Enhanced aqueous dissolution of a poorly water soluble drug by novel particle engineering technology: spray-freezing into liquid with atmospheric freeze-drying.
OBJECTIVE
The purpose of this work was to investigate spray-freezing into liquid (SFL) and atmospheric freeze-drying (ATMFD) as industrial processes for producing micronized SFL powders with enhanced aqueous dissolution. Micronized SFL powders dried by ATMFD were compared with vacuum freeze-dried SFL powders.


METHODS
Danazol was formulated with polyvinyl alcohol (MW 22,000), polyvinylpyrrolidone K-15, and poloxamer 407 to produce micronized SFL powders that were freeze-dried under vacuum or dried by ATMFD. The powders were characterized using Karl-Fischer titration, gas chromatography, differential scanning calorimetry, X-ray diffraction, scanning electron microscopy, surface area, and dissolution testing (SLS 0.75%/Tris 1.21% buffer media).


RESULTS
Micronized SFL powders containing amorphous drug were successfully dried using the ATMFD process. Micronized SFL powders contained less than 5% w/w and 50 ppm of residual water and organic solvent, respectively, which were similar to those contents detected in a co-ground physical mixture of similar composition. Micronized SFL powders dried by ATMFD had lower surface areas than powders produced by vacuum freeze-drying (5.7 vs. 8.9 m2/g) but significantly greater surface areas than the micronized bulk drug (0.5 m2/g) and co-ground physical mixture (1.9 m2/g). Rapid wetting and dissolution occurred when the SFL powders were introduced into the dissolution media. By 5 min, 100% dissolution of danazol from the ATMFD-micronized SFL powder had occurred, which was similar to the dissolution profile of the vacuum freeze-dried SFL powder.


CONCLUSIONS
Vacuum freeze-drying is not a preferred technique in the pharmaceutical industry because of scalability and high-cost concerns. The ATMFD process enables commercialization of the SFL particle-engineering technology as a micronization method to enhance dissolution of hydrophobic drugs.
Rogers
True L
TL
College of Pharmacy, University of Texas at Austin, Austin, Texas 78712, USA.
Nelsen
Andrew C
AC
Sarkari
Marazban
M
Young
Timothy J
TJ
Johnston
Keith P
KP
Williams
Robert O
RO
D002152:Calorimetry, Differential Scanning; D002626:Chemistry, Pharmaceutical; D002849:Chromatography, Gas; D002851:Chromatography, High Pressure Liquid; D003613:Danazol / Q000737:chemistry; D005612:Freeze Drying; D008855:Microscopy, Electron, Scanning; D010316:Particle Size; D011208:Powders / Q000737:chemistry*; D012995:Solubility; D012997:Solvents / Q000737:chemistry*; D013678:Technology, Pharmaceutical; D013696:Temperature; D014867:Water / Q000737:chemistry*; D014961:X-Ray Diffraction
D011208:Powders; D012997:Solvents; D014867:Water; D003613:Danazol