A novel method for preparing nanoparticles of medicinal substances using supercritical carbon dioxide

摘要

Purpose: The purpose of this study is to demonstrate a novel method for preparing nanoparticles of active pharmaceutical ingredients using a continuous system under supercritical carbon dioxide (scCO2) conditions.Methods: An improved system using rapid expansion from supercritical to aqueous solution (RESAS) method was used in order to prepare nanoparticles of medicinal substances. Indomethacin (IMC) was used as a model compound. The scCO2 mixed with a suitable amount of solution of IMC in ethanol was expanded into water. The resultant aqueous suspension was freeze dried, and then powder properties of freeze dried samples were evaluated by particle size, crystallinity, scanning electron microphotograph, and inhalation study.Results: When the solution of IMC in ethanol was sprayed into the vessel of scCO2 at the relatively lower CO2 pressure as 10 MPa at 40 C, a large amount of IMC was precipitated in the vessel. In this case, scCO2 might behave as an antisolvent as reported by the supercritical antisolvent precipitation technique. On the other hand, no precipitation of IMC was observed in the vessel if the CO2 pressure was higher than 15 MPa at 40 C. This finding suggested that the solution of IMC in ethanol was dispersed or dissolved in the high pressured CO2 fluid. When the CO2 fluid containing IMC and ethanol was expanded into water, nanoparticles of IMC were produced. The freeze dried sample of the suspension showed a good redispersibility in water to form a nanoparticle suspension. The particle size of IMC after dispersed varied depending on CO2 pressure and temperature in the vessel. At the optimum conditions, as 25 MPa at 40 C, nanoparticles of IMC (around 350 run) were obtained. The freeze dried powders exhibited mass median diameters in air about 4 μm. Consequently, the freeze dried powders obtained under the optimum conditions showed good inhalation properties compared to the untreated IMC.Conclusions. This method produces fine crystals of IMC with a high yield. The freeze dried sample from IMC suspension shows both a good redispersibility into water and a good inhalation property. Therefore, this method may be promising in developing novel dry powder inhalation forms.