Effect of solid dispersions with polyvinylpyrrolidone on the solubility of GML-3

Background. GML-3 has both anxiolytic and antidepressant effects. However, like about 70 % of аctive pharmaceutical ingredient (API) being developed, GML-3 is practically insoluble in water, which can negatively affect bioavailability. The creation of solid dispersions (SD) by crystallization with eutectic or the transfer of API to an amorphous state is one of the promising methods that allows to achieve high solubility and dissolution rate of API.

Aim. To study the crystallinity and stability of amorphous solid dispersions of GML-3 with polyvinylpyrrolidone (PVP), as well as the release of GML-3 from SD in the Dissolution test. The objects of the study were API GML-3, PVP and SD GML-3.

Materials and methods. SD was created by the method of “solvent removal” using ethanol (GML-3 is soluble in ethanol at a ratio of 1:7) and PVP with a molecular weight of 24–27 kDa. The crystallinity and stability of GML-3 API in SD were studied by differential scanning calorimetry and X-ray phase analysis. The level of release of API GML-3 from SD was evaluated spectrophotometrically at λ = 256 nm.

Results. In SD (1:5, 1:10), crystallization foci were formed, leading to the re-crystallization of API GML-3 during the solvent distillation process (for a concentration of 1:5) or a rapid loss of homogeneity due to the formation of zones of increased polymer content and API (for a concentration of 1:10). In ratios of 1:15.20, SD had high stability (after holding for 146.5 hours at 55 °C) and a high level of release of GML-3 API into purified water (96 %).

Conclusion. Stable amorphous TD GML-3 at API: polymer ratios = 1:15.20 provide a high level of release of GML-3 into purified water, which allows us to conclude that the use of TD GML-3 is promising in the development of dosage forms (tablets and capsules).

1. Mokrov G.V., Deeva O.A., Gudasheva T.A. et al. Design, synthesis and anxiolytic-like activity of 1-arylpyrrolo[1,2-a]pyrazine-3-carboxamides. Bioorg Med Chem 2015;23(13): 3368–78. DOI: 10.1016/j.bmc.2015.04.049

2. Yarkov S.A., Mokrov G.V., Gudasheva T.A. et al. Pharmacological study of new compounds acting as regulators of 18-kDa translocator protein ligands. Eksp Klin Farmakol 2016;79(1):7–11. PMID: 27159950

3. Yarkova M.A., Mokrov G.V., Gudasheva T.A., Seredenin S.B. Anxiolytic activity of original pyrrolo[1,2-a]pyrazine deriva-tives (TSPO ligands) depends on neurosteroid biosynthesis. Pharm Chem J 2016;50(8):3–6. (In Russ.). DOI: 10.30906/0023-1134-2016-50-8-3-6

4. Davis M., Walker G. Recent strategies in spray drying for the enhanced bioavailability of poorly water-soluble drugs. J Con-trolled Release 2018;269(10):110–27. DOI: 10.1016/j.jconrel.2017.11.005

5. Khan K.U., Minhas M.U., Badshah S.F. et al. Overview of nanoparticulate strategies for solubility enhancement of poorly soluble drugs. Life Sci 2022;291:120301. DOI: 10.1016/j.lfs.2022.120301

6. Bazzo G.C., Pezzini B.R., Stulzer H.K. Eutectic mixtures as an approach to enhance solubility, dissolution rate and oral bioavailability of poorly water-soluble drugs. Int J Pharm 2020;588:119741. DOI: 10.1016/j.ijpharm.2020.119741

7. Yousaf A.M., Malik U.R., Shahzad Y. et al. Silymarin-laden PVP-PEG polymeric composite for enhanced aqueous solubility and dissolution rate: Preparation and in vitro characterization. J Pharm Anal 2019;9(1):34–9. DOI: 10.1016/j.jpha.2018.09.003