Influence of additives on the properties of nanodroplets formed in highly supersaturated aqueous solutions of ritonavir

Mol Pharm. 2013 Sep 3;10(9):3392-403. doi: 10.1021/mp400228x. Epub 2013 Jul 30.

Abstract

The formation of colloidal drug aggregates of lipophilic drugs is thought to be of relevance for the oral delivery of poorly water-soluble drugs. In this study, the underlying basis for colloid formation from amorphous solid dispersions and the impact of additives on colloidal stability were evaluated. A relationship was found between the concentration at which colloidal droplets formed upon dissolution of an amorphous solid dispersion and the liquid-liquid phase separation (LLPS) transition concentration, whereby the latter is related to the theoretical amorphous "solubility" value. The composition of the dispersed phase in ritonavir-polymer-water solutions was confirmed to be a noncrystalline, ritonavir-rich droplet phase. Additives were found to impact the size, stability, and crystallization behavior of the colloidal phase. In general, charged additives reduced the kinetics of droplet coalescence, but had a variable effect on crystallization kinetics, either promoting or inhibiting crystallization. Through proper selection of formulation components, it thus appears possible to promote the formation of ∼ 250-350 nm colloidal droplets of ritonavir following dissolution of an amorphous solid dispersion, and to inhibit coalescence and crystallization from these two-phase supersaturated solutions.

Publication types

  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Colloids / chemistry
  • Hydrophobic and Hydrophilic Interactions
  • Molecular Structure
  • Polymers / chemistry
  • Ritonavir / chemistry*
  • Water / chemistry

Substances

  • Colloids
  • Polymers
  • Water
  • Ritonavir