Unraveling the Impact of Stabilizers on Nanocrystal Preparation and Oral Absorption: A Case Study of Poorly Soluble Andrographolide

Drug nanocrystal engineering is an attractive pharmaceutical approach to enhancing the oral bioavailability of poorly soluble drugs. The mechanism of drug nanocrystal stabilization, however, is unclear. Here we developed andrographolide nanocrystals (AG-NCs) with various nonionic surfactants (Pluronic-F127, TPGS, or Brij-S20). We detected AG micelles (AG-MCs) at an andrographolide to nonionic surfactant ratio of 10:10 (w/w) and poor AG-NC size stability. We thus quantified the unbound Pluronic-F127 in AG-NCs and found that the proposed instantaneous binding rate sharply declined with increasing Pluronic-F127 input. We determined that the saturation dose of TPGS on AG-NCs was approximately 10:10 (w/w) and recommend it as a key criterion for nanocrystal formulation. Although AG-NCs exhibited a marginally faster dissolution rate, they possessed better mucus-penetrating and transmembrane transport capacities and significantly enhanced oral absorption compared to AG-MCs. These findings give insights into the impact of a stabilizer during the preparation process and the oral absorption of drug nanocrystals.