penetrate inside the b-CD cavity.
Consequently, each drug molecule would form an inclusion com-
plex with b-CD in diversity of two orientations, namely the aniline
and ligand (L) groups. Schematics that illustrate these two
approaches are shown in Fig. 7.
Fig. 9. HOMO and LUMO of SMZ-b-CD system.

A.D. Bani-Yaseen, A. Mo’ala / Spectrochimica Acta Part A: Molecular and Biomolecular Spectroscopy 131 (2014) 424–431
431
orientation for STM-b-CD and SSX-b-CD systems, whereas it is nota-
bly favored for SMZ-b-CD. For all tested drugs, negative values were
obtained for H and Ebinding indicating the enthalpic and energetic,
respectively, favorability of the encapsulation process, whereas a
positive value for G indicates a non-spontaneous process. Con-
Appendix A. Supplementary material
D
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.saa.2014.04.136.
D
versely, the indication of a nonspontaneous process herein disputes
that the encapsulation process is enthalpic and energetic favorable
by nature. The quantum mechanical semi empirical calculation was
conducted in vacuum implying no contribution from the solvent
molecules, which in fact retards the conclusion driven from the
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Concluding remarks
The inclusion complexation of selected sulfonamide derived
drugs, namely SSX, SMZ, and STM with b-CD has been theoretically
and experimentally characterized. Results obtain using UV–vis
spectroscopy revealed that tested SA drugs can form 1:1 inclusion
complexes with b-CD, where SMZ-b-CD exhibited the strongest
binding with Kb of ꢂ1500 Mꢁ1. Formation of SA:b-CD inclusion
complexes in solid and liquid state has been further confirmed
using DSC and 1H NMR, respectively. Molecular modeling results
revealed that the b-CD encapsulation of SA drugs is fairly and
exceedingly favorable for STM and SSX, and SZM, respectively,
through the inclusion of aniline moiety from the side of the wide
rim of b-CD. Interestingly, the results obtained in this work can
provide informative insights concerning the potential behavior of
the tested drugs in different environments.