Novel ultra-rapid freezing particle engineering process for enhancement of dissolution rates of poorly water-soluble drugs

Eur J Pharm Biopharm. 2007 Jan;65(1):57-67. doi: 10.1016/j.ejpb.2006.07.012. Epub 2006 Jul 26.


An ultra-rapid freezing (URF) technology has been developed to produce high surface area powders composed of solid solutions of an active pharmaceutical ingredient (API) and a polymer stabilizer. A solution of API and polymer excipient(s) is spread on a cold solid surface to form a thin film that freezes in 50 ms to 1s. This study provides an understanding of how the solvent's physical properties and the thin film geometry influence the freezing rate and consequently the final physico-chemical properties of URF-processed powders. Theoretical calculations of heat transfer rates are shown to be in agreement with infrared images with 10ms resolution. Danazol (DAN)/polyvinylpyrrolidone (PVP) powders, produced from both acetonitrile (ACN) and tert-butanol (T-BUT) as the solvent, were amorphous with high surface areas (approximately 28-30 m2/g) and enhanced dissolution rates. However, differences in surface morphology were observed and attributed to the cooling rate (film thickness) as predicted by the model. Relative to spray-freezing processes that use liquid nitrogen, URF also offers fast heat transfer rates as a result of the intimate contact between the solution and cold solid surface, but without the complexity of cryogen evaporation (Leidenfrost effect). The ability to produce amorphous high surface area powders with submicron primary particles with a simple ultra-rapid freezing process is of practical interest in particle engineering to increase dissolution rates, and ultimately bioavailability.

Publication types

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

MeSH terms

  • Acetonitriles / chemistry
  • Chemistry, Pharmaceutical
  • Crystallography, X-Ray
  • Danazol / chemistry
  • Excipients / chemistry*
  • Freeze Drying / methods*
  • Kinetics
  • Microscopy, Electron, Scanning
  • Models, Chemical
  • Particle Size
  • Povidone / chemistry
  • Powders
  • Solubility
  • Solvents / chemistry*
  • Technology, Pharmaceutical*
  • Temperature
  • Thermography
  • Time Factors
  • Water / chemistry
  • tert-Butyl Alcohol / chemistry


  • Acetonitriles
  • Excipients
  • Powders
  • Solvents
  • Water
  • Povidone
  • tert-Butyl Alcohol
  • Danazol
  • acetonitrile