Study of the solubility of betamethasone dipropionate and the conditions for the formation of the stable suspensions

Authors

DOI:

https://doi.org/10.15587/2519-4852.2025.333181

Keywords:

betamethasone dipropionate (BD), solubility, crystallization, propylene glycol (PG), water, solvent, liquid paraffin

Abstract

The aim. To study the solubility of betamethasone dipropionate (BD) in mixed solvents water – propylene glycol (PG) and liquid paraffin, as well as to identify the conditions necessary for the formation of stable BD suspensions.

Materials and methods. The solubility of BD in solvents water – PG was studied using spectrophotometry. The particle size distribution of BD in suspensions was analysed by laser diffraction. The suspensions and creams were subjected to optical microscopy for additional evaluation. Thermogravimetric analysis was conducted to explore the potential formation of BD crystallosolvates with PG, while differential scanning calorimetry was utilised to assess the characteristics of the dissolution processes. Additionally, the study employed the spin probe method, using a steroid spin-label.

Results. The solubility of BD in water – PG solvents was found to increase with rising temperature and to increase sharply with increasing PG concentration, provided that the PG structure dominated the system. The deviations of BD solubility from additivity at 20-35°C were negative, passing through a minimum at a PG concentration of ~35% mol, above which the transition to the structure of a nonaqueous solvent occurred. An elevation in temperature to 45-55°C resulted in a positive deviation of the BD solubility from additive values at specific PG concentrations. It has been demonstrated that PG and BD do not form crystallosolvates. The process of dissolving BD in PG is exothermic, while in liquid paraffin, it is endothermic. The steroid spin probe was found to be localized in the oil phases of creams. Suspensions in which BD particles recrystallize were formed when BD crystallized from solution in PG as a result of lowering the temperature and adding water. When BD was suspended in a water ‒ PG solvent, where the water structure predominates, or in liquid paraffin (oil phase of creams), the BD particle size increased slightly, or there was no recrystallization.

Conclusions. The solubility of BD in solvents water – PG is contingent upon the temperature and concentration of PG; it exhibits a marked increase when the structure of a nonaqueous solvent predominates in the system. It has been demonstrated that BD with PG does not form crystallosolvates. When BD suspensions were obtained by crystallization from a solution in PG, suspensions were formed in which BD particles recrystallized over time. In the case of BD suspensions in solvent water – PG, where the water structure predominates, or in liquid paraffin, recrystallization was practically not observed

Supporting Agency

  • The research was financially supported by the National Academy of Sciences of Ukraine within the framework of the project «Study of dispersed systems with liquid dispersion medium as the primary matrices for medicinal products» (0125U000740).

Author Biographies

Olena Bezuglaya, State Scientific Institution “Institute for Single Crystals” of National Academy of Sciences of Ukraine

PhD, Senior Researcher, Head of Laboratory

Laboratory of Technology and Analysis of Medicinal Products

Institute for Functional Materials Chemistry

Alla Krasnopyorova, V. N. Karazin Kharkiv National University

PhD, Senior Researcher, Head of Department

Department of Radiochemistry and Radioecology

Research Institute of Chemistry

Olga Vashchenko, State Scientific Institution «Institute for Single Crystals» of National Academy of Sciences of Ukraine

Doctor of Physical and Mathematical Sciences, Senior Researcher, Leading Researcher

Yu. V. Malukin Nanostructured Materials Department

Institute for Scintillation Materials

Yurij Stolper, State Scientific Institution «Institute for Single Crystals» of National Academy of Sciences of Ukraine

PhD, Senior Researcher

Laboratory of Technology and Analysis of Medicinal Products

Institute for Functional Materials Chemistry

Anna Liapunova, State Scientific Institution «Institute for Single Crystals» of National Academy of Sciences of Ukraine

PhD, Senior Researcher

Laboratory of Technology and Analysis of Medicinal Products

Institute for Functional Materials Chemistry

Igor Zinchenko, Institute for Functional Materials Chemistry State Scientific Institution «Institute for Single Crystals» of National Academy of Sciences of Ukraine

PhD, Senior Researcher

Laboratory of Technology and Analysis of Medicinal Products

Institute for Functional Materials Chemistry

Oleksii Liapunov, State Scientific Institution «Institute for Single Crystals» of National Academy of Sciences of Ukraine

PhD, Researcher

Laboratory of Technology and Analysis of Medicinal Products

Institute for Functional Materials Chemistry

Yuliia Shliapkina, State Scientific Institution «Institute for Single Crystals» of National Academy of Sciences of Ukraine

Junior Researcher

Laboratory of Technology and Analysis of Medicinal Products

Institute for Functional Materials Chemistry

Nikolay Lyapunov, State Scientific Institution «Institute for Single Crystals» of National Academy of Sciences of Ukraine

Doctor of Pharmaceutical Sciences, Professor, Leading Researcher

Laboratory of Technology and Analysis of Medicinal Products

Institute for Functional Materials Chemistry

References

  1. The European Pharmacopoeia (2022). European Directorate for the Quality of Medicines & HealthCare of the Council of Europe. Strasbourg: Sedex, 6105. Available at: http://pheur.edqm.eu/subhome/11-0
  2. The United States Pharmacopoeia 46 ed. The National Formulary 41 [USP 46 – NF 41] (2023). The United States Pharmacopeial Convention. Rockville: United Book Press, Inc.
  3. British Pharmacopoeia (2025). London: The Stationery Office. Available at: https://www.pharmacopoeia.com/
  4. Buckingham, R. (Ed.) (2020). Martindale: The Complete Drug Reference, 40th Ed. London: Pharmaceutical Press, 4852.
  5. ATC/DDD Index (2025). WHO Collaborating Centre for Drug Statistics Methodology. Oslo: Norwegian Institute of Public Health.
  6. Derzhavnyi reiestr likarskykh zasobiv Ukrainy. Available at: http://www.drlz.kiev.ua/
  7. Sheskey, P. J., Hancock, B. C., Moss, G. P., Goldfarb, D. J. (Eds.) (2020). Handbook of Pharmaceutical Excipients. London: Pharm. Press, 1296.
  8. Bezuhlaia, E. P., Melnykova, E. N., Zhemerova, E. H., Liapunov, A. N., Zynchenko, Y. A. (2016). Efficacy of antimicrobial preservation of certain hydrophilic non-aqueous solvents in aqueous solutions and gels. Farmakom, 1, 51–59.
  9. Bezugla, O. P., Lyapunov, M. O., Zinchenko, I. O., Lisokobilka, O. A., Liapunova, A. M. (2022). Modeling of processes of solvent diffusion from ointment bases using in vitro experiments. Functional materials, 29 (4), 553–558. https://doi.org/10.15407/fm29.04.553
  10. Bendas, B., Schmalfuβ, U., Neubert, R. (1995). Influence of propylene glycol as cosolvent on mechanisms of drug transport from hydrogels. International Journal of Pharmaceutics, 116 (1), 19–30. https://doi.org/10.1016/0378-5173(94)00267-9
  11. Carrer, V., Alonso, C., Pont, M., Zanuy, M., Córdoba, M., Espinosa, S. et al. (2019). Effect of propylene glycol on the skin penetration of drugs. Archives of Dermatological Research, 312 (5), 337–352. https://doi.org/10.1007/s00403-019-02017-5
  12. Liapunova, A. M., Krasnopyorova, А. P., Bezuglа, О. P., Liapunov, O. M., Yukhnо, G. D., Pukhova, T. М. (2024). Polythermal studies of the water – propylene glycol systems by densitometry, viscometry and spin probes method. Functional Materials, 31 (4), 609–618. https://doi.org/10.15407/fm31.04.609
  13. Khattab, I. S., Bandarkar, F., Khoubnasabjafari, M., Jouyban, A. (2017). Density, viscosity, surface tension, and molar volume of propylene glycol + water mixtures from 293 to 323 K and correlations by the Jouyban–Acree model. Arabian Journal of Chemistry, 10, S71–S75. https://doi.org/10.1016/j.arabjc.2012.07.012
  14. Makarov, D. M., Egorov, G. I., Kolker, A. M. (2016). Temperature and composition dependences of volumetric properties of (water + 1,2-propanediol) binary system. Journal of Molecular Liquids, 222, 656–662. https://doi.org/10.1016/j.molliq.2016.07.095
  15. Jimeneze, J., Martinez, F. (2005). Study of some volumetric properties of 1,2-propanediol + water mixtures at several temperatures. Revista Colombiana de Ciencias Químico-Farmacéuticas, 34 (1), 46‒57.
  16. Sun, T., Teja, A. S. (2004). Density, Viscosity and Thermal Conductivity of Aqueous Solutions of Propylene Glycol, Dipropylene Glycol, and Tripropylene Glycol between 290 K and 460 K. Journal of Chemical & Engineering Data, 49 (5), 1311–1317. https://doi.org/10.1021/je049960h
  17. dos Santos, L. J., Espinoza-Velasquez, L. A., Coutinho, J. A. P., Monteiro, S. (2020). Theoretically consistent calculation of viscous activation parameters through the Eyring equation and their interpretation. Fluid Phase Equilibria, 522, 112774. https://doi.org/10.1016/j.fluid.2020.112774
  18. Xu, Y., Xing, L., Cao, X., Li, D., Men, Z., Li, Z. et al. (2023). Hydrogen bonding network dynamics of 1,2-propanediol-water binary solutions by Raman spectroscopy and stimulated Raman scattering. Spectrochimica Acta Part A: Molecular and Biomolecular Spectroscopy, 284, 121825. https://doi.org/10.1016/j.saa.2022.121825
  19. Zhou, Y., Hu, K., Shen, J., Wu, X., Cheng, G. (2009). Microstructure variations with concentration of propylene glycol–water solution probed by NMR. Journal of Molecular Structure, 921 (1-3), 150–155. https://doi.org/10.1016/j.molstruc.2008.12.050
  20. Panahi-Azar, V., Shayanfar, A., Martínez, F., Acree Jr, W. E., Jouyban, A. (2011). Thermodynamic studies of fluphenazine decanoate solubility in propylene glycol+water mixtures and correlation with the Jouyban-Acree model. Fluid Phase Equilibria, 308 (1-2), 72–77. https://doi.org/10.1016/j.fluid.2011.06.008
  21. Zeng, A.-G., Pang, X.-L., Wu, N., Wang, D., Nan, G.-J., Yang, G.-D., Bian, X.-L. (2014). Solubility of daidzein in propylene glycol plus water cosolvent mixtures. Fluid Phase Equilibria, 366, 127–133. https://doi.org/10.1016/j.fluid.2013.12.024
  22. Fathi-Azarjbayjani, A., Mabhoot, A., Martínez, F., Jouyban, A. (2016). Modeling, solubility, and thermodynamic aspects of sodium phenytoin in propylene glycol–water mixtures. Journal of Molecular Liquids, 219, 68–73. https://doi.org/10.1016/j.molliq.2016.02.089
  23. Jouyban-Gharamaleki, V., Rahimpour, E., Hemmati, S., Martinez, F., Jouyban, A. (2020). Mesalazine solubility in propylene glycol and water mixtures at various temperatures using a laser monitoring technique. Journal of Molecular Liquids, 299, 112136. https://doi.org/10.1016/j.molliq.2019.112136
  24. Muñoz, M. M., Rodríguez, C. J., Delgado, D. R., Peña, M. Á., Jouyban, A., Martínez, F. (2015). Solubility and saturation apparent specific volume of some sodium sulfonamides in propylene glycol + water mixtures at 298.15 K. Journal of Molecular Liquids, 211, 192–196. https://doi.org/10.1016/j.molliq.2015.07.016
  25. Pirhayati, F. H., Shayanfar, A., Rahimpour, E., Barzegar-Jalali, M., Martinez, F., Jouyban, A. (2017). Solubility of sildenafil citrate in propylene glycol + water mixtures at various temperatures. Physics and Chemistry of Liquids, 56 (4), 508–517. https://doi.org/10.1080/00319104.2017.1354376
  26. Miron, D. S., Rădulescu, F. Ștefan, Voicu, V. A., Mînea, A., Cardot, J.-M., Shah, V. P. (2021). Rheological and in vitro release measurements of manufactured acyclovir 5% creams: confirming sensitivity of the in vitro release. Pharmaceutical Development and Technology, 26 (7), 779–787. https://doi.org/10.1080/10837450.2021.1945625
  27. Benaouda, F., Jones, S. A., Martin, G. P., Brown, M. B. (2015). Localized Epidermal Drug Delivery Induced by Supramolecular Solvent Structuring. Molecular Pharmaceutics, 13 (1), 65–72. https://doi.org/10.1021/acs.molpharmaceut.5b00499
  28. Bakhbakhi, Y., Charpentier, P., Rohani, S. (2009). The Solubility of Beclomethasone-17,21-dipropionate in Selected Organic Solvents: Experimental Measurement and Thermodynamic Modeling. Organic Process Research & Development, 13 (6), 1322–1326. https://doi.org/10.1021/op900142j
  29. Derzhavna Farmakopeia Ukrainy. Vol. 2 (2024). Kharkiv: Derzhavne pidpryiemstvo «Ukrainskyi naukovyi farmakopeinyi tsentr yakosti likarskykh zasobiv», 424.
  30. ICH Q8 (R2) Pharmaceutical development – Scientific guideline EMEA/CHMP/167068/2004 (2009). European Medicines Agency. Available at: www.ema.europa.eu/en/ich-q8-r2-pharmaceutical-scientific-guideline
  31. Bezugla, O. P., Lyapunova, A. M., Kirilyuk, I. A., Lyapunov, O. M. (2017). The study of steroid distribution in emulsions by the spin probe method. Clinical pharmacy, 21 (3), 46–54. https://doi.org/10.24959/cphj.17.1430
Study of the solubility of betamethasone dipropionate and the conditions for the formation of the stable suspensions

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Published

2025-06-30

How to Cite

Bezuglaya, O., Krasnopyorova, A., Vashchenko, O., Stolper, Y. ., Liapunova, A., Zinchenko, I., Liapunov, O., Shliapkina, Y., & Lyapunov, N. (2025). Study of the solubility of betamethasone dipropionate and the conditions for the formation of the stable suspensions. ScienceRise: Pharmaceutical Science, (3 (55), 38–54. https://doi.org/10.15587/2519-4852.2025.333181

Issue

No. 3 (55) (2025)

Section

Pharmaceutical Science

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Copyright (c) 2025 Оlena Bezuglaya, Alla Krasnopyorova, Olga Vashchenko, Yurij Stolper, Anna Liapunova, Igor Zinchenko, Oleksii Liapunov, Yuliia Shliapkina, Nikolay Lyapunov

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