Micronizing of steroids for pulmonary delivery by supercritical carbon dioxide

The micronization of various drugs is beset with serious problems due to the insufficient brittleness of crystals when using a jet mill. The purpose of this study was to investigate an alternative micronization technique using the aerosol solvent extraction system (ASES). Several steroids, some for systemic and some for administration by inhalation, were dissolved in an organic solvent and sprayed into supercritical carbon dioxide. The resulting particles were characterized with regard to chemical and physical properties. The following steroids were investigated: beclomethasone-17,21-dipropionate, betamethasone-17-valerate, budesonide, dexamethasone-21-acetate, flunisolide, fluticasone-17-propionate, prednisolone and triamcinolone acetonide. The spraying solution contained 1% (w/w) of drug, the solvents were dichloromethane, methanol or a mixture of both. The median particle size of the steroid particles was in most cases lower than 5 μ and consequently within the respirable range. If a surface active ingredient was added to the spraying solution the particle size increased and the contact angle decreased. HPLC-analysis showed no chemical decomposition of the drug during the process but the crystal properties of certain investigated drugs changed. This was proved by use of X-ray diffraction and scanning electron microscopy (SEM). Most of the steroids used could be micronized by means of the ASES-process with a residual dichloromethane content lower than 350 ppm in all cases.