Facile and energy-efficient magnetic stirrer-assisted media milling enables drug-drug nano-cocrystals with synchronous and fast release.

Gefitinib (GTB) and dasatinib (DAS) are two tyrosine kinase inhibitors with synergistic potential, but their poor and disparate solubility hinders fast and synchronous release in combination therapy. While drug-drug nano-cocrystals offer a solution for synchronous and fast release of two drugs in combination, their development is limited by bottlenecks in low-energy and scalable preparation. Herein, a facile magnetic stirrer-assisted media milling (MS-MM) method was developed to fabricate GTB-DAS drug-drug nano-cocrystals for the first time. The formulation and preparation process of nano-cocrystal suspensions were optimized, validated, and successfully scaled up by 25-fold. Compared with conventional ball mill-based media milling, MS-MM showed a 60% lower theoretical energy consumption when compared on the basis of rated power. Comprehensive characterization (SEM, TEM, PXRD, DSC, FTIR) of the lyophilized powder confirmed the successful fabrication of GTB-DAS nano-cocrystals with cocrystal structure preserved. In vitro dissolution studies demonstrated that the nano-cocrystals integrated synchronous release and a high dissolution rate, achieving nearly 100% release of both drugs within 5 min. This work provides a facile, energy-efficient, and scalable platform for the development of compound formulations involving poorly water-soluble drugs.