Multi-Scale Modelling of the Formation of Adhesive Powder Mixtures for Inhalation
Kyrre Thalberg1, Ingela Niklasson Björn1, Duy Nguyen1,2 & Anders Rasmuson2
1AstraZeneca GOT, SE 431 83 Mölndal, Sweden
2Chalmers University of Technology, SE 412 96 Gothenburg, Sweden
Adhesive powder mixtures for inhalation consist of very fine drug particles (typically 1 – 5 µm in diameter) which are admixed with carrier particles of an inert excipient. In this work, the formation of adhesive mixtures is investigated both using in silico simulations and experimentally, in order to assess the time scales of the different mechanisms involved.
Four mechanisms can be identified in the formation of adhesive powder mixtures. The first one, random mixing of carrier with aggregates of fine particles, was shown to occur within a few seconds of mixing, both from two-fluid Computational Fluid Dynamics (CFD) modelling and from experiments. The second step, which is the disintegration of the fine particle aggregates, has a time scale of around one minute for the placebo studied system, as was experimentally evidenced via particle sizing of the blend as a function of mixing time. The third step, adhesion of fine particles to the carrier, was found to occur instantaneously thereafter, which was also in line with Discrete Element Method (DEM) simulations. The fourth step, redistribution and rearrangement of the fine particles on the carrier surfaces, was experimentally studied by adding coloured carrier to a homogeneous blend of (white) carrier and lactose fines, has a time scale of just a few seconds. This demonstrates the dynamic nature of fine particle attachment to carriers in adhesive powder mixtures.
From the results obtained, it seems obvious that mixing times currently used in the industry may be significantly shortened. The exact mixing time to use will however depend on the specific nature of the API(s) used.