In vitro characterization of jet-milled and in-situ-micronized fluticasone-17-propionate

Particle properties are decisive for therapeutic efficiency of an inhaled pulmonary drug. Jet-milling as the common way for micronization of inhaled powder drugs shows several disadvantages such as a non-homogeneous particle size distribution and unnatural, thermodynamically-activated particle surfaces causing a high agglomeration behavior. For pulmonary use in a dry powder inhaler (DPI) beside a small particle size, a good de-agglomeration activity is required. In this study, fluticasone-17-propionate (FP) is in-situ prepared in a respirable particle size by a controlled crystallization technique. First, the drug is dissolved in acetone and precipitated by a solvent change method in the presence of a cellulose ether (HPMC) as stabilizing hydrocolloid. By rapidly pouring the drug solution into the polymer-rich water phase, the previously molecularly dispersed drug is associated to small particles and stabilized against crystal growth simultaneously by the presence of the hydrophilic polymer. This dispersion was then spray-dried. The mean particle size of the drug was around 2 microm and consequently in the respirable range. The physico-chemical properties of the in-situ-micronized drug were compared to those of an unmilled and a jet-milled quality. Differences in the X-ray patterns and amorphous parts could be detected for the jet-milled but not for the in-situ-micronized drug. In addition, the aerodynamic behavior of the engineered and the jet-milled FP was analyzed using the FlowCaps inhaler as delivery device and compared to the commercial product Flutide Diskus. The fine particle fraction (FPF) (<5 microm) was increased four-fold from approximately 9% for the jet-milled drug to approximately 40% for the in-situ-micronized drug when the pure drug powder was dispersed with the FlowCaps device.