Effect of process variables on morphology and aerodynamic properties of voriconazole formulations produced by thin film freezing

Int J Pharm. 2012 Jun 15;429(1-2):46-57. doi: 10.1016/j.ijpharm.2012.03.010. Epub 2012 Mar 13.


The particle engineering process, thin film freezing (TFF), was used to produce particulate voriconazole (VRC) formulations with enhanced properties. The effect of various processing parameters on the solid state properties and aerodynamic performance of the TFF-processed powders was investigated in order to evaluate the suitability of these formulations for dry powder inhalation and to optimize the aerodynamic properties. Thin film freezing of VRC solution without stabilizing excipients resulted in microstructured, crystalline low density aggregate particles with specific surface areas of approximately 10m(2)/g. Thin film freezing of VRC-PVP solutions produced nanostructured, amorphous low density aggregate particles with specific surface areas ranging from 15 to 180m(2)/g, depending on the solvent system composition, polymer grade, and drug to polymer ratio utilized. VRC formulations manufactured with 1,4-dioxane, with and without PVP K12, resulted in the lowest specific surface areas but displayed the best aerodynamic properties. Using a Handihaler(®) dry powder inhaler (DPI), microstructured crystalline TFF-VRC and nanostructured amorphous TFF-VRC-PVP K12 (1:2) displayed total emitted fractions of 80.6% and 96.5%, fine particle fractions of 43.1% and 42.4%, and mass median aerodynamic diameters of 3.5 and 4.5μm, respectively.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Administration, Inhalation
  • Antifungal Agents / administration & dosage
  • Antifungal Agents / chemistry*
  • Crystallization
  • Dioxanes / chemistry
  • Dry Powder Inhalers
  • Excipients / chemistry*
  • Freezing
  • Nanostructures
  • Particle Size
  • Polymers / chemistry*
  • Povidone / chemistry
  • Powders
  • Pyrimidines / administration & dosage
  • Pyrimidines / chemistry*
  • Solvents / chemistry
  • Technology, Pharmaceutical
  • Triazoles / administration & dosage
  • Triazoles / chemistry*
  • Voriconazole


  • Antifungal Agents
  • Dioxanes
  • Excipients
  • Polymers
  • Powders
  • Pyrimidines
  • Solvents
  • Triazoles
  • Povidone
  • 1,4-dioxane
  • Voriconazole