Preparation and evaluation of solid dispersions of a new antitumor compound based on early-stage preparation discovery concept

Abstract

Ensuring sufficient drug solubility is a crucial problem in pharmaceutical-related research. For water-insoluble drugs, various formulation approaches are employed to enhance the solubility and bioavailability of lead compounds. The goal of this study was to enhance the dissolution and absorption of a new antitumor lead compound, T-OA. Early-stage preparation discovery concept was employed in this study. Based on this concept, a solid dispersion system was chosen as the method of improving drug solubility and bioavailability. Solid dispersions of T-OA in polyvinylpyrrolidone (PVP) K30 were prepared by the solvent evaporation method. Dissolution testing determined that the ideal drug-to-PVP ratio was 1:5. X-ray diffraction, Fourier transform infrared spectroscopy, and differential scanning calorimetry were employed to confirm the formation of solid dispersions. Scanning electron microscopy demonstrated that T-OA was converted into an amorphous form. Both in vitro dissolution testing and the in vivo studies demonstrated that the solubility and bioavailability of T-OA were significantly improved when formulated in a solid dispersion with PVP. The dissolution rate of the T-OA/PVP solid dispersion was greatly enhanced relative to the pure drug, and the relative bioavailability of T-OA solid dispersions was found to be 392.0%, which is 4-fold higher than the pure drug.

Fig. 1

Structure of T-OA, PVPK30, and 43-PH

Fig. 2

Dissolution profiles of T-OA, physical mixture with PVP, and T-OA solid dispersion

Fig. 3

Dissolution profiles of different batches of solid dispersion and different ratio of SLS

Fig. 4

Dissolution profiles of physical mixture of SLS and solid dispersion and solid dispersions with and without SLS

Fig. 5

Dissolution profiles of solid dispersions in different dissolution mediums

Fig. 6

XRD spectra of solid dispersions and physical mixture of T-OA and PVP K30

Fig. 7

FT-IR spectroscopy of T-OA (a), physical mixture of T-OA and PVP K30 (b), solid dispersion of T-OA and PVP K30 (c), and PVP K30 (d)

Fig. 8

DSC traces of pure T-OA (a), solid dispersion of T-OA and PVP K30 (b), and solid dispersion of T-OA, PVP K30, and SLS (c) at a scanning rate of 10°C/min

Fig. 9

Morphology images of T-OA and solid dispersions. T-OA (a), solid dispersion of T-OA and PVP K30 (b, c), and solid dispersion of T-OA, PVP K30, and SLS (d)

Fig. 10

Bioavailability of T-OA solid dispersions and prototype drug in rats