Skip to main content

Advertisement

SpringerLink
Log in

Synthesis of Cocrystals of Betulin with Suberic Acid and Study of Their Properties

  • Published:
Russian Journal of Bioorganic Chemistry Aims and scope Submit manuscript

Abstract—

Betulin and its derivatives belonging to the series of lupane triterpenoids attract a great interest due to a wide spectrum of biological and pharmacological activity. However, poor solubility of triterpenoids in aqueous media reduces significantly their bioavailability. The production of cocrystals, that is, multicomponent crystal systems containing active pharmaceutical ingredients and nontoxic partner molecules in their structure, is used in pharmacy to change physical and chemical properties of the drugs, including dissolution rate and solubility. In this work, cocrystals of betulin with suberic acid were obtained by a mechanochemical processing when adding small amounts of organic solvents of different polarity: ethanol, acetone, ethyl acetate, chloroform, toluene, dioxane. The production of cocrystals was confirmed by the methods of X-ray phase analysis, IR spectroscopy, as well as the methods of thermal analysis. It was demonstrated that cocrystals of betulin with suberic acid contain water molecules in their structure, while anhydrous cocrystals can be obtained by heating the physical mixture of reagents until the acid melts. In comparison with data for cocrystals of betulin with adipic acid, the results of the experiments on the dissolution of cocrystals of betulin with suberic acid demonstrated that an increase in the length of aliphatic acid chain leads to a decrease in the rate of betulin release into the solution.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1.
Fig. 2.
Fig. 3.
Fig. 4.
Fig. 5.
Fig. 6.
Fig. 7.

Similar content being viewed by others

REFERENCES

  1. Amiri, S., Dastghaib, S., Ahmadi, M., Mehrbod, P., Khademe, F., Behroujb, H., Aghanoorif, M-R., Machajg, F., Ghamsaric, M., Rosikg, J., Hudeckih, A., Afkhamic, A., Hashemii, M., Los, M.J., Mokarram, P., Madrakianc, T., and Ghavamia, S., Betulin and its derivatives as novel compounds with different pharmacological effects, Biotechnol. Adv., 2020, vol. 38, p. 107409. https://doi.org/10.1016/j.biotechadv.2019.06.008

    Article  CAS  Google Scholar 

  2. Vorob’eva, O.A., Malygina, D.S., Grubova, E.V., and Mel’nikova, N.B., Betulin derivatives. biological activity and solubility improvement, Khim. Rastit. Syr’ya, 2019, no. 4, pp. 407–430.

  3. Shakhtshneider, T.P., Kuznetsova, S.A., Zamay, A.S., Zamay, T.N., Spivak, E.A., Mikhailenko, M.M., Malyar, Yu.N., Kuznetsov, B.N., Chesnokov, N.V., and Boldyrev, V.V., New composites of betulin esters with arabinogalactan as highly potent anti-cancer agents, Nat. Product Res., 2016, vol. 30, pp. 1382–1387. https://doi.org/10.1080/14786419.2015.1060591

    Article  CAS  Google Scholar 

  4. Król, S.K., Kielbus, M., Rivero-Müller, A., and Stepulak, A., Comprehensive review on betulin as a potent anticancer agent, BioMed Res. Int., 2015, vol. 2015, pp. 1–11. https://doi.org/10.1155/2015/584189

    Article  CAS  Google Scholar 

  5. Kuznetsova, S.A., Skvortsova, G.P., Malyar, Yu.N., Skurydina, E.S., and Veselova, O.F., Extraction betulin from birch bark and study of its physicochemical and pharmacological properties, Khim. Rastit. Syr’ya, 2013, no. 2, pp. 93–100. https://doi.org/10.14258/jcprm.1302093

  6. Mierina, I., Vilskersts, R., and Turks, M., Delivery systems for birch-bark triterpenoids and their derivatives in anticancer research, Curr. Med. Chem., 2018, vol. 25, pp. 1–29.

    Google Scholar 

  7. Healy, A.M., Worku, Z.A., Kumar, D., and Madi, A.M., Pharmaceutical solvates, hydrates and amorphous forms: A special emphasis on cocrystals, Adv. Drug Deliv. Rev., 2017, vol. 117, pp. 25–46. https://doi.org/10.1016/j.addr.2017.03.002

    Article  CAS  Google Scholar 

  8. Jones, W., Motherwell, W.D.S., and Trask, A.V., Pharmaceutical cocrystals: An emerging approach to physical property enhancement, MRS Bull., 2006, vol. 31, pp. 875–879. https://doi.org/10.1557/mrs2006.206

    Article  CAS  Google Scholar 

  9. Qiao, N., Li, M., Schlindwein, W., Malek, N., Davies, A., and Trappitt, G., Pharmaceutical cocrystals: An overview, Int. J. Pharm., 2011, vol. 419, pp. 1–11. https://doi.org/10.1016/j.ijpharm.2011.07.037

    Article  CAS  Google Scholar 

  10. Weng, J.W., Wong, S.N., Xu, X.Y., Xuan, B.F., Wang, C.G., Chen, R.P., Sun, C.C., Lakerveld, R., Kwok, P.C.L., and Chow, S.F., Cocrystal engineering of itraconazole with suberic acid via rotary evaporation and spray drying, Cryst. Growth Des., 2019, vol. 19, pp. 2736–2745. https://doi.org/10.1021/acs.cgd.8b01873

    Article  CAS  Google Scholar 

  11. Rodrigues, M., Baptista, B., Lopes, J.A., and Sarraguca, M.C., Pharmaceutical cocrystallization techniques. Advances and challenges, Int. J. Pharm., 2018, vol. 547, pp. 404–420. https://doi.org/10.1016/j.ijpharm.2018.06.024

    Article  CAS  Google Scholar 

  12. Hasa, D. and Jones, W., Screening for new pharmaceutical solid forms using mechanochemistry: A practical guide, Adv. Drug Deliv. Rev., 2017, vol. 117, pp. 147–161. https://doi.org/10.1016/j.addr.2017.05.001

    Article  CAS  Google Scholar 

  13. Mikhailenko, M.A., Shakhtshneider, T.P., Brezgunova, M.E., Drebushchak, V.A., Kuznetsova, S.A., and Boldyrev, V.V., Preparation and study of the physicochemical properties of betulin solvates, Khim. Rastit. Syr’ya, 2010, no. 2, pp. 63–70.

  14. Myz, S.A., Mikhailovskaya, A.V., Mikhailenko, M.A., Bulina, N.V., Kuznetsova, S.A., and Shakhtshneider, T.P., New crystalline betulin-based materials: Improving betulin solubility via cocrystal formation, Mater. Today: Proc., 2019, vol. 12, pp. 82–85. https://doi.org/10.1016/j.matpr.2019.03.069

    Article  CAS  Google Scholar 

  15. Mikhailovskaya, A.V., Myz, S.A., Bulina, N.V., Gerasimov, K.B., Kuznetsova, S.A., and Shakhtshneider, T.P., Screening and characterization of cocrystal formation between betulin and terephthalic acid, Mater. Today: Proc., 2020, vol. 25, pp. 381–383. https://doi.org/10.1016/j.matpr.2019.12.096

    Article  CAS  Google Scholar 

  16. Myz’, S.A., Mikhailenko, M.A., Mikhailovskaya, A.V., Politov, A.A., Kuznetsova, S.A., and Shakhtshneider, T.P., Mechanochemical synthesis of cocrystals of betulin with adipic acid, Zh. Sib. Fed. Univ., Khim., 2020, vol. 13, no. 4, pp. 511–524.

    Google Scholar 

  17. Shevchenko, A., Miroshnyk, I., Pietila, L-O., Haarala, J., Salmia, J., Sinervo, K., Mirza, S., van Veen, B., Kolehmainen, E., and Yliruusi, J., Diversity in itraconazole cocrystals with aliphatic dicarboxylic acids of varying chain length, Cryst. Growth Des., 2013, vol. 13, pp. 4877–4884. https://doi.org/10.1021/cg401061t

    Article  CAS  Google Scholar 

  18. Kuznetsova, S.A., Kuznetsov, B.N., Mikhailov, A.G., and Levdanskii, V.A., Method for obtaining betulin, RF Patent no. 2264411, 2005.

  19. Qiushuo, Y., Xiaoxun, M., and Wenyu, G., Determination of the solubility, dissolution enthalpy and entropy of suberic acid in different solvents, Fluid Phase Equilib., 2012, vol. 330, pp. 44–47. https://doi.org/10.1016/j.fluid.2012.06.012

    Article  CAS  Google Scholar 

  20. Cao, D., Zhao, G., and Yan, W., Solubilities of betulin in fourteen organic solvents at different temperatures, J. Chem. Eng. Data, 2007, vol. 52, pp. 1366–1368. https://doi.org/10.1021/je700069g

    Article  CAS  Google Scholar 

  21. Myz’, S.A., Shakhtshneider, T.P., Tumanov, N.A., and Boldyreva, E.V., Preparation and studies of the co-crystals of meloxicam with carboxylic acids, Russ. Chem. Bull., 2012, vol. 61, no. 9, pp. 1798–1809.

    Article  Google Scholar 

  22. Drebushchak, T.N., Mikhailovskaya, A.V., Drebushchak, V.A., Mikhailenko, M.A., Myz’, S.A., Shakhtshneider, T.P., and Kuznetsova, S.A., Crystalline forms of betulin. Polymorphism of pseudopolymorphism?, J. Struct. Chem., 2015, vol. 51, no. 10, pp. 1260–1266.

    Google Scholar 

Download references

Funding

This work was supported within the state task of the Institute of Solid State Chemistry and Mechanochemistry, Siberian Branch, Russian Academy of Sciences (project no. FWUS-2021-0009) and the Institute of Chemistry and Chemical Technology, Siberian Branch, Russian Academy of Sciences (project no. 0287-2021-0017).

Author information

Authors and Affiliations

  1. Institute of Solid State Chemistry and Mechanochemistry, Siberian Branch, Russian Academy of Sciences, 630128, Novosibirsk, Russia

    A. V. Mikhailovskaya, S. A. Myz, K. B. Gerasimov & T. P. Shakhtshneider

  2. Institute of Chemistry and Chemical Technology, Federal Research Center Krasnoyarsk Science Center, Siberian Branch, Russian Academy of Sciences, 660036, Krasnoyarsk, Russia

    S. A. Kuznetsova

Authors
  1. A. V. Mikhailovskaya
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. S. A. Myz
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. K. B. Gerasimov
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. S. A. Kuznetsova
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. T. P. Shakhtshneider
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to T. P. Shakhtshneider.

Ethics declarations

The authors declare that they have no conflicts of interest. This article does not contain any studies involving human participants or animals performed by any of the authors.

Additional information

Translated by A. Barkhash

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Mikhailovskaya, A.V., Myz, S.A., Gerasimov, K.B. et al. Synthesis of Cocrystals of Betulin with Suberic Acid and Study of Their Properties. Russ J Bioorg Chem 48, 1498–1505 (2022). https://doi.org/10.1134/S1068162022070184

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1134/S1068162022070184

Keywords:

Search

Navigation