Synthesis of complex compounds of the monoammonium salt of glycyrrhizic acid and thiourea

. 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.


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][2][3][4][5].
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 antiinflammatory, antiviral effects, strengthens the immune system, promotes the restoration of liver cells, has antitumor, healing, antitoxic activity. [12][13][14].
In the composition of licorice roots, glycyrrhizinic acid occurs in the form of sodium, potassium, calcium, and magnesium salts [15][16][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][19][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].

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.

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). *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). 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.). 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. 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.). 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].
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•10 4 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: • ∆A258 ∆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.

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%.