Fine excipient materials in carrier-based dry powder inhalation formulations: The interplay of particle size and concentration effects

The contributions of fine excipient materials to drug dispersibility from carrier-based dry powder inhalation (DPI) formulations are well recognized, although they are not completely understood. To improve the understanding of these contributions, we investigated the influences of the particle size of the fine excipient materials on characteristics of carrier-based DPI formulations. We studied two particle size grades of silica microspheres, with volume median diameters of 3.31 μm and 8.14 μm, as fine excipient materials. Inhalation formulations, each composed of a lactose carrier material, one of the fine excipient materials (2.5% or 15.0% w/w), and a drug (fluticasone propionate) material (1.5% w/w) were prepared. The physical microstructure, the rheological properties, the aerosolization pattern, and the aerodynamic performance of the formulations were studied. At low concentration, the large silica microspheres had a more beneficial influence on the drug dispersibility than the small silica microspheres. At high concentration, only the small silica microspheres had a beneficial influence on the drug dispersibility. The results reveal influences of fine excipient materials on mixing mechanics. At low concentration, the fine particles improved deaggregation and distribution of the drug particles over the surfaces of the carrier particles. The large silica microspheres were associated with a greater mixing energy and a greater improvement in the drug dispersibility than the small silica microspheres. At high concentration, the large silica microspheres kneaded the drug particles onto the surfaces of the carrier particles and thus impaired the drug dispersibility. As a critical attribute of fine excipient materials in carrier-based dry powder inhalation formulations, the particle size demands robust specification setting.