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Plastun I. L., Zakharov A. A., Babkov L. M., Yakovlev R. Y. Polymorphism manifestations and aqueous environment influence on the physico-chemical properties of modified succinic acid. Izvestiya of Saratov University. Physics , 2022, vol. 22, iss. 3, pp. 229-243. DOI: 10.18500/1817-3020-2022-22-3-229-243, EDN: GZZXOL

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Polymorphism manifestations and aqueous environment influence on the physico-chemical properties of modified succinic acid

Plastun Inna L'vovna, Yuri Gagarin State Technical University of Saratov
Zakharov Alexander A., Yuri Gagarin State Technical University of Saratov
Babkov Lev Mikhailovich, Saratov State University
Yakovlev Ruslan Yurievich, Smart Polymorph Technologies Company

Background and Objectives: Succinic acid is widely used in medicine, in particular, in the treatment of cardiological, neurological and endocrinological diseases. An urgent task of pharmacology is to increase the degree of bioavailability and solubility of drugs. One of ways to increase the therapeutic effect of drugs is the development of their polymorphic modifications, which contribute to a more pronounced therapeutic effect. One of ways to obtain new forms of succinic acid with better solubility and bioavailability is polymorphic modification nanotechnology based on the recrystallization of organic substances. We analyze the conformers and the influence of the aqueous environment on the physical-chemical properties of succinic acid. Materials and Methods: Spectral manifestations of modified succinic acid polymorphism and aqueous environment influence on spectral and energy characteristics are investigated on the integrated approach (experiment, theory) basis. The IR spectra of succinic acid are measured in the region of 600–4000 cm−1. The structures of an isolated molecule and a fragment of a chain associate of succinic acid conformers and their complexes with water are calculated using the density functional theory (DFT). The IR spectra and structures of complexes are calculated and compared with experimental data. The effect of hydrogen bonding on physical-chemical properties of succinic acid under recrystallization conditions is evaluated. Results: As a result of research, various succinic acid structures have been considered, as a result of which, by analyzing the energy difference, variants of conformers have been found both for one molecule and for the succinic acid dimer of the chain associate fragment. When water molecules are added, the characteristic peaks of the high-frequency region of the spectrum are shifted, that indicates the formation of hydrogen bonds. Conclusions: As a result of studies of the recrystallizated succinic acid physical-chemical properties a change in the crystal morphology has been detected based on the results of scanning electron microscopy. Water molecules, which remain in the structure of the modified molecular complex, have a great influence on the spectral characteristics of succinic acid. This has been discovered by comparing experimentally measured and calculated IR spectra of modified succinic acid. When water molecules are added to the conformers of an isolated molecule and a fragment of a chain associate of succinic acid, a shift of the characteristic peaks of the high-frequency spectral region corresponding to the valence vibrations of the O-H bond of the hydroxyl group of succinic acid is observed, that indicates the formation of hydrogen bonds. Analysis of interaction of succinic acid with water molecules indicates that during the preparation of polymorphic modifications, after the freeze-drying stage, water molecules are present in the modified succinic acid. In turn, the presence of the interaction of succinic acid with water molecules promotes stronger hydrogen bonding, that leads to a change in the physical-chemical properties of succinic acid.

The reported study was funded by RFBR according to the research project No. 20-33-90250.
  1. Babkov L. M., Puchkovskaya G. A., Makarenko S. P., Gavrilko T. A. IK spektroskopiia molekuliarnukh kristallov s vodorodnymi sviaziami [IR Spectroscopy of Molecular Crystals With Hydrogen Bonds]. Kiev, Naukova dumka Publ., 1989, 169 p. (in Russian)
  2. Corradini P., Frasci A., Martuscelli E. Conformational polymorphism of unsaturated dicarboxylic acids. Journal of the Chemical Society D : Chemical Communications, 1969, iss. 14, pp. 778–780.
  3. Smirnov A. V., Nesterova O. B., Golubev R. V. Succinic acid and its application in medicine. Part I. Succinic acid : Metabolite and regulator of metabolism of the human body. Nephrology, 2014, vol. 18, no. 2, pp. 33–41 (in Russian).
  4. Smirnov A. V., Nesterova O. B., Golubev R. V. Succinic acid and its application in medicine. Part II. Application of succinic acid in medicine. Nephrology, 2014, vol. 18, no. 4, pp. 12–24 (in Russian).
  5. Chistyakov D., Sergeev G. The Polymorphism of Drugs : New Approaches to the Synthesis of Nanostructured Polymorphs. Pharmaceutics, 2020, vol. 12, iss. 1. Available at: https://www.mdpi.com/1999-4923/12/1/34 (accessed 01 May 2022).
  6. Javadzadeh S. Y., Dizaj M. D., Vazifehasl Z., Mokhtarpour M. Recrystallization of Drugs – Effect on Dissolution Rate. In: Recrystallization in Materials Processing. London, United Kingdom, IntechOpen, 2015, pp. 191– 211.
  7. Volmer M. Kinetik der phasenbildung [Kinetics of Phase Formation]. Dresden, Leipzig, Steinkopf Verl., 1939, 220 S.
  8. McCoy L. L. The Geometry of Intramolecular Hydrogen Bonding in 1,2-Dicarboxylic Acids. Journal of the American Chemical Society, 1967, vol. 89, iss. 7, pp. 1673–1677. https://doi.org/10.1021/ja00983a024
  9. Yu Q., Dang L., Black S., Wei H., Huang X. Crystallization of the polymorphs of succinic acid via sublimation at different temperatures in the presence or absence of water and isopropanol vapor. Journal of Crystal Growth, 2012, vol. 340, iss. 1, pp. 209–215.
  10. Van der Voort E. The morphology of succinic acid crystals : The role of solvent interaction. Journal of Crystal Growth, 1991, vol. 110, iss. 4, pp. 662–668. https://doi.org/10.1016/0022-0248(91)90621-B
  11. Kohn W. Nobel Lecture : Electronic structure of matter– wave functions and density functionals. Rev. Mod. Phys., 1999, vol. 71, no. 5, pp. 1253–1265. https://doi.org/10.1103/RevModPhys.71.1253
  12. Becke A. D. Density-functional thermochemistry. III. The role of exact exchange. Journal of Chemical Physics, 1993, vol. 98, no. 7, pp. 5648–5652. https://doi.org/10.1063/1.464913
  13. Frisch M. J., Trucks G. W., Schlegel H. B., Scuseria G. E., Robb M. A., Cheeseman J. R., Montgomery J. A., Vreven Jr. T., Kudin K. N., Burant J. C., Millam J. M., Iyengar S. S., Tomasi J., Barone V., Mennucci B., Cossi M., Scalmani G., Rega N., Petersson G. A., Nakatsuji H., Hada M., Ehara M., Toyota K., Fukuda R., Hasegawa J., Ishida M., Nakajima T., Honda Y., Kitao O., Nakai H., Klene M., Li X., Knox J. E., Hratchian H. P., Cross J. B., Adamo C., Jaramillo J., Gomperts R., Stratmann R. E., Yazyev O., Austin A. J., Cammi R., Pomelli C., Ochterski J. W., Ayala P. Y., Morokuma K., Voth G. A., Salvador P., Dannenberg J. J., Zakrzewski V. G., Dapprich S., Daniels A. D., Strain M. C., Farkas O., Malick D. K., Rabuck A. D., Raghavachari K., Foresman J. B., Ortiz J. V., Cui Q., Baboul A. G., Clifford S., Cioslowski J., Stefanov B. B., Liu G., Liashenko A., Piskorz P., Komaromi I., Martin R. L., Fox D. J., Keith T., AlLaham M. A., Peng C. Y., Nanayakkara A., Challacombe M., Gill P. M. W., Johnson B., Chen W., Wong W., Gonzalez C., Pople J. A. Gaussian 03, Revision B.03. Gaussian, Inc., Pittsburgh PA, 2003. 302 p.
  14. Avogadro – Free cross-platform molecular editor – Avogadro. Funding for the Avogadro manual was provided by the University of Pittsburgh Department of Chemistry. Pittsburgh, Pensylvania, 2015. Available at : https://avogadro.cc/ (accessed 10 December 2021).
  15. Yoshida H., Ehara A., Matsuura H. Density functional vibrational analysis using wave number-linear scale factors. Chem. Phys. Lett., 2000, vol. 325, no. 4, pp. 477–483.
  16. Yoshida H., Takeda K., Okamura J., Ehara A., Matsuura H. New approach to vibrational analysis of large molecules by density functional theory : Wavenumberlinear scaling method. J. Phys. Chem. A, 2002, vol. 106, no. 14, pp. 3580–3586.
  17. Selemenev V. F., Rudakov O. B., Mironenko N. V., Karpov S. I., Semenov V. N., Belanova N. A., Sinyaeva L. A., Lukin A. N. Hydration and intermolecular interactions in carboxylic acids. Condensed Matter and Interphases, 2020, vol. 22, no. 3, pp. 373–387.
  18. Werner J., Julin J., Dalirian M., Prisle N. L., Öhrwall G., Persson I., Riipinen I. Succinic acid in aqueous solution : Connecting microscopic surface composition and macroscopic surface tension. Physical Chemistry Chemical Physics, 2014, vol. 16, iss. 39, pp. 21486–21495. https://doi.org/10.1039/c4cp02776k
  19. Chen C., Wang X., Binder K., Ghahremanpour M. M., van der Spoel D., Pöschl U., Su H., Cheng Y. Energetic analysis of succinic acid in water droplets : Insight into the size-dependent solubility of atmospheric nanoparticle. Atmospheric Chemistry and Physics Discuss [preprint], 2021. https://doi.org/10.5194/acp-2020- 1329
  20. Iogansen A. V. Infrared Spectroscopy and Spectral Determination of Hydrogen Bond Energy. In: Sokolov N. D., executive ed. Hydrogen Bond. Moscow, Nauka Publ., 1981, pp. 112–155 (in Russian).
  21. Steed J. W., Atwood J. L. Supramolecular Chemistry. 2nd ed. New York, John Wiley & Sons, 2009. 1002 p.
  22. Nguyen T. H. Hibbs D. E., Sian T. H. Conformations, energies, and intramolecular hydrogen bonds in dicarboxylic acids : Implications for the design of synthetic dicarboxylic acid receptors. Journal of Computational Chemistry, 2005, vol. 26, iss. 12, pp. 1233–1241. https://doi.org/10.1002/jcc.20259