Recovery of amorphous drug-polyelectrolyte nanoparticle complex by salt-induced flocculation to circumvent the need for ultracentrifugation

Amorphous drug-polyelectrolyte nanoparticle complex (or drug nanoplex) has emerged as an attractive solubility enhancement strategy of poorly soluble drugs owed to its supersaturation generation capability and cost-effective preparation. Like most pharmaceutical nanoparticles, however, the recovery and purification of the drug nanoplex remain reliant on ultracentrifugation, which is costly and energy intensive. Herein we developed a new strategy to recover the drug nanoplex by salt-induced flocculation followed by direct-flow filtration, where the resultant nanoplex flocs readily dissociated to primary nanoplex in aqueous environment. Using curcumin nanoplex and Na₃PO₄/Na₂SO₄ as the model drug nanoplex and salt-flocculant, respectively, we characterized the (1) production yield, (2) physical characteristics (i.e. size, zeta potential, drug payload), (3) dissolution characteristics, and (4) in vitro solubility enhancement of the nanoplex recovered by the flocculation-and-filtration platform. The results showed that the flocculation-and-filtration platform led to higher production yield than ultracentrifugation (≈14–17% higher) with significantly lower energy requirement. Compared to the ultracentrifuged nanoplex, the deflocculated nanoplex exhibited similar size (250–350 nm) and drug payload (80%), but with higher zeta potential (55 mV) and polydispersity due to incomplete deflocculation. The deflocculated nanoplex exhibited slower dissolution in the simulated gastrointestinal fluid that led to prolonged supersaturation generation, hence improved solubility enhancement capability.