Design-of-experiments-assisted microfluidic synthesis of sorafenib tosylate nanocrystals for improved oral bioavailability.

Sorafenib tosylate (ST) is a potent multikinase inhibitor used for the treatment of hepatocellular carcinoma, but its poor aqueous solubility limits oral bioavailability. Drug nanocrystals are an effective strategy to enhance dissolution while maintaining high drug loading; however, conventional batch antisolvent precipitation suffers from limited mixing control, heterogeneous nucleation, making it challenging to achieve consistent control of critical product attributes, including particle size, size distribution, and solid-state form, particularly upon scale-up. This study establishes a systematic development approach for continuous microfluidic production of sorafenib tosylate nanocrystals (ST-NCs), integrating formulation screening, design of experiments (DoE)-based process optimisation, physicochemical characterisation, pharmaceutical performance evaluation, and stability assessment. Initial batch screening identified polyvinylpyrrolidone K30 (PVP-K30) as the optimal stabiliser. The formulation was then translated to a microfluidics platform and optimised using a DoE approach to evaluate the effects of drug concentration, total flow rate (TFR), and flow rate ratio (FRR) on particle size, polydispersity index (PDI), and yield. Statistical analysis revealed FRR as the dominant factor controlling nanocrystal size, highlighting the critical role of hydrodynamic regulation of supersaturation and nucleation. Under optimised conditions, microfluidic processing produced ST-NCs with a mean particle size of 169 ± 3 nm and a narrow size distribution (PDI 0.28 ± 0.01), outperforming batch-prepared nanocrystals. Solid-state characterisation by PXRD and DSC confirmed improved polymorphic control and retained crystallinity, with microfluidically prepared ST-NCs maintaining crystalline Form II after lyophilisation and storage, whereas batch samples exhibited mixed forms. The optimised ST-NCs also demonstrated enhanced dissolution efficiency and increased cytotoxicity against HepG2 cells. Overall, microfluidic nanoprecipitation combined with DoE optimisation offers a robust and scalable strategy for producing high-quality ST-NCs with controlled size, stable solid-state properties, and improved pharmaceutical performance.