Pharmaceutical Research

, Volume 24, Issue 1, pp 125–135 | Cite as

In Vitro Investigation of Drug Particulates Interactions and Aerosol Performance of Pressurised Metered Dose Inhalers

  • Daniela Traini
  • Paul M. Young
  • Philippe Rogueda
  • Robert Price
Research Paper



To determine a relationship between adhesive and cohesive inter-particulate forces of interactions and in vitro performance in pressurised metered dose inhalers (pMDIs) suspension formulations.


Interparticulate forces of salbutamol sulphate (SS), budesonide (BUD) and formoterol fumarate dihydrate (FFD) were investigated by in situ atomic force microscopy (AFM) in a model propellant 2H, 3H perfluoropentane (HPFP). Experimental data were analysed using the recently developed cohesive/adhesive analysis method (CAB) and compared with in vitro deposition performances in pMDIs systems using Andersen cascade impactor (ACI).


The in vitro investigation suggested that the micronised drug materials had significantly different aerosolisation profiles when manufactured as single or combination formulations. In general, the greatest significant differences were observed between SS single drug and SS-BUD and SS-FFD combinations. Analysis of the in vitro performance for the SS only formulation suggested that the cohesive nature of SS (as predicted by the CAB and observed with AFM) led to tightly bound flocs that did not fully deaggregate upon aerosolisation.


It is suggested that the relationship between interparticulate interactions and in vitro performance of pMDIs suspension systems, when compared to direct measurement of the adhesion/cohesion forces, indicated good correlation. This approach may be useful in expediting the development of pMDI formulation and predicting performance.

Key words

adhesive/cohesive forces AFM in vitro testing pMDI suspensions 


  1. 1.
    P. J. Barnes, M. M. Grunstein, A. R. Leff, and A. J. Woolcock. Asthma, Lippincott-Raven, Philadelphia, 1997.Google Scholar
  2. 2.
    R. N. Dalby and J. Suman. Inhalation therapy: technological milestones in asthma treatment. Adv. Drug Deliv. Rev. 55:779–791 (2003).PubMedCrossRefGoogle Scholar
  3. 3.
    H. D. C. Smyth. Propellant-driven metered-dose inhalers for pulmonary drug delivery. Expert Opin. Drug Deliv. 2:53–74 (2005).PubMedCrossRefGoogle Scholar
  4. 4.
    A. Brindley. The chlorofluorocarbon to hydrofluoroalkane transition: the effect on pressurised metered dose inhaler suspension stability. J. Allergy Clin. Immunol. 104:S221–S226 (1999).PubMedCrossRefGoogle Scholar
  5. 5.
    D. Traini, P. Rogueda, P. M. Young, and R. Price. Surface energy and interparticle forces correlations in model pMDI formulations. Pharm. Res. 22:816–825 (2005).PubMedCrossRefGoogle Scholar
  6. 6.
    R. J. Good and L. A. Girifalco. A theory for estimation of surface and interfacial energies. III. Estimation of surface energies of solids from contact angle data. J. Phys. Chem. 64:561–565 (1960).Google Scholar
  7. 7.
    F. M. Fowkes. Determination of interfacial tension, contact angles and dispersion forces in surface by assuming additivity of intermolecular interactions in surfaces. J. Phys. Chem. 66:382 (1962).Google Scholar
  8. 8.
    C. J. van Oss. Interfacial Forces in Aqueous Media. Marcel Dekker, New York, U.S.A., 1994.Google Scholar
  9. 9.
    P. Begat, D. A. V. Morton, J. N. Staniforth, and R. Price. The cohesive–adhesive balances in dry powder inhaler formulations I: direct quantification by atomic force microscopy. Pharm. Res. 21:1591–1597 (2004).PubMedCrossRefGoogle Scholar
  10. 10.
    Apparatus D, British Pharmacopoeia. The Stationery Office on behalf of the Medicines and Healthcare Products Regulatory Agency (MHRA). London, UK, 2005.Google Scholar
  11. 11.
    N. J. C. Snell and D. Ganderton. Assessing lung deposition of inhaled medications: consensus statement from a workshop of the British Association for Lung Research. Respir. Med. 93:123–133 (1999).PubMedCrossRefGoogle Scholar
  12. 12.
    C. G. Thiel. Can in vitro particle size measurements be used to predict pulmonary deposition of aerosol from inhalers? J. Aerosol Med. 11:S43–S52 (1998).PubMedGoogle Scholar
  13. 13.
    P. A. Webb and C. Orr. Analytical Methods in Fine Particle Technology, Micrometrics Instrument Corp., Norcross, Georgia, U.S.A., 1997.Google Scholar
  14. 14.
    G. Rhodes. Crystallography—Made Crystal Clear, Academic, New York, USA, 1993.Google Scholar
  15. 15.
    J. Albertsson, A. Oskarsson, and C. Svensson. X-ray study of budesonide: molecular structure and solid solution of the (22S) and (22R) epimers of 11B,21-dihydroxy-16alfa,17 alfa-propylmethylenedioxy-1,4-pregnadiene-3,20-dione. Acta Crystallogr. B34:3027–3036 (1978).Google Scholar
  16. 16.
    Ertan, B. Stensland, and I. Ymen. Crystal and molecular structure of formoterol fumarate dihydrate, Astra Production Chemicals AB, Confidential Report N. 117/97, 1997.Google Scholar
  17. 17.
    P. J. M. Leger, M. Goursolle, and M. Gadret. Structure cristalline du sulphate de salbutamol [ter-butylamino-2-(hydroxy-4hydroxymethyl-3 phenyl)-1 ethanol.1/2 H2SO4]. Acta Crystallogr. B34:1203–1208 (1978).Google Scholar
  18. 18.
    W. A. Ducker, T. J. Senden, and R. M. Pashley. Direct measurement of colloidal forces using an atomic force microscope. Nature 353:239–241 (1991).CrossRefGoogle Scholar
  19. 19.
    P. M. Young. Characterisation of particle–particle interactions using the atomic force microscope, Pharmacy and Pharmacology, University of Bath, Bath, UK, 2002.Google Scholar
  20. 20.
    Y. Michael, M. J. Snowden, B. Z. Chowdhry, I. C. Ashurst, C. J. Davies-Cutting, and T. Ripley. Characterisation of the aggregation behaviour in a salmeterol and fluticasone propionate inhalation aerosol system. Int. J. Pharm. 221:165–174 (2001).PubMedCrossRefGoogle Scholar
  21. 21.
    E. M. Phillips, P. R. Byron, and R. N. Dalby. Axial-ratio measurements for early detection of crystal-growth in suspension-type metered dose inhalers. Pharm. Res. 10:454–456 (1993).PubMedCrossRefGoogle Scholar
  22. 22.
    P. G. A. Rogueda. HPFP, a model propellant for pMDIs. Drug Dev. Ind. Pharm. 29:39–49 (2003).PubMedCrossRefGoogle Scholar
  23. 23.
    J. N. Pritchard. The influence of lung deposition on clinical response. J. Aerosol Med. 14:S19–S26 (2001).PubMedCrossRefGoogle Scholar
  24. 24.
    W. Neumann, D. R. Renzow, H. Reumuth, and J. E. Richter. Vol. 55, Fortschr. Kolloide Polymere 49–54 (1971)Google Scholar
  25. 25.
    G. Buckton. Interfacial Phenomena in Drug Delivery and Targeting, Harwood Academic Publishers, Chur, Switzerland, 1995.Google Scholar

Copyright information

© Springer Science+Business Media, Inc. 2006

Authors and Affiliations

  • Daniela Traini
    • 1
    • 2
  • Paul M. Young
    • 1
  • Philippe Rogueda
    • 3
  • Robert Price
    • 2
  1. 1.Advanced Drug Delivery GroupFaculty of Pharmacy (A15), University of SydneySydneyAustralia
  2. 2.Pharmaceutical Surface Science Research GroupDepartment of Pharmacy, University of BathBathUK
  3. 3.AstraZeneca R&D CharnwoodLoughboroughUK

Personalised recommendations