Development of the "Dissolution" Test Method for Tablets of Sodium 4,4'-(propanediamido)dibenzoate with Sustained Release

Introduction. Non-alcoholic fatty liver disease is one of the most common chronic diseases of this parenchymal organ among the adult population. The search and creation of supporting drugs is an urgent task of modern pharmacy. The malonic acid derivative, sodium 4,4'-(propanediamido) dibenzoate, synthesized by the employees of the Department of Organic Chemistry of the SPСPU, has antisteatous activity, is a potential agent for the treatment of liver diseases. Sustained release tablets were prepared based on sodium 4,4'-(propanediamido)dibenzoate. An integral part of the pharmaceutical development of a medicinal product is the development of a method for conducting the Dissolution test and the selection of optimal conditions, which became the purpose of this study.

Aim. To develop the "Dissolution" test method for the sustained-release tablets based on sodium 4,4'-(propanediamido)dibenzoate.

Materials and methods. The objects of research are the active pharmaceutical ingredient sodium 4,4'-(propanediamido)dibenzoate, as well as sustained-release tablets based on this substance. Equilibrium biopharmaceutical solubility was determined by UV-spectrophotometry. To establish the conditions for the "Dissolution" test, an ERWEKA DT-620 dissolution tester (ERWEKA GmbH, Germany) was used.

Results and discussion. The suitability of the UV-spectrophotometry method for the quantitative determination of sodium 4,4'-(propanediamido) dibenzoate in solutions was determined. The established high biopharmaceutical solubility of sodium 4,4'-(propanediamido)dibenzoate in a buffer solution with a pH of 6,8, as well as in a 0,01 M solution of hydrochloric acid with a pH of 2,6, determined the choice of these media for the "Dissolution" test of the dosage form. The apparatus "Rotating basket" (rotation speed of 100 rpm in a dissolution medium with a volume of 1000 ml) was reasonably chosen for the test on the basis of the obtained linear dependence of the rate of release of the substance on time, as well as the best test results by the end of the experiment.

Conclusion. A study of the biopharmaceutical properties of the original substance with antisteatous activity has been carried out. High biopharmaceutical solubility was established in media with pH 2,6 and pH 6,8. The conditions of the "Dissolution" test for sustained-release tablets based on the original sodium 4,4'-(propanediamido)dibenzoate were experimentally substantiated.

1. Global’nyj doklad po diabetu [Global report on diabetes]. Geneva; World Health Organization. 2018. 88 p. (In Russ.)

2. O’Neill S., O’Driscoll L. Metabolic syndrome: A closer look at the growing epidemic and its associated pathologies. Obesity Reviews. 2015;16(1):1–12. DOI: 10.1111/obr.12229.

3. Xiaoyan Ch., Kirgizova O. Yu. Metabolic syndrome: some results and prospects for solving the problem. Bulletin VSNTS SB RAMS. 2016;1(5):187-194. (In Russ.).

4. Radko S. V. Ocenka vlijanija 4,4”-(propandiamido)dibenzoata natrija na fizicheskuju rabotosposobnost' myshej k jeksperimental'nym steatozom pecheni Sbornik materialov V Vserossijskoj nauchno-prakticheskoj konferencii s mezhdunarodnym uchastiem «Innovacii v zdorov'e nacii» [Evaluation of the effect of 4.4”-(propanediamido) sodium dibenzoate on the physical performance of mice with experimental liver steatosis. Collection of materials of the V All-Russian scientific-practical conference with international participation "Innovations in the health of the nation"]. Sbornik materialov V Vserossijskoj nauchno-prakticheskoj konferencii s mezhdunarodnym uchastiem «Innovacii v zdorov’e nacii»; 2017 Nov 8–9; St. Petersburg: SPKhFU; 2017. P. 29–32 (In Russ.)

5. Grebenkin D. Yu., Stanishevsky Ya. M., Shokhin I. E., Malashenko E. A. A retrospective of the development of the science of dissolution of solid dosage forms. Razrabotka i registratsiya lekarstvennykh sredstv = Drug development & registration. 2016;4(17):158–166. (In Russ.)

6. Grebenkin D. Yu., Stanishevsky Ya. M., Shokhin I. E. Modern approaches to the comparative dissolution kinetics test. Razrabotka i registratsiya lekarstvennykh sredstv = Drug development and registration. 2016;1(14):166–171. (In Russ.)

7. Mustafin R. I., Sitenkova (Bukhovets) A. V., Fotaki N. Features of the predictive test "Dissolution". Razrabotka i registratsiya lekarstvennykh sredstv = Drug development & registration. 2017;1(18):156–162. (In Russ.)

8. Smekhova I. E., Perova Yu. M. Kondratyeva I. A., Rodygina A. N., Turetskova N. N. Dissolution test and modern approaches to assessing the equivalence of drugs. Razrabotka i registratsiya lekarstvennykh sredstv = Drug development & registration. 2013;1(2):50–61. (In Russ.)

9. Demina N. B. Biopharmaceutical classification system as a tool for the development of design and technology of a dosage form. Razrabotka i registratsiya lekarstvennykh sredstv = Drug development & registration. 2017;(2):56–60. (In Russ.)

10. Amidon G. L., Lennerns H., Shah V. P. A Theoretical Basis for a Biopharmaceutics Drug Classification: The Correlation of In Vitro Drug Product Dissolution and In Vivo Bioavailability. Journal of Рharmaceutical Research. 1995;12:413–420.

11. Michele G. I., Humberto G. F. Intrinsic dissolution as a tool for evaluating drug solubility in accordance with the biopharmaceutics classification system. Dissolution Technologies. 2011;3:6–15. DOI: 10.14227/DT180311P6.

12. Dressman J. B., Vertzoni M., Goumas K., Reppas C. Estimating drug solubility in the gastrointestinal tract. Advanced Drug Delivery Reviews. 2007;59:591–602. DOI: 10.1016/j.addr.2007.05.009.

13. Alekseeva G. M., Apraksin V. F., Generalova Yu. E. Study of acid-base properties, development and validation of a method for quantitative determination of an original pharmaceutical substance. Razrabotka i registratsiya lekarstvennykh sredstv = Drug development & registration. 2019;8(1):66–71. (In Russ.) DOI: 10.33380/2305-2066-2019-8-1-66-71.

14. Gosudarstvennaya farmakopeya Rossiyskoy Federatsii. XIV izdaniya. [State Pharmacopoeia of the Russian Federation. XIV Edition]. Available at: http://femb.ru/femb/pharmacopea.php. Accessed: 28.10.2021. (In Russ.)

15. Farmakopeja Evrazijskogo jekonomicheskogo sojuza [Pharmacopoeia of the Eurasian Economic Union]. Available at: https://docs.eaeunion.org/docs/ru-ru/01426917/err_13082020_100. Accessed: 28.10.2021.

16. Garbacz G., Klein S. Dissolution testing of oral modified-release dosage forms. Journal of Pharmacy and Pharmacology. 2012;(64):944–968. DOI: 10.1111/j.2042-7158.2012.01477.x.

17. Walker R., Mwila C. Development and assessment of a USP Apparatus 3 dissolution test method for sustained-release nevirapine matrix tablets. Dissolution Technologies. 2016:22–30. DOI: 10.14227/DT230316P22.

18. Li J., Yang L., Ferguson S. M., Hudson T. J., Watanabe S., Katsuma M., Fix J. A. In vitro evaluation of dissolution behavior for a colon-specific drug delivery system (CODES™) in multi-pH media using United States Pharmacopoeia Apparatus II and III. AAPS PharmSciTech. 2002;3(4):1–9. DOI: 10.1208/pt030433.

19. Kumawat S., Sharma D. M., Rathore S. D., Agarwal M. Review on sustaines release technology. International Journal of Pharmaceutical and Biological Science Archive. 2019;7(6):29–38.

20. Milind J. A., Keyur S. P., Deppa R. P., Zil P. P., Jayanti V. B. Formulation and evaluation of sustained-release pellets of lornoxicam. International Journal of Applied Pharmaceutics. 2021;13(4):221–227. DOI: 10.13040/IJPSR.0975-8232.11(5).2135-46.

21. FDA dissolution methods database. Available at: https://www.accessdata.fda.gov/scripts/cder/dissolution/dsp_getallData.cfm.Accessed: 28.10.2021.

22. Shamal L. L., Yarushok T. A., Shokhin I. E., Ramenskaya G. V. Study of the equilibrium biopharmaceutical solubility of drug substances used in the treatment of oncological diseases. Remedium. 2014;(11):73-76. (In Russ.)

23. Cerea M., Maroni A, Palugan L., Moutaharrik S., Melocchi A., Zema L., Foppoli A., Gazzaniga A. Oral hydrophilic matrices having non-uniform drug distribution for zero-order release: a literature review. Journal of Controlled Release. 2020;325:72–83. DOI: 10.1016/j.jconrel.2020.06.033.

24. Maroni A., Zema L., Cerea M., Foppoli A., Palugan L., Gazzaniga A. Erodible drug delivery systems for time-controlled release into the gastrointestinal tract. Journal of Drug Delivery Science and Technology. 2015:1–7. DOI: 10.1016/j.jddst.2015.10.001.

25. Zhao Y.-N., Xu X., Wen N., Song R., Meng Q., Guan Y., Cheng S., Cao D., Dong Y., Qie J., Liu K., Zhang Y. A drug carrier for sustained zero-order release of peptide therapeutics. Scientific Reports. 2017;7:5524 . DOI: 10.1038/s41598-017-05898-6.