Pharmaceutical Research

, 35:247 | Cite as

Formulating Inhalable Dry Powders Using Two-Fluid and Three-Fluid Nozzle Spray Drying

  • Donglei Leng
  • Kaushik Thanki
  • Camilla Foged
  • Mingshi YangEmail author
Research Paper



The spray drying process is widely applied for pharmaceutical particle engineering. The purpose of this study was to investigate advantages and disadvantages of two-fluid nozzle and three-fluid nozzle spray drying processes to formulate inhalable dry powders.


Budesonide nanocomposite microparticles (BNMs) were prepared by co-spray drying of budesonide nanocrystals suspended in an aqueous mannitol solution by using a two-fluid nozzle spray drying process. Budesonide-mannitol microparticles (BMMs) were prepared by concomitant spray drying of a budesonide solution and an aqueous mannitol solution using a spray drier equipped with a three-fluid nozzle. The resulting dry powders were characterized by using X-ray powder diffraction (XRPD), differential scanning calorimetry (DSC), dynamic mechanical analysis (DMA) and Raman microscopy. A Next Generation Impactor was used to evaluate the aerodynamic performance of the dry powders.


XRPD and DMA results showed that budesonide remained crystalline in the BNMs, whereas budesonide was amorphous in the BMMs. Spray drying of mannitol into microparticles resulted in a crystalline transformation of mannitol, evident from XRPD, DSC and Raman spectroscopy analyses. Both BMMs and BNMs displayed a faster dissolution rate than bulk budesonide. The yield of BNMs was higher than that of BMMs. The mass ratio between budesonide and mannitol was preserved in the BNMs, whereas the mass ratio in the BMMs was higher than the theoretical ratio.


Spray drying is an enabling technique for preparation of budesonide amorphous solid dispersions and nanocrystal-embedded microparticles. Two-fluid nozzle spray drying is superior to three-fluid nozzle spray drying in terms of yield.


budesonide spray drying three-fluid nozzle spray drying two-fluid nozzle spray drying 

Supplementary material

11095_2018_2509_MOESM1_ESM.docx (101 kb)
ESM 1 (DOCX 101 kb)


  1. 1.
    Smith IJ, Parry-Billings M. The inhalers of the future? A review of dry powder devices on the market today. Pulm Pharmacol Ther. 2003;16(2):79–95.CrossRefGoogle Scholar
  2. 2.
    Dolovich MB, Dhand R. Aerosol drug delivery: developments in device design and clinical use. Lancet. 2011;377(9770):1032–45.CrossRefGoogle Scholar
  3. 3.
    Zhou QT, Leung SS, Tang P, Parumasivam T, Loh ZH, Chan HK. Inhaled formulations and pulmonary drug delivery systems for respiratory infections. Adv Drug Deliv Rev. 2015;85:83–99.CrossRefGoogle Scholar
  4. 4.
    Chow AH, Tong HH, Chattopadhyay P, Shekunov BY. Particle engineering for pulmonary drug delivery. Pharm Res. 2007;24(3):411–37.CrossRefGoogle Scholar
  5. 5.
    Vehring R. Pharmaceutical particle engineering via spray drying. Pharm Res. 2008;25(5):999–1022.CrossRefGoogle Scholar
  6. 6.
    Wan F, Maltesen MJ, Bjerregaard S, Foged C, Rantanen J, Yang M. Particle engineering technologies for improving the delivery of peptide and protein drugs. Journal of Drug Delivery Science and Technology. 2013;23(4):355–363.CrossRefGoogle Scholar
  7. 7.
    Wan F, Maltesen MJ, Andersen SK, Bjerregaard S, Baldursdottir SG, Foged C, et al. Modulating protein release profiles by incorporating hyaluronic acid into PLGA microparticles via a spray dryer equipped with a 3-fluid nozzle. Pharm Res. 2014;31(11):2940–51.CrossRefGoogle Scholar
  8. 8.
    Mizoe T, Ozeki T, Okada H. Application of a four-fluid nozzle spray drier to prepare inhalable rifampicin-containing mannitol microparticles. AAPS PharmSciTech. 2008;9(3):755–61.CrossRefGoogle Scholar
  9. 9.
    Ozeki T, Beppu S, Mizoe T, Takashima Y, Yuasa H, Okada H. Preparation of two-drug composite microparticles to improve the dissolution of insoluble drug in water for use with a 4-fluid nozzle spray drier. J Control Release. 2005;107(3):387–94.CrossRefGoogle Scholar
  10. 10.
    Ozeki T, Beppu S, Mizoe T, Takashima Y, Yuasa H, Okada H. Preparation of polymeric submicron particle-containing microparticles using a 4-fluid nozzle spray drier. Pharm Res. 2006;23(1):177–83.CrossRefGoogle Scholar
  11. 11.
    Liu T, Han M, Tian F, Cun D, Rantanen J, Yang M. Budesonide nanocrystal-loaded hyaluronic acid microparticles for inhalation: in vitro and in vivo evaluation. Carbohydr Polym. 2018;181:1143–52.CrossRefGoogle Scholar
  12. 12.
    European Directorate for Quality in Medicines and Healthcare (EDQM): European Pharmacopeia 9.0, Monograph 2.9.18. Preparations for Inhalation: Aerodynamic Assessment of Fine Particles. EDQM, Strasburg, France, 2017.Google Scholar
  13. 13.
    Bandi N, Wei W, Roberts CB, Kotra LP, Kompella UB. Preparation of budesonide- and indomethacin-hydroxypropyl-beta-cyclodextrin (HPBCD) complexes using a single-step, organic-solvent-free supercritical fluid process. Eur J Pharm Sci. 2004;23(2):159–68.CrossRefGoogle Scholar
  14. 14.
    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
  15. 15.
    Peltonen L, Hirvonen J. Pharmaceutical nanocrystals by nanomilling: critical process parameters, particle fracturing and stabilization methods. J Pharm Pharmacol. 2010;62(11):1569–79.CrossRefGoogle Scholar
  16. 16.
    Shegokar R, Muller RH. Nanocrystals: industrially feasible multifunctional formulation technology for poorly soluble actives. Int J Pharm. 2010;399(1–2):129–39.CrossRefGoogle Scholar
  17. 17.
    Yamasaki K, Kwok PC, Fukushige K, Prud'homme RK, Chan HK. Enhanced dissolution of inhalable cyclosporine nano-matrix particles with mannitol as matrix former. Int J Pharm. 2011;420(1):34–42.CrossRefGoogle Scholar
  18. 18.
    Lee YY, Wu JX, Yang M, Young PM, van den Berg F, Rantanen J. Particle size dependence of polymorphism in spray-dried mannitol. Eur J Pharm Sci. 2011;44(1–2):41–8.CrossRefGoogle Scholar
  19. 19.
    Hulse WL, Forbes RT, Bonner MC, Getrost M. The characterization and comparison of spray-dried mannitol samples. Drug Dev Ind Pharm. 2009;35(6):712–8.CrossRefGoogle Scholar
  20. 20.
    Sharma VK, Kalonia DS. Effect of vacuum drying on protein-mannitol interactions: the physical state of mannitol and protein structure in the dried state. AAPS PharmSciTech. 2004;5(1):E10.PubMedGoogle Scholar
  21. 21.
    Mezzena M, Scalia S, Young PM, Traini D. Solid lipid budesonide microparticles for controlled release inhalation therapy. AAPS J. 2009;11(4):771–8.CrossRefGoogle Scholar
  22. 22.
    Kaialy W, Nokhodchi A. Dry powder inhalers: physicochemical and aerosolization properties of several size-fractions of a promising alterative carrier, freeze-dried mannitol. Eur J Pharm Sci. 2015;68:56–67.CrossRefGoogle Scholar
  23. 23.
    Kumon M, Kwok PC, Adi H, Heng D, Chan HK. Can low-dose combination products for inhalation be formulated in single crystalline particles? Eur J Pharm Sci. 2010;40(1):16–24.CrossRefGoogle Scholar
  24. 24.
    Malamatari M, Somavarapu S, Kachrimanis K, Bloxham M, Taylor KMG, Buckton G. Preparation of theophylline inhalable microcomposite particles by wet milling and spray drying: the influence of mannitol as a co-milling agent. Int J Pharm. 2016;514(1):200–11.CrossRefGoogle Scholar
  25. 25.
    Hu J, Dong Y, Ng WK, Pastorin G. Preparation of drug nanocrystals embedded in mannitol microcrystals via liquid antisolvent precipitation followed by immediate (on-line) spray drying. Adv Powder Technol. 2018;29(4):957–63.CrossRefGoogle Scholar
  26. 26.
    Hao HX, Su WY, Barrett M, Caron V, Healy AM, Glennon B. A calibration-free application of Raman spectroscopy to the monitoring of mannitol crystallization and its polymorphic transformation. Org Process Res Dev. 2010;14(5):1209–14.CrossRefGoogle Scholar
  27. 27.
    Maas SG, Schaldach G, Littringer EM, Mescher A, Griesser UJ, Braun DE, et al. The impact of spray drying outlet temperature on the particle morphology of mannitol. Powder Technol. 2011;213(1–3):27–35.CrossRefGoogle Scholar
  28. 28.
    Burger A, Henck JO, Hetz S, Rollinger JM, Weissnicht AA, Stottner H. Energy/temperature diagram and compression behavior of the polymorphs of D-mannitol. J Pharm Sci. 2000;89(4):457–68.CrossRefGoogle Scholar
  29. 29.
    Sosnik A, Seremeta KP. Advantages and challenges of the spray-drying technology for the production of pure drug particles and drug-loaded polymeric carriers. Adv Colloid Interf Sci. 2015;223:40–54.CrossRefGoogle Scholar
  30. 30.
    Maury M, Murphy K, Kumar S, Shi L, Lee G. Effects of process variables on the powder yield of spray-dried trehalose on a laboratory spray-dryer. Eur J Pharm Biopharm. 2005;59(3):565–73.CrossRefGoogle Scholar
  31. 31.
    Parumasivam T, Chang RY, Abdelghany S, Ye TT, Britton WJ, Chan HK. Dry powder inhalable formulations for anti-tubercular therapy. Adv Drug Deliv Rev. 2016;102:83–101.CrossRefGoogle Scholar
  32. 32.
    Islam MIU, Langrish TAG. The effect of different atomizing gases and drying media on the crystallization behavior of spray-dried powders. Dry Technol. 2010;28(9):1035–43.CrossRefGoogle Scholar
  33. 33.
    Hancock BC, Zografi G. Characteristics and significance of the amorphous state in pharmaceutical systems. J Pharm Sci. 1997;86(1):1–12.CrossRefGoogle Scholar
  34. 34.
    Shetty N, Park H, Zemlyanov D, Mangal S, Bhujbal S, Zhou QT. Influence of excipients on physical and aerosolization stability of spray dried high-dose powder formulations for inhalation. Int J Pharm. 2018;544(1):222–34.CrossRefGoogle Scholar
  35. 35.
    Debord B, Lefebvre C, Guyot-Hermann AM, Hubert J, Bouché R, Cuyot JC. Study of different crystalline forms of mannitol: comparative behaviour under compression. Drug Dev Ind Pharm. 2008;13(9–11):1533–46.Google Scholar
  36. 36.
    Ohrem HL, Schornick E, Kalivoda A, Ognibene R. Why is mannitol becoming more and more popular as a pharmaceutical excipient in solid dosage forms? Pharm Dev Technol. 2014;19(3):257–62.CrossRefGoogle Scholar
  37. 37.
    Naini V, Byron PR, Phillips EM. Physicochemical stability of crystalline sugars and their spray-dried forms: dependence upon relative humidity and suitability for use in powder inhalers. Drug Dev Ind Pharm. 1998;24(10):895–909.CrossRefGoogle Scholar
  38. 38.
    Jensen DM, Cun D, Maltesen MJ, Frokjaer S, Nielsen HM, Foged C. Spray drying of siRNA-containing PLGA nanoparticles intended for inhalation. J Control Release. 2010;142(1):138–45.CrossRefGoogle Scholar
  39. 39.
    Adi H, Young PM, Chan HK, Agus H, Traini D. Co-spray-dried mannitol-ciprofloxacin dry powder inhaler formulation for cystic fibrosis and chronic obstructive pulmonary disease. Eur J Pharm Sci. 2010;40(3):239–47.CrossRefGoogle Scholar
  40. 40.
    Eedara BB, Rangnekar B, Doyle C, Cavallaro A, Das SC. The influence of surface active l-leucine and 1,2-dipalmitoyl-sn-glycero-3-phosphatidylcholine (DPPC) in the improvement of aerosolization of pyrazinamide and moxifloxacin co-spray dried powders. Int J Pharm. 2018;542(1–2):72–81.CrossRefGoogle Scholar
  41. 41.
    Adi S, Adi H, Tang P, Traini D, Chan HK, Young PM. Micro-particle corrugation, adhesion and inhalation aerosol efficiency. Eur J Pharm Sci. 2008;35(1–2):12–8.CrossRefGoogle Scholar
  42. 42.
    Noyes AA, Whitney WR. The rate of solution of solid substances in their own solutions. J Am Chem Soc. 1897;19:930–4.CrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2018

Authors and Affiliations

  • Donglei Leng
    • 1
  • Kaushik Thanki
    • 1
  • Camilla Foged
    • 1
  • Mingshi Yang
    • 1
    • 2
    Email author
  1. 1.Department of Pharmacy, Faculty of Health and Medical ScienceUniversity of CopenhagenCopenhagenDenmark
  2. 2.Wuya College of InnovationShenyang Pharmaceutical UniversityShenyangChina

Personalised recommendations