Summary

The efficacy of an inhaled pharmaceutical aerosol is dependent on many physicochemical properties of the active pharmaceutical ingredient, excipients (e.g. propellants and co-solvents). The size and structure of the aerosol at the point of inhalation dictate the microphysical processes that occur during inhalation. The degree to which a particle grows by condensation when inhaled could directly affect both where the dose is delivered and the phase state and structure of the particle upon deposition. A detailed understanding of this dynamic behaviour is crucial to predict regional dose and pharmacokinetic rates. To be reported here are the first measurements collected with a next generation electrodynamic balance, termed the Electrodynamic Lung (EL), of the complex dissolution process of dry powder inhaler (DPI) starting formulations.

Novel features of the EL include: (1) the ability to capture and probe both liquid (originating from an MDI or a nebulizer starting formulation) and solid particles (from a DPI starting formulation); (2) the opportunity to rapidly change the conditions (relative humidity (RH) and temperature) that the levitated droplet/particle experiences in under 0.1 seconds; (3) access to relative humidities greater than 99.5% typical of the respiratory tract; (4) rapid identification of the structure of the levitated particle at high time-resolution based on the light scattering pattern of particle. Taken together, these features can allow measurements of particle dynamics that directly mimic the conditions an inhaled aerosol experiences while simultaneously monitoring changes in both particle size and structure. These features allow for detailed kinetic measurements of droplet drying, particle dissolution and water condensation with a time-resolution of 0.01 s.

To be reported are the first comprehensive measurements of the dissolution of dry powder inhaler particles starting formulations in the aerosol phase, where all the processes of dissolution (initial water uptake, fragmentation of the active pharmaceutical ingredient in the multiphase droplet into a suspension of particles through to complete dissolution) are directly observed. The time taken for dissolution in the aerosol phase is found to be highly variable and dependent on the starting formulation; influencing factors include relative humidity, particle size and composition.

Key Message

We can directly probe the complex dissolution process of pharmaceutical aerosol produced from DPI starting formulations in respiratory relevant environmental conditions in the aerosol phase (e.g. ambient pressure, temperature and relative humidity). Significant dissolution was found to occur for several commercially available DPI starting formulations in under 5 seconds, indicating that inhaled DPI pharmaceuticals may grow during inhalation, potentially affecting regional and total dose.