Development of quality control methods of promising anticonvulsant

Authors

DOI:

https://doi.org/10.15587/2519-4852.2018.152837

Keywords:

pharmaceutical analysis, identification, quantitative determination, impurity, spectroscopy, thin-layer chromatography, anticonvulsant

Abstract

In the previous studies, NUPh scientists proved that the search of potential anticonvulsants among derivatives of 1,3,4-thiadiazole is very perspective [1-3]. At the medicinal chemistry department of NUPh N-(5-ethyl-[1,3,4]-thiadiazole-2-yl)-2-nitrobenzamide was synthesized. This substance demonstrated high anticonvulsive activity on pentylentetrazole model of seizure compared to classic drug «Depakin». The substance is patented and proposed for further preclinical studies. One of the most important stages in the introduction of a new medicinal product or substance into medical practice is the development of quality control techniques.

The aim. The aim of this work was to develop methods of identification, determination of impurities and quantitative determination of N- (5-ethyl- [1,3,4] -thiadiazole-2-yl)-2-nitrobenzamide for further application in standardization of the substance.

Methods. Chromatographically pure sample of N- (5-ethyl- [1,3,4] -thiadiazole-2-yl) -2-nitrobenzamide, methods of IR, UV and 1H NMR spectroscopy.

Results. The physical-chemical properties and spectral characteristics of N-(5-ethyl-[1,3,4]-thiadiazole-2-yl)-2-nitrobenzamide were studied, and chemical identification methods were proposed. The optimal conditions for the determination of the impurities by the method of thin-layer chromatography using the method of internal normalization are selected. The assay for N- (5-ethyl- [1,3,4] -thiadiazol-2-yl) -2-nitrobenzamide was carried out by absorption spectrophotometry in the alcohol solution at the wavelength of 282 nm with the absorption index 631. For application of methods such validation characteristics as robustness, linearity, correctness, stability of analytical solutions, precision, convergence, reproducibility, calculation of uncertainty of samples preparation were studied.

Conclusions. The methods of identification of N- (5-ethyl- [1,3,4] -thiadiazol-2-yl) -2-nitrobenzamide with the use of chemical reactions and spectral methods of analysis - IR and UV and 1H NMR spectroscopy have been developed. To determine the concomitant impurities in the substance, the TLC method is recommended. Specific and nonspecific impurities were determined. The method of quantitative determination of substance by absorption spectrophotometry method in the ultraviolet region by the method of specific absorption index have been developed

Author Biographies

Igor Sych, National University of Pharmacy Pushkinska str., 53, Kharkiv, Ukraine, 61002

Postgraduate Student

Department of Medicinal Chemistry

Natalia Bevz, National University of Pharmacy Pushkinska str., 53, Kharkiv, Ukraine, 61002

PhD, Associate Professor

Department of Pharmaceutical Chemistry

Irina Sych, National University of Pharmacy Pushkinska str., 53, Kharkiv, Ukraine, 61002

PhD, Associate Professor

Department of Medicinal Chemistry

Maryna Rakhimova, National University of Pharmacy Pushkinska str., 53, Kharkiv, Ukraine, 61002

Assistant

Department of Medicinal Chemistry

Vitaliy Yaremenko, National University of Pharmacy Pushkinska str., 53, Kharkiv, Ukraine, 61002

PhD, Associate Professor

department of Medicinal Chemistry

Lina Perekhoda, National University of Pharmacy Pushkinska str., 53, Kharkiv, Ukraine, 61002

Doctor of Pharmacy, Professor, Head of the Department

Head of department of Medicinal Chemistry

References

  1. Noolvi, M. N., Patel, H. M., Kamboj, S., Kaur, A., Mann, V. (2012). 2,6-Disubstituted imidazo[2,1-b][1,3,4]thiadiazoles: Search for anticancer agents. European Journal of Medicinal Chemistry, 56, 56–69. doi: http://doi.org/10.1016/j.ejmech.2012.08.012
  2. Noolvi, M. N., Patel, H. M., Singh, N., Gadad, A. K., Cameotra, S. S., Badiger, A. (2011). Synthesis and anticancer evaluation of novel 2-cyclopropylimidazo[2,1-b][1,3,4]-thiadiazole derivatives. European Journal of Medicinal Chemistry, 46 (9), 4411–4418. doi: http://doi.org/10.1016/j.ejmech.2011.07.012
  3. Yousif, E., Rentschler, E., Salih, N., Salimon, J., Hameed, A., Katan, M. (2014). Synthesis and antimicrobial screening of tetra Schiff bases of 1,2,4,5-tetra (5-amino-1,3,4-thiadiazole-2-yl)benzene. Journal of Saudi Chemical Society, 18 (3), 269–275. doi: http://doi.org/10.1016/j.jscs.2011.07.007
  4. Alagawadi, K. R., Alegaon, S. G. (2011). Synthesis, characterization and antimicrobial activity evaluation of new 2,4-Thiazolidinediones bearing imidazo[2,1-b][1,3,4]thiadiazole moiety. Arabian Journal of Chemistry, 4 (4), 465–472. doi: http://doi.org/10.1016/j.arabjc.2010.07.012
  5. Cressier, D., Prouillac, C., Hernandez, P., Amourette, C., Diserbo, M., Lion, C., Rima, G. (2009). Synthesis, antioxidant properties and radioprotective effects of new benzothiazoles and thiadiazoles. Bioorganic & Medicinal Chemistry, 17 (14), 5275–5284. doi: http://doi.org/10.1016/j.bmc.2009.05.039
  6. Khan, I., Ali, S., Hameed, S., Rama, N. H., Hussain, M. T., Wadood, A. et. al. (2010). Synthesis, antioxidant activities and urease inhibition of some new 1,2,4-triazole and 1,3,4-thiadiazole derivatives. European Journal of Medicinal Chemistry, 45 (11), 5200–5207. doi: http://doi.org/10.1016/j.ejmech.2010.08.034
  7. Kadi, A. A., Al-Abdullah, E. S., Shehata, I. A., Habib, E. E., Ibrahim, T. M., El-Emam, A. A. (2010). Synthesis, antimicrobial and anti-inflammatory activities of novel 5-(1-adamantyl)-1,3,4-thiadiazole derivatives. European Journal of Medicinal Chemistry, 45 (11), 5006–5011. doi: http://doi.org/10.1016/j.ejmech.2010.08.007
  8. Hafez, H. N., Hegab, M. I., Ahmed-Farag, I. S., El-Gazzar, A. B. A. (2008). A facile regioselective synthesis of novel spiro-thioxanthene and spiro-xanthene-9′,2-[1,3,4]thiadiazole derivatives as potential analgesic and anti-inflammatory agents. Bioorganic & Medicinal Chemistry Letters, 18 (16), 4538–4543. doi: http://doi.org/10.1016/j.bmcl.2008.07.042
  9. Jatav, V., Mishra, P., Kashaw, S., Stables, J. P. (2008). CNS depressant and anticonvulsant activities of some novel 3-[5-substituted 1,3,4-thiadiazole-2-yl]-2-styryl quinazoline-4(3H)-ones. European Journal of Medicinal Chemistry, 43 (9), 1945–1954. doi: http://doi.org/10.1016/j.ejmech.2007.12.003
  10. Rzeski, W., Matysiak, J., Kandefer-Szerszeń, M. (2007). Anticancer, neuroprotective activities and computational studies of 2-amino-1,3,4-thiadiazole based compound. Bioorganic & Medicinal Chemistry, 15 (9), 3201–3207. doi: http://doi.org/10.1016/j.bmc.2007.02.041
  11. Chen, C.-J., Song, B.-A., Yang, S., Xu, G.-F., Bhadury, P. S., Jin, L.-H. et. al. (2007). Synthesis and antifungal activities of 5-(3,4,5-trimethoxyphenyl)-2-sulfonyl-1,3,4-thiadiazole and 5-(3,4,5-trimethoxyphenyl)-2-sulfonyl-1,3,4-oxadiazole derivatives. Bioorganic & Medicinal Chemistry, 15 (12), 3981–3989. doi: http://doi.org/10.1016/j.bmc.2007.04.014
  12. Liu, F., Luo, X.-Q., Song, B.-A., Bhadury, P. S., Yang, S., Jin, L.-H. et. al. (2008). Synthesis and antifungal activity of novel sulfoxide derivatives containing trimethoxyphenyl substituted 1,3,4-thiadiazole and 1,3,4-oxadiazole moiety. Bioorganic & Medicinal Chemistry, 16 (7), 3632–3640. doi: http://doi.org/10.1016/j.bmc.2008.02.006
  13. Perekhoda, L. O., Sych, I. V., Shtrigol, S. Yu., Taran, A. V., Drapak, I. V. (2018). Pat. No. 110054 UA. N-(5-ethyl- [1,3,4] thiadiazol-2-yl) -2-nitrobenzamide, which exhibits anticonvulsant activity. MPK A61K 31/165, A61K 31/433, C07D 285/12. No. а 2016 02439; declared: 14.03.2016; published: 25.10.2018, No. 20.
  14. Lyapunov, N. A., Soloviev, A. S., Stetsiv, V. V. et. al. (2012). Standartizatsiya farmatsevticheskoy produktsii – osnova razvitiya farmatsevticheskogo sektora Ukrainy [Standardization of pharmaceutical products is the basis of the development of the pharmaceutical sector of Ukraine]. Weekly Pharmacy, 826 (4).
  15. Perekhoda, L. O. (2013). Molekulyarne modelyuvannya ta tsilespryamovaniy sintez protisudomnih zasobIv pohIdnih p’yatichlennih di(tri)azageterotsikliv [Molecular modeling and purposeful synthesis of anticonvulsants of derivatives of five-membered di (three) azaheterocycles]. National University of Pharmacy. Kharkiv, 46.
  16. Sych, I. V., Perekhoda, L. A., Tsapko, T. O. (2016). Synthesis of 5-substituted 1,3,4-thiadiazol-2-yl-sulfanyl¬acetic acid derivatives. Scripta Scientifica Pharmaceutica, 2 (2), 53–59. doi: http://doi.org/10.14748/ssp.v2i2.1404
  17. Perekhoda, L. O. (2013). Kolichestvennoe issledovanie vzaimosvyazi «struktura – protivosudorozhnaya aktivnost» v ryadah proizvodnyih 1,2,3-triazola(1N), 1,2,4-triazola(4N), 1,3,4-oksadiazola(1N) i 1,3,4–tiadiazola(1N) [Quantitative study of the relationship between "structure – anticonvulsant activity" in the series of derivatives of 1,2,3-triazole (1H), 1,2,4-triazole (4H), 1,3,4-oxadiazole (1H) and 1,3,4 -Thiadiazole (1H)]. Him.-farmats. zhurnal, 47 (11), 42–44.
  18. Sych, I. V., Perekhoda, L. O., Ieromina, Z. G., Grinevich, L. O., Kobzar, N. P., Drapak, I. V. (2016). The synthesis and physicochemical properties of new derivatives of 5-r-phenylamino-2-mercapto-1,3,4-thiadiazole. Visnik Farmacii, 1 (85), 24–28. doi: http://doi.org/10.24959/nphj.16.2074
  19. Derzhavna Farmakopeya Ukrayini. Vol. 1 (2015). Kharkiv: DP «Ukrayinskiy naukoviy farmakopeyniy tsentr yakosti likarskih zasobiv», 1128.
  20. Larkin, P. J. (2011) Infrared and raman spectroscopy: principles and spectral interpretation. Elsevier, 230.
  21. Ivolgina, V. A., Chernov’yants, M. S. (2018). Spectroscopic and structural investigation of interaction of 5-mercapto-3-phenyl-1,3,4-thiadiazole-2-thione potassium salt with molecular iodine. Spectrochimica Acta Part A: Molecular and Biomolecular Spectroscopy, 199, 315–321. doi: http://doi.org/10.1016/j.saa.2018.03.069
  22. Mohamed, T. A., Soliman, U. A., Shaaban, I. A., Zoghaib, W. M., Wilson, L. D. (2015). Raman, infrared and NMR spectral analysis, normal coordinate analysis and theoretical calculations of 5-(methylthio)-1,3,4-thiadiazole-2(3H)-thione and its thiol tautomer. Spectrochimica Acta Part A: Molecular and Biomolecular Spectroscopy, 150, 339–349. doi: http://doi.org/10.1016/j.saa.2015.05.039

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Published

2018-12-04

How to Cite

Sych, I., Bevz, N., Sych, I., Rakhimova, M., Yaremenko, V., & Perekhoda, L. (2018). Development of quality control methods of promising anticonvulsant. ScienceRise: Pharmaceutical Science, (6 (16), 13–21. https://doi.org/10.15587/2519-4852.2018.152837

Issue

No. 6 (16) (2018)

Section

Pharmaceutical Science

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Copyright (c) 2018 Igor Sych, Natalia Bevz, Irina Sych, Maryna Rakhimova, Vitaliy Yaremenko, Lina Perekhoda

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