AAPS PharmSciTech

, Volume 19, Issue 7, pp 3085–3096 | Cite as

Optimization of Ciprofloxacin Hydrochloride Spray-Dried Microparticles for Pulmonary Delivery Using Design of Experiments

  • Mariela RazucEmail author
  • Juliana Piña
  • María V. Ramírez-Rigo
Research Article


Ciprofloxacin is a broad-spectrum antibiotic for treatment of pulmonary diseases such as chronic obstructive pulmonary disease and cystic fibrosis. The purpose of this work was to rationally study the spray drying of ciprofloxacin in order to identify the formulation and operating conditions that lead to a product with aerodynamic properties appropriate for dry powder inhalation. A 24 − 1 fractional factorial design was applied to investigate the effect of selected variables (i.e., ciprofloxacin hydrochloride (CIP) concentration, drying air inlet temperature, feed flow rate, and atomization air flow rate) on several product and process parameters (i.e., particle size, aerodynamic diameter, moisture content, densities, porosity, powder flowability, outlet temperature, and process yield) and to determine an optimal condition. The studied factors had a significant effect on the evaluated responses (higher p value 0.0017), except for the moisture content (p value > 0.05). The optimal formulation and operating conditions were as follows: CIP concentration 10 mg/mL, drying air inlet temperature 110°C, feed volumetric flow rate 3.0 mL/min, and atomization air volumetric flow rate 473 L/h. The product obtained under this set had a particle size that guarantees access to the lung, a moisture content acceptable for dry powder inhalation, fair flowability, and high process yield. The PDRX and SEM analysis of the optimal product showed a crystalline structure and round and dimpled particles. Moreover, the product was obtained by a simple and green spray drying method.


ciprofloxacin hydrochloride dry powder inhaler spray drying design of experiments green process 



The authors thank Lic. F. Cabrera and Dra. A. Di Battista (PLAPIQUI) for their technical assistance and Plastiape (Italy) for kindly supplying the RS01 inhaler device.

Funding Information

Financial support was received from CONICET (PIP 112-2011-0100336112), UNS (PGI 24/B209, PGI 24/M122), and FONCyT (PICT-2014-2421). M. Razuc received financial support from CONICET for her postdoctoral fellowship.

Supplementary material

12249_2018_1137_MOESM1_ESM.docx (131 kb)
ESM 1 (DOCX 131 kb)


  1. 1.
    Siddiqi A, Sethi S. Optimizing antibiotic selection in treating COPD exacerbations. Int J Chron Obstruct Pulmon Dis. 2008;3:31–44.CrossRefPubMedPubMedCentralGoogle Scholar
  2. 2.
    WHO. World Health Organization. Chronic respiratory diseases. Chronic obstructive pulmonary disease (COPD). (Accessed 19 September 2017).
  3. 3.
    Sethi S, Murphy T. Bacterial infection in chronic obstructive pulmonary disease in 2000. Clin Microbiol Rev. 2001;14:336–63.CrossRefPubMedPubMedCentralGoogle Scholar
  4. 4.
    Emerson J, Rosenfeld M, McNamara S, Ramsey B, Gibson R. Pseudomonas aeruginosa and other predictors of mortality and morbidity in young children with cystic fibrosis. Pediatr Pulmonol. 2002;34:91–100.CrossRefGoogle Scholar
  5. 5.
    Döring G, Flume P, Heijerman H, Elborn J. Treatment of lung infection in patients with cystic fibrosis: current and future strategies. J Cyst Fibros. 2012;11:461–79.CrossRefGoogle Scholar
  6. 6.
    Eller J, Ede A, Schaberg T, Niederman M, Mauch H, Lode H. Infective exacerbations of chronic bronchitis: relation between bacteriologic etiology and lung function. Chest. 1998;113:1542–8.CrossRefGoogle Scholar
  7. 7.
    Redmond A, Sweeney L, Macfarland M, Mitchell M, Daggett S, Kubin R. Oral ciprofloxacin in the treatment of pseudomonas exacerbations of pediatric cystic fibrosis: clinical efficacy and safety evaluation using magnetic resonance image scanning. J Int Med Res. 1998;26:304–12.CrossRefGoogle Scholar
  8. 8.
    WHO, World Health Organization. Model formulary. 2008. (Accessed 19 Sept 2017).
  9. 9.
    Kontou P, Chatzika K, Pitsiou G, Stanopoulos I, Argyropoulou-Pataka P, Kioumis I. Pharmacokinetics of ciprofloxacin and its penetration into bronchial secretions of mechanically ventilated patients with chronic obstructive pulmonary disease. Antimicrob Agents Chemother. 2011;55:4149–53.CrossRefPubMedPubMedCentralGoogle Scholar
  10. 10.
    Cipolla D. Will pulmonary drug delivery for systemic application ever fulfill its rich promise? Expert Opin Drug Deliv. 2016;13:1337–40.CrossRefGoogle Scholar
  11. 11.
    Dimer F, de Souza Carvalho-Wodarz C, Haupenthal J, Hartmann R, Lehr C. Inhalable clarithromycin microparticles for treatment of respiratory infections. Pharm Res. 2015;32:3850–61.CrossRefGoogle Scholar
  12. 12.
    Devarajan P, Jain S. Targeted drug delivery: concepts and design. New York: Springer; 2015. p. 22–3.Google Scholar
  13. 13.
    Adi H, Young P, Chan H, Stewart P, Agus H, Traini D. Cospray dried antibiotics for dry powder lung delivery. J Pharm Sci. 2008;97:3356–66.CrossRefGoogle Scholar
  14. 14.
    Pilcer G, De Bueger V, Traina K, Traore H, Sebti T, Vanderbist F, et al. Carrier-free combination for dry powder inhalation of antibiotics in the treatment of lung infections in cystic fibrosis. Int J Pharm. 2013;451:112–20.CrossRefGoogle Scholar
  15. 15.
    Alagusundaram M, Deepthi N, Ramkanth S, Angalaparameswari S, Saleem T, Gnanaprakash T, et al. Dry powder inhalers - an overview. Int J Res Pharm Sci. 2010;1:34–42.Google Scholar
  16. 16.
    Sosnik A, Seremeta K. 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
  17. 17.
    Seville P, Li H, Learoyd T. Spray-dried powders for pulmonary drug delivery. Crit Rev Ther Drug Carrier Syst. 2007;24:307–60.CrossRefGoogle Scholar
  18. 18.
    Vicente J, Pinto J, Menezes J, Gaspar F. Fundamental analysis of particle formation in spray drying. Powder Technol. 2013;247:1–7.CrossRefGoogle Scholar
  19. 19.
    Adi H, Young P, Chan H, 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;40:239–47.CrossRefGoogle Scholar
  20. 20.
    Osman R, Kan P, Awad G, Mortada N, EL-Shamy A, Alpar O. Spray dried inhalable ciprofloxacin powder with improved aerosolisation and antimicrobial activity. Int J Pharm. 2013;449:44–58.CrossRefGoogle Scholar
  21. 21.
    Yang Y, Tsifansky M, Shin S, Lin Q, Yeo Y. Mannitol-guided delivery of ciprofloxacin in artificial cystic fibrosis mucus model. Biotechnol Bioeng. 2011;108:1441–9.CrossRefGoogle Scholar
  22. 22.
    Ely L, Roa W, Finlay W, Lobenberg R. Effervescent dry powder for respiratory drug delivery. Eur J Pharm Biopharm. 2007;65:346–53.CrossRefGoogle Scholar
  23. 23.
    Karimi K, Pallagi E, Szabó-Révész P, Csóka I, Ambrus R. Development of a microparticle-based dry powder inhalation formulation of ciprofloxacin hydrochloride applying the quality by design approach. Drug Des Dev Ther. 2016;10:3331–43.CrossRefGoogle Scholar
  24. 24.
    Cayli Y, Sahin S, Buttini F, Balducci A, Montanari A, Vural I, et al. Dry powders for the inhalation of ciprofloxacin or levofloxacin combined with a mucolytic agent for cystic fibrosis patients. Drug Dev Ind Pharm. 2017;43:1378–89.CrossRefGoogle Scholar
  25. 25.
    Zhao H, Le Y, Liu H, Hu T, Shen Z, Yun J, et al. Preparation of microsized spherical aggregates of ultrafine ciprofloxacin particles for dry powder inhalation (DPI). Powder Technol. 2009;194:81–6.CrossRefGoogle Scholar
  26. 26.
    Cotabarren I, Bertín D, Razuc M, Ramírez-Rigo M, Piña J. Modelling of the spray drying process for particle design. Chem Eng Res Des. 2018;132:1091–104.CrossRefGoogle Scholar
  27. 27.
    Adi H, Young P, Chan H, Salama R, Traini D. Controlled release antibiotics for dry powder lung delivery. Drug Dev Ind Pharm. 2010;36:119–26.CrossRefGoogle Scholar
  28. 28.
    Lee SH, Teo J, Heng D, Zhao Y, Kiong W, Ng H, et al. A novel inhaled multi-pronged attack against respiratory bacteria. Eur J Pharm Sci. 2015;70:37–44.CrossRefGoogle Scholar
  29. 29.
    ACS-GCIPR. American Chemical Society, Green Chemistry Institute, Pharmaceutical Roundtable. (Accessed 19 Sept 2017).
  30. 30.
    Paluch K, McCabe T, Müller-Bunz H, Corrigan O, Healy A, Tajber L. Formation and physicochemical properties of crystalline and amorphous salts with different stoichiometries formed between ciprofloxacin and succinic acid. Mol Pharm. 2013;10:3640–54.CrossRefGoogle Scholar
  31. 31.
    Gallo L, Llabot J, Allemandi D, Bucalá V, Piña J. Influence of spray-drying operating conditions on Rhamnus purshiana (Cáscara sagrada) extract powder physical properties. Powder Technol. 2011;208:205–14.CrossRefGoogle Scholar
  32. 32.
    Anderson M, Whitcomb P. DOE Simplified. Practical tool for effective experimentation. 3rd ed. New York: CRC Press; 2007.Google Scholar
  33. 33.
    Ceschan N, Bucalá V, Ramírez-Rigo M. New alginic acid-atenolol microparticles for inhalatory drug targeting. Mater Sci Eng. 2014;41:255–66.CrossRefGoogle Scholar
  34. 34.
    USP. United States Pharmacopeia. United States Pharmacopeia and National Formulary. Rockville. MD. 2007. (USP 30-NF 25).Google Scholar
  35. 35.
    Ceschan N. Development of particles for inhalation administration based on polyelectrolyte-drug systems (Doctoral dissertation). 2017. (Accessed 19 Sept 2017).
  36. 36.
    Wang H, John W. Particle density correction for the aerodynamic particle sizer. Aerosol Sci Technol. 1987;6:191–8.CrossRefGoogle Scholar
  37. 37.
    Copley Scientific Ltd. Quality solutions for inhaler testing. Nottingham, UK 2015. (Accessed 19 Sept 2017).
  38. 38.
    Stass H, Nagelschmitz J, Willmann S, Delesen S, Gupta A, Baumann S. Inhalation of a dry powder ciprofloxacin formulation in healthy subjects: a phase I study. Clin Drug Investig. 2013;33:419–27.CrossRefPubMedPubMedCentralGoogle Scholar
  39. 39.
    De Soyza A, Aksamit T, Bandel T, Criollo M, Elborn J, Krahn U, et al. Late-breaking abstract: respire 1: ciprofloxacin DPI 32.5mg b.d. administered 14 day on/off or 28 day on/off vs placebo for 48 weeks in subjects with non-cystic fibrosis bronchiectasis (NCFB). Eur Respir J. 2016;48:272.CrossRefGoogle Scholar
  40. 40.
    Marple V, Olson B, Santhanakrishnan K, Mitchell J, Murray S, Hudson-Curtis B. Next generation pharmaceutical impactor part II: archival calibration. J Aerosol Med. 2003;16:301–24.CrossRefGoogle Scholar
  41. 41.
    Gallo L, Bucalá V, Ramírez-Rigo M. Formulation and characterization of polysaccharide microparticles for pulmonary delivery of sodium cromoglycate. AAPS PharmSciTech. 2017;18:1634–45.CrossRefGoogle Scholar
  42. 42.
    Stahl K, Claesson M, Lilliehorn P, Linden H, Backstrom K. The effect of process variables on the degradation and physical properties of spray dried insulin intended for inhalation. Int J Pharm. 2002;233:227–37.CrossRefGoogle Scholar
  43. 43.
    Liu Y, Wang J, Yin Q. The crystal habit of ciprofloxacin hydrochloride monohydrate crystal. J Cryst Growth. 2005;276:237–42.CrossRefGoogle Scholar
  44. 44.
    Turel I, Bukovec P. Comparison of the thermal stability of ciprofloxacin and its compounds. Thermochim Acta. 1996;287:311–8.CrossRefGoogle Scholar
  45. 45.
    Behboudi-Jobbehdar S, Soukoulis C, Yonekura L, Fisk I. Optimization of spray-drying process conditions for the production of maximally viable microencapsulated L. acidophilus NCIMB 701748. Dry Technol. 2013;31:1274–83.CrossRefGoogle Scholar
  46. 46.
    Elversson J, Millqvist-Fureby A, Alderborn G, Elofsson U. Droplet and particle size relationship and shell thickness of inhalable lactose particles during spray drying. J Pharm Sci. 2003;92:900–10.CrossRefGoogle Scholar
  47. 47.
    Tontul I, Topuz A. Spray-drying of fruit and vegetable juices: effect of drying conditions on the product yield and physical properties. Trends Food Sci Technol. 2017;63:91–102.CrossRefGoogle Scholar
  48. 48.
    Nimmo J. Porosity and pore size distribution. In: Hillel D, editor. Encyclopedia of soils in the environment. London: Elsevier; 2003. p. 295–303.Google Scholar
  49. 49.
    Giovagnoli S, Palazzo F, Di Michele A, Schoubben A, Blasi P, Ricci M. The influence of feedstock and process variables on the encapsulation of drug suspensions by spray-drying in fast drying regime: the case of novel antitubercular drug–palladium complex containing polymeric microparticles. J Pharm Sci. 2014;103:1255–68.CrossRefGoogle Scholar
  50. 50.
    Candioti L, De Zan M, Cámara M, Goicoechea H. Experimental design and multiple response optimization. Using the desirability function in analytical methods development. Talanta. 2014;124:123–38.CrossRefGoogle Scholar
  51. 51.
    Vehring R. Pharmaceutical particle engineering via spray drying. Pharm Res. 2008;25:999–1022.CrossRefGoogle Scholar
  52. 52.
    Robinson S, Stewart Smith S. 2005. Formulation for inhalation. US 6,926,908 B2. 09-12-2005.Google Scholar
  53. 53.
    Vippaguntaa S, Brittainb H, Granta D. Crystalline solids. Adv Drug Deliv Rev. 2001;48:3–26.CrossRefGoogle Scholar
  54. 54.
    Razavi Rohani S, Abnous K, Tafaghodi M. Preparation and characterization of spray-dried powders intended for pulmonary delivery of insulin with regard to the selection of excipients. Int J Pharm. 2014;465:464–78.CrossRefGoogle Scholar
  55. 55.
    Anastas P, Kirchhoff M. Origins, current status, and future challenges of green chemistry. Acc Chem Res. 2002;35:686–94.CrossRefGoogle Scholar
  56. 56.
    McCray S and Lyon D. Green drug delivery formulations, Chapter 23 in Green techniques for organic chemistry and medicinal chemistry, W. Zhang and B.W. Cue Jr. (ed.). John Wiley & Sons, New York. 2012.Google Scholar
  57. 57.
    Hoppentocht M, Hagedoorn P, Frijlink H, de Boer A. Technological and practical challenges of dry powder inhalers and formulations. Adv Drug Deliv Rev. 2014;75:18–31.CrossRefGoogle Scholar

Copyright information

© American Association of Pharmaceutical Scientists 2018

Authors and Affiliations

  • Mariela Razuc
    • 1
    • 2
    Email author
  • Juliana Piña
    • 2
    • 3
  • María V. Ramírez-Rigo
    • 1
    • 2
  1. 1.Departamento de Biología, Bioquímica y FarmaciaUniversidad Nacional del Sur (UNS)Bahía BlancaArgentina
  2. 2.Planta Piloto de Ingeniería Química (PLAPIQUI), UNS- CONICETBahía BlancaArgentina
  3. 3.Departamento de Ingeniería QuímicaUNSBahía BlancaArgentina

Personalised recommendations