Phase Equilibrium of Biologically Active Systems 4,6-dinitro-5,7-dichlorobenzofuroxane and 5-nitro-4,6-dichlorobenzofuroxane

Introduction. One of the intensive ways to increase the therapeutic efficacy and safety of a drug is a combination of several already known substances or chemical compounds, leading to the appearance of a synergistic effect. This method of creating a medicinal product is one of the most important trends in recent times, since the synergistic effect allows one to achieve greater pharmacological activity, expand the range of medical applications and reduce the toxic effect of the drug on the organism. These pharmaceutical active substances include a binary mixture "Dimixan"(mixture 4,6-dinitro-5,7-dichlorobenzofuroxan (4,6-DNDHBFO) and 5-nitro-4,6-dichlorobenzofuroxan (5-NDHBFO). They demonstrate potentiated synergism to the ultra-resistant mold fungus of the species Aspergillius niger. However, the synergy mechanism of the mixture of 5-NDHBFO and 4,6-DNDHBFO is not fully studied. The results of determining the thermodynamic characteristics and phase equilibria in these systems will make it possible to determine the nature of the interaction between 5-NDCBPO and 4,6-DNDCBPO, which will undoubtedly contribute to the optimal organization of the production of a promising drug.

Aim. Establishing the nature of the interaction between 5-NDHBFO and 4,6-DNDHBFO in the system.

Materials and methods. Using differential scanning calorimetry (DSC), phase equilibria in the 5-NDHBFO and 4,6-DNDHBFO systems were studied in a wide range of component concentrations. From the state diagram, the thermodynamic characteristics of the eutectic were determined: the enthalpy and entropy of melting of mixtures of 5-NDHBFO – 4,6-DNDHBFO at different ratios of components.

Results and discussion. Based on the results of the study, phase reactions with the physicochemical interaction of 5-NDHBFO and 4,6-DNDHBFO in two-component systems with the formation of eutectic alloys of the "solid solution" type are identified. The specific values of the enthalpies of melting of alloys of eutectic compositions were determined, from which the entropies of melting were calculated. The results of a study of the density of eutectic compositions of 5-NDHBFO – 4,6-DNDHBFO indicate the formation of an interstitial solid solution.

Conclusion. The nature of the interaction between 5-NDHBFO and 4,6-DNDHBFO in the system, leading to the appearance of a synergy effect, has been established. The results obtained are important for predicting the eutectic compositions of 5-NDHBFO and 4,6-DNDHBFO as active pharmaceutical ingredient with increased biological activity.

1. Nikolaev S. M. On a rational approach to the development of multicomponent drugs. Ulan-Ude: BF SO AN SSSR. 1986. 48 p. (In Russ.).

2. Kant I. A. Combined chemotherapy. Obshchie voprosy primeneniya lekarstv = General questions about the use of drugs. 2017;5:35–39. (In Russ.).

3. Yusupova L. M., Garmonov S. Yu., Zakharov I. M., Bykov A. R., Garipov T. V., Falyakhov I. F. Multipurpose biological protection agents based on chlorine derivatives of nitrobenzofuroxan. Vestnik Kazanskogo tekhnologicheskogo universiteta = Bulletin of the Technological University. 2004;1:103–111. (In Russ.).

4. Yusupova L. M., Garmonov S. Yu., Zakharov I. M., Zykova I. E., Mukhametshina A. M., Falyakhov I. F., Garipov T. V. Biological activity of chlorine derivatives of nitrobenzofuroxan. Voprosy biologicheskoj, medicinskoj i farmacevticheskoj himii = Problems of Biological, Medical and Pharmaceutical Chemistry. 2005;4:45–48. (In Russ.).

5. Khamed A. A. Synergy and antagonism of veterinary drugs. Veterinary. Zhivotnovodstvo v Rossii = Animal husbandry of Russia. 2013. Р. 2–3. (In Russ.).

6. Kiseleva T. L., Dronova M. A. Synergistic aspects of modern phytopharmacotherapy. Novosti mediciny i farmacii. 2012;7(49):4– 8. (In Russ.).

7. Kershengolts B. M., Chernobrovkina T. V., Shein A. A., Khlebnyi E. S., Anshakov V. V. Nonlinear dynamics (synergy) in chemical, biological and biotechnological systems. Yakutsk: GOU VPO YAkutskij gosudarstvennyj universitet im. M. K. Ammosova. 2009. Р. 92–163. (In Russ.).

8. Yusupova L. M., Buzykin B. I., Molody Zh. V., Falyakhov I. F., Abdrakhmanov I. Sh., Khisamutdinov G. Kh., Belyaev P. G., Ugryumova V. S., Ravilov A. Z., Yusupova G. R., Sharnin G. P., Bulidorov V. V., Sviridov S. I., Anisimova N. N. Method of obtaining a mixture of 4-nitro-and 6-nitro-5,7-dichlorobenzofuroxanes and a mixture of 4-nitro- and 6-nitro-5,7-dichlorobenzofuroxans having bactericidal, virucidal and sporocidal activity. Patent 2051913 of the Russian Federation. Declared 22. 04.1992. Publ. 10.01.1996. (In Russ.).

9. Moshchenskii Yu. V., Fedotov S. V., Zhniakina L. E., Smelova S. G., Tkachenko M. L. Differential scanning calorimetry system for research of medicinal objects. Himiko-farmacevticheskij zhurnal = Pharmaceutical Chemistry Journal. 2005;39(11):46–49. (In Russ.).

10. Tkachenko M. L., Zhniakina L. E., Moshchenskii Yu. V., Loseva M. A., Levaniuk I. A. Thermal studies and some technological properties of the «caffeine-paracetamol-urea» triple drug system. Farmaciya = Pharmacy. 2008;2:29–32. (In Russ.).

11. State Pharmacopoeia of the Russian Federation. XIV. V. 1. OFS.1.2.1.0027.18. Moscow: Nauchnyj centr ekspertizy sredstv medicinskogo primeneniya = Scientific Centre for Expert Evaluation of Medicinal Products. 2018. (In Russ.).

12. Standard samples of temperatures and heats of phase transitions (SOTSF set). SSS 2312-82/2316-82. 2019. (In Russ.).

13. Gatta G. D., Richardson M. J., Sarge S. M., Stolen S. Standard, calibration and guidelines in microcalorimetry. Part 2. Calibration standards for differential scanning calorimetry (IUPAC Technical Report). Pure and Applied Chemistry. 2006;78(7):1455–1476.

14. Petkov V. I., Grudzinskaya E. Yu. Isomorphism. Solid solutions. Nizhny Novgorod: Nizhegorodskij gosudarstvennyj universitet im. N. I. Lobachevskogo = National Research Lobachevsky State University of Nizhni Novgorod. 2010. 144 p. (In Russ.).

15. Moshchenskii Yu. V., Tkachenko M. L. Physicochemical analysis of eutectic systems of medicinal compositions. Izvestiya Samarskogo nauchnogo centra RAN. Himiya i himicheskaya tekhnologiya. 2004. Р. 87–91. (In Russ.).

16. Stepanovskikh E. I., Brusnitsyna L. A. Calculation of changes in entropy in systems without chemical transformation. Yekaterinburg: UGTU-UPI. 2008. 44 p. (In Russ.).

17. Agafonova E. V., Moshchensky Yu. V., Tkachenko M. L. Determination of the thermodynamic parameters of the melting of sulfamethoxazole, trimethoprim, urea, nicodine and their double eutectics using differential scanning calorimetry. Zhurnal fizicheskoj himii. 2013;87(8):1301–1304. (In Russ.).