The limited aqueous solubility of active pharmaceutical ingredients (APIs) remains a major challenge in drug development, severely compromising clinical performance. Crystal engineering has emerged as a powerful and versatile approach to address this issue by rationally designing API crystal structures through precise control of intermolecular interactions, thereby enhancing solubility, dissolution rates, and ultimately bioavailability. This review systematically summarizes recent advances in crystal engineering strategies for poorly water-soluble drugs, including polymorphs, cocrystals, solvates/hydrates, nanocrystals, organic framework solids, solid solutions, liquid crystals, amorphous solids, and salts. Additionally, key challenges in translational applications are discussed, including structure-property relationship, AI-driven computational modeling, in vitro-in vivo correlation establishment, and advanced crystallization techniques. The review aims to provide strategic insights of crystal engineering for overcoming solubility barriers in next-generation drug formulations.

Crystal engineering  /  Poorly water-soluble drugs  /  Aqueous solubility  /  Oral bioavailability  /  Prediction  /  Design  /  Application  /  AI-driven computational modeling