Describing the Dissolution of a Poorly Soluble Inhaled Corticosteroid Using a Mixed Kinetic Control Model

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Summary

The dissolution kinetics of the poorly water-soluble active pharmaceutical ingredient fluticasone propionate were investigated. Dissolution is a key step in the delivery of drug molecules to their site of action and is often the rate limiting step in their pharmacokinetics. Dissolution occurs in two broad steps. First is the transport of molecules from the surface of the particles into solution directly adjacent and the second is the diffusive transport of the molecules away from the surface into the bulk dissolution medium. Many commonly used kinetic models describing dissolution treat the process as limited only by diffusive transport which may not be the case when the material is poorly soluble in the dissolution medium such as for inhaled corticosteroids. In this study, the dissolution kinetics of fluticasone propionate aerosolised from a pressurised metered dose inhaler and three dry powder inhalers were modelled. It was found that the dissolution kinetics could not be described by a diffusion limited model but could be described if surface transport kinetics were also incorporated. The use of this mixed kinetic control model allowed geometric parameters describing the dissolution process to be extracted which correlated well with measurements of the agglomeration state of the particles.

Key Message

The dissolution kinetics of the poorly water-soluble inhaled corticosteroid fluticasone propionate could not be described by a diffusion limited kinetic model but rather by a model also incorporating surface transport. More detailed kinetic models are required to understand the implications of dissolution kinetics on the rate at which poorly water-soluble active pharmaceutical ingredients become available at their site of action.