Skip to main content
SpringerLink
Log in

Nanoparticles of Poorly Water-Soluble Drugs Prepared by Supercritical Fluid Extraction of Emulsions

  • Research Paper
  • Published:
Pharmaceutical Research Aims and scope Submit manuscript

Purpose

The aim of the study was to develop and evaluate a new method for the production of micro- and nanoparticles of poorly soluble drugs for drug delivery applications.

Methods

Fine particles of model compounds cholesterol acetate (CA), griseofulvin (GF), and megestrol acetate (MA) were produced by extraction of the internal phase of oil-in-water emulsions using supercritical carbon dioxide. The particles were obtained both in a batch or a continuous manner in the form of aqueous nanosuspensions. Precipitation of CA nanoparticles was used for conducting a mechanistic study on particle size control and scale-up. GF and MA nanoparticles were produced in several batches to compare their dissolution behavior with that of micronized materials. The physical analysis of the particles produced was performed using dynamic light scattering (particle size), scanning electron microscopy (morphology), powder X-ray diffraction (crystallinity), gas chromatography (residual solvent), and a dissolution apparatus.

Results

Particles with mean volume diameter ranging between 100 and 1000 nm were consistently produced. The emulsion droplet size, drug solution concentration, and organic solvent content in the emulsion were the major parameters responsible for particle size control. Efficient and fast extraction, down to low parts-per-million levels, was achieved with supercritical CO2. The GF and MA nanoparticles produced were crystalline in nature and exhibited a 5- to 10-fold increase in the dissolution rate compared with that of micronized powders. Theoretical calculations indicated that this dissolution was governed mainly by the surface kinetic coefficient and the specific surface area of the particles produced. It was observed that the necessary condition for a reliable and scalable process was the sufficient emulsion stability during the extraction time.

Conclusion

The method developed offers a viable alternative to both the milling and constructive nanoparticle formation processes. Although preparation of a stable emulsion can be a challenge for some drug molecules, the new technique significantly shortens the processing time and overcomes the current limitations of the conventional precipitation techniques in terms of large waste streams, product purity, and process scale-up.

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

Access this article

Log in via an institution

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

Similar content being viewed by others

References

  1. B. Sjostrom B. Kronberg J. Carlfors (1993) ArticleTitleA method for 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. 82 579–583 Occurrence Handle1:STN:280:DyaK3szit12itQ%3D%3D Occurrence Handle8331529

    CAS  PubMed  Google Scholar 

  2. C. Jacobs R. H. Muller (2002) ArticleTitleProduction and characterization of a budesonide nanosuspension for pulmonary administration Pharm. Res. 19 189–194 Occurrence Handle10.1023/A:1014276917363 Occurrence Handle1:CAS:528:DC%2BD38XitVSlsro%3D Occurrence Handle11883646

    Article  CAS  PubMed  Google Scholar 

  3. B. E. Rabinow (2004) ArticleTitleNanosuspensions in drug delivery Nat. Rev., Drug Discov. 3 785–796 Occurrence Handle10.1038/nrd1494 Occurrence Handle1:CAS:528:DC%2BD2cXntFCns7o%3D

    Article  CAS  Google Scholar 

  4. E. Merisko-Liversidge (1996) ArticleTitleFormulation and antitumor activity evaluation of nanocrystalline suspensions of poorly soluble anticancer drugs Pharm. Res. 13 272–278 Occurrence Handle1:CAS:528:DyaK28Xht1Oku7w%3D Occurrence Handle8932448

    CAS  PubMed  Google Scholar 

  5. E. Merisko-Liversidge G. G. Liversidge E. Cooper (2003) ArticleTitleNanosizing: a formulation approach for poorly water-soluble compounds Eur. J. Pharm. Sci. 18 113–120 Occurrence Handle1:CAS:528:DC%2BD3sXht1Kltrg%3D Occurrence Handle12594003 Occurrence Handle10.1016/S0928-0987(02)00251-8

    Article  CAS  PubMed  Google Scholar 

  6. R. H. Muller K. Peters (1998) ArticleTitleNanosuspensions for the formulation of poorly water soluble drugs. I. Preparation by a size reductions technique Int. J. Pharm. 160 229–237 Occurrence Handle1:CAS:528:DyaK1cXot12iuw%3D%3D

    CAS  Google Scholar 

  7. M. Sarkari J. Brown X. Chen S. Swinnea R. O. Williams K. P. Johnston (2002) ArticleTitleEnhanced drug dissolution using evaporative precipitation into aqueous solution Int. J. Pharm. 243 17–31 Occurrence Handle10.1016/S0378-5173(02)00072-8 Occurrence Handle1:CAS:528:DC%2BD38Xmt1ygt7c%3D Occurrence Handle12176292

    Article  CAS  PubMed  Google Scholar 

  8. P. Bagchi, R. P. Scaringe, and H. W. Bosch. Coprecipitation of nanoparticulate pharmaceutical agents with crystal growth modifiers. U. S. Patent No. 5665331 (1997).

  9. X. Chen T. J. Young M. Sarkari R. O. Williams K. P. Johnston (2002) ArticleTitlePrecipitation of cyclosporine A nanoparticles by evaporative precipitation into aqueous solutions Int. J. Pharm. 242 3–14 Occurrence Handle10.1016/S0378-5173(02)00147-3 Occurrence Handle1:CAS:528:DC%2BD38Xmt1ygtbc%3D Occurrence Handle12176220

    Article  CAS  PubMed  Google Scholar 

  10. B. Subramanium R. A. Rajewski K. Snavely (1997) ArticleTitlePharmaceutical processing with supercritical carbon dioxide J. Pharm. Sci. 86 885–890

    Google Scholar 

  11. J. Baldyga M. Henczka B. Y. Shekunov (2004) Fluid dynamics, mass-transfer and particle formation in supercritical fluids P. York U.B. Kompella B.Y. Sthekunov (Eds) Supercritical Fluid Technology for Drug Product Development. Drugs and the Pharmaceutical Sciences, vol. 138 Marcel Dekker Series New York 91–157

    Google Scholar 

  12. J. Jung M. Perrut (2001) ArticleTitleParticle design using supercritical fluids: literature and patent survey J. Supercrit. Fluids 20 179–219 Occurrence Handle10.1016/S0896-8446(01)00064-X Occurrence Handle1:CAS:528:DC%2BD3MXksV2ltbs%3D

    Article  CAS  Google Scholar 

  13. M. Trotta M. Gallarate M. E. Carlotti S. Morel (2003) ArticleTitlePreparation of griseofulvin nanoparticles from water-dilutable microemulsions Int. J. Pharm. 254 235–242 Occurrence Handle10.1016/S0378-5173(03)00029-2 Occurrence Handle1:CAS:528:DC%2BD3sXhsFOru70%3D Occurrence Handle12623199

    Article  CAS  PubMed  Google Scholar 

  14. M. Trotta M. Gallarate F. Pattarino S. Morel (2001) ArticleTitleEmulsions containing partially water-miscible solvents for the preparation of drug nanosuspensions J. Control. Release 76 119–128 Occurrence Handle10.1016/S0168-3659(01)00432-1 Occurrence Handle1:CAS:528:DC%2BD3MXmt1Glsrc%3D Occurrence Handle11532318

    Article  CAS  PubMed  Google Scholar 

  15. B. Sjostrom B. Bergenstahl (1992) ArticleTitlePreparation of submicron drug particles in lecithin stabilized o/w emulsions. I. Model studies of the precipitation of cholesteryl acetate Int. J. Pharm. 88 53–62 Occurrence Handle10.1016/0378-5173(92)90303-J

    Article  Google Scholar 

  16. D. Kashchiev (2000) Nucleation: Basic Theory with Applications Butterworth-Heinemann Oxford

    Google Scholar 

  17. P. Chattopadhyay R. B. Gupta (2001) ArticleTitleProduction of griseofulvin nanoparticles using supercritical CO2 antisolvent with enhanced mass transfer Int. J. Pharm. 228 19–31 Occurrence Handle10.1016/S0378-5173(01)00803-1 Occurrence Handle1:CAS:528:DC%2BD3MXntVWku7k%3D Occurrence Handle11576765

    Article  CAS  PubMed  Google Scholar 

  18. E. Reverchon G. Porta ParticleDella (1999) ArticleTitleProduction of antibiotic micro- and nano-particles by supercritical antisolvent precipitation Powder Technol. 106 23–29 Occurrence Handle1:CAS:528:DyaK1MXotFOrsLk%3D

    CAS  Google Scholar 

  19. P. Chattopadhyay B. Y. Shekunov J. S. Seitzinger R. Huff (2003) ArticleTitleParticles from supercritical fluid extraction of emulsions (PSFEE): preparation of composite particles for drug targeting and controlled release AAPS PharmSci 5 W5099

    Google Scholar 

  20. J. W. Mullin (1993) Crystallization EditionNumber3rd Edn Butterworth Heinemann Oxford

    Google Scholar 

  21. A. A. Chernov (1984) Modern Crystallography III, Crystal Growth, Springer Series in Solid State Physics Springer Berlin

    Google Scholar 

Download references

Acknowledgments

The authors thank Dave Gnizak and Sara Freeman, Ferro Analytical Department, for the SEM analysis and XRD studies, respectively. The authors also thank Dr. Carl Lentz for his advice during the design of the experimental studies.

Author information

Authors and Affiliations

  1. Posnick Center of Innovative Technology, Ferro Corporation, Independence, Ohio, 44131, USA

    Boris Y. Shekunov, Pratibhash Chattopadhyay, Jeff Seitzinger & Robert Huff

Authors
  1. Boris Y. Shekunov
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Pratibhash Chattopadhyay
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Jeff Seitzinger
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Robert Huff
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Boris Y. Shekunov.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Shekunov, B.Y., Chattopadhyay, P., Seitzinger, J. et al. Nanoparticles of Poorly Water-Soluble Drugs Prepared by Supercritical Fluid Extraction of Emulsions. Pharm Res 23, 196–204 (2006). https://doi.org/10.1007/s11095-005-8635-4

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11095-005-8635-4

Key Words

Search

Navigation