Engineering Lawsone-Flavonoid Co-Amorphous Architectures: A Dual Strategy to Overcome Solubility Barriers and Amplify Anticancer Potential

Objective: To enhance solubility, dissolution, and anticancer efficacy of Lawsone by developing an optimized Naringenin-based co-amorphous system. Methods: Five flavonoids were screened preliminarily and Naringenin was selected through molecular docking. Co-amorphous formulations (EF1–EF9) were prepared by solvent evaporation and optimized using a 32 factorial design. Physicochemical characterization (DSC, PXRD, FTIR, SEM), multi-media dissolution studies (0.1N HCl, phosphate buffer pH 4.5, 6.8, and 7.2), and MCF-7 cytotoxicity assays were performed. Results: EF9 (150 mg Lawsone: 300 mg Naringenin) achieved 31.84±1.59 μg/ml solubility (15.84-fold enhancement). Dissolution followed pH-dependent rank order (pH 6.8>pH 7.2>pH 4.5>0.1N HCl), with EF9 releasing 98.4±2.6%, 96.4±2.8%, 95.1±2.7%, and 90.6±2.8% at 120 min respectively. DSC, PXRD, and FTIR confirmed successful amorphization and intermolecular hydrogen bonding. IC₅₀ improved from 42.3±1.8 to 18.7±1.2 μg/ml against MCF-7 cells. Conclusion: The optimized Lawsone–Naringenin co-amorphous system demonstrated significant improvements in solubility, gastrointestinal dissolution, and anticancer activity, offering a rational scalable platform for BCS Class II drug bioavailability enhancement warranting further in vivo evaluation.