23-08-2012, 03:43 PM
Application of Dense Gas Techniques for the Production of Fine Particles
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ABSTRACT
The feasibility of using dense gas techniques such as rapid expansion of supercritical solutions (RESS) and aerosol solvent extraction system (ASES) for microni-zation of pharmaceutical compounds is demonstrated. The chiral nonsteroidal anti-inflammatory racemic ibu-profen is soluble in carbon dioxide at 35°C and pres-sures above 90 bar. The particle size decreased to less than 2 μm while the degree of crystallinity was slightly decreased when processed by RESS. The dissolution rate of the ibuprofen (a poorly water-soluble com-pound) was significantly enhanced after processing by RESS. The nonsteroidal anti-inflammatory drug Cu2(indomethacin)4L2(Cu-Indo); (L = dimethylforma-mide [DMF]), which possessed very low solubility in supercritical CO2, was successfully micronized by ASES at 25°C and 68.9 bar using DMF as the solvent and CO2 as the antisolvent. The concentration of solute dramatically influenced the precipitate characteristics. The particles obtained from the ASES process were changed from bipyramidal to spherical,
INTRODUCTION
The product quality of materials including explosives, catalysts, pigments, and pharmaceuticals can be signifi-cantly influenced by their physical properties such as par-ticle size distribution and morphology.1,2 Fine particles of pharmaceuticals with a narrow particle size distribu-tion are essential for the development of inhalation aero-sols, injectable suspensions, controlled release dosage forms, and other specialized drug delivery systems. In addition, particle size is a critical parameter that deter-mines the rate of dissolution of the drug in the biological fluids and, hence, has a significant effect on the bioavail-ability of the poorly water-soluble drugs for which the dissolution is the rate-limiting step in the absorption process.
MATERIALS AND METHODS
Materials
Racemic ibuprofen (99.8% purity) was purchased from Sigma Chemical Co (St. Louis, MO). Potassium phos-phate monobasic (99% purity, Sigma), sodium hydroxide (98% purity, Sigma), and sodium lauryl sulfate (SLS) (Sigma) were used to prepare phosphate buffer solution for the dissolution studies. Copper indomethacin (≥90% purity) was donated by Biochemical Veterinary Research Company (NSW, Australia). N,N-dimethylformamide (DMF) (99.9% purity) was purchased from Honeywell Burdick & Jackson (Muskegon, MI). Carbon dioxide (in-dustrial grade, 99.95% purity) (BOC Gases, Australia) was used as a dense gas fluid. All chemicals and reagents were used without further purifications.
Particle Characterization
Particle morphology of the solid precipitate was determined using a scanning electron microscope (SEM) (Hitachi S4500, Pleasanton, CA). The samples were mounted on metal plates and gold coated using a sputter coater under vacuum. Particle size distributions of the powders were de-termined using laser diffraction (Mastersizer, Malvern, UK). The experimental techniques for the dissolution rate of the drug have been described in detail in previous papers.7,8
RESULTS AND DISCUSSION
Micronization of Ibuprofen by RESS Process
The particle size of the original racemic ibuprofen received from Sigma was as high as 250 μm as shown in Figure 3A. Ibuprofen particles precipitated by the RESS process at 35°C and 190 bar were significantly smaller than the origi-nal material. The SEM images of processed particles, as illustrated in Figure 3B, reveal that particle size was less than 2 μm. Although the SEM images showed that the par-ticles were aggregated.
CONCLUSION
The results of this study demonstrate that poorly water-soluble ibuprofen and Cu-Indo were successfully mi-cronized by the dense gas techniques. Many factors have to be considered in the selection of the appropriate technique. Ibuprofen with a high level of solubility in CO2 was proc-essed using RESS, while Cu-Indo with no solubility in CO2 was processed by the ASES technique. The particle size of the ibuprofen was less than 5 μm and was not substantially changed by variation of operating parameters. The particle size and morphology of Cu-Indo was a function of solution concentration. The dissolution rate of both drugs was sub-stantially improved after processing by the dense gas tech-niques.