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Pharmaceutical Research

, Volume 31, Issue 11, pp 3211–3224 | Cite as

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

  • Sabine May
  • Birte Jensen
  • Claudius Weiler
  • Markus Wolkenhauer
  • Marc Schneider
  • Claus-Michael Lehr
Research Paper

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.

KEY WORDS

aerodynamic diameter (MMAD) Andersen cascade impactor Nernst Brunner equation paddle apparatus 

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

LIST OF SYMBOLS

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

Notes

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.

Supplementary material

11095_2014_1413_MOESM1_ESM.docx (65 kb)
Fig. S1 (DOCX 64 kb)
11095_2014_1413_MOESM2_ESM.docx (16 kb)
Table S1 (DOCX 15 kb)

References

  1. 1.
    Gray VA, Hickey AJ, Balmer P, Davies NM, Dunbar C, Foster TS, et al. The inhalation ad hoc advisory panel for the USP performance tests of inhalation dosage forms. Pharmacopeial Forum. 2008;34:1068–74.Google Scholar
  2. 2.
    United States Pharmacopeial Convention. Dissolution. In United States Pharamacopeia and National Formulary, Rockville, 2011.Google Scholar
  3. 3.
    United States Pharmacopeial Convention. Drug release. In United States Pharmacopeia and National Formulary, Rockville, 2013.Google Scholar
  4. 4.
    United States Pharmacopeial Convention. Aerosol, nasal sprays, metered dose inhalers, and dry powder inhaler. In United States Pharmacopeia and National Formulary, Maryland, 2012.Google Scholar
  5. 5.
    Labouta HI, Schneider M. Tailor-made biofunctionalized nanoparticles using layer-by-layer technology. Int J Pharm. 2010;395:236–42.PubMedCrossRefGoogle Scholar
  6. 6.
    Riley T, Christopher D, Arp J, Casazza A, Colombani A, Cooper A, et al. Challenges with developing in vitro dissolution tests for orally inhaled products (OIPs). AAPS PharmSciTech. 2012;13:978–89.PubMedCrossRefPubMedCentralGoogle Scholar
  7. 7.
    May S, Jensen B, Wolkenhauer M, Schneider M, Lehr CM. Dissolution techniques for in vitro testing of dry powders for inhalation. Pharm Res. 2012;29:2157–66.PubMedCrossRefGoogle Scholar
  8. 8.
    Salama RO, Traini D, Chan HK, Young PM. Preparation and characterisation of controlled release co-spray dried drug-polymer microparticles for inhalation 2: evaluation of in vitro release profiling methodologies for controlled release respiratory aerosols. Eur J Pharm Biopharm. 2008;70:145–52.PubMedCrossRefGoogle Scholar
  9. 9.
    Haghi M, Traini D, Bebawy M, Young PM. Deposition, diffusion and transport mechanism of dry powder microparticulate salbutamol, at the respiratory epithelia. Mol Pharm. 2012;9:1717–26.PubMedCrossRefGoogle Scholar
  10. 10.
    Arora D, Shah KA, Halquist MS, Sakagami M. In vitro aqueous fluid-capacity-limited dissolution testing of respirable aerosol drug particles generated from inhaler products. Pharm Res. 2010;27:786–95.PubMedCrossRefGoogle Scholar
  11. 11.
    Son YJ, Horng M, Copley M, McConville JT. Optimization of an in vitro dissolution test method for inhalation formulations. Dissolution Technol. 2010;17:6–13.Google Scholar
  12. 12.
    Davies NM, Feddah MR. A novel method for assessing dissolution of aerosol inhaler products. Int J Pharm. 2003;255:175–87.PubMedCrossRefGoogle Scholar
  13. 13.
    Sakagami M, Arora Lakhani D. Understanding dissolution in the presence of competing cellular uptake and absorption in the airways. In: Dalby RN, Byron PR, Peart J, Suman JD, Farr SJ, Young PM, editors. Respiratory Drug Delivery. 2012, pp. 185–192.Google Scholar
  14. 14.
    Mees J, Fulton C, Wilson S, Bramwell N, Lucius M, Cooper A. Development of dissolution methodology for dry powder inhalation aerosols. IPAC-RS Conference In 2011.Google Scholar
  15. 15.
    Veldhuizen R, Nag K, Orgeig S, Possmayer F. The role of lipids in pulmonary surfactant. Biochim Biophys Acta Mol basis Dis. 1998;1408:90–108.CrossRefGoogle Scholar
  16. 16.
    Dokoumetzidis A, Macheras P. A century of dissolution research: from Noyes and Whitney to the Biopharmaceutics classification system. Int J Pharm. 2006;321:1–11.PubMedCrossRefGoogle Scholar
  17. 17.
    Hsu W-L, Lin M-J, Hsu J-P. Dissolution of solid particle in liquids: a shrinking core model. World Acad Sci Eng Technol. 2009;53:913–8.Google Scholar
  18. 18.
    Wang J, Flanagan DR. General solution for diffusion-controlled dissolution of spherical particles. 1. Theory. J Pharm Sci. 1999;88:731–8.PubMedCrossRefGoogle Scholar
  19. 19.
    Son YJ, McConville JT. Development of a standardized dissolution test method for inhaled pharmaceutical formulations. Int J Pharm. 2009;382:15–22.PubMedCrossRefGoogle Scholar
  20. 20.
    Jensen B, Reiners M, Wolkenhauer M, Ritzheim P, May S, Schneider M, et al. Dissolution testing for inhaled products. Respiratory Drug Delivery, Europe In 2011, pp. 303–308.Google Scholar
  21. 21.
    May S, Jensen B, Wolkenhauer M, Schneider M, Lehr CM. Impact of deposition and the presence of surfactants on in vitro dissolution of inhalation powders. Respiratory Drug Delivery Europe In 2013.Google Scholar
  22. 22.
    Food and Drug Administration. Guidance for Industry; Dissolution testing of immediate release solid oral dosage forms. http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ucm070237.pdf online (1997).
  23. 23.
    European Medicines Agency. Guideline on the investigation of bioequivalence. http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2010/01/WC500070039.pdf online (2008).
  24. 24.
    Sertsou G. Analytical derivation of time required for dissolution of monodisperse drug particles. J Pharm Sci. 2004;93:1941–4.PubMedCrossRefGoogle Scholar
  25. 25.
    Hayduk W, Laudie H. Prediction of diffusion coefficients for nonelectrolytes in dilute aqueous solutions. AIChe. 1974;20:611–5.CrossRefGoogle Scholar
  26. 26.
    Sheng JJ, Sirois PJ, Dressman JB, Amidon GL. Particle diffusional layer thickness in a USP dissolution apparatus II: a combined function of particle size and paddle speed. J Pharm Sci. 2008;97:4815–29.PubMedCrossRefGoogle Scholar
  27. 27.
    Bisrat M, Nystrom C. Physicochemical aspects of drug release. VIII. The relation between particle size and surface specific dissolution rate in agitated suspensions. Int J Pharm. 1988;47:223–31.CrossRefGoogle Scholar
  28. 28.
    Lu ATK, Frisella ME, Johnson KC. Dissolution modeling: factors affecting the dissolution rates of polydisperse powders. Pharm Res. 1993;10:1308–14.PubMedCrossRefGoogle Scholar
  29. 29.
    Hintz RJ, Johnson KC. The effect of particle size distribution on dissolution rate and oral absorption. Int J Pharm. 1989;51:9–17.CrossRefGoogle Scholar
  30. 30.
    Sugano K. Theoretical comparison of hydrodynamic diffusion layer models used for dissolution simulation in drug discovery and development. Int J Pharm. 2008;363:73–7.PubMedCrossRefGoogle Scholar
  31. 31.
    Voigt R. Pharmazeutische Technologie. Stuttgart: Deutscher Apotheker Verlag; 2006.Google Scholar
  32. 32.
    Nichols SC. Calibration and mensuration issues for the standard and modified andersen cascade impactor. Pharmacopeial Forum. 2000;26:1466–7.Google Scholar
  33. 33.
    Okazaki A, Mano T, Sugano K. Theoretical dissolution model of poly-disperse drug particles in biorelevant media. J Pharm Sci. 2008;97:1843–52.PubMedCrossRefGoogle Scholar
  34. 34.
    Davies CN. Particle-fluid interaction. J Aerosol Sci. 1979;10:477–513.CrossRefGoogle Scholar
  35. 35.
  36. 36.
    Sadler RC, Prime D, Burnell PK, Martin GP, Forbes B. Integrated in vitro experimental modelling of inhaled drug delivery: deposition, dissolution and absorption. J Drug Deliv Sci Technol. 2011;21:331–8.Google Scholar
  37. 37.
    Wauthoz N, Deleuze P, Saumet A, Duret C, Kiss R, Amighi K. Temozolomide-based dry powder formulations for lung tumor-related inhalation treatment. Pharm Res. 2011;28:762–75.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2014

Authors and Affiliations

  • Sabine May
    • 1
    • 2
  • Birte Jensen
    • 2
  • Claudius Weiler
    • 2
  • Markus Wolkenhauer
    • 2
  • Marc Schneider
    • 1
    • 3
  • Claus-Michael Lehr
    • 1
    • 4
    • 5
  1. 1.PharmBioTec GmbHSaarbrückenGermany
  2. 2.Boehringer Ingelheim Pharma GmbH & Co KGIngelheimGermany
  3. 3.Pharmaceutics and BiopharmacyPhilipps-Universität MarburgMarburgGermany
  4. 4.Biopharmaceutics and Pharmaceutical TechnologySaarland UniversitySaarbrückenGermany
  5. 5.Helmholtz Institute for Pharmaceutical Sciences SaarlandHelmholtz Center for Infection ResearchSaarbrückenGermany

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