Application of charge-transfer complexation for evaluation of the drug-receptor mechanism of interaction: Spectroscopic and structure morphological properties of procaine and pilocarpine complexes with chloranilic acid acceptor

Article abstract of DOI:10.1134/S1070363214060292

Study of the charge-transfer or proton-transfer interaction of drugs is important for understanding the drug-receptor interactions and the mechanism of drug action. In the current research the corresponding data were accumulated in the course of synthesis

Full text of DOI:10.1134/S1070363214060292

ISSN 1070–3632, Russian Journal of General Chemistry, 2014, Vol. 84, No. 6, pp. 1225–1236. © Pleiades Publishing, Ltd., 2014.
Application of Charge-Transfer Complexation
for Evaluation of the Drug-Receptor Mechanism
of Interaction: Spectroscopic and Structure
Morphological Properties of Procaine and Pilocarpine
Complexes with Chloranilic Acid Acceptor1
Abdel Majid A. Adam
Department of Chemistry, Faculty of Science, Taif University,
Al-Haweiah, P.O. Box 888, Zip Code 21974, Taif, Saudi Arabia
e-mail: majidadam@yahoo.com
Received April 25, 2014
Abstract—Study of the charge-transfer or proton-transfer interaction of drugs is important for understanding
the drug-receptor interactions and the mechanism of drug action. In the current research the corresponding data
were accumulated in the course of synthesis and study of the H-bonded complexes originated from the
interaction between procaine (Pro) or pilocarpine (Pil) drugs and chloranilic acid (CLA). The targeted
microstructure products have been isolated and characterized by elemental and spectral (electronic and
vibrational) data. Microstructural properties of the reported complexes were studied with XRD and SEM
techniques. The Pil drug containing complex exhibited a specific electronic spectrum with a strong, broad
absorption band with much longer wavelength, λmax, than those typical for the individual reagents. It is
noteworthy that the complex had good crystallinity. Application of Debye–Scherrer equation indicated that the
reported complexes were in the range of nanosize.
Keywords: drug-acceptor interaction; hydrogen bonds; XRD; SEM; surface structure
DOI: 10.1134/S1070363214060292
INTRODUCTION
(Pro; C13H20N2O2·HCl), chemically 2-(diethylamino)
ethyl-4-aminobenzoate hydrochloride, the structure of
which is shown in Scheme 1, is a synthetic local
anesthetic drug of the amino ester family that produces
a reversible loss of sensitivity by diminishing the
conduction of sensory nerve impulses. It has long been
employed as a pharmacological agent in the life
science and in clinical therapeutic studies. This drug is
primarily used to reduce pain induced by the
intramuscular injection of penicillin, and it is also used
in dentistry [12–14]. Pilocarpine hydrochloride (Pil;
Over the recent decade a big number of studies
reported drug-acceptor interactions in solid state and in
solutions. The study of the drug-acceptor complexation
is useful for understanding the drug-receptor
interactions and the mechanism of drug action.
Furthermore, the drug-acceptor complexation is an
important technique that is cheaper, simpler, and more
efficient than the methods of drug determination
described in a number of publications. The crystalline
drug-acceptor complexes play a vital role in biological
systems such as antimicrobial activity and DNA-
binding. Beyond that, such complexes exhibit potential
antimicrobial properties against Gram-positive and
Gram-negative bacteria as well as fungi [1–11]. In the
current study the drug-acceptor interaction between
drug procaine or pilocarpine and chloranilic acid
(CLA) acceptor is reported. Procaine hydrochloride
.
C11H16N2O2 HCl), chemically (3S,4R)-3-ethyl-4-[(1-
methyl-1H-imidazol-5-yl)methyl]dihydrofuran-2(3H)-
one, the structure of which is shown in Scheme 1, is a
naturally occurring compound derived from the leaves
of South American shrub Pilocarpus jaborandi. It is a
parasympathomimetic agent that acts primarily as a
muscarinic agonist with mild beta-adrenergic activity.
This alkaloid causes pharmacologic stimulation of
exocrine glands in humans, leading to diaphoresis,
salivation, lacrimation, and gastric and pancreatic
1 The text was submitted by the author in English.
1225

1226
ABDEL MAJID A. ADAM
O
O
O
O
HO
Cl
Cl
O
O
H3C
.
.
HCl
N
HCl
N
H2N
OH
H3C
CH3 CH3
Procaine
Scheme 1. The chemical structures of CLA, Pro, and Pil.
N
Chloranilic acid
Pilocarpine
secretion. Topical ophthalmic pilocarpine has long
been used to treat glaucoma [15, 16]. Based on the
fruitful data of the complexation properties of drug-
acceptor that had been accumulated by me [17–19], I
carried out more studies of drug compounds. Accumula-
tion of basic data that could be useful for under-
standing drug-receptor mechanism of interaction, the
following objectives were pursued:
room temperature. Scanning electron micrography
(Quanta FEG 250) instrument was used for morpho-
logical evaluation. The instrument was operated at an
accelerating voltage of 30 kV.
Synthetic procedure. The solid H-bonded com-
plexes were prepared by mixing the saturated solution
of the drug (1 mmol) in pure methanol (25 mL) with
saturated solution of CLA acceptor (1 mmol) also in
methanol (25 mL). The solutions were stirred for
approximately 30 min. A change in color developed
and the resulting solution was allowed to evaporate
slowly at room temperature to lead to precipitation of
the solid complexes. The formed precipitate was
filtered off and rinsed well with methanol. Then, the
complexes were dried in vacuum over anhydrous
calcium chloride for 24 h. The melting point of the
formed complexes was measured to be >300°C. The
H-bonded complexes were characterized spectrophoto-
metrically (IR and UV-vis) and by elemental analysis.
(1) Synthesis of the H-bonded complexes of Pro or
Pil drugs with CLA acceptor.
(2) Study of the complexes formed based on
elemental analysis and spectroscopic data (electronic
and vibrational).
(3) Analysis of the microstructures of the reported
complexes using XRD and SEM techniques.
EXPERIMENTAL
General. All compounds used throughout this
study were of analytical reagent grade and all solutions
were freshly prepared. Pro, Pil, CLA, and methanol
(Aldrich and Merck Chemical) were used without
further purification. The elemental analyses of carbon,
hydrogen and nitrogen content were performed with a
Perkin-Elmer CHN 2400 (USA). The electronic absorp-
tion spectra of the reagents and complexes synthesized
were recorded in methanol over a wavelength range of
250–800 nm using a Perkin-Elmer Lambda 25 UV/Vis
double-beam spectrophotometer. The instrument was
fitted with a quartz cell that had a path length of
1.0 cm. The IR spectra of the corresponding KBr
tablets were recorded within the range of 4000–400 cm–1
at room temperature using a Shimadzu FT-IR spectro-
photometer with 30 scans at 2 cm–1 resolution. The diffrac-
tion experiments were carried out with a PANalytical
X’Pert PRO X-ray powder diffractometer with a
Ge(III) monochromator. A CuKα1 X-ray beam of wave-
length 0.154056 nm was used. The samples were
measured in 0.35 mm diameter glass capillaries at
Spectrophotometric measurements. The spectro-
photometrically controlled titrations of the detectable
absorption bands were performed for the reactions of
the drugs with CLA acceptor as follows. Portions of
0.25, 0.50, 0.75, 1.00, 1.50, 2.0, 2.50, 3.00, 3.50 or
4.00 mL of a standard solution (5.0 × 10–4 M) of the
CLA acceptor in methanol was added to 1.00 mL of
5.0 × 10–4 M Pro or Pil, dissolved in the same solvent.
The final volume of the mixture was 5 mL. The
concentration of the drug (Cd) was maintained at 5.0 ×
10–4 M, whereas the concentration of the acceptor (Ca)
varied from 0.25 × 10–4 M to 4.00 × 10–4 M to produce
solutions with a (drug : acceptor) molar ratio range
between 1 : 0.25 and 1 : 4. The stoichiometry of the
formed complexes was evaluated by determination of
the conventional spectrophotometric molar ratio
according to a known method [20]. The peak
absorbencies that appeared in the spectra of the formed
complexes were measured for all solutions in each case
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 84 No. 6 2014

APPLICATION OF CHARGE-TRANSFER COMPLEXATION
1227
Table 1. Spectroscopic data for the H-bonded complexes in methanol at room temperature
Absorption,
nm
K,
emax
,
ECT,
eV
∆G0,
Complex
Color
f
μ
L mol–1
L mol–1 cm–1
8.45 × 103
3.32 × 104
J mol–1
–35.731
–32.458
[(Pro)(CLA)]
[(Pil)(CLA)]
Dark red
334
320
1.59 × 104
1.44 × 104
4.20
4.33
32.87
21.60
44.69
38.05
Dark orange
and plotted as a function of the drug to acceptor molar
ratio (Cd : Ca ratio).
synthesized complexes are presented in Fig. 1. The
spectrum of the Pro complex revealed the presence of
a new broad band at 334 nm that was assigned to the
drug-acceptor interaction. Spectrophotometric titration
curve based on this absorption band justified a reaction
stoichiometry of 1 : 1 (Pro : CLA) as shown in Fig. 2.
The absorption spectrum of CLA acceptor had a λmax at
303 nm, while Pil drug displayed no detectable
absorption band. Upon mixing Pil and CLA together, a
new strong broad band appeared at a much longer
wavelength (320 nm). This strong broad band at longer
wavelength was indicative of the formation of the H-
bonded complex. The composition of the formed
complex was determined by spectrophotometric titra-
tions based on this characteristic absorption band.
Accordingly, it is evident from Fig. 2 that this complex
had a 1 : 1 stoichiometric ratio (Pil : CLA). This was in
good agreement with the elemental analysis data of the
resulting solid complex.
RESULTS AND DISCUSSION
Analytical results. The result of the elemental
analyses (C, H, and N) of the formed H-bonded
complexes is presented as; [(Pro)(CLA)]: C19H23N2O6Cl3;
Mw = 481.76; Calculated, %: C 47.33; H 4.77; N 5.81,
Found, %: C 47.20; H 4.81; N 5.77. [(Pil)(CLA)]:
C17H19N2O6Cl3; Mw = 453.7; Calculated, %: C 44.96;
H 4.19; N 6.17. Found, %: C 44.90; H 4.15; N 6.21.
Elemental analysis justified formation of the Pro and
Pil complexes of the type [(Drug)(CLA)]. Formation
of 1 : 1 complexes was strongly supported by spectro-
photometric titrations. The Pro and Pil complexes had
a dark red and dark orange color, respectively.
Electronic spectra. The Spectroscopic data, molar
ratio and color of the formed H-bonded complexes are
presented in Table 1. The electronic absorption spectra
of the reactants, drugs (Pro and Pil) (5.0 × 10–4 M) and
CLA acceptor (5.0 × 10–4), along with those of the
Calculation of K and ε. Based on the electronic
spectra of the synthesized H-bonded complexes, the
formation constant; K (L mol–1) and the molar
(a)
(b)
3.0
320 nm
1
2.0
1.0
2
3
0.0
300
350
λ, nm
400
450
λ, nm
Fig. 1. Electronic spectra of (a) Pro and (b) Pil complexes in methanol solution. (1) CLA, (2) Pil, and (3) complex.
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 84 No. 6 2014

1228
ABDEL MAJID A. ADAM
Absorbance
Absorbance
(CdCa/A) × 10–8
(CdCa/A) × 10–8
6
4
2
0
1.2
0.9
0.6
0.3
(Cd + Ca) × 10–6
CLA, mL
Fig. 2. Spectrophotometric titration curves of (1) Pro and
(2) Pil complexes in methanol solutions.
Fig. 3. The Benesi–Hildebrand plot of (1) Pro and (2) Pil
complexes.
extinction coefficient; ε (L mol–1 cm–1) were calculated
using the 1 : 1 Benesi–Hildebrand equation:
produced, which supports the formation of a 1 : 1
complex. In the plot, the slope and intercept were
measured as 1/ε and 1/Kε, respectively. The Benesi–
Hildebrand plots are shown in Fig. 3, and the values of
Cd, Ca, (Cd + Ca) and (CaCd)/A are listed in Table 2.
The correlation coefficient (r) value for the straight
line was found to be 0.999. The values of the K for the
Pro and Pil complexes were calculated to be 1.59 × 104,
and 1.44 × 104 L mol–1, respectively. The corresponding
(CaCd)/A = 1/Kε + (Ca + Cd)/ε,
(1)
where Ca and Cd are the initial concentrations of the
acceptor (CLA) and the drug, respectively, while A is
the absorbance at the mentioned absorption band. By
plotting the values of (CaCd)/A as a function of the
corresponding values of (Ca + Cd), a straight line was
Table 2. The values of Cd, Ca, Cd + Ca, and CdCa /A, for the formed complexes
Pro–CLA complex
Pil–CLA complex
A : D
ratio
(Cd + Ca)× (CdCa)×
Cd × 10–4
Ca× 10–4
10–6
10–8
absorbance
[(CdCa)/A] ×
absorbance [(CdCa)/A] ×
(334 nm)
0.4018
0.4829
0.5569
0.6309
0.6618
0.6905
0.7172
0.7405
0.7717
0.7896
10–8
(320 nm)
1.2212
1.8900
2.3357
2.8745
2.9066
2.9391
2.9664
2.9988
3.0293
3.0630
10–8
0.25
0.50
0.75
1.00
1.50
2.00
2.50
3.00
3.50
4.00
1.00
1.00
1.00
1.00
1.00
1.00
1.00
1.00
1.00
1.00
0.25
0.50
0.75
1.00
1.50
2.00
2.50
3.00
3.50
4.00
125
150
175
200
250
300
350
400
450
500
0.25
0.50
0.75
1.00
1.50
2.00
2.50
3.00
3.50
4.00
0.6222
1.0354
1.3467
1.5850
2.2665
2.8965
3.4858
4.0513
4.5354
5.0659
0.2047
0.2646
0.3211
0.3479
0.5161
0.6805
0.8428
1.0004
1.1554
1.3059
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 84 No. 6 2014

APPLICATION OF CHARGE-TRANSFER COMPLEXATION
1229
Table 3. IR spectral data (cm–1) and tentative assignments of donors, acceptor and complexes
Acceptor
Donors
Complexes
Pro–CLA
Assignments
ν(N–H); Pro
CLA
Pro
3349
–
Pil
–
Pil–CLA
–
3230
–
3386
3163
2961
2865
–
3077
–
–
ν(OH); CLA
3206
2973
–
ν(C–H); aromatic
νs(C–H) + νas(C–H)
–
3108
3021
3023
2990
–
–
–
2728
2683
2708
2667
2600
2554
Hydrogen bonding
–
2583
2493
–
2615
1714
–
ν(+N–H); hydrogen of HCl
ν(C=O); Pro, Pil
1663
1629
1692
1761
1671
1760
–
–
–
–
1644
1603
–
–
1631
1528
–
–
δdef(N–H); Pro
1615
1584
1442
1609
1561
1450
ν(C–N); Pro, Pil
ν(C=N); Pil
1520
1463
1438
1376
ν(C–H); alkanes; Pro, Pil
1368
1260
1363
1308
1268
1362
1315
1240
1338
1270
1393
1329
1281
1225
ν(C–C) + ν(C–O) + ν(C–N)
–
1169
1113
1172
1114
1181
1117
1175
C–H in-plane bending
–
–
1049
848
–
1011
–
δrock, NH; Pro
1021
982
977
836
1025
928
C–H out of plane bending
838
751
–
–
–
–
805
717
820
715
ν(C–Cl); CLA
ν(C–Cl); CLA
ε values were 8.45 × 103 and 3.32 × 104 L mol–1 cm–1,
respectively. These results indicated that Pro complex
exhibited a higher K value then that of Pil complex,
which indicates a strong interaction between the Pro–
CLA pairs and confirmed high stability of the Pro
complex as a result of the stroger donation ability of
Pro drug. Accordingly, donation from the drug to CLA
acceptor was in the order Pro > Pil. The Pil complex
exhibited a higher ε value than Pro complex.
(E), the oscillator strength (f), the transition dipole
moment (μ) and the standard free energy (ΔG0), were
estimated for the formed complexes dissolved in
methanol at 25°C. The calculations are summarized
below.
The energy values of the complexes (E) of the
n→π* and π–π* interactions between the drug donors
and the acceptor were calculated using the equation
derived by Briegleb [21]:
Calculation of the spectroscopic data. The
spectroscopic data, such as the energy of the complex
ECT = (hνCT) = 1243.667/λCT,
(2)
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 84 No. 6 2014

1230
(a)
ABDEL MAJID A. ADAM
(b)
ν, cm–1
ν, cm–1
(c)
ν, cm–1
Fig. 4. Infrared spectra of (a) CLA, (b) Pro, and (c) the their complex.
where λCT, nm, is the wavelength of the complexation
The transition dipole moments (μ) of the complexes
band.
were calculated in accodance with Eq. (5) [23]:
μ(Debye) = 0.0958 [εCTν1/2/νmax]1/2.
(5)
The oscillator strength (f) is a dimensionless
quantity used to express the transition probability of
the band. From the absorption spectra, the oscillator
strength (f) can be calculated using the approximate
formula [22]:
The transition dipole moment (μ) can be
determined if a particular transition is allowed. The
transition from a bonding π orbital to an antibonding π*
orbital is allowed because the integral that defines the
transition dipole moment is nonzero.
f = 4.319 × 10–9∫εCTdν,
(3)
The standard free energy changes of complexation
(ΔG0) for each complex were calculated based on the
formation constants using Eq. (6) [24]:
where ∫εCTdν is the area under the curve of the
extinction coefficient of the absorption band plotted as
a function of the frequency. To a first approximation,
ΔG0 = –2.303RT log KCT,
(6)
f = 4.319 × 10–9εCTν1/2,
(4)
where ΔG0 is the standard free energy change of the
complexes (kJ/mol), R is the gas constant (8.314 J mol–1 K–1),
T is the absolute temperature in Kelvin, and K is the
formation constant of the complex (L mol–1) at room
temperature.
where εCT is the maximum extinction coefficient of the
CT band and ν1/2 is the half-bandwidth (i.e., the
bandwidth at half of the maximum extinction coef-
ficient value), cm–1.
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 84 No. 6 2014

APPLICATION OF CHARGE-TRANSFER COMPLEXATION
1231
O
O
O
. HCl
N
H2N
O
CH3
CH3
. HCl
N
H2N
Procaine
CH3 CH3
H
O
O
O
Cl
O
O
HO
Cl
Cl
OH
Cl
OH
O
O
H3C
O
O
Chloranilic Acid
H3C
N
. HCl
.
N
H3C
HCl
O
O
N
H3C
N
Cl
O
H
Pilocarpine
Cl
OH
Scheme 2. Proposed structure of the reported complexes.
The calculated values of the spectroscopic data for
the reported complexes deduced from Eqs. (2)–(6) are
presented in Table 1. The Pro complex exhibited a
higher value for both the oscillator strength (f) and the
transition dipole moment (μ). All the ΔG0 values are
negative. These values indicate that the interaction
between the drug donors and the CLA acceptor was
spontaneous. The ΔG0 values of the complexes are in
the order Pro > Pil.
the H-bonded OH group. Also, the δdef(N–H) vibration
at 1644 cm–1 characteristic for free Pro drug, was
shifted to 1631 cm–1 in the spectrum of the product
confirming the complex formation. In the spectrum of
the complex ν(C–Cl) bands were recorded at 805 and
717 cm–1 whereas in pure CLA the corresponding
bands were recorded at 838 and 751 cm–1. All these
observations indicated the formation of intermolecular
H-bond between the (–NH2) group in the Pro drug and
the (–OH) group in the CLA acceptor [25–28].
IR spectral studies. The infrared spectra of the Pro
and CLA as well as the formed complex are presented
in Fig. 4, and the corresponding bands are listed in
Table 3. However, the appearance of a group of IR
bands in the spectrum of Pro complex supported the
conclusion that a deformation of the electronic
environment of the complex occurred due to formation
of intermolecular H-bond. The characteristic band of
ν(N–H) at 3349 cm–1 in the free Pro drug was shifted
to 3386 cm–1 in the complex. The outlined changes in
ν(N–H) in the Pro drug upon complexation clearly
justified the involvement of the nitrogen atom of the
(–NH2) group in hydrogen bonding with CLA. This
bonding was confirmed by the appearance of weak
absorption bands at 2728 and 2683 cm–1, assigned to
Figure 4 presents the IR spectra of the Pil, CLA and
their solid complex, and Table 3 their characteristic
band assignments. As expected, the characteristic IR
bands of Pil and CLA in the complex exhibited small
changes in the band intensities and frequency values.
The IR spectrum of this complex was characterized by
a group of bands that appears in the range 2554–
2708 cm–1. This group of bands was not registered in
the spectra of pure Pil or CLA, and was attributed to
the stretching vibration of protons attached to the
donation center of the Pil (electrons lone pair on the
nitrogen atom of the C=N group). This was supported
by a shift of ν(C=N) band from 1584 cm–1 (in pure Pil)
to 1561 cm–1 (in the complex). Furthermore, ν(C–Cl)
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 84 No. 6 2014

1232
Table 4. XRD spectral data for the reported complexes
ABDEL MAJID A. ADAM
Complex
[(Pro)(CLA)]
[(Pil)(CLA)]
Position 2θ, deg d-Spacing value, Å
Relative intensity, %
β; FWHM
0.3499
Particle size, nm
47.578
8.41640
17.9388
10.50592
4.940770
100.0
100.0
0.2362
71.163
vibrational bands were recorded at 820 and 715 cm–1
in the spectrum of the complex. In pure CLA those
were recorded at 838 and 751 cm–1. These data stood
for the intermolecular H-bond formation in the com-
plex [25–28]. Based on the above, the H-bonds
between the drugs and the CLA acceptor are presented
in Scheme 2.
the selected diffraction peak in radians. Table 4
presents the XRD spectral data [i.e., 2θ, β, d (the
interplanar spacing between atoms) and D in nm] for
the obtained complexes, whereas Table 5 lists all the
characteristic XRD lines with their d-spacing, FWHM
and relative intensity.
The XRD study produced the following results:
XRD characterization. The X-ray diffraction
(XRD) patterns were recorded for 2θ = 5°–80° at a
scanning speed of 3 deg/min using a PANalytical
model X’PERT-PRO X-ray powder diffractometer
system. The XRD patterns of the reported complexes
are shown in Fig. 5. The mean particle size of the
complexes based on the highest intensity line (Fig. 6)
were calculated using the Debye–Scherrer formula
[29]:
(1) The primary characteristic scattering peak of the
Pro and Pil complexes occurred at 8.4164° and
17.9388° in the diffraction pattern, respectively.
(2) The XRD patterns of the Pro and Pil complexes
differed from each other.
(3) The appearance of a sharp and strong Bragg
peak indicated the formation of a well-defined
crystalline structure.
(4) Using the Debye–Scherrer equation, the particle
size values of the complexes were calculated to be 47.6
and 71 nm for the [(Pro)(CLA)] and [(Pil)(CLA)]
complexes, respectively.
D = 0.94λ /β cos θ,
(7)
where D is the mean particle size of the grains, 0.94 in
the Scherrer constant; λ is the wavelength of the
incident X-ray (CuKα; 1.5406 Å), θ is the position of
the selected diffraction peak (Bragg diffraction angle)
and β is the full-width at half-maximum (FWHM) of
(5) The above values indicated nanoscale particle
sizes.
(a)
(b)
2θ, deg
2θ, deg
Fig. 5. X-ray diffraction patterns of (a) Pro and (b) Pil complexes.
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 84 No. 6 2014

APPLICATION OF CHARGE-TRANSFER COMPLEXATION
Table 5. Characteristic XRD lines for the reported complexes
[(Pro)(CLA)] complex
1233
[(Pil)(CLA)] complex
position 2θ,
d-spacing
value, Å
relative
intensity, %
position 2θ,
d-spacing
value, Å
relative
intensity, %
FWHM
FWHM
deg
deg
8.4164
11.1186
13.8221
17.1639
20.0994
23.3061
26.0292
27.7349
28.4300
30.6500
35.9300
40.1733
41.7900
10.50592
7.95796
6.40696
5.16632
4.41792
3.81681
3.42336
3.21657
3.13949
2.91697
2.49950
2.24475
2.16157
100.00
29.56
33.15
21.47
27.53
14.55
24.94
21.43
13.20
11.08
18.60
14.68
4.92
0.3499
0.6071
0.3335
0.4378
0.3952
0.5414
0.3154
0.8964
0.0010
0.0010
0.2164
0.2050
0.0900
5.4764
8.1033
16.12439
10.90210
7.76333
7.03878
6.48635
5.97519
5.24609
4.94077
4.84660
4.30716
4.06741
3.72432
3.64498
3.47109
3.38729
3.31125
3.23231
3.15618
3.08629
2.92246
2.87704
2.77877
2.69779
2.59218
2.52114
2.47083
2.39157
2.32690
2.03019
1.86958
21.87
4.70
0.3936
0.4723
0.2362
0.3542
0.2165
0.3149
0.2165
0.2362
0.1574
0.1968
0.2362
0.2165
0.2362
0.2362
0.2558
0.2558
0.1771
0.1968
0.2362
0.2362
0.2165
0.3936
0.2362
0.3149
0.2558
0.3149
0.3140
0.6298
0.2755
0.3840
11.3888
12.5657
13.6407
14.8139
16.8869
17.9388
18.2903
20.6046
21.8336
23.8732
24.4008
25.6435
26.2891
26.9040
27.5739
28.2527
28.9062
30.5651
31.0597
32.1874
33.1810
34.5746
35.5808
36.3304
37.5787
38.6639
44.5958
48.6633
6.56
13.63
27.21
7.74
19.58
100.00
25.47
25.42
13.61
24.93
39.91
87.84
60.69
17.98
23.89
39.20
9.01
11.73
16.07
12.51
20.69
12.47
8.46
3.77
7.28
5.85
7.87
4.54
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 84 No. 6 2014

1234
ABDEL MAJID A. ADAM
(a)
(b)
2θ, deg
2θ, deg
Fig. 6. The highest intensity XRD line of the (a) Pro and (b) Pil complexes.
100 μm
50 μm
30 μm
10 μm
Fig. 7. SEM photographs of Pro complex at various magnifications.
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 84 No. 6 2014

APPLICATION OF CHARGE-TRANSFER COMPLEXATION
1235
50 μm
30 μm
5 μm
10 μm
Fig. 8. SEM images of Pil complex at various magnifications.
Surface morphology characterization. Mor-
phology of the new H-bond supported complexes was
studied by means of scanning electron microscopy
(SEM) technique. The surface images obtained with
the SEM technique provided general information
regarding the microstructure, surface morphology,
particle size, chemical composition, and porous
structures of the surfaces. The morphological phases of
the formed H-bonded complexes revealed some
uniform matrixes in the SEM micrographs indicating
the formation of a homogeneous material. Mor-
phological difference was observed between Pro and
Pil complexes. Pil complex exhibited a higher degree
of crystallinity than that of Pro complex. The size of
the particles differed substantially for each drug.
Figure 7 presents the SEM photographs of the Pro
complex at various magnifications. The photographs
demonstrated the presence of agglomerated particles
with irregular shape and sizes with the latter in the
range of 10–50 μm. Some higher magnification SEM
photographs of representative complex are displayed.
The highly magnified SEM image demonstrated the
presence of particles with shape close to spherical.
Some particles of imperfect structures could also be
observed in the matrix. Figure 8 displays the surface
morphology of the nanoscale Pil complex. The
complexation of Pil with CLA led to a very interesting
morphology. The multi SEM photographs with various
degrees of magnification of the complex indicated rod-
like structure with particles size in the range of 5–
10 μm. A SEM photograph at a high magnification
(×20 000) demonstrated a well-defined microstructure.
This image demonstrated complex homogeneous
surface with clear individual grins of uniformly
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 84 No. 6 2014

1236
ABDEL MAJID A. ADAM
10. Eldaroti, H.H., Gadir, S.A., Refat, S.A., and Adam, A.M.A.,
distributed size and shape. The morphology of Pro
complex and Pil complex were of different
microstructures.
J. Pharm. Anal., 2013, in press.
11. Eldaroti, H.H., Gadir, S.A., Refat, S.A., and Adam, A.M.A.,
Int. J. Electrochem. Sci., 2013, no. 8, pp. 5774–5800.
CONCLUSIONS
12. Yuan, J., Yin, J., Wang, E., J. Chromatogr. A, 2007,
Lately considerable attention has been paid to
formation of stable charge-transfer (CT) complexes
that resulted from the reaction of acceptors with drugs.
This interest was initiated by important physical and
chemical properties of such complexes. The CT
complexes of procaine (Pro) and pilocarpine (Pil)
drugs with chloranilic acid (CLA) were synthesized
and studied spectroscopically in both solid and liquid
phases at room temperature. The newly synthesized
complexes were characterized in terms of elemental
analysis, IR and UV-visible spectroscopy. Their
microstructure characteristics were evaluated by means
of XRD and SEM techniques. The reaction stoichio-
metry was 1 : 1, and the resulting CT complexes had
the general formula: [(Drug)(CLA)]. Physical param-
eters such as formation constant (KCT), molar extinct-
tion coefficient (εCT) and other spectroscopic data were
calculated using the Benesi–Hildebrand method. The
sharp, well-defined Bragg reflections at specific 2θ
angles were identified from the powder X-ray dif-
fraction patterns.
no. 1154, pp. 368–372.
13. Chen, Y., Lu, K., Hsiao, R., Lee, Y., Tsai, H., Lin, C.H.,
and Tsai, M., J. Comp. Biochem. Physiol. C, 2008,
no. 148, pp. 128–135.
14. Karadaş, Ö, Omaç, Ö.K., Tok, F., Özgül, A., and
Odabaşı, Z., J. Neurological Sci., 2012, no. 316, pp. 76–
78.
15. Johnson, J.T., Ferretti, G.A., Nethery, W.J., Valdez, I.H.,
Fox, P.C., Ng, D., Muscoplat, C.C., and Gallagher, S.C.,
N. Engl. J. of Med., 1993, no. 5, pp. 390–395.
16. Vivino, F.B., Al-Hashimi, I., Khan, Z., LeVeque, F.G.,
Salisbury, P.L., Tran-Johnson, T.K., Muscoplat, C.C.,
Trivedi, M., Goldlust, B., and Gallagher, S.C., Arch.
Intern. Med., 1999, no. 159, pp. 174–181.
17. Adam, A.M.A., J. Mol. Struct., 2012, no. 1030, pp. 26–
39.
18. Adam, A.M.A., Refat, M.S., Saad, H.A., and Eldaroti, H.H.,
Eur. Chem. Bull., 2012, vol. 1(7), pp. 241–249.
19. Adam, A.M.A., Salman, M., Sharshar, T., and Refat, M.S.,
Int. J. Electrochem. Sci., 2013, no. 8, pp. 1274–1294.
20. Skoog, D.A., Principle of Instrumental Analysis, 3 ed.,
Saunders College Publishing, New York, USA, 1985.
REFERENCES
21. Briegleb, G., Z. Angew. Chem., 1964, no. 3, pp. 617–
632.
1. Saravanabhavan, M., Sathya, K., Puranik, V.G., and
Sekar, M., Spectrochim. Acta A 2014, no. 118, pp. 399–
406.
22. Tsubomura, H. and Lang, R.P., J. Am. Chem. Soc.,
1961, no. 83, pp. 2085–2092.
2. Khan, I.M., Ahmad, A., and Ullah, M.F., J. Photochem.
Photobio. B, 2011, no. 103, pp. 42–49.
23. Rathone, R., Lindeman, S.V., and Kochi, J.K., J. Am.
Chem. Soc., 1997, no. 119, pp. 9393–9404.
3. Khan, I.M., Ahmad, A., and Ullah, M.F., Spectrochim.
Acta A, 2013, no. 102, pp. 82–87.
4. Khan, I.M., Ahmad, A., and Aatif, M., J. Photochem.
Photobio. B, 2011, no. 105, pp. 6–13.
5. Khan, I.M. and Ahmad, A., J. Mol. Struct., 2010,
no. 975, pp. 381–388.
6. Khan, I.M. and Ahmad, A., J. Mol. Struct., 2010,
24. Martin, A.N., Swarbrick, J., and Cammarata, V,
Physical Pharmacy, 3 ed., Lee and Febiger, Phila-
delphia, PA, 1969, p. 344.
25. Adam, A.M.A., Refat, M.S., and Saad, H.A., J. Mol.
Struct., 2013, no. 1051, pp. 144–163.
26. Adam, A.M.A., Refat, M.S., and Saad, H.A., J. Mol.
Struct., 2013, no. 1037, pp. 376–392.
no. 977, pp. 189–196.
27. Adam, A.M.A., Spectrochim. Acta A, 2013, no. 104,
7. Khan, I.M., Ahmad, A., and Kumar, S., J. Mol. Struct.,
pp. 1–13.
2013, no. 1035, pp. 38–45.
28. Khan, I.M. and Ahmad, A., J. Mol. Struct., 2013,
8. Eldaroti, H.H., Gadir, S.A., Refat, S.A., and Adam, A.M.A.,
no. 1050, pp. 122–127.
Spectrochim. Acta A, 2013, no. 115, pp. 309–323.
29. Klug, H.P. and Alexander, L.E., X-Ray Diffraction
Procedures for Polycrystalline and Amorphous
Materials, New York: Wiley, 1974.
9. Eldaroti, H.H., Gadir, S.A., Refat, S.A., and
Adam, A.M.A., Spectrochim. Acta A, 2013, no. 109,
pp. 259–271.
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 84 No. 6 2014