Hydrodynamically decoupled nanoprecipitation (HDNP): A multi-stage strategy for supersaturation, controlled delayed nucleation, and stabilization of low LogP poorly-water soluble drugs.

Poor aqueous solubility is a major drawback of modern drug candidates, affecting their biopharmaceutical performance. Solvent-antisolvent methods involving rapid mixing, such as Flash Nanoprecipitation and Sequential Nanoprecipitation, have advanced the field. However, these remain restricted to compounds with relatively high hydrophobicity (minimum LogP ≥4.5-6). To address this limitation, we introduce Hydrodynamically Decoupled Nanoprecipitation (HDNP). The approach enables decoupling supersaturation, nucleation, and stabilization by controlling the hydrodynamic environments. Dexamethasone (DEX, LogP: 1.83) was used as a model drug. A mechanistically and physics-informed framework was developed, integrating in-line dynamic light scattering for count rate evolution assessment, Computational Fluid Dynamics (CFD), and Design of Experiments for design space establishment. CFD revealed periodic shear stress, high turbulent dissipation rates, and local flow reversal during pulsatile flow under various Womersley numbers, providing favorable hydrodynamic conditions for controlled delayed nucleation. HDNP of DEX successfully produced mainly amorphous nanoparticles (DEX-NPs) stabilized with P407. DEX-NPs exhibited a hydrodynamic diameter of 241 nm, PdI of 0.246, loading efficiency of 77%, enhanced dissolution relative to the micronized drug, and physicochemical stability for at least two weeks. The approach was further evaluated using prednisolone (LogP: 1.62). These findings demonstrate the applicability of HDNP to the nanoprecipitation of the used corticosteroids and highlights its potential as a promising platform for other poorly water-soluble compounds with low LogP.