Impact of molecular rearrangement of amphiphilic stabilizers on physical stability of itraconazole nanoparticles prepared by flash nanoprecipitation

Abstract

Flash nanoprecipitation (FNP) is a controlled antisolvent precipitation process that has proven effective for consistent production of drug nanoparticles with a defined mean particle size and narrow particle size distribution. However, physical instability of the generated nanoparticles remains a major challenge in the application of this technology in pharmaceutical formulation. Aimed at resolving this problem, the present study has investigated the FNP process and associated stabilization mechanism of itraconazole (ITZ) nanoparticles through in-depth nanoparticle characterization. Results showed that ITZ nanoparticles could be reproducibly produced with a mean particle size <100 nm and a polydispersity index <0.2 in the presence of amphiphilic stabilizers (ASs). Surface analysis of freshly formed nanoparticles by X-ray photoelectron spectroscopy (XPS) revealed initially a disordered packing structure and subsequently a time-dependent molecular rearrangement of incorporated AS towards a micelle-like structure. The faster the molecular rearrangement of AS, the more stable the nanoparticles, as monitored by the change in particle size with time. These findings may have important implications for the selection of effective ASs for formulating stable drug nanoparticles. The present study is the first of its kind to demonstrate the utility of XPS to track the molecular transport of stabilizers in rapidly generated nanoparticles.

In Vitro Release Study of the Polymeric Drug Nanoparticles: Development and Validation of a Novel Method

“…The stream flowrates remained the same for all sample preparation, while the formulation parameters such as organic solvent, initial drug concentration, drug-TPGS ratio, and co-stabilizer, varied in order to generate nanoparticles with adequate particle size (<100 nm) and stability for subsequent analysis. The preparation method of the ITZ and FLU nanoparticles were based on the previous research works [29,34].…”

Recent Advances in Polymeric Nanoparticle-Encapsulated Drugs against Intracellular Infections

“…Microfluidics require only very small volumes of nanoparticle precursors and provides precise control of phases mixing to produce reproducible PNs with different physicochemical properties [ 62 ]. In this context, antifungal itraconazole nanoencapsulated by FNP with different amphiphilic stabilizers has been studied and their mobility on nanoparticles’ surface and physical storage stability evaluated [ 110 ]. Although still in its infancy, other novel approaches involve electrohydrodynamic atomization-based methodologies, where liquid droplets are generated by the application of a large electrical potential difference.…”

Application of flash nanoprecipitation to fabricate poorly water-soluble drug nanoparticles

“…In general, the higher the log P of the drug molecule, the better the physical stability of the formed drug nanoparticles. Therefore, the highly hydrophobic APIs including β -carotene 43 , 44 , 45 , curcumin 46 , 47 , cyclosporine A 48 , 49 , doxorubicin 50 , 51 and itraconazole 52 were commonly used as model drugs in FNP reports. Moreover, some prodrugs with higher hydrophobicity than parent drug have been synthesized to facilitate encapsulation and/or improve nanoparticle stability 41 , 42 , 53 , 54 .…”

“…Hydrophobic blocks, such as PLGA, PLA and PCL are commonly used as core materials 42 , 43 , 44 . It has been found that the incorporation of some hydrophobic molecule as co-stabilizer such as cholesterol could facilitate the rearrangement of amphiphilic stabilizer toward a micelle-like structure, and thus prolonging the particle stability 52 . For electrostatic stabilization, the charged ionic polymer and surfactant can offer repulsive force between particles due to similar charges on particle surface.…”