Pharmaceutical Research

, 36:100 | Cite as

Multi-Solvent Microdroplet Evaporation: Modeling and Measurement of Spray-Drying Kinetics with Inhalable Pharmaceutics

  • Mani Ordoubadi
  • Florence K. A. Gregson
  • Omar Melhem
  • David Barona
  • Rachael E. H. Miles
  • Dexter D’Sa
  • Sandra Gracin
  • David Lechuga-Ballesteros
  • Jonathan P. Reid
  • Warren H. Finlay
  • Reinhard VehringEmail author
Research Paper



Evaporation and particle formation from multi-solvent microdroplets containing solid excipients pertaining to spray-drying of therapeutic agents intended for lung delivery were studied. Various water and ethanol co-solvent systems containing a variety of actives and excipients (beclomethasone, budesonide, leucine, and trehalose) were considered.


Numerical methods were used to predict the droplet evaporation rates and internal solute transfers, and their results verified and compared with results from two separate experimental setups. In particular, an electrodynamic balance was used to measure the evaporation rates of multicomponent droplets and a monodisperse droplet chain setup collected dried microparticles for further analytical investigations and ultramicroscopy.


The numerical results are used to explain the different particle morphologies dried from solutions at different co-solvent compositions. The obtained numerical data clearly show that the two parameters controlling the general morphology of a dried particle, namely the Péclet number and the degree of saturation, can change with time in a multi-solvent droplet. This fact complicates product development for such systems. However, this additional complexity vanishes at what we define as the iso-compositional point, which occurs when the solvent ratios and other composition-dependent properties of the droplet remain constant during evaporation, similar to the azeotrope of such systems during distillation.


Numerical and experimental analysis of multi-solvent systems indicate that spray-drying near the iso-compositional ratio simplifies the design and process development of such systems.


co-solvents inhaled therapeutics microparticles multi-solvent spray-drying particle engineering 



  1. 1.
    Haddrell AE, Davies JF, Miles REH, Reid JP, Dailey LA, Murnane D. Dynamics of aerosol size during inhalation: hygroscopic growth of commercial nebulizer formulations. Int J Pharm. 2014;463(1):50–61.CrossRefGoogle Scholar
  2. 2.
    Rovelli G, Miles REH, Reid JP, Clegg SL. Accurate measurements of aerosol hygroscopic growth over a wide range in relative humidity. J Phys Chem A. 2016;120(25):4376–88.CrossRefGoogle Scholar
  3. 3.
    Cai B, Tuo X, Song Z, Zheng Y, Gu H, Wang H. Modeling of spray flash evaporation based on droplet analysis. Appl Therm Eng. 2018;130:1044–51.CrossRefGoogle Scholar
  4. 4.
    Brewster MQ. Evaporation and condensation of water mist/cloud droplets with thermal radiation. Int J Heat Mass Transf. 2015;88:695–712.CrossRefGoogle Scholar
  5. 5.
    Sazhin SS. Modelling of fuel droplet heating and evaporation: recent results and unsolved problems. Fuel. 2017;196:69–101.CrossRefGoogle Scholar
  6. 6.
    Arpagaus C, Collenberg A, Rütti D, Assadpour E, Jafari SM. Nano spray drying for encapsulation of pharmaceuticals. Int J Pharm. 2018;546(1–2):194–214.CrossRefGoogle Scholar
  7. 7.
    Chalvatzaki E, Lazaridis M. Α dosimetry model of hygroscopic particle growth in the human respiratory tract. Air Qual Atmos Heal. 2018;11(4):471–82.CrossRefGoogle Scholar
  8. 8.
    Boraey MA, Hoe S, Sharif H, Miller DP, Lechuga-Ballesteros D, Vehring R. Improvement of the dispersibility of spray-dried budesonide powders using leucine in an ethanol–water cosolvent system. Powder Technol. 2013;236:171–8.CrossRefGoogle Scholar
  9. 9.
    Kauppinen A, Broekhuis J, Grasmeijer N, Tonnis W, Ketolainen J, Frijlink HW, et al. Efficient production of solid dispersions by spray drying solutions of high solid content using a 3-fluid nozzle. Eur J Pharm Biopharm. 2018;123:50–8.CrossRefGoogle Scholar
  10. 10.
    Ivey JW, Bhambri P, Church TK, Lewis DA, McDermott MT, Elbayomy S, et al. Humidity affects the morphology of particles emitted from beclomethasone dipropionate pressurized metered dose inhalers. Int J Pharm. 2017;520(1–2):207–15.CrossRefGoogle Scholar
  11. 11.
    Boraey MA, Vehring R. Diffusion controlled formation of microparticles. J Aerosol Sci. 2014;67:131–43.CrossRefGoogle Scholar
  12. 12.
    Grasmeijer N, Frijlink HW, Hinrichs WLJ. Model to predict inhomogeneous protein–sugar distribution in powders prepared by spray drying. J Aerosol Sci. 2016;101:22–33.CrossRefGoogle Scholar
  13. 13.
    Widmann JF, Davis EJ. Evaporation of multicomponent droplets. Aerosol Sci Technol. 1997;27(2):243–54.CrossRefGoogle Scholar
  14. 14.
    Lupo G, Duwig C. A numerical study of ethanol–water droplet evaporation. J Eng Gas Turbines Power. 2017;140(2):021401.CrossRefGoogle Scholar
  15. 15.
    Tonini S, Cossali GE. A multi-component drop evaporation model based on analytical solution of Stefan–Maxwell equations. Int J Heat Mass Transf. 2016;92:184–9.CrossRefGoogle Scholar
  16. 16.
    Tonini S, Cossali GE. A novel formulation of multi-component drop evaporation models for spray applications. Int J Therm Sci. 2015;89:245–53.CrossRefGoogle Scholar
  17. 17.
    Kuchma AE, Shchekin AK, Martyukova DS. The Stefan outflow in a multicomponent vapor–gas atmosphere around a droplet and its role for cloud expansion. J Aerosol Sci. 2016;102:72–82.CrossRefGoogle Scholar
  18. 18.
    Fuchs NA. Evaporation and droplet growth in gaseous media. Oxford: The Pergamon Press; 1959.Google Scholar
  19. 19.
    Learoyd TP, Burrows JL, French E, Seville PC. Modified release of beclometasone dipropionate from chitosan-based spray-dried respirable powders. Powder Technol. 2008;187(3):231–8.CrossRefGoogle Scholar
  20. 20.
    Ozyazici M, Yurdasiper A, Arici M. Triamcinolone acetonide dry powder inhalation: a new approach for treathing asthma. J Pharm Drug Deliv Res. 2016;5(6).Google Scholar
  21. 21.
    Khandouzi F, Daman Z, Gilani K. Optimized particle engineering of fluticasone propionate and salmeterol xinafoate by spray drying technique for dry powder inhalation. Adv Powder Technol. 2017;28(2):534–42.CrossRefGoogle Scholar
  22. 22.
    Knox KJ, Reid JP, Hanford KL, Hudson AJ, Mitchem L. Direct measurements of the axial displacement and evolving size of optically trapped aerosol droplets. J Opt A Pure Appl Opt. 2007;9(8):S180–8.CrossRefGoogle Scholar
  23. 23.
    Davies JF, Haddrell AE, Reid JP. Time-resolved measurements of the evaporation of volatile components from single aerosol droplets. Aerosol Sci Technol. 2012;46(6):666–77.CrossRefGoogle Scholar
  24. 24.
    Baldelli A, Boraey MA, Nobes DS, Vehring R. Analysis of the particle formation process of structured microparticles. Mol Pharm. 2015;12(8):2562–73.CrossRefGoogle Scholar
  25. 25.
    Baldelli A, Power RM, Miles REH, Reid JP, Vehring R. Effect of crystallization kinetics on the properties of spray dried microparticles. Aerosol Sci Technol. 2016;50(7):693–704.CrossRefGoogle Scholar
  26. 26.
    Vehring R, Foss WR, Lechuga-Ballesteros D. Particle formation in spray drying. J Aerosol Sci. 2007;38(7):728–46.CrossRefGoogle Scholar
  27. 27.
    Kulmala M, Vesala T, Wagner PEE. An analytical expression for the rate of binary condensational particle growth: comparison with numerical results. J Aerosol Sci. 1992;23(1):133–6.CrossRefGoogle Scholar
  28. 28.
    Finlay WH. The mechanics of inhaled pharmaceutical aerosols: an introduction. 2nd ed: Elsevier; 2019.Google Scholar
  29. 29.
    Tonini S, Cossali GE. An analytical model of liquid drop evaporation in gaseous environment. Int J Therm Sci. 2012;57:45–53.CrossRefGoogle Scholar
  30. 30.
    Periasamy Ravindran E, Davis J. Multicomponent evaporation of single aerosol droplets. J Colloid Interface Sci. 1982;85(1):278–88.CrossRefGoogle Scholar
  31. 31.
    Newbold FR, Amundson NR. A model for evaporation of a multicomponent droplet. AICHE J. 1973;19(1):22–30.CrossRefGoogle Scholar
  32. 32.
    Abramzon B, Sirignano WA. Droplet vaporization model for spray combustion calculations. Int J Heat Mass Transf. 1989;32(9):1605–18.CrossRefGoogle Scholar
  33. 33.
    Hopkins RJ, Reid JP. A comparative study of the mass and heat transfer dynamics of evaporating ethanol/water, methanol/water, and 1-propanol/water aerosol droplets. J Phys Chem B. 2006;110(7):3239–49.CrossRefGoogle Scholar
  34. 34.
    Seinfeld JH, Pandis SN. Atmospheric Chemistry and Physics : From Air Pollution to Climate Change. New York, UNITED States: John Wiley & Sons, Incorporated; 2016.Google Scholar
  35. 35.
    Sirignano WA. Fluid dynamics and transport of droplets and sprays: Cambridge university press; 1999.Google Scholar
  36. 36.
    Gebreyohannes S, Neely BJ, Gasem KAM. One-parameter modified nonrandom two-liquid (NRTL) activity coefficient model. Fluid Phase Equilib. 2014;379:196–205.CrossRefGoogle Scholar
  37. 37.
    Khattab IS, Bandarkar F, Fakhree MAA, Jouyban A. Density, viscosity, and surface tension of water+ethanol mixtures from 293 to 323K. Korean J Chem Eng. 2012;29(6):812–7.CrossRefGoogle Scholar
  38. 38.
    Vehring R. Pharmaceutical particle engineering via spray drying. Pharm Res. 2008;25:999–1022.Google Scholar
  39. 39.
    Ekdawi-Sever N, de Pablo JJ, Feick E, von Meerwall E. Diffusion of sucrose and α,α-Trehalose in aqueous solutions. J Phys Chem A. 2003;107(6):936–43.CrossRefGoogle Scholar
  40. 40.
    Taylor R, Krishna R. Multicomponent mass transfer, vol. 2: John Wiley & Sons; 1993.Google Scholar
  41. 41.
    Wilke CR. Diffusional properties of multicomponent gases. Chem Eng Prog. 1950;46(2):95–104.Google Scholar
  42. 42.
    Fairbanks DF, Wilke CR. Diffusion coefficients in multicomponent gas mixtures. Ind Eng Chem. 1950;42(3):471–5.CrossRefGoogle Scholar
  43. 43.
    Tang YP, Himmelblau DM. Effective binary diffusion coefficients in mixed solvents. AICHE J. 1965;11(1):54–8.CrossRefGoogle Scholar
  44. 44.
    Bird RB, Stewart WE, Lightfoot EN. Transport phenomena. Revised 2n. New York: John Wiley & Sons; 2006.Google Scholar
  45. 45.
    Smith JM, Van Ness HC, Abbott MM. Introduction to chemical engineering thermodynamics. 7th ed. New York: McGraw-Hill; 2005.Google Scholar
  46. 46.
    Horsley LH. Table of azeotropes and nonazeotropes. Anal Chem. 1947;19(8):508–600.CrossRefGoogle Scholar
  47. 47.
    Bader A, Keller P, Hasse C. The influence of non-ideal vapor–liquid equilibrium on the evaporation of ethanol/iso-octane droplets. Int J Heat Mass Transf. 2013;64:547–58.CrossRefGoogle Scholar
  48. 48.
    Jouyban A, Acree WE. In silico prediction of drug solubility in water-ethanol mixtures using Jouyban- Acree model. J Pharm Pharm Sci ( 2006;9(2):262–269.
  49. 49.
    D’Sa DJ, Lechuga-Ballesteros D, Chan HK. Isothermal microcalorimetry of pressurized systems I: a rapid method to evaluate pressurized metered dose inhaler formulations. Pharm Res. 2014;31(10):2716–23.CrossRefGoogle Scholar
  50. 50.
    Tajber L, Corrigan DO, Corrigan OI, Healy AM. Spray drying of budesonide, formoterol fumarate and their composites—I. physicochemical characterisation. Int J Pharm. 2009;367(1–2):79–85.CrossRefGoogle Scholar
  51. 51.
    Feng AL, Boraey MA, Gwin MA, Finlay PR, Kuehl PJ, Vehring R. Mechanistic models facilitate efficient development of leucine containing microparticles for pulmonary drug delivery. Int J Pharm. 2011;409(1):156–63.CrossRefGoogle Scholar
  52. 52.
    Ógáin ON, Li J, Tajber L, Corrigan OI, Healy AM. Particle engineering of materials for oral inhalation by dry powder inhalers. I—particles of sugar excipients (trehalose and raffinose) for protein delivery. Int J Pharm. 2011;405(1–2):23–35.CrossRefGoogle Scholar
  53. 53.
    Mishra J, Rades T, Löbmann K, Grohganz H. Influence of solvent composition on the performance of spray-dried co-amorphous formulations. Pharmaceutics. 2018;10(2):47.CrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2019

Authors and Affiliations

  • Mani Ordoubadi
    • 1
  • Florence K. A. Gregson
    • 2
  • Omar Melhem
    • 1
  • David Barona
    • 1
  • Rachael E. H. Miles
    • 2
  • Dexter D’Sa
    • 3
  • Sandra Gracin
    • 4
  • David Lechuga-Ballesteros
    • 3
  • Jonathan P. Reid
    • 2
  • Warren H. Finlay
    • 1
  • Reinhard Vehring
    • 1
    Email author
  1. 1.Department of Mechanical EngineeringUniversity of AlbertaEdmontonCanada
  2. 2.School of ChemistryUniversity of BristolBristolUK
  3. 3.Pharmaceutical Technology & DevelopmentAstraZeneca R&D South San FranciscoSan FranciscoUSA
  4. 4.Pharmaceutical Technology & DevelopmentAstraZeneca R&D GothenburgGothenburgSweden

Personalised recommendations