Enhancing the stability of amorphous drug-polyelectrolyte nanoparticle complex using a secondary small-molecule drug as the stabilizer: A case study of ibuprofen-stabilized curcumin-chitosan nanoplex.

While the solubility enhancement capability of amorphous drug-polyelectrolyte nanoparticle complex (nanoplex) has been widely established, its amorphous form stability during long-term storage is often lacking for poorly-soluble drugs with high crystallization propensity, such as curcumin (CUR). Herein we presented a new stabilization strategy of amorphous CUR nanoplex using a secondary small-molecule drug - ibuprofen (IBU) - as the auxiliary stabilizer to the polyelectrolytes (i.e. chitosan). The results showed that, unlike the single-drug CUR nanoplex, the dual-drug CUR-IBU nanoplex with CUR/IBU payload ratio of 1.7 remained stable after 24-month storage. The CUR-IBU nanoplex also exhibited superior CUR solubility enhancement (4-fold higher) than the CUR nanoplex. These improvements, however, were not evident for the CUR-IBU nanoplex prepared at higher CUR/IBU payload ratio of 14 due to insufficient IBU presence. Compared to the CUR nanoplex, the CUR-IBU nanoplex exhibited smaller size with less spherical morphology (100 nm), higher zeta potential (42 versus 19 mV), lower total drug payload (73% versus 83%), and lower CUR utilization rate (53% versus 94%) due to the competition with IBU in the drug-PE complexation. These results successfully established the use of a secondary drug to not only stabilized, but also improved solubility enhancement of amorphous drug nanoplex systems.