Screening, Synthesis, Characterization, and Quantum Chemical Calculation of Sunitinib-Hydrogen Glutarate: Enhancing Biopharmaceutical Performance and Oral Bioavailability

Sunitinib, a widely used multi-target tyrosine kinase inhibitor in clinical practice, is limited by low bioavailability attributable to its poor solubility and permeability. To mitigate these limitations, the Conductor-like Screening Model for Real Solvents (COSMO-RS) model was utilized to identify suitable counter acids for salt formation with sunitinib. A novel sunitinib salt, sunitinib-hydrogen glutarate was successfully virtual screened and experimental synthesized. The salt was comprehensively characterized, and its crystal structure was determined. Subsequent evaluations included solubility and dissolution testing, permeability assessment, theoretical calculations, in vivo pharmacokinetic studies, and in vitro cytotoxicity assays. Compared to sunitinib, the salt exhibited a 57.95-fold increase in solubility in pH 6.8 buffer, a markedly accelerated dissolution rate, and significantly enhanced membrane permeability, with a 1557.9 % rise in cumulative drug permeation over 480 min. Quantum chemical calculations revealed multiple non-covalent interactions within the salt at the molecular level and indicated that the strong solvation effect of water on the salt species is key to its improved aqueous solubility. Analysis of salt passive diffusion across lipid bilayers by the Cosmoperm model demonstrated that ion pairs permeate much more efficiently than dissociated ions. In vivo pharmacokinetic studies in rats demonstrated that the sunitinib-hydrogen glutarate achieved faster absorption and significantly higher relative bioavailability, suggesting potentially superior antitumor efficacy. This work not only provides a practical strategy to enhance the bioavailability of poorly soluble drugs like sunitinib, but also establishes a theoretical and technical foundation for the development of novel drug delivery systems and the improvement of therapeutic outcomes, thereby supporting further innovation in the formulation of sparingly soluble active pharmaceutical ingredients.