E3S Web of Conferences 383, 04023 (2023) https://doi.org/10.

1051/e3sconf/202338304023
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Synthesis of complex compounds of the

monoammonium salt of glycyrrhizic acid and
thiourea
Ibrahim Askarov1, Yusup Isaev1, Gulnoza Tashtemirova2, Sanjar Rustamov1,
Mahamadzarif Kadirov3, and Kamoliddin Shadmanov4*
1
Andijan State University, University street, house 129, 170100 Andijan, Uzbekistan
2
Tashkent State Pedagogical University, Bunyodkor avenue, 27, 100070 Tashkent, Uzbekistan
3
Tashkent Pediatric Medical Institute, 223 Bogishamol St, Tashkent 100140 Tashkent, Uzbekistan
4
Pharmaceutical Institute of Education and Research, Mirabad district, st. Oybek, 45, 100015
Tashkent, Uzbekistan

Abstract. With poor (low) solubility in the aquatic environment, highly

toxic drugs (aspirin, doxorubicin, daunorubicin, sulfonamides and others),
a low level of glycyrrhizic acid (HA) leads to a decrease in the toxicity of
drugs and increases their biological activity due to poor solubility in water.
The stability constants (stability) and the value of the Gibbs energy of the
synthesized supramolecular complex have been calculated, theoretical and
experimental research methods were used to determine the conditions for
obtaining supramolecular complexes of glycyrrhizic acid and thiourea.
These researches were carried out as part of joint work to study the effect
of the toxicity of medicines on a living organism, under an interuniversity
program between Andijan State University and the Tashkent
Pharmaceutical Institute of the Republic of Uzbekistan. The aim of the
research is to determine the stability constant (stability) of the synthesized
supramolecular complex of the monoammonium salt of glycyrrhizic acid
(MASHA) with thiourea and the value of the Gibbs energy. To determine
the structure and composition of the resulting supramolecular complex of
MASHA with thiourea, UV and IR spectroscopy and the isomolar series
method were used.

1 Introduction
Licorice root is one of the medicinal plants known since ancient times, the literary sources
provide evidence that in Chinese folk medicine, licorice root was used as far back as 2800
BC. Currently, licorice root is used in folk medicine and practical medicine [1-5].
Science knows 33 species of plants belonging to the genus "Glycyrrhiza", including
Glycyrrhizaglabra L, Glycyrrhizauralensis Fish, GlycyrrhizakorshiniskyGrig,
GlycyrrhizainflataBatal,many biologically active substances are obtained out of them in the
form of a mixture of various components (root syrup, root powder, etc.).They also include


ΎCorresponding author: shodman@mail.ru

© The Authors, published by EDP Sciences. This is an open access article distributed under the terms of the Creative Commons
Attribution License 4.0 (http://creativecommons.org/licenses/by/4.0/).
E3S Web of Conferences 383, 04023 (2023) https://doi.org/10.1051/e3sconf/202338304023
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preparations based on HA (Glycyram, Gliderinin, Carbenzoxolone, Niglisin, Epigenintim,

Phosphogliv) [6-9].
One of the main active components in the composition of the plant is glycyrrhizic acid,
its content, depending on the age of the root, plant species, growing season and soil
conditions, is up to 2-24% [1,5,10,11]. Licorice is considered a plant that has anti-
inflammatory, antiviral effects, strengthens the immune system, promotes the restoration of
liver cells, has antitumor, healing, antitoxic activity. [12-14].
In the composition of licorice roots, glycyrrhizinic acid occurs in the form of sodium,
potassium, calcium, and magnesium salts [15–17]. An aqueous extract of licorice roots, in
addition to glycyrrhizin, also contains other triterpene glycosides and flavonoids.
Glycyrrhizic acid in food additives is used as a food additive - flavor and odor enhancer (E
958). Glycyrrhizic acid has a taste that is 50-100 times sweeter than sucrose, due to which it
is actively used in the confectionery industry. [18-20].
One of the most commonly used derivatives of glycyrrhizic acid is the monoammonium
salt of glycyrrhizic acid, which is sold under the name Glycyram. Glycyram in practical
medicine is used as an expectorant and remedy for various dermatitis. [1,4,11].
Anthracycline antibiotics are also widely used in the treatment of cancer. Most of these
antibiotics, along with a very strong effect, also have many side effects.
Therefore, we synthesized molecular complexes of antibiotics used in oncology, namely
the antibiotics doxorubicin and daunorubicin (rubomycin) with glycyrrhizic acid. The
resulting complexes were characterized using UV and IR spectra. As the authors point out,
as part of the complex, the level of side effects of antibiotics is sharply reduced, and their
biological activity is increased. [12,13,21].
Molecular complexes of MASHA with a number of sulfanilamide preparations were
obtained. In particular, employees of the X.Zhou company (China) obtained MASHA
compounds with streptomycin and rifampicin [22,23]. There was the 2-5 times increase in
the efficiency of interferon induction of complex compounds MASGC obtained on the
basis of sulgin, sulfadimezin, analgin and other drugs, compared with MASGC [10,24].
It is known that HA exhibits peculiar physicochemical properties. These include the
surface activity of HA, the ability to solubilize, and the possibility of gel formation in an
aqueous medium. Due to these features of HA, it is possible to achieve dissolution in water
of many non-water-soluble compounds (for example, hydrocortisone, prednisolone, uracil,
nystatin, etc.) [10,16]. One of the unique features of HA is also the ability to form cyclic
conformational structures due to the interaction in part of the carboxyl group of the
aglycone part of HA and the carboxyl in the glucuronic acid residue [25,26].

2 Materials and methods

The nature of intermolecular interactions of the components of the obtained supramolecular
complexes of MASHA and thiourea were characterized using ultraviolet and infrared
spectroscopy methods.

2.1 Discussion of the obtained results

Based on the above assumptions, supramolecular complexes of glycyram and thiourea were
synthesized in a ratio of 1:1, 2:1, and also 4:1. (presented in Table 1).


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Table 1. Based on the above assumptions, supramolecular complexes of glycyram and thiourea were
synthesized in a ratio of 1:1, 2:1, and also 4:1.
Complex Dt IR spectrum UVλмах(Н2О)lgε Rf * Output
(ratio) oС ν, cm-1 %
>С=О -OH
MASHA:ТМ 186 1716-1700 3330-3190 238(4.4) 0.53 91
1:1
MASHA:ТМ 185 1720-1700 3330-3190 240(4.4) 0.67 90
2:1
MASHA:ТМ 187 1725-1700 3320-3180 245 (4.2) 0.58 86
4:1

*system: alcohol: chloroform

During the analysis of the UV spectra of the synthesized supramolecular compounds in
a ratio of 1:1, we observed the presence of an absorption maximum in the wavelength range
of 240 nm, which is characteristic of the 11-en-12-on system. And for the initial MASHA,
the absorption maximum related to this group is observed in the wavelength range of 254
nm, the absorption maximum related to thiourea is observed in the wavelength range of 236
nm (Fig.1).

Fig. 1. Ultraviolet spectra of the complex compound MASHA:TM and its components.
In the course of the analysis of the IR spectra, the presence of absorption bands related
to the stretching vibrations inherent in the hydroxyl groups in MASHC was observed in the
wavelength range within 3330-3200 cm-1, and in the spectrum of the obtained compounds,
a shift of these lines to a lower frequency region by 25–30 cm was observed. This can be
seen in the change in the corresponding absorption bands (Fig.2.).

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100
5

%T
3748,65

3722,61
3851,85

3734,19

3646,43
98

1907,60
2255,75

1963,53
2007,90
2016,58
2186,31

1978,97
2164,13
2357,01
95

3200,87

1722,43

1509,30
1698,32
2867,18
93 2926,98

509,21
1326,06

476,42
455,20
1645,28

867,97
1652,03

819,75
880,50
90

1262,41

792,74
1278,81
1362,71

920,05
1463,01

546,82
1455,29

1212,26

946,08
1588,38

1386,82

564,18
1417,68

1170,79

434,95
88

596,97
750,31

684,73
978,87

698,23

665,44
85

83

80

1032,88
4000 3500 3000 2500 2000 1750 1500 1250 1000 750 500
cm-1

Fig. 2. IR spectrum of the complex compound MASHA:TM.

Based on the above data, the structure of the formed supramolecular complex can be
represented as follows (fig. 3.):

O
H

S
H2N C
H
NH2 O O
C C
O
O OH O O
O H
O OH

OH OH
HOOC OH

Fig. 3. The structure of the formed supramolecular complex.

Thus, supramolecular complex compounds of MASHA and thiourea were obtained by
the preparative method, and some of their physicochemical parameters were studied. The
degree of purity of the obtained compounds was also determined by thin layer
chromatography.

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At the next stage of our study, the stability constants and the Gibbs energy level of the
obtained supramolecular complexes were determined. For this, the method of isomolar
series was used. This method is relatively simple and convenient, used in the study of the
composition of complex compounds. [23,24]. The essence of the method is as follows: the
amount of reagents is taken in a different ratio in such a way that its total concentration
remains unchanged. In our study, by changing the ratio of reagents from 1 ml to 9 ml and
from 9 ml to 1 ml with a total volume of 10 ml, we determined the optical density of the
resulting solutions. Based on the results obtained, a corresponding graph was constructed,
based on the intersection point of the vertical and horizontal tangents drawn through the
corresponding points, the ratio of the components in the complex was determined (Fig. 4.).

∆A258
ϭ͘Ϯ

Ϭ͘ϴ
●
Ϭ͘ϲ

Ϭ͘ϰ

Ϭ͘Ϯ

Ϭ
Ϭ ϭ Ϯ ϯ ϰ ϱ ϲ ϳ ϴ ϵ ϭϬ

Fig. 4. Diagram for determining the c-stability constant and the Gibbs energy level.
To determine the composition of the complex and its stability constant Ks, an
independent experiment was carried out five times. UV spectra were obtained at 27 °C and
λ=258 nm, in quartz cuvettes (l=1 cm).
Based on the values of optical densities, the stability constant of the complex was
determined using the following formula [26,29].

∆𝐴𝐴0 ∙△ 𝐴𝐴1
𝐾𝐾𝑠𝑠 =
𝑐𝑐(𝛥𝛥𝐴𝐴0 − 𝛥𝛥𝐴𝐴1 )2

where, Кs– complex stability constant;

c– total concentration, 10-4 М,
∆А0 –change in the optical density of the complex in the complete absence of
dissociation;
∆А1 – change in optical density corresponding to the current curve.
According to the results obtained, Ks = 155293 M or 1,55•104 М.
Based on the determined value of Ks, the change in the Gibbs free energy of the
complex formation process ΔG is calculated according to the following formula:

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∆G = - 2,3RTlgKs
∆G = 3,3147·8,31·300Кslg155293=-29,956 kJ/mol

Thus, the ratio of components and the Gibbs free energy ΔG in the obtained and studied
complex compounds were determined. The value of ΔG shows the shift of equilibrium
under given conditions towards the formation of a complex.

3 Experimental part
UV spectra were recorded and studied on a Shimadzu-1280 spectrophotometer (Japan), IR
spectra were taken on an IRTracer-100 IR-Fourier spectrometer (Shimadzu, Japan). Thin
layer chromatography (TLC) was carried out on Silufol UV-254 plates (Czech Republic),
on basic solutions of alcohol and chloroform.

4 Getting complexes
1. The supramolecular complex of MASHA and thiourea is a complex compound in a ratio
of 1:1. 1.680 g (0.002 mol) of MASHA and 0152 g (0.002 mol) of thiourea were constantly
stirred in a magnetic stirrer in 50 ml of 50% alcohol at a temperature of 40-50°C for 4-5
hours. The alcohol was distilled off using a rotary evaporator, the residue was dried using
freeze drying equipment. Efficiency 91%.
Supramolecular complexes in the ratio of 2:1 and 4:1 were also synthesized by the
above described method:
2. MASHA: ТМ (2:1) m (MASHA) = 1,680 g (0.002 mol);
m(ТМ) = 0,076 g (0,002 mol), Output 90%
3. MASHA: ТМ (4:1) m (MASHA) = 1,680 g (0,002 mol);
m(ТМ) = 0,038 g (0,002 mol), Output 91%
Determination of the stability constant of the complex. To prepare an isomolar series,
aqueous solutions of glycyram and thiourea with a concentration of 10-4 M in a phosphate
buffer solution (Na2HPO4–NaH2PO4, pH=7,2) were used. The reagents were mixed in
antibatic ratios (from 1:9 to 9:1) at a constant volume. The mixtures were constantly stirred
at 30oC for 40 minutes.

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