Revealing the mechanism of morphological variation of amorphous drug nanoparticles formed by aqueous dispersion of ternary solid dispersion

Abstract

Probucol (PBC)/hypromellose (HPMC)/sodium dodecyl sulfate (SDS) ternary solid dispersions (SDs) of various weight ratios were prepared and evaluated to unveil the effect of HPMC and SDS on the formation of amorphous PBC nanoparticles. The morphological variation of the PBC nanoparticles prepared using SDs of different compositions was determined using dynamic light scattering and cryogenic transmission electron microscopy (cryo-TEM). Statistical analysis of particle size versus roundness of PBC nanoparticles was carried out based on cryo-TEM images. A clear correlation was observed between the morphologies of the PBC nanoparticles and the amounts of HPMC and SDS, either admixed in SDs or pre-dissolved in an aqueous solution. The admixed HPMC in SDs was demonstrated to play the major role in determining the primary particle sizes of discrete amorphous PBC nanoparticles. Based on 13C solid-state NMR spectroscopy, this phenomenon should be due to the enlarged size of the PBC-rich domains in SDs, which depended on the decreasing amounts of admixed HPMC. Although the pre-dissolved part of HPMC had less impact on the primary particle sizes, it was found to inhibit the particle agglomeration and recrystallization of amorphous PBC nanoparticles. On the other hand, sufficient SDS admixed in SDs could suppress the size enhancement of the PBC-rich domains during water immersion and nanoparticle evolution (agglomeration and crystallization) after aqueous dispersion. The pre-dissolved SDS could restrain the agglomeration of amorphous PBC nanoparticles, ultimately forming hundreds of irregular nanometer-order structures. Since the increase in size during water immersion, their sizes were still slightly larger than those obtained with a high portion of admixed SDS. The findings of this study clarified the usefulness and necessity of adding polymers and surfactants to SDs to fabricate drug nanoparticle formulations.