Millifluidic synthesis of amorphous drug-polysaccharide nanoparticle complex with tunable size intended for supersaturating drug delivery applications

The conventional bulk mixing method to prepare amorphous drug-polysaccharide nanoparticle complex (or drug nanoplex in short) has a major drawback in the lack of size control for the nanoplex produced, hence limiting its potential applications as a supersaturating drug delivery system for bioavailability enhancement of poorly soluble drugs. For this reason, we developed a continuous millifluidic synthesis platform of the drug nanoplex exhibiting high size tunability using curcumin (CUR) and chitosan (CHI) as the models for drug and polysaccharides, respectively. The nanoplex size tunability was achieved by controlling the residence time of the CUR and CHI solutions in the millifluidic reactor, where their slow diffusive mixing at the liquid-liquid interface resulted in a well-regulated nanoplex growth as a function of the residence time. The effects of the preparation pH, molecular weight of CHI, millifluidic tube diameter, and flowrate on the nanoplex size tunability were investigated from which the optimal preparation condition was determined. At the optimal condition, the CUR nanoplex was roughly ≈115 nm in size with zeta potential of ≈15 mV and ≈72% (w/w) CUR payload. The millifluidic synthesis also maintained the high CUR utilization rate (≈80%) exhibited by the bulk mixing method. Most importantly, the ability to produce significantly smaller nanoplex (sixfold smaller) via millifluidics led to the generation of higher (≈8.5× of CUR saturation solubility) and prolonged (≈8 h) supersaturation level. These results bode well for the bioavailability enhancement potential of the drug nanoplex.