Drug Nanocrystals: From Formulation Design to Clinical Translation

Poor aqueous solubility remains a critical challenge in pharmaceutical development, leading to limited drug absorption, high variability in systemic exposure, and reduced therapeutic efficiency. Conventional approaches such as salt formation, amorphous systems, and lipid-based formulations often face limitations related to stability, scalability, and regulatory complexity. Drug nanocrystals have emerged as a clinically established strategy to address these challenges by enhancing dissolution and bioavailability without altering the intrinsic pharmacological properties of the drug. This review provides a structured and critical overview of drug nanocrystal technology, encompassing fabrication methods, stabilization strategies, surface engineering, biological fate, and route-specific applications. Emphasis is placed on distinguishing mechanistic understanding from translational outcomes, supported by representative studies and marketed products. The review further discusses regulatory considerations, safety aspects, and factors influencing clinical translation. By integrating formulation design with in vivo behavior and regulatory perspectives, this work highlights the role of nanocrystals as a scalable and effective platform for poorly soluble drugs. Current challenges, including stability, targeting efficiency, and manufacturing reproducibility, are critically addressed, and future directions are outlined to support continued advancement and broader clinical adoption.