Computational Method to Elucidate Formation and Stabilization Mechanism of Amorphous Solid Dispersion System from Alpha-Mangostin and Poly-Vinylpyrrolidone Using Molecular Dynamics Simulation
Keywords:
Alpha-mangostin, poly-vinylpyrrolidone, amorphous solid dispersion, hydrogen bond, molecular dynamics
Abstract
The amorphous solid dispersion (ASD) system is a pharmaceutical formulation strategy designed to improve the physical stability and solubility of amorphous drugs. In a previous study, experimental methods suggest that interactions between alpha-mangostin (AM) and poly-vinylpyrrolidone (PVP) can stabilize the amorphous form and maintain the supersaturation levels. Therefore, this study aimed to investigate the formation of the ASD system from alpha-mangostin (AM) and poly-vinylpyrrolidone (PVP) through the computational method. The result of experimental methods showed that the interaction between AM and PVP was confirmed by powder X-ray diffraction, differential scanning calorimetry, and Fourier Transform Infrared Spectroscopy measurement. The hydrogen bonding interactions between AM and PVP were achieved through molecular dynamics (MD) simulation, mimicking the melt-cooling and solvent-evaporation methods. In a direct comparison between the two methods, melt-cooling showed superior attributes, including the lowest binding energy value, as well as reduced root mean square deviation (RMSD), root mean square fluctuation (RMSF), and radius of gyration (Rg) values. Nevertheless, ASD was formed by both the melt-cooling and solvent-evaporation methods. Based on the results, the computational method through molecular dynamics simulation provided information on drug-polymer interactions that were difficult to obtain using experimental methods. This method enhanced the current understanding regarding the formation and stabilization mechanism of the ASD system.
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https://doi.org/10.1055/s-0042-119651
Atsukawa, K., Amari, S., & Takiyama, H. (2021). Solid dispersion melt crystallization (SDMC) concept using binary eutectic system for improvement of dissolution rate. Journal of Industrial and Engineering Chemistry, 101, 21–27. https://doi.org/10.1016/j.jiec.2021.05.032
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Budiman, A., Higashi, K., Ueda, K., & Moribe, K. (2021). Effect of drug-coformer interactions on drug dissolution from a coamorphous in mesoporous silica. International Journal of Pharmaceutics, 600 120492. https://doi.org/10.1016/j.ijpharm.2021.120492
Budiman, A., Husni, P., Shafira, & Alfauziah, T. Q. (2019). The development of glibenclamide-saccharin cocrystal tablet formulations to increase the dissolution rate of the drug. International Journal of Applied Pharmaceutics, 11(4), 359–364. https://doi.org/10.22159/ijap.2019v11i4.33802
Budiman, A., Kalina, K., Aristawidya, L., Shofwan, A. A. Al, Rusdin, A., & Aulifa, D. L. (2023). Characterizing the impact of chitosan on the nucleation and crystal growth of ritonavir from supersaturated solutions. Polymers, 15(5). https://doi.org/10.3390/polym15051282
Budiman, A., Nurani, N. V., Laelasari, E., Muchtaridi, M., Sriwidodo, S., & Aulifa, D. L. (2023). Effect of drug–polymer interaction in amorphous solid dispersion on the physical stability and dissolution of drugs: the case of alpha-mangostin. Polymers, 15(14). https://doi.org/10.3390/polym15143034
Budiman, A., Nurfadilah, N., Muchtaridi, M., Sriwidodo, S., Aulifa, D. L., & Rusdin, A. (2022). The impact of water-soluble chitosan on the inhibition of crystal nucleation of alpha-mangostin from supersaturated solutions. Polymers, 14(20). https://doi.org/10.3390/polym14204370
Carugo, O. (2003). How root-mean-square distance (r.m.s.d.) values depend on the resolution of protein structures that are compared. Journal of Applied Crystallography, 36(1), 125–128. https://doi.org/10.1107/S0021889802020502
Chavan, R. B., Lodagekar, A., Yadav, B., & Shastri, N. R. (2020). Amorphous solid dispersion of nisoldipine by solvent evaporation technique: preparation, characterization, in vitro, in vivo evaluation, and scale up feasibility study. Drug Delivery and Translational Research, 10(4), 903–918. https://doi.org/10.1007/s13346-020-00775-8
Cooke, G., & Rotello, V. M. (2002). Methods of modulating hydrogen bonded interactions in synthetic host-guest systems. Chemical Society Reviews, 31(5), 275–286. https://doi.org/10.1039/b103906g
Dong, Y. W., Liao, M. L., Meng, X. L., & Somero, G. N. (2018). Structural flexibility and protein adaptation to temperature: Molecular dynamics analysis of malate dehydrogenases of marine molluscs. Proceedings of the National Academy of Sciences of the United States of America, 115(6), 1274–1279. https://doi.org/10.1073/pnas.1718910115
Frank, D. S., & Matzger, A. J. (2018). Probing the Interplay between amorphous solid dispersion stability and polymer functionality. Mol Pharm, 15(7), 2714–2720. https://doi.org/10.1021/acs.molpharmaceut.8b00219.
Gigliobianco, M. R., Casadidio, C., Censi, R., & Di Martino, P. (2018). Nanocrystals of poorly soluble drugs: drug bioavailability and physicochemical stability. Pharmaceutics, 10(3). https://doi.org/10.3390/pharmaceutics10030134
Grohganz, H., Löbmann, K., Priemel, P., Tarp Jensen, K., Graeser, K., & Strachan C, et al. (2013). Amorphous drugs and dosage forms. J Drug Deliv Sci Technol., 23(4), 403–408. https://doi.org/10.1016/S1773-2247(13)50057-8
Gupta, J., Nunes, C., Vyas, S., & Jonnalagadda, S. (2011). Prediction of solubility parameters and miscibility of pharmaceutical compounds by molecular dynamics simulations. Journal of Physical Chemistry B, 115(9), 2014–2023. https://doi.org/10.1021/jp108540n
Huynh, L., Grant, J., Leroux, J. C., Delmas, P., & Allen, C. (2008). Predicting the solubility of the anti-cancer agent docetaxel in small molecule excipients using computational methods. Pharmaceutical Research, 25(1), 147–157. https://doi.org/10.1007/s11095-007-9412-3
Ibrahim, M. Y., Hashim, N. M., Mariod, A. A., Mohan, S., Abdulla, M. A., Abdelwahab, S. I., & Arbab, I. A. (2016). α-Mangostin from Garcinia mangostana Linn: an updated review of its pharmacological properties. Arabian Journal of Chemistry, 9(3), 317–329. https://doi.org/10.1016/j.arabjc.2014.02.011
Ishizuka, Y., Ueda, K., Okada, H., Takeda, J., Karashima, M., Yazawa, K., Higashi, K., Kawakami, K., Ikeda, Y., & Moribe, K. (2019). Effect of drug-polymer interactions through hypromellose acetate succinate substituents on the physical stability on solid dispersions studied by fourier-transform infrared and solid-state nuclear magnetic resonance. Molecular Pharmaceutics, 16(6), 2785–2794. https://doi.org/10.1021/acs.molpharmaceut.9b00301
Knopp, M. M., Nguyen, J. H., Becker, C., Francke, N. M., Jørgensen, E. B., Holm, P., Holm, R., Mu, H., Rades, T., & Langguth, P. (2016). Influence of polymer molecular weight on in vitro dissolution behavior and in vivo performance of celecoxib:PVP amorphous solid dispersions. European Journal of Pharmaceutics and Biopharmaceutics, 101, 145–151. https://doi.org/10.1016/j.ejpb.2016.02.007
Kuo, S. W. (2008). Hydrogen-bonding in polymer blends. Journal of Polymer Research, 15(6), 459–486.
https://doi.org/10.1007/s10965-008-9192-4
LaFountaine, J. S., Prasad, L. K., Brough, C., Miller, D. A., McGinity, J. W., & Williams, R. O. (2016). Thermal processing of PVP- and HPMC-based amorphous solid dispersions. AAPS PharmSciTech, 17(1), 120–132. https://doi.org/10.1208/s12249-015-0417-7
Lehmkemper, K., Kyeremateng, S. O., Heinzerling, O., Degenhardt, M., & Sadowski, G. (2017). Long-term physical stability of PVP- and PVPVA-amorphous solid dispersions. Molecular Pharmaceutics, 14(1), 157–171. https://doi.org/10.1021/acs.molpharmaceut.6b00763
Li, P., Tian, W., & Ma, X. (2014). Alpha-mangostin inhibits intracellular fatty acid synthase and induces apoptosis in breast cancer cells. Molecular Cancer, 13(1), 1–11. https://doi.org/10.1186/1476-4598-13-138
Li, X., Liu, W., Sun, L., Aifantis, K. E., Yu, B., Fan, Y., Feng, Q., Cui, F., & Watari, F. (2015). Effects of physicochemical properties of nanomaterials on their toxicity. Journal of Biomedical Materials Research - Part A, 103(7), 2499–2507.
https://doi.org/10.1002/jbm.a.35384
Ma, X., Higashi, K., Fukuzawa, K., Ueda, K., Kadota, K., Tozuka, Y., E., Y., & Moribe, K. (2022). Computational approach to the formation and stabilization mechanism of amorphous formulation using molecular dynamics simulation and molecular orbital calculation. Int J Pharm, 615, 121477.
Que, C., Qi, Q., Zemlyanov, D. Y., Mo, H., Deac, A., Zeller, M., Indulkar, A. S., Gao, Y., Zhang, G. G. Z., & Taylor, L. S. (2020). Evidence for halogen bonding in amorphous solid dispersions. Crystal Growth and Design, 20(5), 3224–3235. https://doi.org/10.1021/acs.cgd.0c00073
Sarode, A. L., Wang, P., Obara, S., & Worthen, D. R. (2014). Supersaturation, nucleation, and crystal growth during single- and biphasic dissolution of amorphous solid dispersions: polymer effects and implications for oral bioavailability enhancement of poorly water soluble drugs. European Journal of Pharmaceutics and Biopharmaceutics, 86(3), 351–360. https://doi.org/10.1016/j.ejpb.2013.10.005
Teodorescu, M., Bercea, M., & Morariu, S. (2019). Biomaterials of PVA and PVP in medical and pharmaceutical applications: Perspectives and challenges. Biotechnology Advances, 37(1), 109–131. https://doi.org/10.1016/j.biotechadv.2018.11.008
Wegiel, L. A., Mauer, L. J., Edgar, K. J., & Taylor, L. S. (2013). Molecular nanomedicine towards cancer . Journal of Pharmaceutical Sciences, 102(1), 171.184. https://doi.org/10.1002/jps
Xiang, T.-X., & Anderson, B. D. Molecular dynamics simulation of amorphous poly(3-hexylthiophene). Pharmaceutics, 10, 102–114. https://doi.org/10.1021/acs.macromol.0c00454
Yang, H., Li, Z. S., Qian, H. J., Yang, Y. B., Zhang, X. Bin, & Sun, C. C. (2004). Molecular dynamics simulation studies of binary blend miscibility of poly (3-hydroxybutyrate) and poly(ethylene oxide). Polymer, 45(2), 453–457. https://doi.org/10.1016/j.polymer.2003.11.021
Yoshie, K., Yada, S., Ando, S., & Ishihara, K. (2021). Chemical structural effects of amphipathic and water-soluble phospholipid polymers on formulation of solid dispersions. Journal of Pharmaceutical Sciences, 110(8), 2966–2973. https://doi.org/10.1016/j.xphs.2021.03.02
Yuan, X., Sperger, D., & Munson, E. J. (2014). Investigating miscibility and molecular mobility of nifedipine-PVP amorphous solid dispersions using solid-state NMR spectroscopy. Molecular Pharmaceutics, 11(1), 329–337. https://doi.org/10.1021/mp400498n
Zhang, K. J., Gu, Q. L., Yang, K., Ming, X. J., & Wang, J. X. (2017). Anticarcinogenic effects of α -mangostin: a review. Planta Medica, 83(3–4), 188–202.
https://doi.org/10.1055/s-0042-119651
Published
2025-11-24
How to Cite
Budiman, A., Fakih , T. M., Rusdin, A., Muchtaridi, M., Aulifa, D. L., & Subra, L. (2025). Computational Method to Elucidate Formation and Stabilization Mechanism of Amorphous Solid Dispersion System from Alpha-Mangostin and Poly-Vinylpyrrolidone Using Molecular Dynamics Simulation. Indonesian Journal of Pharmacy. https://doi.org/10.22146/ijp.17992
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Research Article
