Spectroscopic and thermal investigations on the charge transfer interaction between risperidone as a schizophrenia drug with some traditional π-acceptors: Part 2

Article abstract of DOI:10.1016/j.molstruc.2012.12.021

The focus of present investigation was to assess the utility of non-expensive techniques in the evaluation of risperidone (Ris) in solid and solution states with different traditional π-acceptors and subsequent incorporation of the analytical determination into pharmaceutical formulation for a faster release of risperidone. Charge-transfer complexes (CTC) of risperidone with picric acid (PA), 2,3-dichloro-5,6-dicyano-p-benzoquinon (DDQ), tetracyanoquinodimethane (TCNQ), tetracyano ethylene (TCNE), tetrabromo-p-quinon (BL) and tetrachloro-p-quinon (CL) have been studied spectrophotometrically in absolute methanol at room temperature. The stoichiometries of the complexes were found to be 1:1 ratio by the photometric molar ratio between risperidone and the π-acceptors. The equilibrium constants, molar extinction coefficient (ε_CT) and spectroscopic-physical parameters (standard free energy (ΔG^o), oscillator strength (f), transition dipole moment (μ), resonance energy (R_N) and ionization potential (I_D)) of the complexes were determined upon the modified Benesi-Hildebrand equation. Risperidone in pure form was applied in this study. The results indicate that the formation constants for the complexes depend on the nature of electron acceptors and donor, and also the spectral studies of the complexes were determined by (infrared, Raman, and ¹H NMR) spectra and X-ray powder diffraction (XRD). The most stable mono-protonated form of Ris is characterized by the formation of ⁺NH (pyrimidine ring) intramolecular hydrogen bonded. In the high-wavenumber spectral region ～3400 cm^-1, the bands of the ⁺NH stretching vibrations and of the pyrimidine nitrogen atom could be potentially useful to discriminate the investigated forms of Ris. The infrared spectra of both Ris complexes are confirming the participation of ⁺NH pyrimidine ring in the donor-acceptor interaction.

Full text of DOI:10.1016/j.molstruc.2012.12.021

Journal of Molecular Structure 1036 (2013) 464–477
Contents lists available at SciVerse ScienceDirect
Journal of Molecular Structure
journal homepage: www.elsevier.com/locate/molstruc
Spectroscopic and thermal investigations on the charge transfer interaction between
risperidone as a schizophrenia drug with some traditional
p-acceptors: Part 2
Abeer A. El-Habeeb a, Foziah A. Al-Saif a, Moamen S. Refat b,c,
⇑
a Department of Chemistry, Faculty of Science, Princess Nora Bint Abdul Rahman University, Riyadh, Saudi Arabia
b Department of Chemistry, Faculty of Science, Port Said University, Port Said, Egypt
c Department of Chemistry, Faculty of Science, Taif University, 888 Taif, Saudi Arabia
h i g h l i g h t s
"
"
"
"
Spectroscopic studies on the reaction between risperidone with p-acceptors.
Synthesis of charge transfer complex of some nervous and brain drugs.
The stoichiometry of these complexes was found to be 1:1 M ratio.
These complexes were also tested for their antimicrobial activity.
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 4 October 2012
Received in revised form 8 December 2012
Accepted 10 December 2012
Available online 22 December 2012
The focus of present investigation was to assess the utility of non-expensive techniques in the evaluation
of risperidone (Ris) in solid and solution states with different traditional -acceptors and subsequent
p
incorporation of the analytical determination into pharmaceutical formulation for a faster release of ris-
peridone. Charge-transfer complexes (CTC) of risperidone with picric acid (PA), 2,3-dichloro-5,6-dicyano-
p-benzoquinon (DDQ), tetracyanoquinodimethane (TCNQ), tetracyano ethylene (TCNE), tetrabromo-p-
quinon (BL) and tetrachloro-p-quinon (CL) have been studied spectrophotometrically in absolute meth-
anol at room temperature. The stoichiometries of the complexes were found to be 1:1 ratio by the pho-
Keywords:
Spectroscopic
Charge-transfer complexes
Risperidone
tometric molar ratio between risperidone and the
extinction coefficient ( CT) and spectroscopic-physical parameters (standard free energy (
strength (f), transition dipole moment ( ), resonance energy (RN) and ionization potential (ID)) of the
p
-acceptors. The equilibrium constants, molar
e
D
Go), oscillator
l
p-Acceptors
complexes were determined upon the modified Benesi–Hildebrand equation. Risperidone in pure form
was applied in this study. The results indicate that the formation constants for the complexes depend
on the nature of electron acceptors and donor, and also the spectral studies of the complexes were deter-
mined by (infrared, Raman, and 1H NMR) spectra and X-ray powder diffraction (XRD). The most stable
mono-protonated form of Ris is characterized by the formation of +NAH (pyrimidine ring) intramolecular
hydrogen bonded. In the high-wavenumber spectral region ꢀ3400 cmꢁ1, the bands of the +NAH stretch-
ing vibrations and of the pyrimidine nitrogen atom could be potentially useful to discriminate the inves-
tigated forms of Ris. The infrared spectra of both Ris complexes are confirming the participation of +NAH
pyrimidine ring in the donor–acceptor interaction.
Ó 2012 Elsevier B.V. All rights reserved.
1. Introduction
Risperidone is a tetrahydropyrido[1,2-a]-pyrimidin-4-one deriva-
tive with 6-fluoro-3-(4-piperidinyl)-1,2-benzisoxazole group, as
Risperidone (Scheme 1) is used for the treatment of schizophre-
nia, bipolar disorder and behaviour problems in people with aut-
ism. Risperidone represents atypical neuroleptics and is classified
on the basis of chemical constitution among neuroleptics that are
derivatives of various heterocyclic systems with cyclic structure.
shown below [1,2].
By contrast little is known about the protonated forms of Ris. At
physiological pH of 7.4 Ris exists in prevalence as a mono-proton-
ated species in equilibrium with the neutral form (pK1 = 8.1–8.6)
and as a di-protonated compound in acidic conditions (pK2 = 3.1)
[3,4]. Since protolytic equilibria play a crucial role in controlling
absorption, distribution and metabolic processes of pharmacologi-
cally active substances [5], it is extremely important to investigate
protonation effects on structural and physico-chemical properties.
⇑
Corresponding author at: Department of Chemistry, Faculty of Science, Port Said
University, Port Said, Egypt.
E-mail address: msrefat@yahoo.com (M.S. Refat).
0022-2860/$ - see front matter Ó 2012 Elsevier B.V. All rights reserved.
http://dx.doi.org/10.1016/j.molstruc.2012.12.021

A.A. El-Habeeb et al. / Journal of Molecular Structure 1036 (2013) 464–477
465
2.2. Synthesis of charge transfer complexes of Ris drug donor
12
O
22
6
23
7
N
19
20
18
O
5
The six risperidone solid charge transfer complexes with gen-
eral formula [(Ris)(p-acceptor)] were synthesized as a solid col-
17
15
N
13
4
24
8
21
29
25
26
ours, by mixing a (0.25 mmol, 0.103 g) of risperidone drug in
20 ml methanol to a 0.25 mmol of each acceptors; PA (0.06 g),
DDQ (0.06 g), TCNQ (0.051 g), TCNE (0.032 g), p-BL (0.105 g) and
p-CL (0.061 g) in 20 ml methanol solvent. All mixtures were stirred
for 45 min at room temperature and the solid products were fil-
tered off, washed with minimum amounts of chloroform and dried
under vacuum over anhydrous CaCl2.
3
N
10
14
9
N
1
2
16
28
11
F
27
30
Scheme 1. Risperidone (Ris) drug.
2.3. Physical measurements and analytical estimations
Structures of Ris in the neutral [6] and mono-protonated [7]
forms were determined in the solid, establishing that protonation
occurs preferentially at the N(1) or N(15) nitrogen atoms [8–10]
of the pyrimidine or piperidine rings (Scheme 1). IR and Raman
spectroscopy are widely employed to characterize pharmaceutical
compounds [11,12] and to investigate effects of protonation
which can be very significant, as documented in many recent
experimental and theoretical works [13,14]. Donor–acceptor
interactions are vital and important subject in biochemical and
bioelectrochemical energy transfer process [15]. The charge trans-
fer complexes have been widely studied spectrophotometrically
in the determination of the drug based on the CT complexes
The elemental analyses of carbon, hydrogen and nitrogen con-
tents were performed using a Perkin Elmer CHN 2400. The molar
conductivities of freshly prepared 1.0 ꢂ 10ꢁ3 mol/cm3 dimethyl-
sulfoxide (DMSO) solutions were measured for the dissolved Ris
complexes using Jenway 4010 conductivity meter. The electronic
absorption spectra of the resulted charge transfer complexes were
recorded in methanol within 800–200 nm range using a Perkin-El-
mer Precisely Lambda 25 UV/Vis double beam Spectrometer fitted
with a quartz cell of 1.0 cm path length. Infrared spectra within the
range of 4000–400 cmꢁ1 for the free reactants and the resulted CT-
complexes were recorded from KBr discs using a Shimadzu FT-IR
Spectrometer with 30 scans and 2 cmꢁ1 resolution, while Raman
laser spectra of samples were measured on the Bruker FT-Raman
with laser 50 mW. 1H NMR was recorded as DMSO solutions on a
Bruker 600 MHz spectrometer using TMS as the internal standard.
TG–DTG thermograms of the Ris charge transfer complexes were
obtained on a Shimadzu TGA-50H. Samples in solid form were
placed in platinum pans with a pierced lid, and heated rate of
30 °C minꢁ1 under static air flow. Scanning electron microscopy
(SEM) images and Energy Dispersive X-ray Detection (EDX) were
taken in Joel JSM-6390 equipment, with an accelerating voltage
of 20 kV. The X-ray diffraction patterns for both risperidone com-
plexes were recorded on Bruker Advanced X-ray powder diffrac-
formation with some
p-acceptors [16–18]. The interactions of
the charge-transfer complexes are well known in many chemical
reactions such as addition, substitution and condensation [16,19].
The molecular interactions between electron donors and accep-
tors are generally associated with the formation of intensely col-
oured charge transfer complexes, which absorb radiation in the
visible region [20]. Electron donor–acceptor CT-interactions are
also important in the field of drug–receptor binding mechanism
[21], in solar energy storage [22] and in surface chemistry [22]
as well as in many biological fields [21]. On the other hand, the
CT-reactions of
p-acceptors have successfully utilized in pharma-
ceutical analysis [23] and electrochemical properties [24,25].
Many drugs are easy to be determined by spectrophotometric
methods based on formation of coloured charge-transfer (CT)
tion, target Cu K
a radiation, step scan mode with step = 0.05°
and counting time 3.0 s/step.
complexes between electron acceptors, either
r- or p-acceptors
and drugs as electron donors [26,27] or formation of coloured
compounds with a number of organic acid dyes. In continuation
of our studies of charge transfer complexes [28–30], the main
aim of this paper is to develop fast, simple, inexpensive methods
that can readily be adapted for routine analysis at relatively low
cost to the different requirements of analytical problems. To the
best of our knowledge, little attentions have been made to deter-
mine risperidone using charge transfer interaction method and
the literature are still poor in such analytical procedure. The
methods are based on the ability of the cited drug to form ion
associations with PA, DDQ, TCNQ, TCNE, p-BL and p-CL. The spec-
tral characteristic and the stability of the formed ion associate
were also included.
2.4. Antibacterial and antifungal activities
Antimicrobial activity of the tested samples was determined
using a modified Kirby–Bauer disc diffusion method [31]. Briefly,
100
ia until they reached a count of approximately108 cells/ml for bac-
teria or 105 cells/ml for fungi [32]. 100 l of microbial suspension
ll of the best bacteria/fungi were grown in 10 ml of fresh med-
l
was spread onto agar plates corresponding to the broth in which
12
22
N
6
O
23
7
19
20
18
5
N
O
17
13
4
24
8
21
29
25
26
N15
3
10
14
9
N
2
16
28
11
2. Experimental
1
F
27
30
2.1. Chemicals and reagents
Protonation
O
All chemicals and reagents used in this study were of
analytical grade. Risperidone was received from Egyptian Interna-
tional Pharmaceutical Industries Company EIPICO. Picric acid (PA),
2,3-dichloro-5,6-dicyano-p-benzoquinon (DDQ), tetracyanoquino-
dimethane (TCNQ), tetracyano ethylene (TCNE), tetrabromo-p-
quinon (BL) and tetrachloro-p-quinon (CL) were obtained from
Merck and Aldrich Chemical Companies.
N
O
N
N
N
H
F
Scheme 2. Protonation of Ris in N(1)AH atom.

466
A.A. El-Habeeb et al. / Journal of Molecular Structure 1036 (2013) 464–477
they were maintained. Isolated colonies of each organism that
might be playing a pathogenic role should be selected from pri-
mary agar plates and tested for susceptibility by disc diffusion
method [33,34]. Of the many media available, National Committee
for Clinical Laboratory Standards (NCCLS) recommends Mueller–
Hinton agar due to: it results in good batch-to-batch reproducibil-
ity. Disc diffusion method for filamentous fungi tested by using ap-
proved standard method (M38-A) developed by the NCCLS [35] for
evaluating the susceptibility of filamentous fungi to antifungal
agents. Disc diffusion method for yeast developed standard meth-
od (M44-P) by the NCCLS [36]. Plates inoculated with filamentous
fungi as Aspergillus flavus at 25 °C for 48 h; Gram (+) bacteria as
Staphylococcus aureus, Bacillus subtilis; Gram (ꢁ) bacteria as
Escherichia coli, Pseudomonas aeruginosa they were incubated at
35–37 °C for 24–48 h and yeast as Candida albicans incubated at
30 °C for 24–48 h and, then the diameters of the inhabitation zones
were measured in millimeters [31]. Standard discs of Tetracycline
(Antibacterial agent), Amphotericin B (Antifungal agent) served as
positive controls for antimicrobial activity but filter disc impreg-
6
5
4
3
2
1
0
PA
DDQ
TCNQ
TCNE
BL
p-CL
nated with 10 ll of solvent (distilled water, chloroform, DMSO)
were used as a negative control.
The agar used is Meuller–Hinton agar that is rigorously tested
for composition and pH. Further the depth of the agar in the plate
is a factor to be considered in the disc diffusion method. This meth-
od is well documented and standard zones of inhabitation have
been determined for susceptible values. Blank paper disks
(Schleicher and Schuell, Spain) with a diameter of 8.0 mm were
200
300
400
500
600
700
800
900
impregnated 10 ll of tested concentration of the stock solutions.
Wavelength (nm)
When a filter paper disc impregnated with a tested chemical is
placed on agar the chemical will diffuse from the disc into the agar.
This diffusion will place the chemical in the agar only around the
disc. The solubility of the chemical and its molecular size will
determine the size of the area of chemical infiltration around the
disc. If an organism is placed on the agar it will not grow in the area
around the disc if it is susceptible to the chemical. This area of no
growth around the disc is known as a ‘‘Zone of inhibition’’ or ‘‘Clear
zone’’. For the disc diffusion, the zone diameters were measured
with slipping calipers of the National for Clinical Laboratory Stand-
ers [33]. Agar-based methods such as Etest disk diffusion can be
good alternatives because they are simpler and faster than broth
methods [37,38].
Fig. 1. Electronic absorption spectra of [(Ris)(p-acceptor)] charge transfer com-
plexes in methanol solvent.
The chemical formulas, molecular weights, conductivity, yield,
colours as well as elemental analysis CHN of risperidone charge
transfer complexes were listed in Table 1. The percentage of ele-
ments (carbon, hydrogen and nitrogen) agreement with the
1:1 M ratios between Ris drug (base) and some traditional
p-
acceptors like PA, DDQ, TCNQ, TCNE, BL and p-CL. The conductivity
measurements of starting materials and resulted Ris charge trans-
fer complexes were performed in DMSO with 1.0 ꢂ 10ꢁ3 mol/dm3
concentration. The conductivities of risperidone CT-complexes
were listed in Table 1. The molar conductance values of Ris com-
3. Results and discussions
plexes inserted within 38 and 45
X
ꢁ1 cmꢁ1 molꢁ1 region. The con-
ductance values indicate that the charge transfer complexes have
slightly electrolytic nature. Slightly electrolytic complexes as-
signed to the formation of positive and negative datives anions un-
der the donor–acceptor chelation [40].
The risperidone drug has high electron density sites, so it may
act as a powerful electron donor. The structure of Ris is shown in
Scheme 1. As can be seen the existence of a pyrimidine ring in
the structure of Ris after protonation of N(1)AH [39] (Scheme 2)
acts as a base and n-donor to form a charge transfer complex with
an
p-acceptors. Sphectrophotometric properties of the coloured CT
3.1. Electronic spectra studies
complexes as well as the different parameters affecting the colour
development between the different acceptors and Ris drug were
extensively spectroscopically studied to determine the optimal
conditions for chelation behaviour.
The electronic spectra of PA, DDQ, TCNQ, TCNE, BL and p-CL of
risperidone charge-transfer complexes were measured in a pure
grade of methanol solvent. The CT complexes are formed by adding
Table 1
Analytical and physical data for risperidone charge transfer complexes.
Compound (M. wt. g/mol)
Colour
Km (X
ꢁ1 cmꢁ1 molꢁ1
)
Elemental analysis (%) found (calcd.)
Yield (%)
C
H
N
Ris 410.485
White
19
43
40
45
38
39
38
67.24
6.58
13.64
–
[(Ris)(PA)] 641.604
[(Ris)(DDQ)] 639.504
[(Ris)(TCNQ)] 616.687
[(Ris)(TCNE)] 540.591
[(Ris)(BL)] 851.214
[(Ris)(p-CL)] 673.410
Shiny yellow
Shiny brown
Dark brown
Brown
Brown
Brown
54.09 (54.29)
58.01 (58.22)
67.97 (68.17)
64.33 (64.43)
42.19 (42.33)
53.44 (53.51)
4.97 (5.03)
4.43 (4.57)
5.31 (5.39)
5.21 (5.41)
3.44 (3.79)
4.65 (4.79)
14.98 (15.28)
12.87 (13.14)
18.11 (18.17)
20.39 (20.73)
6.45 (6.58)
8.21 (8.32)
98
97
72
81
75
98

A.A. El-Habeeb et al. / Journal of Molecular Structure 1036 (2013) 464–477
467
X ml of 5.0 ꢂ 10ꢁ4 M (PA, DDQ, TCNQ, TCNE, BL and p-CL) where
(X = 0.25, 0.50, 0.75, 1.00, 1.50, 2.00, 2.50 and 3.00 ml) to 1.00 ml
of 5.0 ꢂ 10ꢁ4 M Ris. The total volume of each system was com-
pleted to 5 ml with CH3OH solvent. The concentration of Ris in
the reaction mixture was kept fixed at 1.00 ꢂ 10ꢁ4 M in CH3OH sol-
vent, while the concentration of PA, DDQ, TCNQ, TCNE, BL or p-CL
was varied over the range of 0.25 ꢂ 10ꢁ4 M to 3.00 ꢂ 10ꢁ4 M for
in methanol together with the reactants (
p
-acceptor) are shown in
Fig. 1a–f. The spectra reveal the characterization of the real absorp-
tion bands which are not present in the spectra of free reactants.
These bands are assigned at 436 nm, 406 nm, (739 and 837 nm),
500 nm, 536 nm and 450 nm due to the CT complexes formed in
the reaction of Ris with PA, DDQ, TCNQ, TCNE, BL and p-CL, respec-
tively, in methanol solvent. Photometric titration curves based on
these characterized absorption bands are given in Fig. 2. These
photometric titration curves were obtained according to known
methods [41] by the plot of the absorbance against the X ml added
Ris/
p
-acceptor systems in CH3OH solvent. These concentrations
produce Ris:
p-acceptor ratios extending along the range from
1:0.25 to 1:3.00. The electronic absorption spectra of the 1:1 ratios
1.5
1.04
6
3.18
5
1.0
500 nm
436 nm
1.02
4
3.17
3
0.5
2
3.16
3.15
3.14
3.13
3.12
1
0
1.00
TCNE
400
0.0
PA
450
500
550
600
Wavelength (nm)
300
350
400
450
500
Wavelength (nm)
0.98
0.96
0.94
1 : 1 ratio
0.5 1.0
1 : 1 ratio
0.5 1.0
0.0
1.5
2.0
2.5
3.0
0.0
1.5
2.0
2.5
3.0
ml added of PA
ml added of TCNE
0.6
0.48
0.46
0.44
0.42
0.40
0.38
0.36
0.34
0.32
0.30
3.45
3.40
3.35
3.30
3.25
3.20
6
5
4
3
2
1
0
0.4
0.2
0.0
536 nm
407 nm
BL
350 400 450 500 550 600 650
Wavelength (nm)
DDQ
250 300 350 400 450 500
Wavelength (nm)
1 : 1 ratio
1 : 1 ratio
0.0
0.5
1.0
1.5
2.0
2.5
3.0
0.0
0.5
1.0
1.5
2.0
2.5
3.0
ml added of BL
ml added of DDQ
2.0
1.5
1.0
0.5
0.0
1.38
1.36
1.34
1.32
1.30
1.28
1.26
1.24
1.22
837 nm
739 nm
0.52
0.50
0.48
0.46
0.44
0.42
TCNQ
500
600
700
800
900
1.0
0.8
0.6
0.4
0.2
Wavelength (nm)
450 nm
p-CL
0.0
350 400 450 500 550 600 650
Wavelength (nm)
1 : 1 ratio
0.5
1 : 1 ratio
0.5 1.0
0.0
1.5
2.0
2.5
3.0
0.0
1.0
1.5
2.0
2.5
3.0
ml added of TCNQ
ml added of p-CL
Fig. 2. Photometric titration spectra of [(Ris)(p-acceptor)] charge transfer systems in methanol solvent.

468
A.A. El-Habeeb et al. / Journal of Molecular Structure 1036 (2013) 464–477
7
6
5
4
3
2
1
0
DDQ
PA
TCNQ
TCNE
DDQ
TCNQ
TCNE
BL
p-CL
4000
3500
3000
2500
2000
1500
)
1000
500
-1
Wavenumbers (cm
100
150
200
250
300
350
400
(C o +C o )x10-6
d
a
Fig. 4b. IR spectra of [(Ris)(DDQ)], [(Ris)(TCNQ)] and [(Ris)(TCNE)] charge transfer
complexes.
Fig. 3. The modified Benesi–Hildebrand plot of [(Ris)(p-acceptor)] charge transfer
systems in methanol solvent.
PA
of the PA, DDQ, TCNQ, TCNE, BL and p-CL as
equivalence points shown in these curves clearly indicate that
the formed CT complexes between Ris and respective -acceptors
are 1:1. It was of interest to observe that the solvent has a pro-
nounced effect on the spectral intensities of the formed [(Ris)(
p-acceptors. The
BL
p-CL
p
p
-
acceptors)] complexes. The 1:1 modified Benesi–Hildebrand equa-
tion [42] was used in the calculations.
CoaCodl
A
1
Coa þ Cod
¼
þ
:
ð1Þ
K
e
e
where Coa and Cod are the initial concentrations of the studied
p-
acceptors and the donor Ris, respectively, K is a formation constant,
4000
3500
3000
2500
2000
1500
)
1000
500
e
is a molar extinction coefficient, and A is the absorbance of the
-1
Wavenumbers (cm
definite bands around 436 nm, 406 nm, (739 and 837 nm),
500 nm, 536 nm and 450 nm of Ris with PA, DDQ, TCNQ, TCNE, BL
and p-CL, systems, respectively. The Coa ꢃ Cdo=A values are plotted
against the corresponding Cao þ Cod values, straight lines were ob-
Fig. 4a. IR spectra of [(Ris)(PA)], [(Ris)(BL)] and [(Ris)(p-CL)] charge transfer
complexes.
tained with a slope of 1/e and intercept of 1/ke as shown in
1=2
Fig. 3a–f. The oscillator strength f was obtained from the approxi-
mate formula given in the following equation [43]
l
¼ 0:0958½emaxm1=2
=mmax
ꢄ
:
ð3Þ
where m1/2 is the bandwidth at half-maximum of absorbance, emax
and mmax are the extinction coefficient and wavenumber at maxi-
mum absorption peak of the CT complexes, respectively. The ioniza-
tion potential (Ip) of the free Ris donor was determined from the CT
energies of the CT band of its complexes with different p-acceptors
using the following relationships derived by Aloisi and Piganatro
f ¼ ð4:319 ꢂ 10ꢁ9
Þ
emax
:
m1=2
ð2Þ
where m
1/2 is the band-width for half-intensity in cmꢁ1. The oscilla-
tor strength values together with the corresponding dielectric con-
stants, D, of the solvent used are given in Table 2. The trend of the
values in this table reveals two facts.
[48,49].
The [(Ris)(p-acceptors)] shows high values of both the equilib-
ID ðeVÞ ¼ 5:76 þ 1:53 ꢂ 10ꢁ4mCT
:
ð4Þ
rium constant (K) and the extinction coefficient (
of K reflects the high stability of the Ris charge transfer complexes
e
). This high value
where ECT is the energy of the CT of the Ris complexes, the energy of
as a result of the expected high donation of the Ris consequently
the
p–
pꢅ or n–pꢅ interaction (ECT) is calculated using the following
high value of
[44–46]. The transition dipole moment (
(Table 2) have been calculated from the following equation [47]
e
which is known to have a high absorptivity values
equation [47]
l) of the Ris complexes
ECT ðeVÞ ¼ ðhmCT Þ ¼ 1243:667=kCT ðnmÞ:
ð5Þ
Table 2
Spectorophotometric data of the risperidone charge transfer systems [(Ris)(
p
-acceptor)] in methanol.
Parameter
kmax (nm)
ECT (eV)
K (l molꢁ1
)
emax (l molꢁ1 cmꢁ1
)
f
l
Ip
D
RN
D )
G° (25 °C) (kJ molꢁ1
PA
436
406
739
500
536
450
2.85
3.06
1.68
2.48
2.32
2.76
10,123
10,397
10,635
10,000
13,231
11,239
31,746
34,246
13,717
10,298
4887
27
29
8
10
2
50
50
36
33
14
15
9.269
9.528
7.830
8.820
8.614
9.160
33
0.481
0.533
0.185
0.227
0.121
0.154
22,853
22,920
22,976
22,823
23,517
23,113
DDQ
TCNQ
TCNE
BL
p-CL
5345
2.5

A.A. El-Habeeb et al. / Journal of Molecular Structure 1036 (2013) 464–477
469
Table 3
Assignments of the IR spectral bands (cmꢁ1) of Ris, PA, BL, p-CL, and their [(Ris)(
p
-acceptor)] charge transfer complexes.
Ris
PA
BL
p-CL
[(Ris)(
PA
p
–acceptor)] CT-complexes
Assignments(b)
BL
p-CL
–
3416
3103
–
–
–
–
3419
3413
3405
m(OAH)
Hydrogen bonding
3058
2942
2757
2980
2872
3079
2959
2868
3070
2943
3077
2950
ms(CAH)
ms(CAH)
+
+
mas(CAH) aromatic
mas(CAH) aliphatic
–
–
–
–
–
2729
2675
2696
2629
2547
2696
2637
2539
Hydrogen bonding
1652
1682
1673
1680
1698
1726
1689
1659
1614
1432
1495
1435
1689
1651
m(C@O); Ris
m(C@O);BL and p-CL
1535
1448
1413
1632
1608
1529
1432
1665
1641
1564
1547
1476
1583
1555
1528
1458
1625
1570
1530
1487
1432
1614
1569
1532
1495
1442
1412
m(C@C) + m(C@N)
CAH deformation
1352
1131
1343
1312
1263
1150
1278
1266
1215
1166
1319
1277
1236
1194
1097
1367
1312
1267
1193
1165
1119
1368
1264
1249
1189
1122
1361
1315
1270
1204
1159
1122
1092
m(CAC)
m(CAF)
CH, in-plane bend
+ m(CAN) + m(CAO)
959
866
818
1086
917
829
781
732
703
652
1066
1055
1030
876
868
705
986
916
764
722
1073
1018
963
907
833
788
742
705
613
1062
1009
957
897
838
756
704
666
622
980
957
898
868
831
793
719
666
622
CH-deformation
m(CACl)
m(CABr)
695
542
460
522
–
472
430
530
466
525
465
569
532
473
Skeletal vibration
CH bend
CH out-of-plane bend
CNC def.
d(NO2)
where kCT is the wavelength of the complexation band. Determina-
tion of resonance energy (RN), from Briegleb and Czekalla [50] the-
oretically derived the relation given in the following equation
3.2. Infrared and Raman studies
The infrared spectra of risperidone charge transfer complexes
are depicted in Figs. 4a and 4b and their band assignments are gi-
ven in Table 3,4. Risperidone spectrum shows a respective band at
3058 cmꢁ1 corresponding to the aromatic CAH stretching and at
2942 cmꢁ1 and 2757 cmꢁ1 due to aliphatic CAH stretching. A char-
acteristic band at 1652 cmꢁ1 corresponds to C@O stretching of the
pyrimidine ring and bands at 1535 cmꢁ1 and 1448 cmꢁ1 related to
C@C and C@N stretching. Bands at 1413 cmꢁ1 are due to aliphatic
CAH bending and at 959, 866 and 818 cmꢁ1 due to aromatic CAH
bending. Other bands at 1352 cmꢁ1 and 1131 cmꢁ1 corresponds to
CAN stretching and CAF stretching respectively. The IR spectrum
emaxðl molꢁ1 cmꢁ1Þ ¼ 7:7 ꢂ 10ꢁ4=½h
mCT =½RNꢄ ꢁ 3:5ꢄ:
ð6Þ
where
emax is the molar extinction coefficient of the complex at the
maximum CT absorption,
m
CT is the frequency of the CT peak, and RN
is the resonance energy of the complex in the ground state, which
obviously is a contributing factor to the stability constant of the
complex (a ground state property). The values of RN for the
p-accep-
tor complexes under study are given in Table 2. The standard free
energy changes of complexation (
association constants by [51]
D
Go) were calculated from the
of risperidone/
free donor, while it closely resembles the spectrum of both drug
and acceptors. The characteristic bands of -acceptors either have
p-acceptor complex is different from risperidone
Go ¼ ꢁ2:303RT log KCT
:
ð7Þ
p
D
disappeared or reduced in intensities. The same is true with ris-
peridone complexes which has spectrum similar to free risperi-
done drug but with a few bands of risperidone decreased in
intensity probably due to the restriction of configuration upon
charge transfer complexation. In order to collect a better compar-
ison among the investigated compounds, analysis of the infrared
and Raman spectra were carried out on three spectral regions:
where
D
Go is the free energy change of the complexes (kJ molꢁ1), R
is the gas constant (8.314 J molꢁ1 K), T is the temperature in Kelvin
degrees (273 + °C), and KCT is the association constant of the com-
plexes (l molꢁ1) in different solvents at room temperature, the val-
ues thus calculated are represented in Table 2. The data of
D
Go has a
negative value according to the higher values of formation constant,
and then the formation process of Ris charge transfer complexes is
exothermic feature reactions.
high-wavenumber (3500–2300 cmꢁ1),
(1800–800 cmꢁ1) and low-wavenumber (800–300 cmꢁ1) zones.
medium-wavenumber

470
A.A. El-Habeeb et al. / Journal of Molecular Structure 1036 (2013) 464–477
Table 4
Assignments of the IR spectral bands (cmꢁ1) of Ris, DDQ, TCNQ, TCNE, and their [(Ris)(
p-acceptor)] charge transfer complexes.
Ris
–
DDQ
TCNQ
TCNE
[(Ris)(
DDQ
p
–acceptor)] CT-complexes
Assignments(b)
TCNQ
3427
TCNE
–
–
–
–
3405
3338
3211
m(OAH)
Hydrogen bonding
3058
2942
2757
3137
3050
2969
2851
2956
2925
2864
3077
3017
2957
3077
3024
2957
3069
2950
ms(CAH)
ms(CAH)
+
+
mas(CAH) aliphatic
mas(CAH) aromatic
–
–
–
–
2703
2637
2532
2749
2674
2569
2816
2764
Hydrogen bonding
–
2250
2236
2220
2252
2229
2214
2204
2173
2122
2196
1644
m(C„N)
1652
1680
–
–
1741
1651
1643
m(C@O); Ris
m(C@O); DDQ
1535
1448
1413
1555
1458
1430
1540
1455
1378
1607
1532
1502
1442
1599
1533
1502
1480
1442
1412
1614
1533
1495
1420
m(C@C) + m(C@N)
CAH deformation
1351
1131
1389
1250
1166
1083
1352
1285
1205
1355
1306
1234
1361
1270
1361
1315
1270
1241
1174
1353
1315
1271
1235
m(CAC)
m(CAF)
CH, in-plane bend
+ m(CAN) + m(CAO)
959
866
818
902
778
708
611
1117
1044
997
962
860
1181
1155
1138
1116
1088
1027
969
935
806
722
1189
1122
1069
1024
980
957
897
831
785
1114
1009
957
897
831
704
651
614
1122
1024
987
957
898
838
816
779
711
622
CH-deformation
m(CACl)
808
755
679
607
666
542
460
528
458
473
–
532
473
539
480
562
547
532
Skeletal vibration
CH bend
CH out-of-plane bend
CNC def.
attached to the donation site N(1)AH of pyrimidine ring in the pro-
tonated donor [39]. These results caused by the intermolecular
hydrogen bond occur in PA acceptor from AOH group to the basic
centre nitrogen atom. The increasing in the stretching vibration
O
N
O
N
N
+
N
motions of the carbonyl group m(C@O) in the pyrimidine ring from
F
1652 cmꢁ1 (free Ris donor) to 1698 cmꢁ1 can be assigned to the
nonparticipation of (C@O)oxygen in the complexation. During the
complexation, charge transfer transitions occur with the excitation
of an electron from HOMO of the donor to LUMO of the acceptor.
Accordingly, the hydrogen bonding between the Ris and the picric
acid acceptor, the suggested formula can be designed as Scheme 3.
With respect of [(Ris)(BL)] and [(Ris)(p-CL)] CT-complexes, the
infrared spectra of the two solid products contain the characteristic
H
H
O
N
O
O
O
N
O
N
O
O
bands for both Ris (donor) and halogenic p-acceptors like bromanil
(BL) and p-chloranil (p-CL). The C@O stretching vibrations of BL
Scheme 3. Suggested structure of [(Ris)(PA)] complex.
and p-CL show a noticeable shift to higher values. The distinguish
stretching vibration of m(C@O) of the free BL and p-CL is observed
at (1682 and 1673) cmꢁ1 and 1680 cmꢁ1 as prominent peaks, but
in the case of [(Ris)(BL)] and [(Ris)(p-CL)] charge transfer complex,
it means that after complexation, these peaks were exhibited at
(1726 and 1689) cmꢁ1 and 1689 cmꢁ1 values and having a
strong-to-very strong band intensities. On the other hand, the
The infrared spectrum of PA complex is characterized by a
group of bands appearing at 3416 cmꢁ1 (medium strong broaden-
ing) 2729 and 2675 cmꢁ1 (medium-to-weak intensities), which are
not appearing in the spectra of the free Ris donor and acceptors.
These bands are attributed to the stretching vibration of a proton

A.A. El-Habeeb et al. / Journal of Molecular Structure 1036 (2013) 464–477
471
O
N
O
N
N
N
F
+
H
N
O
N
Cl
O
Cl
O
N
O
N
N
N
F
+
N
N
N
H
N
O
N
O
N
N
N
F
+ H
N
Scheme 4. Suggested structures of [(Ris)(BL)] and [(Ris)(p-CL)] complexes.
N
N
new bands presence at ꢀ3400 cmꢁ1 and within the 2500–
2700 cmꢁ1 range was assigned to hydrogen bonding. This is rea-
sonable based on the increasing polarity of the AC@OꢁAHN+ band
during complexation. The other observation through the decreas-
ing of stretching vibration motions of C@C bands in the aromatic
ring was supported
interaction of both BL and p-CL with risperidone on the basis of
infrared spectra can be suggested as Scheme 4.
N
Scheme 5. Suggested structures of [(Ris)(DDQ)], [(Ris)(TCNQ)] and [(Ris)(TCNE)]
complexes.
p–
pꢅ transitions from donor to acceptor. The
1.8
1.6
1.4
1.2
1.0
0.8
0.6
Infrared spectra of the risperidone CT-complexes with some of
cyano
p-acceptors such as DDQ, TCNQ and TCNE are shown in
Fig. 4b. In the spectra of the CT-complexes, each spectrum shows
almost the main characteristic bands for both the donor and accep-
tor in each case. This observation strongly supports the formation
of the CT-interactions between donor and acceptors. However, the
bands of the donor and acceptors in these complexes reveal small
shifts in both band intensities and wave number values from those
of the free molecules. This is normal due to the expected changes of
molecular symmetries and electronic structures of the reactants
PA
0.4
BL
p-CL
0.2
upon complexation. For example, the
m(C„N) vibrations of TCNE
0.0
alone are observed as a triplet at 2252, 2229 and 2214 cmꢁ1 and
4000 3500 3000 2500 2000 1500 1000 500
the m(C„N) vibrations of DDQ and TCNQ alone are observed at
-1
(2250 and 2236) cmꢁ1 and 2220 cmꢁ1, respectively. These vibra-
tions occur at 2204, (2173 and 2122) and 2196 cmꢁ1 after com-
plexation by Ris-DDQ, Ris-TCNQ and Ris-TCNE, respectively.
Wavenumbers (cm )
Fig. 5a. Raman spectra of [(Ris)(PA)], [(Ris)(BL)] and [(Ris)(p-CL)] charge transfer
complexes.
Contrary changes are observed for the
m(C@O) vibrations for each
p
-acceptors (DDQ, TCNQ and TCNE) upon complexation. The
(C@O) of alone Ris is 1652 cmꢁ1 and still unshifted or gently
ward acceptors. Same kind of results such as presence of some new
bands within 2500–2800 cmꢁ1 wavenumber values after complex-
ation are assigned to hydrogen bonding observed in the literature
[52,53], that cyano groups of TCNQ actively participate in CAHꢃ ꢃ ꢃN
hydrogen bonds with pyrimidine molecule. Charge transfer
m
shifted to 1651, 1643 and 1644 cmꢁ1 upon complexation by Ris-
DDQ, Ris-TCNQ and Ris-TCNE, respectively. The mild changes of
the wavenumber values upon complexation are clearly associated
with that the oxygen of carbonyl group in Ris donor not sharing to-

472
A.A. El-Habeeb et al. / Journal of Molecular Structure 1036 (2013) 464–477
0.50
0.45
0.40
0.35
0.30
0.25
0.20
0.15
0.10
0.05
0.00
-0.05
3.893, 3.439 and 3.598 ppm for PA, DDQ, TCNQ, TCNE, BL and
p-CL, respectively, can be assigned to the intermolecular hydro-
gen bond between ANH of pyrimidine ring in Ris donor and
AOH of (PA), ACN of (DDQ, TCNQ and TCNE), AC@O of (BL and
p-CL) for respective
p-acceptors.
3.4. SEM, EDX, and XRD studies
Shape and surface morphology characterization of risperidone
[56] and [(Ris)(p-acceptors)] charge transfer complexes where p-
DDQ
acceptors = PA, DDQ, TCNQ, TCNE, BL and p-CL performed by scan-
ning electron microscopy (SEM, JSM-6390 LV, JEOL, Taif EMU, KSA)
(Fig. 7) measured with an accelerated voltage of 25 kV. The surface
morphology shows that shape of the different risperidone charge
transfer complexes depend on the acceptor present, due to the dif-
ferent chemical structure of the adducts produced. The EDX spec-
tra (Fig. 8) corroborates the presence of carbon, oxygen, halogens
(chlorine and fluorine) in the Ris adducts. The uniformity and sim-
ilarity between the particles forms of synthesized risperidone
charge transfer complexes indicate that the existence of morpho-
TCNQ
TCNE
4000 3500 3000 2500 2000 1500 1000 500
Wavenumbers (cm-1)
Fig. 5b. Raman spectra of [(Ris)(DDQ)], [(Ris)(TCNQ)] and [(Ris)(TCNE)] charge
transfer complexes.
logical phases of
p-acceptors (PA, DDQ, TCNQ, TCNE, BL and p-
transition reactions of Ris-DDQ, Ris-TCNQ and Ris-TCNE are shown
in Scheme 5.
CL) complexes have a homogeneous matrix. Volcanic rocks small-
to-large particles shapes (Fig. 7) are observed in case of all Ris com-
plexes except for p-CL complexes presence in leaf shape with the
Raman spectra of [(Ris)(p-acceptors)] complexes were per-
formed and recorded differentiation that the PA, BL and p-CL
complexes Fig. 5a have a four regions with wavenumbers data at
3100–2900 cmꢁ1, 1600–1400 cmꢁ1, 1350–1050 cmꢁ1 and 940–
particle size 500-to-5.00 lm. The diffractogram of risperidone
[56] exhibited its crystalline nature as indicated by peaks at (2h)
value of 19.7°, 20.6°, 22.43°, 24.58°, 27.33°, 31.79° and 43.79°. X-
ray powder patterns of risperidone charge transfer complexes have
given in Fig. 9 along with the prominent data. The XRD features of
risperidone charge transfer complexes in Figs. 9a and 9b gave an
impression about the amorphous and partially crystalline shapes
which different from Ris free drug due to take place complexation
600 cmꢁ1 which assigned to
phatic, (C@C) +
(CAO), ꢃ (CAF) and CH, in-plane bend and CH-deformation,
(CACl) and (CABr), respectively. The lower shift in the (CAN),
(C@C) + (C@N), (C@O) and CAH deformation bands for pyrimi-
m
s(CAH) +
m
as(CAH) aromatic and ali-
(CAC) + (CAN) +
m
m
(C@N) and CAH deformation,
m
m
m
m
m
m
m
m
m
m
dine and aromatic moieties of Ris inside complexation led us to re-
fer the take place of charge transfer chelation via ANH of Ris and
AOH of picric acid complex and between oxygen of C@O with
between Ris donor and
p-CL).
p-acceptors (PA, DDQ, TCNQ, TCNE, BL and
ANH of Ris as well as
p–
pꢅ through aromatic rings in both donor
and acceptors in case of BL and p-CL complexes. On the other hand,
the spectra of DDQ, TCNQ and TCNE complexes (Fig. 5b) has a
sharp broadening with distorted in the stretching vibration band
of cyano groups, this can be discussed under the knowledge that
Raman analysis of fluorescent materials and compounds is a chal-
lenging task experimentally due to the overlap of fluorescence
which, even when very weak, can overwhelm the inherently weak
Raman scattering signal [54,55].
3.5. Thermal studies
The DSC thermogram of the risperidone drug [56] showed a
sharp endothermic peak at 170 °C corresponding to the melting
point of risperidone that further confirmed its crystallinity. The
thermal decomposition curves (Fig. 10) of the resulted Ris charge
transfer complexes were discussed within 30–600 °C temperature
range. The thermal decomposition of [(Ris)(PA)], [(Ris)(DDQ)],
[(Ris)(TCNQ)], [(Ris)(TCNE)], [(Ris)(BL)] and [(Ris)(p-CL)] com-
plexes have one, four, two, three, five, five detectable peaks re-
corded in DTG curves, these steps are endothermic and assigned
to the loss of organic moieties with weight losses 85.35%,
59.452%, 50.996%, 69.186%, 76.830% and 75.038%, respectively.
The few carbon atoms is a residual products in all risperidone
charge transfer complexes due to the lack of an abundance of oxy-
gen atoms correspond to the large number of carbon atoms present
3.3. 1H NMR spectra
1H NMR spectra of the electron donor risperidone and its CT-
complexes with using acceptors such as PA, DDQ, TCNQ, TCNE,
BL and p-CL are shown in Fig. 6a–f. 1H NMR of risperidone CT
complexes was carried out in DMSO. The chemical shifts (d) of
the different types of protons of the ligand Ris and their charge
transfer complexes are listed in Table 5. By studying the 1H
NMR spectrum of risperidone free drug, there are different peaks
were found at d = 7.052, 7.237, 7.709 ppm due to protons of
Benzo[d]isoxazol, d = 2.100, 2.320, 3.085, 3.172 ppm for the pro-
tons of Piperidine, d = 2.774, 2.554 pm for 4H of Ethyl, d = 2.344
for the 3H of methyl group and d = 1.785, 1.964, 2.150, 2.280,
3.945, 4.515 ppm assigned to 6,7,8,9-Tetrahydro-pyrido[1,2-
in the supermolecular of Ris donor and each of p-acceptors. Takes a
closer look at the curves of thermal degradation, we find that the
charge transfer complexes produced are more stable than free ris-
peridone (170 °C) and recorded values DTGmax = 264, 212, 348,
242, 257, 260 °C for PA, DDQ, TCNQ, TCNE, BL and p-CL, respec-
tively. It so difficult to locate units liberated thermally at every
decomposition steps due to the convergence of severe between
thermal degradation steps, but we can say that the particles termi-
nal is starting to be free before main nuclei and this is clear from
the small values of the weight loss in the initial decomposition
steps in thermo gravimetric curves which expressed the loss in
weight with gain increased temperature.
a]pyrimidin-4-one, respectively. The AOH signal of picric acid
moiety found at ꢀ11.00 ppm in the spectrum of the free acceptor
is absence in the spectrum of PA complex, this support the shar-
ing of the ANH group of (Ris) in charge transfer chelation with
AOH for PA. The presence of new peaks at 3.000, 3.500, 3.537,

A.A. El-Habeeb et al. / Journal of Molecular Structure 1036 (2013) 464–477
473
Fig. 6. Proton NMR spectra of (a) PA, (b) DDQ, (c) TCNQ, (d) TCNE, (e) BL and (f) p-CL.

474
A.A. El-Habeeb et al. / Journal of Molecular Structure 1036 (2013) 464–477
Fig. 6. (continued)

A.A. El-Habeeb et al. / Journal of Molecular Structure 1036 (2013) 464–477
475
Table 5
Assignments of the proton NMR spectral data (ppm) of Ris, [(Ris)(p-acceptors)] charge transfer complexes.
Compounds Assignments chemical shift (ppm)
Benzo[d]isoxazol
Piperidine
Ethyl, hydrogen bonding
Methyl 6,7,8,9-Tetrahydro-pyrido[1,2-
]pyrimidin-4-one
a
Ris
7.052, 7.237, 7.709
2.100, 2.320, 3.085,
3.172
2.774, 2.554
2.344
1.785, 1.964, 2.150, 2.280, 3.945, 4.515
PA
7.120, 7.150, 7.250, 7.300, 7.600, 7.650, 8.900
7.150, 7.380, 7.950
2.200, 3.050
2.350
2.450
2.315
1.850, 1.950, 2.050, 3.850
2.700, 2.800, 3.000
2.800, 3.500
DDQ
TCNQ
TCNE
2.150, 2.980, 3.200
3.022, 2.865
1.850, 1.950, 2.200, 2.280, 3.700, 3.850
1.885, 1.894, 1.905, 2.241, 3.897, 3.918
1.889, 1.988, 2.153, 3.914
6.991, 7.130, 7.302, 7.319, 7.657, 7.784, 7.798
7.111, 7.296, 7.701, 7.812
2.455, 2.594, 3.537
2.852, 2.874, 3.286,
3.304
2.585, 2.595, 2.696, 2.796, 2.302
3.893
BL
7.150, 7.315, 7.740, 8.150
3.107, 3.156, 3.258
3.137, 3.189, 3.250
2.518, 2.592, 2.669, 3.334, 2.343
3.439
1.950, 2.109, 2.281, 3.814, 5.199
p-CL
6.889, 7.472, 7.486, 7.747, 7.753, 8.068,
8.074,8.079, 8.084
2.577, 2.699,2.714,3.421,
2.290
1.950, 2.095, 3.796, 3.833, 3.945, 4.233
3.598
Fig. 7. SEM photomicrographs of [(Ris)(p-acceptors)] charge transfer complexes where p-acceptors = PA, DDQ, TCNQ, TCNE, BL and p-CL.
3.6. Biological activity studies
(A. flavus and C. albicans). The antimicrobial activity data indicated
that all the charge transfer complexes were found to be more
active against all the micro-organisms than the free risperidone
drug (Table 6, Fig. 11). This may be explained by Tweedy’s chela-
tion theory [57], according to which on chelation (donor/acceptor)
the polarity will be reduced due to the overlap of the donor orbital
The risperidone and charge transfer complexes of PA, DDQ,
TCNQ, TCNE, BL and p-CL were screened for antimicrobial activity
against four bacteria, gram-positive (B. subtilis and S. aureus) and
gram-negative (E. coli and P. aeruginosa) and two strains of fungus

476
A.A. El-Habeeb et al. / Journal of Molecular Structure 1036 (2013) 464–477
001
8000
7200
6400
5600
4800
4000
3200
2400
1600
800
700
600
500
400
300
200
100
DDQ
TCNQ
TCNE
0
0.00 1.00 2.00 3.00 4.00 5.00 6.00 7.00 8.00 9.00 10.00
keV
0
10
20
30
40
50
60
70
80
Fig. 8a. EDX spectrum of [(Ris)(PA)] charge transfer complex.
2θ
001
12000
Fig. 9b. XRD powder diffraction spectra of DDQ, TCNQ and TCNE charge transfer
10500
9000
7500
6000
4500
3000
1500
0
complexes.
9
8
7
6
5
0.00 1.00 2.00 3.00 4.00 5.00 6.00 7.00 8.00 9.00 10.00
keV
4
PA
Fig. 8b. EDX spectrum of [(Ris)(TCNQ)] charge transfer complex.
3
2
1
DDQ
TCNQ
TCNE
BL
001
5600
p-CL
4800
4000
3200
2400
1600
800
0
100
200
300
400
500
600
Temp. [oC]
Fig. 10. TG/DTG and DSC curves of (a) [(HPL)(PA)] and (b) [(HPL)(TCNQ)] charge
transfer complexes.
B.subtilis
E.coli
0
P.aeruginosa
0.00 1.00 2.00 3.00 4.00 5.00 6.00 7.00 8.00 9.00 10.00
100
S.aureus
A.flavus
keV
C.albicans
80
60
40
20
0
Fig. 8c. EDX spectrum of [(Ris)(p-CL)] charge transfer complex.
200
150
100
PA
BL
Ris
PA
DDQ
TCNQ
Compounds
TCNE
BL
p-CL
50
0
p-CL
Fig. 11. Biological activities (%) of Ris and their charge transfer complexes.
10
20
30
40
50
60
70
80
and partial sharing of the negative charge of the acceptor with the
donor groups, due to which the lipophillic character of the charge
transfer complexes increases and favours its permeation through
the lipid layer of the cell membrane.
θ
2
Fig. 9a. XRD powder diffraction spectra of PA, BL and p-CL charge transfer
complexes.

A.A. El-Habeeb et al. / Journal of Molecular Structure 1036 (2013) 464–477
477
[21] A. Korolkovas, Essentials of Medical Chemistry, second ed., Wiley, New York,
1998 (Chapter 3).
4. Conclusion
[22] K. Takahasi, K. Horino, T. Komura, K. Murata, Bull. Chem. Soc. Jpn. 66 (1993)
733.
[23] F.M. Abou Attia, Farmaco 55 (2000) 659.
[24] B. Dhokale, P. Gautam, R. Misra, Tetrahedron Lett. 53 (2012) 2354.
[25] R. Maragani, T. Jadhav, S.M. Mobin, R. Misra, Tetrahedron 68 (2012) 7302.
[26] A.A. Mostafa, L.I. Bebawy, H.H. Refaat, J. Pharm. Biomed. Anal. 27 (2002) 89.
[27] H.M.A. Salman, U.M. Rabie, E.A. Abd-Alla, Can. J. Anal. Sci. Spectrosc. 49 (2004)
1.
[28] M.S. Refat, S.A. El-Korashy, I.M. El-Deen, S.M. El-Sayed, Drug Test. Anal. 3 (2)
(2011) 116.
[29] M.S. Refat, J. Mol. Struct. 985 (2011) 380.
[30] A.A. El-Habeeb, F.A. Al-Saif, M.S. Refat, J. Mol. Struct. 1034 (2013) 1.
[31] A.W. Bauer, W.M. Kirby, C. Sherris, M. Turck, Am. J. Clin. Pathol. 45 (1966) 493.
[32] M.A. Pfaller, L. Burmeister, M.A. Bartlett, M.G. Rinaldi, J. Clin. Microbiol. 26
(1988) 1437.
[33] National Committee for Clinical Laboratory Standards, Performance, vol.
Antimicrobial Susceptibility of Flavobacteria, 1997.
This paper reports simple, direct and sensitive spectrophoto-
metric method for the determination of risperidone drug with
some p-acceptors such as PA, DDQ, TCNQ, TCNE, BL and p-CL. Stoi-
chiometries, equilibrium constants and physical spectroscopic
parameters of the charge transfer complexes were determined.
And also, the CT complexes of the risperidone/p-acceptors were
determined by FT-IR, X-ray powder diffraction and proton-NMR
spectroscopy. In conclusion, the spectroscopic methods have
advantage of being simple, sensitive, accurate and suitable for rou-
tine analysis in laboratories. The methods can be used as general
methods for the spectrophotometric determination of drugs in
bulk powder and in commercial formulations.
[34] National Committee for Clinical Laboratory Standards, Methods for Dilution
Antimicrobial Susceptibility Tests for Bacteria that Grow Aerobically,
Approved Standard M7-A3, National Committee for Clinical Laboratory
Standards, Villanova, PA, 1993.
[35] National Committee for Clinical Laboratory Standards, Reference Method for
Broth Dilution Antifungal Susceptibility Testing of Conidium-Forming
Filamentous Fungi: Proposed Standard M38-A, NCCLS, Wayne, PA, USA, 2002.
[36] National Committee for Clinical Laboratory Standards, Methods for Antifungal
Disk Diffusion Susceptibility Testing of Yeast: Proposed Guideline M44-P,
NCCLS, Wayne, PA, USA, 2003.
Acknowledgement
This work was supported by grants from Princess Nora Bint Ab-
dul Rahman University, Riyadh, Saudi Arabia under project Grants
No. 25/32.
References
[37] L.D. Liebowitz, H.R. Ashbee, E.G.V. Evans, Y. Chong, N. Mallatova, M. Zaidi, D.
Gibbs, Global Antifungal Surveillance Group, Diagn. Microbiol. Infect. Dis. 4
(2001) 27.
[38] M.J. Matar, L. Ostrosky-Zeichner, V.L. Paetznick, J.R. Rodriguez, E. Chen, J.H.
Rex, Antimicrob. Agents Chemother. 47 (2003) 1647.
[39] A. Alparone, Spectrochim. Acta Part A 81 (2011) 631.
[40] M.S. Refat, H.A. Saad, A.A. Adam, J. Mol. Struct. 995 (1–3) (2011) 116.
[41] D.A. Skoog, Principle of Instrumental Analysis, third ed., Saunders College
Publishing, New York, USA, 1985 (Chapter 7).
[1] A. Zejc, M. Gorczyca, Chemistry of Drugs, PZWL, Warszawa, 2002 (in Polish).
[2] L. Scahill, J.F. Leckman, R.T. Schultz, L. Katsovich, B.S. Peterson, Neurology 60
(2003) 1130.
[3] F. Luan, W. Ma, H. Zhang, X. Zhang, M. Liu, Z. Hu, B. Fan, Pharm. Res. 22 (2005)
1454.
[4] H. Wan, M. Rehngren, F. Giordanetto, F. Bergstrom, A. Tunek, J. Med. Chem. 50
(2007) 4606.
[5] A. Avdeef, Curr. Top. Med. Chem. 1 (2001) 277.
[42] H.A. Benesi, J.H. Hilderbrand, J. Am. Chem. Soc. 71 (1949) 2703.
[43] H. Tsubomura, R.P. Lang, J. Am. Chem. Soc. 86 (1964) 3930.
[44] W. Kiefer, H.J. Bernstein, Chem. Phys. Lett. 16 (1972) 5.
[45] L. Andrews, E.S. Prochaska, A. Loewenschuss, Inorg. Chem. 19 (1980) 463.
[46] K. Kaya, N. Mikami, Y. Udagawa, M. Ito, Chem. Phys. Lett. 16 (1972) 151.
[47] R. Rathone, S.V. Lindeman, J.K. Kochi, J. Am. Chem. Soc. 119 (1997) 9393.
[48] G. Briegleb, Z. Angew. Chem. 76 (1964) 326.
[49] G. Aloisi, S. Pignataro, J. Chem. Soc. Faraday Trans. 69 (1972) 534.
[50] G. Briegleb, J. Czekalla, Z. Physikchem. (Frankfurt) 24 (1960) 237.
[51] A.N. Martin, J. Swarbrick, A. Cammarata, Physical Pharmacy, third ed., Lee and
Febiger, Philadelphia, PA, 1969. p. 344.
[6] D.-H. Wang, M.-H. Zhou, X.-R. Hu, Acta Crystallogr. E 62 (2006) o3527.
[7] Y. Sun, H.-H. Zhang, Acta Crystallogr. E 65 (2009) o1647.
[8] M.G. Orkoula, C.G. Kontoyannis, J. Pharm. Biomed. Anal. 47 (2008) 631.
[9] M.A. Tawakkul, R.B. Shah, A. Zidan, V.A. Sayeed, M.A. Khan, Pharm. Dev.
Technol. 14 (2009) 409.
[10] I. Karabas, M.G. Orkoula, C.G. Kontoyannis, Talanta 71 (2007) 1382.
[11] A. Alparone, S. Millefiori, J. Mol. Struct. (Theochem) 911 (2009) 144.
[12] A. Alparone, S. Millefiori, J. Mol. Struct. (Theochem) 955 (2010) 178.
[13] J.G. Mesu, T. Visser, F. Soulimani, B.M. Weckhuysen, Vib. Spectrosc. 39 (2005)
114.
[14] B.E. Billinghurst, S.A. Oladepo, G.R. Loppnow, J. Phys. Chem. B 113 (2009) 7392.
[15] M.E. El-Zaria, Spectrochim. Acta A 69 (2008) 216.
[16] M.S. Refat, N.M. El-Metwally, Chin. Sci. Bull. 56 (2011) 1993.
[17] M. Pandeeswaran, K.P. Elango, Spectrochim. Acta A 75 (2010) 1462.
[18] M.S. Refat, S.A. El-Korashy, I.M. El-Deen, S.M. El-Sayed, J. Mol. Struct. 980
(2010) 124.
[52] L.J. Bellamy, The Infrared Spectra of Complex Molecules, Chapman & Hall,
London, 1975.
[53] C.V.K. Sharma, R.D. Rogers, Cryst. Eng. 1 (2) (1998) 139.
[54] S.E.J. Bell, N.M.S. Sirimuthu, Chem. Soc. Rev. 37 (2008) 1012.
[55] M.R. Kagan, R.L. McCreery, Anal. Chem. 66 (1994) 4159.
[56] Z. Rahman, A.S. Zidan, M.A. Khan, Int. J. Pharm. 400 (2010) 49.
[57] B.G. Tweedy, Phytopathology 55 (1964) 910–914.
[19] F.P. Fla, J. Palou, R. Valero, C.D. Hall, P. Speers, JCS Perkin Trans. 2 (1991) 1925.
[20] R. Foster, Organic Charge Transfer Complexes, Academic Press, London, 1969.