Dissolution Testing of Powders for Inhalation: Influence of Particle Deposition and Modeling of Dissolution Profiles
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The aim of this study was to investigate influencing factors on the dissolution test for powders for pulmonary delivery with USP apparatus 2 (paddle apparatus).
We investigated the influence of dose collection method, membrane holder type and the presence of surfactants on the dissolution process. Furthermore, we modeled the in vitro dissolution process to identify influencing factors on the dissolution process of inhaled formulations based on the Nernst-Brunner equation.
A homogenous distribution of the powder was required to eliminate mass dependent dissolution profiles. This was also found by modeling the dissolution process under ideal conditions. Additionally, it could be shown that influence on the diffusion pathway depends on the solubility of the substance.
We demonstrated that the use of 0.02% DPPC in the dissolution media results in the most discriminating and reproducible dissolution profiles.
In the model section we demonstrated that the dissolution process depends strongly on saturation solubility and particle size. Under defined assumptions we were able show that the model is predicting the experimental dissolution profiles.
KEY WORDSaerodynamic diameter (MMAD) Andersen cascade impactor Nernst Brunner equation paddle apparatus
Abbreviated Andersen cascade impactor
Andersen cascade impactor
Active pharmaceutical ingredient
European Medicines Agency
Food and Drug Administration
Fine particle dose
High performance liquid chromatography
Abbreviated Andersen cascade impactor with stage extension and modified filter stage
Phosphate buffered saline
Regenerated cellulose membrane
Sodium dodecyl sulfate
Scanning electron microscopy
United States Pharmacopoeia
LIST OF SYMBOLS
Dynamic viscosity of water at 37°C
Solubility of drug
Concentration of the drug in the solution at time t
Diffusion coefficient of substance in the solvent
Aerodynamic particle diameter
Geometric particle diameter
Mass of solid material at time t
Diffusion (boundary) layer thickness
Amount of drug released
Number of particles in a particle size fraction
Mean percent drug released at each time point for reference product
The surface area of the particles
The surface area of each particle size fraction
Mean percent drug released at each time point for test product
Van der Waals volume
- Xe (0)
The amount of undissolved drug in a particle size group
The amount of undissolved drug in a particle size group e
Total amount of undissolved drug at time t
ACKNOWLEDGMENTS AND DISCLOSURES
Thanks to Dr. Holger Wagner, Dr. Peter Häbel and team (Boehringer Ingelheim) for calculating the van der Waals volumes of the substances and to Wolfgang Bootz (Boehringer Ingelheim) and Dr. Bernhard Meier for the SEM pictures.
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