An acid-base neutralization technique generated interest for the ability to achieve an enhanced dissolution of pH-dependent weakly basic or acidic poorly water-soluble drugs. However, the underlying nanonization mechanism, following acid-base neutralization, requires further elucidation. We hypothesized that nanonization of drug particles after neutralization could be attributed to the “salt-induced effect” and surfactant-driven micellization. Rebamipide (RBM) and valsartan (VAL) were chosen as model drugs owing to poor water solubility and pH-dependent aqueous solubility. The drug nanosuspension was rapidly obtained via salt formation (NaCl) after neutralization of the drug in basic NaOH solution and poloxamer 407 (POX 407) in acidic HCl solution. The nanosuspension surrounded by NaCl salt was further stabilized by POX 407. The resulting NaCl salt modulated the critical micelle aggregation of POX 407, stabilizing the drug-loaded nanosuspension in a cage of salt and micellar surfactant. In non-assisted homogenization, size analysis indicated the relationship between salt concentration and size reduction. Fourier transform infrared (FTIR) spectra revealed that the existence of hydrogen bonding between the drug and surfactant after neutralization, attributed to nanosuspension size reduction. Changes in drug crystallinity to nano-amorphous state were confirmed by powder X-ray diffraction (PXRD). Overall, the salt-induced drug nanosuspension synergistically enhanced the dissolution rate, narrowing a gap between drug dissolution profiles in different pH environment.
