Granulation of drug particles for dry powder inhalation was conducted by means of a novel granulation method, named as Advanced Freeze Granulation by Supercritical Fluid. In this method, drug particles were micronized and granulated by the following steps: 1) drug particles were micronized by beads milling in a supercritical carbon dioxide (SC-CO
2); 2) additional micronization were took place by shear force when particles together with SC-CO
2 were sprayed into atmosphere through a nozzle; 3) the micronized particles were instantaneously granulated with dry ices generated by a rapid temperature decrease when spraying the SC-CO
2; and 4) the dry ices in granules were immediately sublimated by a hot air, resulting in porous spherical granules with high flowability and dispersibility.
In this study, sodium cromoglicate was used as a model drug and granules were prepared by a novel Advanced Freeze Granulation by Supercritical Fluid under various operating parameters. Physical properties of granules and their inhalation performance were evaluated. It was found that temperature and pressure of the SC-CO
2 were the most important parameters which determine size of the micronized particles and the inhalation performance. The granule generation mechanism by this method was also discussed.
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