Amorphization Strategy Affects the Stability and Supersaturation Profile of Amorphous Drug Nanoparticles

Abstract

Amorphous drug nanoparticles have recently emerged as a promising bioavailability enhancement strategy of poorly soluble drugs attributed to the high supersaturation solubility generated by the amorphous state and fast dissolution afforded by the nanoparticles. Herein we examine the effects of two amorphization strategies in the nanoscale, i.e., (1) molecular mobility restrictions and (2) high energy surface occupation, both by polymer excipient stabilizers, on the (i) morphology, (ii) colloidal stability, (iii) drug loading, (iv) amorphous state stability after three-month storage, and (v) in vitro supersaturation profiles, using itraconazole (ITZ) as the model drug. Drug-polyelectrolyte complexation is employed in the first strategy to prepare amorphous ITZ nanoparticles using dextran sulfate as the polyelectrolyte (ITZ nanoplex), while the second strategy employs pH-shift precipitation using hydroxypropylmethylcellulose as the surface stabilizer (nano-ITZ), with both strategies resulting in >90% ITZ utilization. Both amorphous ITZ nanoparticles share similar morphology (∼300 nm spheres) with the ITZ nanoplex exhibiting better colloidal stability, albeit at lower ITZ loading (65% versus 94%), due to the larger stabilizer amount used. The ITZ nanoplex also exhibits superior amorphous state stability, attributed to the ITZ molecular mobility restriction by electrostatic complexation with dextran sulfate. The higher stability, however, is obtained at the expense of slower supersaturation generation, which is maintained over a prolonged period, compared to the nano-ITZ. The present results signify the importance of selecting the optimal amorphization strategy, in addition to formulating the excipient stabilizers, to produce amorphous drug nanoparticles having the desired characteristics.

Bioavailability Improvement Strategies for Poorly Water-Soluble Drugs Based on the Supersaturation Mechanism: An Update

“…The amorphous nanoparticle complex (nanoplex) prepared by electrostatic complexation of drug molecules with oppositely charged carriers (such as dextran sulfate or carrageenan) represents a promising bioavailability enhancement strategy for poorly soluble drugs owing to their high supersaturation generation ability and simple preparation (74). Because the supersaturation of the amorphous nanoparticles in their aqueous suspension is always adversely affected after drying, only one adjuvant type is always ineffective in preserving the supersaturation.…”

Preparation of amorphous drug nanoparticles by high-gravity reactive precipitation technique

“…Two known mechanisms to increase the bioavailability of water insoluble drugs are to increase the surface area and to create stable amorphous forms [2,3]. The metastable state of the amorphous form generates a high degree of drug supersaturation, resulting in an apparent saturation solubility that is multi-folds higher than that of the crystalline form, hence the improved bioavailability [4,5].…”

Amorphous nanodrugs prepared by complexation with polysaccharides: Carrageenan versus dextran sulfate

“…Second, they contribute to the generation of a sustained supersaturation level as the drug molecules can only be released upon their decomplexation from the polysaccharides in the presence of electrolytes, as opposed to burst dissolution of drug molecules in conventional amorphous nanodrugs (Sun & Lee, 2013). On this note, amorphous drug nanoplex has been found to exhibit a more prolonged supersaturation level and higher amorphous state stability than amorphous nanodrugs prepared by pH-shift precipitation (Cheow, Kiew, Yang, & Hadinoto, 2014).…”