Molecular Distribution of Indomethacin: Impact on the Precipitation of Glassy Curcumin pH-Responsive Nanoparticles with Enhanced Solubility

Co-amorphous nanoparticles (NPs) formation is a relatively new strategy to improve the solubility of drugs with poor water solubility. Curcumin (CUR) is a natural product having many pharmacological effects, but its clinical translation is limited by poor stability and aqueous solubility. Co-amorphous NPs of CUR are rarely reported in the literature. In the present study, co-amorphous NPs of CUR and indomethacin (INDO) were prepared through the evaporation-assisted solvent-antisolvent interaction approach using chitosan (CHI) as a stabilizer. Here, both CHI and INDO act as co-formers for the successful precipitation of a co-amorphous solid form of CUR. However, the molecular distribution of INDO was found to greatly affect the solid state of precipitated CUR NPs as analyzed through powder X-ray diffraction and differential scanning calorimetry measurement. A strong hydrogen bonding and CH-pi interaction among CUR, INDO, and CHI were evidenced through experimental techniques such as nuclear magnetic resonance (H-1 NMR), ultraviolet-visible light, and Fourier transform infrared spectroscopies and theoretical calculations using density functional theory. The formation of the co-amorphous NPs led to multifold enhancement in the intrinsic dissolution rate and equilibrium solubility of CUR. CHI coating over co-amorphous NPs also provides pH-dependent release behavior of CUR. The co-amorphous NPs were highly stable against recrystallization for more than a year, under low humidity conditions (<5% humidity, RT), while exhibiting stability for more than a month under accelerating conditions (75% humidity, 40 degrees C). Improved solubility and stability of co-amorphous NPs is speculated to be a result of strong molecular interactions between CUR, INDO, and CH.