Enhanced Aqueous Dissolution of a Poorly Water Soluble Drug by Novel Particle Engineering Technology: Spray-Freezing into Liquid with Atmospheric Freeze-Drying

Enhanced Aqueous Dissolution of a Poorly Water Soluble Drug by Novel Particle Engineering Technology: Spray-Freezing into Liquid with Atmospheric Freeze-Drying
2003
True L. Rogers1, 2, Andrew C. Nelsen1, Marazban Sarkari2, 3, Timothy J. Young3, Keith P. Johnston2 and Robert O. Williams III1
(1) College of Pharmacy, University of Texas at Austin, Austin, Texas, 78712
(2) Present address: The Dow Chemical Company, Midland, Michigan, 48674
(3) Present address: RxKINETIX, Westminster, Colorado, 80031
Pharmaceutical Research, Volume 20 Number 3
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Abstract
Purpose. 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.