Polymeric Amorphous Solid Dispersions of Dasatinib: Formulation and Ecotoxicological Assessment

Abstract

Dasatinib (DAS), a potent anticancer drug, has been subjected to formulation enhancements due to challenges such as significant first-pass metabolism, poor absorption, and limited oral bioavailability. To improve its release profile, DAS was embedded in a matrix of the hydrophilic polymer polyvinylpyrrolidone (PVP). Drug amorphization was induced in a planetary ball mill by solvent-free co-grinding, facilitating mechanochemical activation. This process resulted in the formation of amorphous solid dispersions (ASDs). The ASD capsules exhibited a notable enhancement in the release rate of DAS compared to capsules containing the initial drug. Given that anticancer drugs often undergo limited metabolism in the body with unchanged excretion, the ecotoxicological effect of the native form of DAS was investigated as well, considering its potential accumulation in the environment. The highest ecotoxicological effect was observed on the bacteria Vibrio fischeri, while other test organisms (bacteria Pseudomonas putida, microalgae Chlorella sp., and duckweed Lemna minor) exhibited negligible effects. The enhanced drug release not only contributes to improved oral absorption but also has the potential to reduce the proportion of DAS that enters the environment through human excretion. This comprehensive approach highlights the significance of integrating advances in drug development while considering its environmental implications.

Keywords: amorphous solid dispersion; dasatinib; drug release; ecotoxicological evaluation; mechanochemical activation.

Figure 1

DSC thermograms of the initial drug, polymer, and obtained solid dispersions.

Figure 2

FTIR spectra of the initial drug and polymer.

Figure 3

FTIR spectra of obtained solid dispersions.

Figure 4

Diffractograms of the initial drug and polymer.

Figure 5

Diffractograms of obtained solid dispersions.

Figure 6

Drug release profiles of capsules containing solid dispersions (obtained under various conditions) and initial DAS.

Figure 7

Concentration–response curve for DAS concentration in the range 25–150 µg L⁻¹ obtained by ecotoxicity tests with marine bacterium Vibrio fischeri.

Figure 8

Concentration–response curve for DAS concentration in the range 25–150 µg L⁻¹ obtained by ecotoxicity tests with saprophytic bacterium Pseudomonas putida.

Figure 9

Concentration–response curve for DAS concentration in the range 25–150 µg L⁻¹ obtained by ecotoxicity tests with microalgae Chlorella sp.

Figure 10

Changes of specific growth rate (A), average root length (B), and average concentration of chlorophyll (C) obtained after 7 days of exposure of duckweed Lemna minor to the concentration of DAS in the range 25–150 µg L⁻¹ compared to control.