Packing, Flow and Aerosolization Properties of Binary Adhesive Mixtures Containing Micronized and Spray-Dried Drugs

Background/Objectives: Packing, flow, and aerosolization properties of a series of binary adhesive mixtures containing micronized or spray-dried drugs were investigated, and the relationships between these blend properties and the blend structure were studied. Methods: Micronized or spray-dried terbutaline sulfate and salbutamol sulfate were used as model drugs, and an α-lactose powder was used as the carrier. Binary mixtures with drug loads ranging from 2 to 20% were prepared. The bulk density, compressibility, permeability, and shearing properties of the carrier powder and mixtures were determined, along with the in vitro aerosolization propensity of the mixtures using two types of inhalers. Imaging of the mixtures was used to assess the blend structure. Conclusions: The particle engineering method gave differences in particle crystallinity and morphology. The development of the adhesive layer with drug load was broadly consistent with the blend state concept. Spray-dried particles, however, exhibited a higher propensity to localize within surface cavities on the carrier and produced a more voluminous enveloped adhesive layer. The spray-dried particles gave a higher bulk density, a lower Hausner ratio, comparable shear strength, and a lower angle of internal friction. Aerosolization performance, including metrics such as fine particle fraction (FPF), depended on inhaler design; nevertheless, for both inhalers, aerosolization behavior was influenced by blend state and physicochemical properties of the drug. At low drug loads, spray-dried particles dispersed to a lower degree, while at high drug loads, the dispersion performance of the two particle types converged. For example, at an intermediate drug load of 7.4%, the FPF was about 20% for the spray-dried drugs and about 30% for the micronized drugs using the Screenhaler device, while the corresponding FPF:s were about 25% and 50% for spray-dried drugs and 40% and 55% for crystalline drugs using the Monodose inhaler. Overall, the physical characteristics of the drug particles were found to influence the structural evolution of the blends, as well as their mechanical and aerosolization properties.