Skip to main content

Effects of Formulation Variables on Lung Dosimetry of Albuterol Sulfate Suspension and Beclomethasone Dipropionate Solution Metered Dose Inhalers


The performance of pressurized metered dose inhalers (MDIs) is affected by formulation and device variables that impact delivered dose, aerodynamic particle size distribution, and consequently lung deposition and therapeutic effect. Specific formulation variables of relevance to two commercially available products—Proventil® HFA [albuterol sulfate (AS) suspension] and Qvar® [beclomethasone dipropionate (BDP) solution]—were evaluated to determine their influence on key performance attributes measured experimentally with in vitro cascade impaction studies. These commercial MDIs, utilized as model systems, provided mid-points for a design of experiments (DoE) plan to manufacture multiple suspension and solution MDI formulations. The experimental results were utilized as input variables in a computational dosimetry model to predict the effects of MDI formulation variables on lung deposition. For the BDP solution DoE MDIs, increased concentrations of surfactant oleic acid (0–2% w/w) increased lung deposition from 24 to 46%, whereas changes in concentration of the cosolvent ethanol (7–9% w/w) had no effect on lung deposition. For the AS suspension DoE MDIs, changes in oleic acid concentration (0.005–0.25% w/w) did not have significant effects on lung deposition, whereas lung deposition decreased from 48 to 26% as ethanol concentration increased from 2 to 20% w/w, and changes in micronized drug volumetric median particle size distribution (X50, 1.4–2.5 μm) increased deposition in the tracheobronchial airways from 5 to 11%. A direct correlation was observed between fine particle fraction and predicted lung deposition. These results demonstrate the value of using dosimetry models to further explore relationships between performance variables and lung deposition.

This is a preview of subscription content, access via your institution.

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7
Fig. 8


  1. Myrdal PB, Sheth P, Stein SW. Advances in metered dose inhaler technology: formulation development. AAPS PharmSciTech. 2014;15(2):434–55.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  2. Newman SP, Chan H-K. In vitro/in vivo comparisons in pulmonary drug delivery. J Aerosol Med Pulm Drug Deliv. 2008;21(1):77–84.

    Article  PubMed  CAS  Google Scholar 

  3. Finlay WH, Stapleton KW, Zuberbuhler P. Comparisons between inhaled fine particle fractions and lung dose for nebulized aerosols. J Aerosol Med. 1998;11:S65–72.

    Article  PubMed  Google Scholar 

  4. US Department of Health and Human Services – Food and Drug Administration – Center for Drug Evaluation and Research (CDER). Metered dose inhaler (MDI) and dry powder inhaler (DPI) drug products—chemistry, manufacturing, and controls documentation. In: Guidance for Industry – Draft; 1998.

    Google Scholar 

  5. Smyth HDC, Martonen TB, Isaacs KK, Hickey AJ. Estimation of particle deposition in the airways from different inhaler formulations using an in silico model. KONA Powder Part J. 2011;29:107–16.

    Article  CAS  Google Scholar 

  6. Martonen TB. Mathematical model for the selective deposition of inhaled pharmaceuticals. J Pharm Sci. 1993;82:1191–9.

    Article  PubMed  CAS  Google Scholar 

  7. Asgharian B, Hoffmann W, Bergmann R. Particle deposition in a multiple-path model of the human lung. Aerosol Sci Technol. 2001;34:332–9.

    Article  CAS  Google Scholar 

  8. Sheth P, Sandell D, Conti DS, Holt JT, Hickey AJ, Saluja B. Influence of formulation factors on the aerosol performance of suspension and solution metered dose inhalers: a systematic approach. AAPS J. 2017;19(5):1396–410.

    Article  PubMed  CAS  Google Scholar 

  9. Stapleton KW, Guentsch E, Hoskinson MK, Finlay WH. On the suitability of k–ε turbulence modeling for aerosol deposition in the mouth and throat: a comparison with experiment. J Aerosol Sci. 2000;31(6):739–49.

    Article  CAS  Google Scholar 

  10. Grgic B, Finlay WH, Burnell PKP, Heenan AF. In vitro intersubject and intrasubject deposition measurements in realistic mouth–throat geometries. J Aerosol Sci. 2004;35(8):1025–40.

    Article  CAS  Google Scholar 

  11. FDA Draft Guidance on Albuterol Sulfate. Recommended April 2013; Revised June 2013; Revised December 2016.

  12. Roberts DL, Mitchell JP. The effect of nonideal cascade impactor stage collection efficiency curves on the interpretation of the size of inhaler-generated aerosols. AAPS PharmSciTech. 2013;14(2):497–510.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  13. Asgharian B, Price OT, Hofmann W. Prediction of particle deposition in the human lung using realistic models of lung ventilation. J Aerosol Sci. 2006;37:1209–21.

    Article  CAS  Google Scholar 

  14. Yu CP. Exact analysis of aerosol deposition during steady breathing. Powder Technol. 1978;21:55–62.

    Article  Google Scholar 

  15. Leach CL, Davidson PJ, Hasselquist BE, Boudreau RJ. Lung deposition of hydrofluoroalkane-134a beclomethasone is greater than that of chlorofluorocarbon fluticasone and chlorofluorocarbon beclomethasone. Chest. 2002;122(2):510–6.

    Article  PubMed  CAS  Google Scholar 

  16. Leach CL, Davidson PJ, Boudreau RJ. Improved airway targeting with the CFC-free HFA-beclomethasone metered-dose inhaler compared with CFC-beclomethasone. Eur Respir J. 1998;12:1346–53.

    Article  PubMed  CAS  Google Scholar 

  17. Howarth PH. Why particle size should affect clinical response to inhaled therapy. J Aerosol Med. 2001;14:S27–34.

    Article  PubMed  CAS  Google Scholar 

  18. Hickey AJ, Martonen TB, Yang Y. Theoretical relationship of lung deposition to the fine particle fraction of inhalation aerosols. Pharmaeutica Acta Helvetiae. 1996;71:185–90.

    Article  CAS  Google Scholar 

  19. Vervaet C, Byron PR. Drug–surfactant–propellant interactions in HFA-formulations. Int J Pharm. 1999;186:13–30.

    Article  PubMed  CAS  Google Scholar 

  20. Stein SW, Myrdal PB. The relative influence of atomization and evaporation on metered dose inhaler drug delivery efficiency. Aerosol Sci Technol. 2006;40(5):335–47.

    Article  CAS  Google Scholar 

  21. Sheth P, Fazel M, Stein SW, Myrdal PB. Formulation effects on differential throat deposition for pMDIs with USP inlet and Alberta idealized throat. Respir Drug Deliv Proc. 2014;3:631–6.

    Google Scholar 

  22. Ivey JW, Vehring R, Finlay WH. Understanding pressurized metered dose inhaler performance. Expert Opin Drug Deliv. 2015;12(6):901–16.

    Article  PubMed  CAS  Google Scholar 

  23. Stein SW, Sheth P, Myrdal PB. A model for predicting size distributions delivered from pMDIs with suspended drug. Int J Pharm. 2012;422(1):101–15.

    Article  PubMed  CAS  Google Scholar 

  24. Sheth P, Sandell D, Svensson M, Vallorz E, Sullivan JB, Saluja B, et al. The influence of formulation variables on mometasone furoate pMDIs. Respir Drug Deliv. 2016;2:285–90.

    Google Scholar 

  25. Stein SW. Aiming for a moving target: challenges with impactor measurements of MDI aerosols. Int J Pharm. 2008;355:53–61.

    Article  PubMed  CAS  Google Scholar 

  26. Smyth HDC, Hickey AJ. Multimodal particle size distributions emitted from HFA-134a solution pressurized metered-dose inhalers. AAPS PharmSciTech. 2003;4(3):38.

    Article  Google Scholar 

  27. Mitchell J, Newman S, Chan H-K. In vitro and in vivo aspects of cascade impactor tests and inhaler performance: a review. AAPS PharmSciTech. 2007;8(4):E1–E12.

    Article  Google Scholar 

  28. Finlay WH, Stapleton KW. The effect on regional lung deposition of coupled heat and mass transfer between hygroscopic droplets and their surrounding phase. J Aerosol Sci. 1995;26:655–70.

    Article  CAS  Google Scholar 

Download references


Funding for this work was made possible, in part, by the Food and Drug Administration through grant 1U01FD004943-01. Views expressed in this publication do not necessarily reflect the official policies of the Department of Health and Human Services, nor does any mention of trade names, commercial practices, or organization imply endorsement by the US Government.

Author information

Authors and Affiliations


Corresponding author

Correspondence to Jeffry D. Schroeter.

Ethics declarations


The opinions expressed in this paper by the authors do not necessarily reflect the views or policies of the Food and Drug Administration (FDA).

Electronic Supplementary Material


(DOCX 612 kb)

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Schroeter, J.D., Sheth, P., Hickey, A.J. et al. Effects of Formulation Variables on Lung Dosimetry of Albuterol Sulfate Suspension and Beclomethasone Dipropionate Solution Metered Dose Inhalers. AAPS PharmSciTech 19, 2335–2345 (2018).

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI:


  • metered dose inhaler (MDI)
  • design of experiments (DoE)
  • lung deposition modeling
  • multiple-path particle dosimetry model (MPPD)
  • fine particle fraction (FPF)
  • coarse particle fraction (CPF)