Skip to main content

Advertisement

Log in

Influence of Formulation and Processing Variables on Properties of Itraconazole Nanoparticles Made by Advanced Evaporative Precipitation into Aqueous Solution

AAPS PharmSciTech Aims and scope Submit manuscript

Abstract

Nanoparticles, of the poorly water-soluble drug, itraconazole (ITZ), were produced by the Advanced Evaporative Precipitation into Aqueous Solution process (Advanced EPAS). This process combines emulsion templating and EPAS processing to provide improved control over the size distribution of precipitated particles. Specifically, oil-in-water emulsions containing the drug and suitable stabilizers are sprayed into a heated aqueous solution to induce precipitation of the drug in form of nanoparticles. The influence of processing parameters (temperature and volume of the heated aqueous solution; type of nozzle) and formulation aspects (stabilizer concentrations; total solid concentrations) on the size of suspended ITZ particles, as determined by laser diffraction, was investigated. Furthermore, freeze-dried ITZ nanoparticles were evaluated regarding their morphology, crystallinity, redispersibility, and dissolution behavior. Results indicate that a robust precipitation process was developed such that size distribution of dispersed nanoparticles was shown to be largely independent across the different processing and formulation parameters. Freeze-drying of colloidal dispersions resulted in micron-sized agglomerates composed of spherical, sub-300-nm particles characterized by reduced crystallinity and high ITZ potencies of up to 94% (w/w). The use of sucrose prevented particle agglomeration and resulted in powders that were readily reconstituted and reached high and sustained supersaturation levels upon dissolution in aqueous media.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

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

Similar content being viewed by others

REFERENCES

  1. Strickley RG. Solubilizing excipients in oral and injectable formulations. Pharm Res. 2004;21(2):201–30.

    Article  PubMed  CAS  Google Scholar 

  2. Singla AK, Garg A, Aggarwal D. Paclitaxel and its formulations. Int J Pharm. 2002;235(1–2):179–92.

    Article  PubMed  CAS  Google Scholar 

  3. Pouton CW. Formulation of poorly water-soluble drugs for oral administration: physicochemical and physiological issues and the lipid formulation classification system. Eur J Pharm Sci. 2006;29(3–4):278–87.

    Article  PubMed  CAS  Google Scholar 

  4. Miele E, Spinelli GP, Miele E, Tomao F, Tomao S. Albumin-bound formulation of paclitaxel (Abraxane ABI-007) in the treatment of breast cancer. Int J Nanomedicine. 2009;4:99–105.

    PubMed  CAS  Google Scholar 

  5. Gradishar WJ, Tjulandin S, Davidson N, Shaw H, Desai N, Bhar P, et al. Phase III trial of nanoparticle albumin-bound paclitaxel compared with polyethylated castor oil-based paclitaxel in women with breast cancer. J Clin Oncol. 2005;23(31):7794–803.

    Article  PubMed  CAS  Google Scholar 

  6. Keck CM, Müller RH. Drug nanocrystals of poorly soluble drugs produced by high pressure homogenisation. Eur J Pharm Biopharm. 2006;62(1):3–16.

    Article  PubMed  CAS  Google Scholar 

  7. Van Eerdenbrugh B, Van den Mooter G, Augustijns P. Top–down production of drug nanocrystals: nanosuspension stabilization, miniaturization and transformation into solid products. Int J Pharm. 2008;364(1):64–75.

    Article  PubMed  Google Scholar 

  8. Ali HSM, York P, Blagden N. Preparation of hydrocortisone nanosuspension through a bottom–up nanoprecipitation technique using microfluidic reactors. Int J Pharm. 2009;375(1–2):107–13.

    Article  PubMed  CAS  Google Scholar 

  9. de Waard H, Hinrichs WLJ, Frijlink HW. A novel bottom–up process to produce drug nanocrystals: controlled crystallization during freeze-drying. J Control Release. 2008;128(2):179–83.

    Article  PubMed  Google Scholar 

  10. D’Addio SM, Prud’homme RK. Controlling drug nanoparticle formation by rapid precipitation. Adv Drug Deliv Rev. 2011;63(6):417–26.

    Article  PubMed  Google Scholar 

  11. Chen X, Young TJ, Sarkari M, Williams RO, Johnston KP. Preparation of cyclosporine A nanoparticles by evaporative precipitation into aqueous solution. Int J Pharm. 2002;242(1–2):3–14.

    Article  PubMed  CAS  Google Scholar 

  12. Sarkari M, Brown J, Chen X, Swinnea S, Williams RO, Johnston KP. Enhanced drug dissolution using evaporative precipitation into aqueous solution. Int J Pharm. 2002;243(1–2):17–31.

    Article  PubMed  CAS  Google Scholar 

  13. Chen X, Benhayoune Z, Williams RO, Johnston KP. Rapid dissolution of high potency itraconazole particles produced by evaporative precipitation into aqueous solution. J Drug Deliv Sci Technol. 2004;14(4):299–304.

    CAS  Google Scholar 

  14. Sinswat P, Gao X, Yacaman MJ, Williams RO, Johnston KP. Stabilizer choice for rapid dissolving high potency itraconazole particles formed by evaporative precipitation into aqueous solution. Int J Pharm. 2005;302(1–2):113–24.

    Article  PubMed  CAS  Google Scholar 

  15. Margulis-Goshen K, Kesselman E, Danino D, Magdassi S. Formation of celecoxib nanoparticles from volatile microemulsions. Int J Pharm. 2010;393(1–2):230–7.

    PubMed  CAS  Google Scholar 

  16. Sjöström B, Kronberg B, Carlfors J. A method for the preparation of submicron particles of sparingly water-soluble drugs by precipitation in oil-in-water emulsions. I. Influence of emulsification and surfactant concentration. J Pharm Sci. 1993;82(6):579–83.

    Article  PubMed  Google Scholar 

  17. Peeters J, Neeskens P, Tollenaere JP, Van Remoortere P, Brewster ME. Characterization of the interaction of 2-hydroxypropyl-beta-cyclodextrin with itraconazole at pH 2, 4, and 7. J Pharm Sci. 2002;91(6):1414–22.

    Article  PubMed  CAS  Google Scholar 

  18. Matteucci ME, Miller MA, Williams RO, Johnston KP. Highly supersaturated solutions of amorphous drugs approaching predictions from configurational thermodynamic properties. J Phys Chem B. 2008;112(51):16675–81.

    Article  PubMed  CAS  Google Scholar 

  19. Chen X, Vaughn JM, Yacaman MJ, Williams RO, Johnston KP. Rapid dissolution of high-potency danazol particles produced by evaporative precipitation into aqueous solution. J Pharm Sci. 2004;93(7):1867–78.

    Article  PubMed  CAS  Google Scholar 

  20. Lefebvre A. General considerations. In: Tamburrino S, Prescott M, editors. Atomization and sprays. New York: Taylor & Francis; 1989. p. 1–24.

    Google Scholar 

  21. Fowler K. In: Rowe RC, Sheskey PJ, Owen SC, editors. Handbook of pharmaceutical excipients. London: Pharmaceutical Press and American Pharmacists Association; 2006. p. 409–11.

    Google Scholar 

  22. Fillery-Travis AJ, Foster LH, Robins MM. Stability of emulsions stabilised by two physiological surfactants: l-alpha-phosphatidylcholine and sodium taurocholate. Biophys Chem. 1995;54(3):253–60.

    Article  PubMed  CAS  Google Scholar 

  23. Wickham M, Garrood M, Leney J, Wilson PDG, Fillery-Travis A. Modification of a phospholipid stabilized emulsion interface by bile salt: effect on pancreatic lipase activity. J Lipid Res. 1998;39(3):623–32.

    PubMed  CAS  Google Scholar 

  24. Islam MS, Alam SMR, Sadat SMA, Chowdhury JA, Jalil R-ul. Preparation and characterization of polyvinyl acetate (Kollidon® SR) microspheres containing diclofenac sodium I: effect of stirring rate and total solid content. Dhaka Univ J Pharm Sci. 2010;8(2):111–6.

    Google Scholar 

  25. Sorensen J, Arlt W. Liquid–liquid equilibrium data collection: binary mixtures. In: Behrens D, Eckermann R, editors. Chemistry data series, vol I. Frankfurt/Main: Deutsche Gesellschaft für Chemisches Apparatewesen; 1979. pp. 20–1

  26. Yang YY, Chia HH, Chung TS. Effect of preparation temperature on the characteristics and release profiles of PLGA microspheres containing protein fabricated by double-emulsion solvent extraction/evaporation method. J Control Release. 2000;69(1):81–96.

    Article  PubMed  CAS  Google Scholar 

  27. FDA. International Conference on Harmonization - Guidance for Industry. Q3C Impurities: Residual Solvents [Internet]. Available from: http://www.fda.gov/downloads/RegulatoryInformation/Guidances/ucm128317.pdf. Accessed on 7 March 2012

  28. Verma S, Kumar S, Gokhale R, Burgess DJ. Physical stability of nanosuspensions: investigation of the role of stabilizers on Ostwald ripening. Int J Pharm. 2011;406(1–2):145–52.

    Article  PubMed  CAS  Google Scholar 

  29. Abdelwahed W, Degobert G, Stainmesse S, Fessi H. Freeze-drying of nanoparticles: formulation, process and storage considerations. Adv Drug Deliv Rev. 2006;58(15):1688–713.

    Article  PubMed  CAS  Google Scholar 

  30. Konno H, Taylor LS. Influence of different polymers on the crystallization tendency of molecularly dispersed amorphous felodipine. J Pharm Sci. 2006;95(12):2692–705.

    Article  PubMed  CAS  Google Scholar 

  31. Van den Mooter G, Wuyts M, Blaton N, Busson R, Grobet P, Augustijns P, et al. Physical stabilisation of amorphous ketoconazole in solid dispersions with polyvinylpyrrolidone K25. Eur J Pharm Sci. 2001;12(3):261–9.

    Article  PubMed  Google Scholar 

  32. Yoshioka M, Hancock BC, Zografi G. Inhibition of indomethacin crystallization in poly(vinylpyrrolidone) coprecipitates. J Pharm Sci. 1995;84(8):983–6.

    Article  PubMed  CAS  Google Scholar 

  33. Mukhopadhyay S, Maitra U. Chemistry and biology of bile acids. Curr Sci. 2004;87(12):1666–83.

    CAS  Google Scholar 

  34. Tadros T. Polymeric surfactants in disperse systems. Adv Colloid Interface Sci. 2009;147–148:281–99.

    Article  PubMed  Google Scholar 

  35. Lindfors L, Skantze P, Skantze U, Rasmusson M, Zackrisson A, Olsson U. Amorphous drug nanosuspensions. 1. Inhibition of Ostwald ripening. Langmuir. 2006;22(3):906–10.

    Article  PubMed  CAS  Google Scholar 

  36. Margulis-Goshen K, Weitman M, Major DT, Magdassi S. Inhibition of crystallization and growth of celecoxib nanoparticles formed from volatile microemulsions. J Pharm Sci. 2011;100(10):4390–400.

    Article  CAS  Google Scholar 

  37. Lindfors L, Skantze P, Skantze U, Westergren J, Olsson U. Amorphous drug nanosuspensions. 3. Particle dissolution and crystal growth. Langmuir. 2007;23(19):9866–74.

    Article  PubMed  CAS  Google Scholar 

  38. Lindfors L, Forssén S, Westergren J, Olsson U. Nucleation and crystal growth in supersaturated solutions of a model drug. J Colloid Interface Sci. 2008;325(2):404–13.

    Article  PubMed  CAS  Google Scholar 

  39. Rumondor ACF, Stanford LA, Taylor LS. Effects of polymer type and storage relative humidity on the kinetics of felodipine crystallization from amorphous solid dispersions. Pharm Res. 2009;26(12):2599–606.

    Article  PubMed  CAS  Google Scholar 

  40. Wen H, Morris KR, Park K. Synergic effects of polymeric additives on dissolution and crystallization of acetaminophen. Pharm Res. 2008;25(2):349–58.

    Article  PubMed  CAS  Google Scholar 

  41. Bhugra C, Pikal MJ. Role of thermodynamic, molecular, and kinetic factors in crystallization from the amorphous state. J Pharm Sci. 2008;97(4):1329–49.

    Article  PubMed  CAS  Google Scholar 

  42. Konan YN, Gurny R, Allémann E. Preparation and characterization of sterile and freeze-dried sub-200 nm nanoparticles. Int J Pharm. 2002;233(1–2):239–52.

    Article  PubMed  CAS  Google Scholar 

  43. Miller MA, Dinunzio J, Matteucci ME, Ludher BS, Williams RO, Johnston KP. Flocculated amorphous itraconazole nanoparticles for enhanced in vitro supersaturation and in vivo bioavailability. Drug Dev Ind Pharm. 2012;38(5):557–70.

    Article  PubMed  CAS  Google Scholar 

  44. Miller DA, DiNunzio JC, Yang W, McGinity JW, Williams RO. Enhanced in vivo absorption of itraconazole via stabilization of supersaturation following acidic-to-neutral pH transition. Drug Dev Ind Pharm. 2008;34(8):890–902.

    Article  PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Stephanie Bosselmann.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Bosselmann, S., Nagao, M., Chow, K.T. et al. Influence of Formulation and Processing Variables on Properties of Itraconazole Nanoparticles Made by Advanced Evaporative Precipitation into Aqueous Solution. AAPS PharmSciTech 13, 949–960 (2012). https://doi.org/10.1208/s12249-012-9817-0

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1208/s12249-012-9817-0

KEY WORDS

Navigation