PEG- 4000 increases solubility and dissolution rate of vinpocetin in solid dispersion system Chimica Techno Acta ARTICLE published by Ural Federal University 2022, vol. 9(2), No. 202292S11 eISSN 2411-1414; chimicatechnoacta.ru DOI: 10.15826/chimtech.2022.9.2.S11 1 of 6 PEG-4000 increases solubility and dissolution rate of vinpocetin in solid dispersion system Yulia A. Polkovnikova а* İD , Tamara N. Glizhova b İD , Naira V. Arutyunova b İD , Natalya N. Sokulskaya b İD a: Faculty of Pharmacy, Voronezh State University, Voronezh 394018, Russia b: Faculty of Pharmacy, North-Caucasus Federal University, Stavropol 355029, Russia * Corresponding author: polkovnikova@pharm.vsu.ru This paper belongs to the MOSM2021 Special Issue. © 2022, the Authors. This article is published open access under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/). Abstract In the present work, we determined the optimal ratio of vinpocetine and polyethylene glycol within a solid dispersion (1:2 or 1:5) accord- ing to the simulation results in the framework of molecular dynamics associated with the release of the reactant into aqueous medium. For the simulation of vinpocetine release from its alloy with polyethylene glycol, a technique of coarse-grained molecular dynamics in the force field of Martini 2.2 was applied using the Gromacs 2018 computer program. The results of the simulation demonstrated that at pH 6.8 polyethylene glycol facilitated vinpocetine solubilization and thus considerably enhanced its solubility in water. The data obtained show that the values of the energies of van der Waals interaction be- tween vinpocetine and the polymer are similar to those vinpocetine and water, both at a ratio of 1:2 and at a ratio of 1:5. Keywords vinpocetin solid dispersion system PEG- 4000 dissolution rate molecular dynamics Received: 05.04.22 Revised: 26.06.22 Accepted: 27.06.22 Available online: 30.06.22 1. Introduction Vinpocetine is a vasoactive and nootropic preparation that is a semisynthetic derivative of the common periwinkle plant alkaloid. Vinpocetine is practically insoluble in water [1, 2]. It provides certain problems in provision of the bio- availability, particularly, the rate of attaining its therapeu- tic concentration in blood. Recently, keeping in mind an increase of bioavailability of poorly soluble pharmaceutical preparations, solid dis- persed systems have attracted more and more attention as a new basis for the elaboration of new rational drug for- mulations [3]. Solid dispersions are bi- or multi- component systems composed of the pharmaceutical sub- stances and a carrier, representing a highly-dispersed sol- id phases of the pharmaceutical substances or alloys with a partial formation of the complexes of variable composi- tion with a carrier material [4–6]. Fabrication of the solid dispersions is considered as one of the most efficient ways for decreasing the particle sizes to the colloid and/or molecular level values. Under the effect of environment, the soluble matrix of a polymer is dissolved and colloid particles or molecules of the pharmaceutical substances are immediately released into the solution medium, resulting in a rapid solubilization of the pharmaceutical substance [7–9]. Solid dispersions are of a great importance when establishing peroral solid drug formulations with enhanced dissolution rate for the phar- maceutical substances that are weakly dissolved in water. Thus the application of solid dispersions facilitates bioa- vailability under peroral medication [10–12].Various solu- ble polymer matrices on the basis of polyvinylpyrrolidone, polyethylene glycols, methyl cellulose, as well as rather simple sub-stances, for example, urea, lactose, were pro- posed as carriers for soluble dispersions [13]. In the present work , we investigated the optimal ratio between vinpocetine and PEG-4000 in the drug formula- tion (1:2 or 1:5) using the simulation employed for the molecular dynamics release of the reactant into aqueous medium. 2. Experimental In order to simulate vinpocetine release from its alloy with polyethylene glycol, the method of coarse-grain molecular dynamics in a force field of Martini 2.2 was applied using the Gromacs 2018 software suite [14]. The method of coarse-grain molecular dynamics consists in representing the groups of atoms (consisting of 2–6 atoms) in the mole- http://chimicatechnoacta.ru/ https://doi.org/10.15826/chimtech.2022.9.2.S11 https://orcid.org/0000-0003-0123-9526 https://orcid.org/0000-0002-9477-7851 https://orcid.org/0000-0002-2111-4299 https://orcid.org/0000-0002-5269-6471 mailto:polkovnikova@pharm.vsu.ru http://creativecommons.org/licenses/by/4.0/ https://crossmark.crossref.org/dialog/?doi=https://doi.org/10.15826/chimtech.2022.9.2.S11&domain=pdf&date_stamp=2022-6-30 Chimica Techno Acta 2022, vol. 9(2), No. 202292S11 ARTICLE 2 of 6 cule by the particles of different types. In the same way, a group of molecules can be represented by a single particle. An assembly of the simulated systems, alloys of vinpocetine with polyethylene glycol, was performed with Gromacs 2018 program. To simulate vinpocetine diffusion process using the coarse-grain molecular dynamics method, the model of the vinpocetine molecule was designed in the HyperChem pro- gram; after that geometry of the molecule was optimized by mm+ method [15, 16]. The vinpocetine molecule was nomi- nally divided into the fragments corresponding to the cycles and functional groups. The compositions of the simulated systems are pre- sented in Table 1. Table 1 The number of molecules of the components of the simu- lated alloys. Substance Vinpoce- tine-PEG 1:2 Vinpoce- tine-PEG 1:5 Vinpoce- tine cation- PEG 1:2 Vinpoce- tine cation- PEG 1:5 Vinpoce- tine 119 48 – – Vinpoce- tine-cation – – 119 48 Cl- ion – – 119 48 PEG-4000 21 21 21 21 Water 10968 7228 11860 9484 3. Results and discussion The modeled system included molecules of polyethylene glycol (Figure 1) with a length of 90 monomers with the atomic mass of 3.978 kDa, as well as molecules of vinpoce- tine base or its cations and Cl- ions (Figure 2). During the simulation, the diffusion of PEG-4000 into water was observed. When the ratio of vinpocetine and PEG-4000 is 1:2, some of the vinpocetine molecules lose their bond with the polymer and combine into clusters (Figure 3). The energies of van der Waals interaction of vinpocetine with the polymer and with the solvent are stabilized after the 40th nanosecond of simulation. An increased proportion of vinpocetine molecules unbound with PEG-4000 is due to the formation of clusters of substance molecules (Figures 4, 5). Figure 1 The structure of the polyethylene glycol molecule and its representation in the Martini force field 2.2. SNa–SН2–…–SН2– SNa; SNa – terminal OH group; SН2 is a polyethylene glycol mon- omer. Figure 2 Chemical structure and spatial structure of vinpocetine and vinpocetine cation and their representation in the Martini 2.2 force field. Figure 3 Simulation of the molecular dynamics of the release of vinpocetine from an alloy with PEG-4000 1:2 by weight into water. Time is 0 ns (a), 40 ns (b), 100 ns (c). P5 Vinpocetine Vinpocetine- cation Chimica Techno Acta 2022, vol. 9(2), No. 202292S11 ARTICLE 3 of 6 When modeling the release of vinpocetine from PEG- 4000 into water at a substance-to-carrier ratio of 1:5, the formation of clusters is also observed, but their size is much smaller (Figure 6). The energy of van der Waals interaction of vinpocetine with PEG-4000 at a ratio of 1:5 stabilizes faster – at the 20th nanosecond of simulation (Figures 7, 8). This is due to the smaller number of vinpocetine molecules in the system. Figure 4 Van der Waals interaction energy of vinpocetine with PEG-4000 and solvent in terms of one molecule of vinpocetine at a ratio of vinpocetine and PEG-4000 1:2 by weight. Figure 5 Estimation of the proportion of vinpocetine molecules not bound to PEG-4000 in water at a ratio of vinpocetine to PEG- 4000 1: 2 by weight. When simulating the release of vinpocetine from PEG- 4000 in an acidic medium, no significant formation of clusters of substance molecules is observed, but a uniform distribution of vinpocetine molecules over the volume of the simulated system occurs (Figure 9). -200 -180 -160 -140 -120 -100 -80 -60 -40 -20 0 0 20 40 60 80 100 V a n d e r W a a s in te ra ct io n e n e rg y, k J/ m o l Ti me , ns Van der Waas inter action energy PEG-4000- vinpocetine, kJ/mol Figure 7 Van der Waals interaction energy of vinpocetine with PEG-4000 and solvent in terms of one molecule of vinpocetine at a ratio of vinpocetine and PEG-4000 1:5 by weight. Figure 8 Estimation of the proportion of vinpocetine molecules not bound to PEG-4000 in water at a ratio of vinpocetine to PEG- 4000 1:5 by weight. Figure 6 Simulation of the molecular dynamics of the release of vinpocetine from an alloy with polyethylene glycol-4000 1:5 by weight into water. Time is 0 ns (a), 40 ns (b), 100 ns (c). Chimica Techno Acta 2022, vol. 9(2), No. 202292S11 ARTICLE 4 of 6 Figure 9 Modeling of the molecular dynamics of the release of vinpocetine from an alloy with PEG-4000 1:2 by weight into water with pH 2.0. Time is 0 ns (a), 40 ns (b), 100 ns (c). The energy of van der Waals interaction of vinpocetine with PEG-4000 when released in an acidic medium is stabi- lized after 40 ns of simulation at a ratio of 1:2 (Figures 10, 11). Figure 10 Van der Waals interaction energy of vinpocetine with PEG- 4000 and with a solvent (water at pH 2.0) in terms of one molecule of vinpocetine at a ratio of vinpocetine and PEG-4000 1:2 by weight. When the ratio of vinpocetine and PEG-4000 is 1:5 in an acidic medium, vinpocetine is also evenly distributed in the volume of the modeled system without the formation of large clusters (Figure 12). Van der Waals interaction energy between Vinpocetine and PEG-4000 stabilizes after 30 ns of simulation (Figures 13, 14). Based on the results of the computational experiments, the average values of the van der Waals binding energies of vinpocetine with carriers and with the solvent, as well as the average fraction of vinpocetine molecules not bound to the carrier, were calculated (Table 2). Figure 11 Estimation of the proportion of vinpocetine molecules not bound to PEG-4000 in water at pH 2.0 at a ratio of vinpoce- tine to PEG-4000 1: 2 by weight. Figure 12 Simulation of the molecular dynamics of the release of vinpocetine from an alloy with PEG-4000 1:5 by weight into water with a pH of 2.0. Time is 0 ns (a), 40 ns (b), 100 ns (c). Chimica Techno Acta 2022, vol. 9(2), No. 202292S11 ARTICLE 5 of 6 Figure 13 Van der Waals interaction energy of vinpocetine with PEG-4000 and with a solvent (water at pH 2.0) in terms of one molecule of vinpocetine at a ratio of vinpocetine and PEG-4000 1:5 by weight. Figure 14 Estimation of the proportion of vinpocetine molecules not bound to PEG-4000 in water at pH 2.0 at a ratio of vinpoce- tine to PEG-4000 1: 5 by weight. Table 2 Average values of vinpocetine release parameters from the studied complexes with polymers. System Average energy of van der Waals interaction vinpocetine with polymer, kJ/mol Average energy of van der Waals interaction of vinpocetine with a solvent, kJ/mol The average proportion of vinpocetine molecules not associated with the carrier, % Vinpocetine- PEG-4000 1:2 –57.88±3.80 –106.25±4.75 15.274±3.44 Vinpocetine- PEG-4000 1:5 –97.74±6.93 –116.21±7.64 2.060±2.24 Vinpocetine- PEG-4000 1:2 pH 2.0 –88.58±4.18 –173.95±5.60 5.893±1.00 Vinpocetine- PEG-4000 1:5 pH 2.0 –120.51±8.41 –165.37±6.10 1.898±2.06 4. Conclusions The data obtained show similar values of the energies of van der Waals interaction between vinpocetine and the pol- ymer, as well as vinpocetine and water, both at a ratio of 1:2 and at a ratio of 1:5. In a neutral medium, when released from PEG-4000, clusters of vinpocetine molecules are formed. There is an increased release of vinpocetine mole- cules in an acidic medium and with an increase in the ratio in the alloy towards vinpocetine. Supplementary materials No supplementary materials are available. Funding This research had no external funding. Acknowledgments None. Author contributions Conceptualization: Y.A.P., T.N.G., N.N.S. Data curation: Y.A.P. Formal Analysis: Y.A.P., N.N.S. Methodology: Y.A.P., T.N.G. Resources: Y.A.P., T.N.G., N.V.A. Supervision: Y.A.P. Visualization: Y.A.P., T.N.G. Writing –original draft: Y.A.P., N.V.A. Writing –review & editing: Y.A.P. Conflict of interest The authors declare no conflict of interest. Additional information Author IDs: Yulia A. Polkovnikova, Scopus ID 57060554300; Tamara N. Glizhova, Scopus ID 57209733391. Websites: Voronezh State University, https://www.vsu.ru/en/; North-Caucasus Federal University, http://eng.ncfu.ru/. References 1. Golob S, Perry M, Lusi M, Chierotti MR, Grabnar I, Lassiani L, Voinovich D, Zaworotko MJ. Improving biopharmaceutical properties of vinpocetine through cocrystallization. J Pharm Sci. 2016;105(12):3626–3633. doi:10.1016/j.xphs.2016.09.017 2. Verma S, Rudraraju VS. A systematic approach to design and prepare solid dispersions of poorly water-soluble drug. AAPS Pharm Sci Tech. 2014;15(3):641–657. doi:10.1208/s12249- 014-0093-z https://www.scopus.com/authid/detail.uri?authorId=57060554300 https://www.scopus.com/authid/detail.uri?authorId=57209733391 https://www.vsu.ru/en/ http://eng.ncfu.ru/ https://doi.org/10.1016/j.xphs.2016.09.017 https://doi.org/10.1208/s12249-014-0093-z https://doi.org/10.1208/s12249-014-0093-z Chimica Techno Acta 2022, vol. 9(2), No. 202292S11 ARTICLE 6 of 6 3. Allawadi D, Singh N, Singh S, Arora S. Solid dispersions: a review on drug delivery system and solubility enhancement. Int J Pharm Sci Res. 2013;4(6);2094–2105. doi:10.13040/IJPSR.0975-8232.4(6).2094-05 4. Patil RM, Maniyar AH, Kale MT, Akarte AP, Baviskar DT. Solid dispersion: strategy to enhance solubility. Int J Pharm Sci Rev Res. 2011;8(2):66–73. doi:10.1007/s10973-016-5759-1 5. Di L, Fish PV, Mano T. Bridging solubility between drug dis- covery and development. Drug Discov Today. 2012;17(9– 10):486–495. doi:10.1016/j.drudis.2011.11.007 6. Good DJ, Rodríguez-Hornedo N. Solubility Advantage of Phar- maceutical Cocrystals. Crys Growth Des. 2009;9(5):2252– 2264. doi:10.1021/cg801039j 7. Brough C, Williams III RO. Amorphous solid dispersions and nano-crystal technologies for poorly water-soluble drug deliv- ery. Int J Pharm. 2013;453(1):157–166. doi:10.1016/j.ijpharm.2013.05.061 8. Chiou WL, Riegelman S. Pharmaceutical applications of solid dispersion systems. J Pharm Sci. 1971;60:1281–1302. doi:10.1002/jps.2600600902 9. Akiladevi D, Shanmugapandian P, Jebasingh D, Sachinandan B. Preparation and evaluation of Paracetamol by solid dispersion technique. Int J Pharm. 2011; 3(11): 88–191. doi:10.13040/IJPSR.0975-8232.5(10).4478-8 10. Dubey A, Kharia AA, Chatterjee DP. Enhancement of aqueous solubility and dissolution of telmisartan using solid dispersion technique. IJPSR. 2014;5(10):4478–4485. doi:10.13040/IJPSR.0975-8232.5(10).4478-85 11. Biswal S, Sahoo J, Murthy PN, Giradkar RP. Enhancement of dissolution rate of gliclazide using solid dispersions with pol- yethylene glycol 6000. AAPS Pharm Sci Tech. 2008;9(2):563– 570. doi:10.1208/s12249-008-9079-z 12. Sharma A, Jain CP. Preparation and characterization of solid dispersions of carvedilol with PVP K30. Res Pharm Sci. 2010;5(1):49–56. doi:10.1007/s40005-013-0058-3 13. Setyawan D, Setiawardani F, Amrullah Z, Sari R. PEG 8000 increases solubility and dissolution rate of quercetin in solid dispersion system. Marmara Pharm J. 2018;22(2):445–456. doi:10.12991/mpj.2018.63 14. Arroyo ST, Sansón Martín JA, Hidalgo García A. Molecular dynamics simulation of acetamide solvation using interaction energy components: Application to structural and energy properties. Chem Phys. 2006;327(1):187-192. doi:10.1016/j.chemphys.2006.04.018 15. Marrink SJ, Risselada HJ, Yefimov S, Tieleman DP, de Vries AH. The MARTINI force field: Coarse grained model for bio- molecular simulations. J Phys Chem B. 2007;111(27):7812– 7824. doi:10.1021/jp071097f 16. Berendsen HJC, Postma JPM, Gunsteren WF, DiNola A, Haak JR. Molecular dynamics with coupling to an external bath. J Chem Phys. 1984;81(8):3684–3690. doi:10.1063/1.448118 https://doi.org/10.13040/IJPSR.0975-8232.4(6).2094-05 https://doi.org/10.1016/j.drudis.2011.11.007 https://doi.org/10.1021/cg801039j https://doi.org/10.1016/j.ijpharm.2013.05.061 https://doi.org/10.1002/jps.2600600902 https://doi.org/10.13040/IJPSR.0975-8232.5(10).4478-8 https://doi.org/10.13040/IJPSR.0975-8232.5(10).4478-85 https://doi.org/10.1208/s12249-008-9079-z https://doi.org/10.1007/s40005-013-0058-3 https://doi.org/10.12991/mpj.2018.63 https://doi.org/10.1016/j.chemphys.2006.04.018 https://doi.org/10.1021/jp071097f https://doi.org/10.1063/1.448118