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Dissolution Testing of Powders for Inhalation: Influence of Particle Deposition and Modeling of Dissolution Profiles

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Abstract

Purpose

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).

Methods

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.

Results

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.

Conclusion

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.

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Abbreviations

aACI:

Abbreviated Andersen cascade impactor

ACI:

Andersen cascade impactor

ACN:

Acetonitrile

API:

Active pharmaceutical ingredient

DPPC:

Dipalmytoylphosphatidylcholine

EMA:

European Medicines Agency

FDA:

Food and Drug Administration

FPD:

Fine particle dose

HPLC:

High performance liquid chromatography

mACI:

Abbreviated Andersen cascade impactor with stage extension and modified filter stage

PBS:

Phosphate buffered saline

RC:

Regenerated cellulose membrane

RP:

Reversed phase

SDS:

Sodium dodecyl sulfate

SE:

Stage extension

SEM:

Scanning electron microscopy

USP:

United States Pharmacopoeia

ρ:

Density

ηwater :

Dynamic viscosity of water at 37°C

cs :

Solubility of drug

ct :

Concentration of the drug in the solution at time t

D:

Diffusion coefficient of substance in the solvent

daero :

Aerodynamic particle diameter

dgeo :

Geometric particle diameter

dm:

Mass of solid material at time t

dt:

Time interval

f1 :

Difference factor

f2 :

Similarity factor

h:

Diffusion (boundary) layer thickness

k:

Shape factor

m:

Amount of drug released

Ne :

Number of particles in a particle size fraction

r:

Radius

Rt :

Mean percent drug released at each time point for reference product

S:

The surface area of the particles

Se :

The surface area of each particle size fraction

t:

Time

Tt :

Mean percent drug released at each time point for test product

V:

Volume

VM :

Van der Waals volume

Xe (0):

The amount of undissolved drug in a particle size group

Xe(t):

The amount of undissolved drug in a particle size group e

Xsum(t):

Total amount of undissolved drug at time t

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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.

Author information

Authors and Affiliations

  1. PharmBioTec GmbH, Saarbrücken, Germany

    Sabine May, Marc Schneider & Claus-Michael Lehr

  2. Boehringer Ingelheim Pharma GmbH & Co KG, Ingelheim, Germany

    Sabine May, Birte Jensen, Claudius Weiler & Markus Wolkenhauer

  3. Pharmaceutics and Biopharmacy, Philipps-Universität Marburg, Marburg, Germany

    Marc Schneider

  4. Biopharmaceutics and Pharmaceutical Technology, Saarland University, Saarbrücken, Germany

    Claus-Michael Lehr

  5. Helmholtz Institute for Pharmaceutical Sciences Saarland, Helmholtz Center for Infection Research, Saarbrücken, Germany

    Claus-Michael Lehr

Authors
  1. Sabine May
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  2. Birte Jensen
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  3. Claudius Weiler
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  4. Markus Wolkenhauer
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  5. Marc Schneider
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  6. Claus-Michael Lehr
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Corresponding author

Correspondence to Claus-Michael Lehr.

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May, S., Jensen, B., Weiler, C. et al. Dissolution Testing of Powders for Inhalation: Influence of Particle Deposition and Modeling of Dissolution Profiles. Pharm Res 31, 3211–3224 (2014). https://doi.org/10.1007/s11095-014-1413-4

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  • DOI: https://doi.org/10.1007/s11095-014-1413-4

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