AI-directed formulation strategy design initiates rational drug development.

Rational drug development would be impossible without selecting the appropriate formulation route. However, pharmaceutical scientists often rely on limited personal experiences to perform trial-and-error tests on diverse formulation strategies. Such an inefficient screening manner not only wastes research investments but also threatens the safety of clinical volunteers and patients. A design-oriented paradigm for formulation strategy determination is urgently needed to initiate rational drug development. Herein, we introduce FormulationDT, the first data-driven and knowledge-guided artificial intelligence (AI) platform for rational formulation strategy design. Learning from approved drug formulations, FormulationDT devised a comprehensive formulation strategy design system containing 12 decisions for both oral and injectable administration. Utilizing PU-Decide, our specialized partially supervised learning framework designed for positive-unlabeled (PU) scenarios, FormulationDT developed precise and interpretable classification models for each decision, achieving area under the receiver operating characteristic curve (ROC_AUC) scores ranging from 0.78 to 0.98, with an average above 0.90. Incorporating extensive domain knowledge, FormulationDT is now accessible through a user-friendly web platform (http://formulationdt.computpharm.org/). Moreover, FormulationDT demonstrates its value by showcasing its application in proteolysis targeting chimeras (PROTACs) and recent drug approvals. Overall, this study created the first approved drug formulation dataset and tailored the PU-Decide framework to develop a high-performance, interpretable, and user-friendly AI formulation strategy design platform, which holds promise for driving risk reduction and efficiency gains across the life cycle of drug discovery and development.