The development of methods for assessing the quality of the substance 2,4,5-tribromo-1-(1-oxathiolanes-3)-imidazole

Summary

The physicochemical properties of the developed methods of proof of identity and quantification substances of 2,4,5-tribrom-1-(1-oksotietanil-3) imidazole, recommended for pre-clinical studies as an antidepressant agent.

Keywords: standardization, imidazole, 2,4,5-tribrom-1-(1-3-oksotietanil)-imidazole, substance, methods of quality assessment.

According to World Health Organization the depression takes 12% in the structure of all causes of disability in the world and by 2020 this figure will rise to 20%. Antidepressants used in the treatment of depressive syndromes to date are poorly understood drugs. At the moment there is no drug that meets the requirements of high efficiency and safety, therefore, the search and introduction of new antidepressants remains an important issue [4].

A special interests shows derivative of halogen imidazoles, as reaction to their basis of electofilic and nucleofilic substitution synthesized a large number of potential biological active substances. At the Department of pharmaceutical with courses of analytical and toxicological chemistry GBOU VPO BGMU ( Ufa,Russia) Sharipova I.M. with co-athors, synthesized a new active compound 2,4,5-tribrom- 1-(1-3-oksotietanil)-imidazole, which shows the high antidepressant activity[6,8].

In connection with the recommendation for preclinical studies raises the need for developing methods of quality control and standardization of substance.

The purpose of this study was to investigate the physico-chemical properties, development of methods for proof of identity and quantification of the substance 2,4,5-Tribromo-1-(1-oxathiolanes-3)- imidazole

Materials and methods. In this work we used the substance 2,4,5-tribrom-1-(1-3-oksotietanil)- imidazole ( I-81),sources and intermediate products of synthesis 2,4,5-tribrom-1-(1-3-oksotietanil)- imidazole ( TBI ) and 2-[4,5-dibromo-1-(thietanyl-3) imidazolyl -2-thio] acetic acid ( I-13), which obtained in the Department of pharmaceutical with courses of analytical and toxicological chemistry, faculty of pharmacy, Bashkir State medical university, Ufa, Russia.

Quality specification and standardization of I-81 are developed on laboratory samples of the substance in accordance with the requirements of the State Pharmacopoeia of the Republic of Kazakhstan in the parameters: description of appearance, solubility, loss in weight when dried, melting point, identification and quantification [2].

The melting point of a substance is defined on the device M70 Melting Point System (Mettler Toledo, Switzerland).

For identification of I-81 studied the possibility of using reactions similar to halogen derivatives of imidazoles.

The developed technique of thin layer chromatography (TLC) for identification and determination of impurities in a substance. Study of the chromatographic behaviour of the substance And- 81 and possible impurities And-13, of TBI was conducted on the plates "Sorbfil" (10 x 10, Russia) ensuring the reproducibility of experiments. The sample plates was applied by using microspaces (MSH, Russia) and microvascular volume of 2 gl (Russia).

Studied the possibility of using the spectral characteristics for identification and quantitative determination of I-81 by UV-spectrophotometry and IR spectroscopy.

UV spectra were recorded on a spectrophotometer SF-2000 (Russia) in the wavelength range 200-700nm, in cuvettes with layer thickness of 10 mm.

The IR-spectrum of substance was taken on a spectrophotometer INFRALUM Ft-08 (Russia), in diskes with potassium bromide in area from 4000 to 400 sm^-1.

In physical, chemical and physic-chemical researches was used 5 series of laboratory samples of the researching compound.

Table 1 - Result of researching solubility of substance I-81

The results and discussion. 2,4,5-Tribromo-1-(1-oxathiolanes-3)-imidazole is a light-yellow crystalline powder, bitter taste without smell. Soluble in chloroform, dioxane, dimethylformamide, glacial acetic acid, when heated in ethanol and other lower alcohols, slightly soluble in acetone, very slightly soluble in acetonitrile and hexane, practically insoluble in acids and alkalis, as well as in ethyl acetate and benzene, not soluble in water and ether (table 1).

The loss in weight upon drying for samples weighing about 0.5 g (precise linkage), dried at a temperature of 100-105оС to constant weight, amounted to no more than 0.5%.The melting point of I-81 is in the range of 191-195оС with decomposition (table 2).

Table 2- The physical composition of 2,4,5-tribrom-1-(1-oksotietanil-3)imidazole

To determine the authenticity of a new derivative of imidazole has been proposed the following reaction. The presence in the molecule of a tertiary nitrogen species, compounds imidazole ring allowed us to carry out the reaction with obmelchanie precipitant reagents: reagent Dragendorf, Bouchard, Lieberman, the molybdophosphoric and picric acid.

The presence of halogen in the substance of I-81 was proven by the reaction with silver nitrate in nitric acid medium after sintering with anhydrous sodium carbonate (formed yellow precipitate cheesy).

A specific reaction to confirm the presence of the sulfur atom was performed with plumbum acetate after mineralization (drop black sludge) [6].

IR- spectrum connection, was taken in spectrometer INFRALUM Ft-08 (Russia), in diskes with potassium bromide in area from 4000 to 400 cm^-1, has characteristic absorption bands. In area 1042 sm^-1 apprearing stretching vibrations sulfoxide group (S=O), absorption bands in areas 685, 661 and 606 cm^-1 corresponds to the valence vibrations of halogenated organic compounds (C-Br). Characteristic brands absorbtion of the valence vibration carbon-carbon and carbon- nitrogen connection of imidazole ring apprearing in 1553, 1503, 1417, 1337 cm^-1 (picture 1) [7].

The main reason of appearing outside impurities in preparation as fact is disturbance of technological regime of production and not keeping of storage condition of preparation. For that reason the impurities in preparation can be as products and synthesis intermediates also degradation products of the drug during storage.

We made the methods of TLC For determination of identiy and outside impurities in researching substance.It was researched the influence of mobile phase (MP) different formulation and the polarity of the mobility I-81 and selectivity of Chromatographic system. The mobility of substance and its components were assessed on the basis of the quantitied Rf. As part of the study chromatographic mobility of 2,4,5-tribrom-1-(1-3-oksotietanil)-imidazole and its specific impurities (2,4,5-tribrom- imidazole) has been tested 10 system solvents of different compounds. As a result of this was taken the optimal compound og MP for analys of substance I-81 and the possible impurities: Chloroform- acetone (9:1).

It has studied the possibility of using spectral characteristics for identification and for quantification of preparation. Studying of UV-spectrums in systems of acidic, neutral and the main character showed that

the maximum absorbtion of I-81 is appeared in medium neutral-ethyl spirite at a wavelength 245 ± 2 пм, specific absorption rate is E1%1cm 219.8 [3].

Conclusion. In this way, at first time it has studied the physical and chemical properties, identified specific quality of and was done the standartization of 2,4,5-tribrom-1-(1-3-oksotietanil)-imidazole as a drug substance.

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