Engineering micro- and nanosized pharmaceutical salt crystals using high-pressure homogenization

This study presents an innovative application of high-pressure homogenization (HPH) for the synthesis of micro- and nanocrystalline pharmaceutical salts, offering a scalable and environmentally sustainable alternative to conventional crystallization techniques. Using ketoconazole (KTZ) and oxalic acid (OA) as a model system, salt formation was successfully achieved through HPH processing in the presence of various stabilizers (Pharmacoat® 606, Pluronic® F127, Soluplus®, and TPGS) at different concentrations and process temperatures. Structural analysis by XRPD and FT-IR confirmed the formation of a new multicomponent salt through proton transfer and hydrogen bonding, while SEM imaging revealed controlled crystal morphology and significant particle size reduction to the submicron range. The process demonstrated remarkable reproducibility and flexibility, allowing morphological tuning through simple adjustments in stabilizer concentration and temperature. Dissolution studies performed at pH 4.4 showed up to an 80% drug release within 15 min for HPH-processed KTZ:OA salts, a substantial improvement over bulk KTZ. The findings establish HPH as a versatile, solvent-free, and continuous manufacturing platform for the production of high-purity pharmaceutical salts with superior dissolution performance, highlighting its potential to transform solid-state drug formulation and process intensification strategies in pharmaceutical development.