Development and In Vitro Evaluation of Gefitinib-Salicylic Acid Nanocrystals for Improved Bioavailability

Background: Non-small cell lung cancer (NSCLC), a malignant tumor with high global incidence and mortality rates, urgently requires more effective targeted drug delivery systems for its treatment. As an EGFR tyrosine kinase inhibitor, gefitinib has its clinical efficacy limited by poor solubility and low bioavailability. This study aimed to develop a gefitinib-salicylic acid salt (Gef-Sa) and its nano-formulation (Gef-Sa-NPs) via a combined strategy of crystal engineering and nanotechnology to improve its pharmaceutical properties. Methods: Gef-Sa was prepared using a suspension method, and its salt formation and thermal stability were predicted by the ΔpKa rule and confirmed by various solid-state characterization techniques, including single crystal/powder X-ray diffraction, thermal analysis, and infrared spectroscopy. Gef-Sa-NPs were prepared via an ultrasound-assisted anti-solvent precipitation method. Their performance was evaluated through in vitro dissolution tests, pharmacokinetic studies, and in vitro antitumor experiments. Results: Gef-Sa-NPs with a particle size of 31 nm (PDI = 0.15) were successfully prepared. In vitro dissolution tests demonstrated that the nano-formulation exhibited a significantly higher dissolution rate in pH 1.2, pH 4.5, pH 6.8 and pure water when compared with the raw drug (p < 0.01). Pharmacokinetic studies revealed that Gef-Sa and Gef-Sa-NPs increased the oral bioavailability in rats to 1.5-fold and 1.9-fold that of the raw drug, respectively. In vitro antitumor experiments confirmed that the Gef-Sa-NPs increased the inhibition rate against A549 cells compared with the Gef. Conclusions: This study innovatively combines salt formation and nanonization technologies to systematically address the key issue of the poor solubility of Gef. The resulting nano-formulation demonstrates excellent dissolution characteristics, pharmacokinetic behavior, and antitumor efficacy. This strategy not only provides a novel drug delivery system with translational potential for NSCLC treatment but also offers a paradigm for the formulation design of poorly soluble drugs. Subsequent research will focus on scaling up production and evaluating pre-clinical safety.