Effect of Process Conditions on the Morphological Characteristics of Particles Obtained by Supercritical Antisolvent Precipitation

  • Diego T. SantosEmail author
  • Ádina L. Santana
  • M. Angela A. Meireles
  • Ademir José Petenate
  • Eric Keven Silva
  • Juliana Q. Albarelli
  • Júlio C. F. Johner
  • M. Thereza M. S. Gomes
  • Ricardo Abel Del Castillo Torres
  • Tahmasb Hatami
Part of the SpringerBriefs in Applied Sciences and Technology book series (BRIEFSAPPLSCIENCES)


A supercritical particle formation equipment, designed and constructed by our research group, was validated in this study using supercritical CO2 as an antisolvent. Ibuprofen sodium salt was successfully micronized by supercritical antisolvent (SAS) precipitation. Ethanol and CO2 was used as solvent and antisolvent, respectively, and the effect of the operating conditions on the precipitation yield, residual organic solvent content and particle morphology were evaluated using a split-plot experimental design and the analysis of variance (ANOVA) method. This study showed that when selecting appropriate process conditions, it is possible to produce a sheet-like morphology, which is the best for tableting purposes, with high precipitation yield (70%) and low residual solvent content (4.7 mg kg−1).



The authors are grateful to CNPq (470916/2012-5) and FAPESP (2012/10685-8) for their financial support. M. Thereza M. G. Rosa and Eric Keven Silva thanks CNPq (140641/2011-4 and 140275/2014-2) for the Ph.D. assistantship. Diego T. Santos thanks the FAPESP (10/16485-5; 12/19304-7) and CAPES for the postdoctoral fellowships. M. Angela A. Meireles thanks CNPq for a productivity grant (301301/2010-7). The authors also thank Moyses N. Moraes for his assistance with the statistical analyses.


  1. 1.
    Z. Knez, E. Weidner, Particles formation and particle design using supercritical fluids. Curr. Opin. Solid State Mater. Sci. 7, 353–361 (2003)CrossRefGoogle Scholar
  2. 2.
    S. Dalziel, G. Foggin, W. Ford, H. Gommeren, High pressure media milling system and process of forming particles, Patent US 20050258288 A1, Google Patents (2004)Google Scholar
  3. 3.
    P.J. Linstrom, W. Mallard, NIST Chemistry, National Institute of Standards and Technology. Gaithersburg (2003)Google Scholar
  4. 4.
    P. Gruber, M. Reher, Dosage form of sodium ibuprofen, Patent US 20040102522 A1, Google Patents (2004)Google Scholar
  5. 5.
    T.L. Rogers, K.P. Johnston, R.O. Williams 3rd, Solution-based particle formation of pharmaceutical powders by supercritical or compressed fluid CO2 and cryogenic spray-freezing technologies. Drug Dev. Ind. Pharm. 27, 1003–1015 (2001)CrossRefGoogle Scholar
  6. 6.
    K.M. Sharif, M.M. Rahman, J. Azmir, A. Mohamed, M.H.A. Jahurul, F. Sahena, I.S.M. Zaidul, Experimental design of supercritical fluid extraction—A review. J. Food Eng. 124, 105–116 (2014)CrossRefGoogle Scholar
  7. 7.
    G.E. Box, J.S. Hunter, W.G. Hunter, Statistics for experimenters: design, innovation, and discovery, 2nd edn. (Wiley, New York, 2005)Google Scholar
  8. 8.
    Á. Martín, K. Scholle, F. Mattea, D. Meterc, M.J. Cocero, Production of Polymorphs of Ibuprofen Sodium by Supercritical Antisolvent (SAS) Precipitation. Cryst. Growth Des. 9, 2504–2511 (2009)CrossRefGoogle Scholar
  9. 9.
    C.J. Chang, K.-L. Chiu, C.-Y. Day, A new apparatus for the determination of P–x–y diagrams and Henry’s constants in high pressure alcohols with critical carbon dioxide. J. Supercrit. Fluids 12, 223–237 (1998)CrossRefGoogle Scholar
  10. 10.
    C.S. Su, W.S. Lo, L.H. Lien, Micronization of fluticasone propionate using supercritical antisolvent (SAS) process. Chem. Eng. Technol. 34, 535–541 (2011)CrossRefGoogle Scholar
  11. 11.
    A. Visentin, S. Rodríguez-Rojo, A. Navarrete, D. Maestri, M.J. Cocero, Precipitation and encapsulation of rosemary antioxidants by supercritical antisolvent process. J. Food Eng. 109, 9–15 (2012)CrossRefGoogle Scholar
  12. 12.
    V. Majerik, G. Charbit, E. Badens, G. Horváth, L. Szokonya, N. Bosc, E. Teillaud, Bioavailability enhancement of an active substance by supercritical antisolvent precipitation. J. Supercrit. Fluids 40, 101–110 (2007)CrossRefGoogle Scholar
  13. 13.
    X. Sui, W. Wei, L. Yang, Y. Zu, C. Zhao, L. Zhang, F. Yang, Z. Zhang, Preparation, characterization and in vivo assessment of the bioavailability of glycyrrhizic acid microparticles by supercritical anti-solvent process. Int. J. Pharm. 423, 471–479 (2012)CrossRefGoogle Scholar
  14. 14.
    P. Imsanguan, S. Pongamphai, S. Douglas, W. Teppaitoon, P.L. Douglas, Supercritical antisolvent precipitation of andrographolide from Andrographis paniculata extracts: Effect of pressure, temperature and CO2 flow rate. Powder Technol. 200, 246–253 (2010)CrossRefGoogle Scholar
  15. 15.
    ICH, International Conference on Harmonization (ICH) of Technical Requirements for the Registration of Pharmaceuticals for Human Use. Guideline for Residual Solvents Step 4 (1997)Google Scholar
  16. 16.
    R. Adami, E. Reverchon, E. Järvenpää, R. Huopalahti, Supercritical AntiSolvent micronization of nalmefene HCl on laboratory and pilot scale. Powder Technol. 182, 105–112 (2008)CrossRefGoogle Scholar
  17. 17.
    M.-S. Kim, S. Lee, J.-S. Park, J.-S. Woo, S.-J. Hwang, Micronization of cilostazol using supercritical antisolvent (SAS) process: effect of process parameters. Powder Technol. 177, 64–70 (2007)CrossRefGoogle Scholar
  18. 18.
    E. Reverchon, G. Caputo, I. De Marco, Role of phase behavior and atomization in the supercritical antisolvent precipitation. Ind. Eng. Chem. Res. 42, 6406–6414 (2003)CrossRefGoogle Scholar
  19. 19.
    Y. Bakhbakhi, S. Alfadul, A. Ajbar, Precipitation of Ibuprofen Sodium using compressed carbon dioxide as antisolvent, European journal of pharmaceutical sciences: official journal of the European Federation for. Pharm. Sci. 48, 30–39 (2013)Google Scholar
  20. 20.
    E. Reverchon, Supercritical antisolvent precipitation of micro- and nano-particles. J. Supercrit. Fluids 15, 1–21 (1999)CrossRefGoogle Scholar
  21. 21.
    P.J. Linstrom, W. Mallard, NIST chemistry webbook (National Institute of Standards and Technology Gaithersburg, MD, 2001)Google Scholar
  22. 22.
    P. Pathak, M.J. Meziani, T. Desai, Y.-P. Sun, Formation and stabilization of ibuprofen nanoparticles in supercritical fluid processing. J. Supercrit. Fluids 37, 279–286 (2006)CrossRefGoogle Scholar
  23. 23.
    Y. Li, D.J. Yang, S.L. Chen, S.B. Chen, A.S.C. Chan, Comparative physicochemical characterization of phospholipids complex of puerarin formulated by conventional and supercritical methods. Pharm. Res. 25, 563–577 (2008)CrossRefGoogle Scholar
  24. 24.
    D.H. Won, M.S. Kim, S. Lee, J.S. Park, S.J. Hwang, Improved physicochemical characteristics of felodipine solid dispersion particles by supercritical anti-solvent precipitation process. Int. J. Pharm. 301, 199–208 (2005)CrossRefGoogle Scholar
  25. 25.
    R.E. Gordon, S.I. Amin, Crystallization of ibuprofen, Patent US 4476248 A, Google Patents (1984)Google Scholar

Copyright information

© The Author(s), under exclusive license to Springer Nature Switzerland AG 2019

Authors and Affiliations

  • Diego T. Santos
    • 1
    Email author
  • Ádina L. Santana
    • 2
  • M. Angela A. Meireles
    • 3
  • Ademir José Petenate
    • 4
  • Eric Keven Silva
    • 5
  • Juliana Q. Albarelli
    • 6
  • Júlio C. F. Johner
    • 7
  • M. Thereza M. S. Gomes
    • 8
  • Ricardo Abel Del Castillo Torres
    • 9
  • Tahmasb Hatami
    • 10
  1. 1.LASEFI/DEA, School of Food EngineeringUniversity of Campinas—UNICAMPCampinasBrazil
  2. 2.LASEFI/DEA, School of Food EngineeringUniversity of Campinas—UNICAMPCampinasBrazil
  3. 3.LASEFI/DEA, School of Food EngineeringUniversity of Campinas—UNICAMPCampinasBrazil
  4. 4.Process ImprovementEDTICampinasBrazil
  5. 5.LASEFI/DEA, School of Food EngineeringUniversity of Campinas—UNICAMPCampinasBrazil
  6. 6.LASEFI/DEA, School of Food EngineeringUniversity of Campinas—UNICAMPCampinasBrazil
  7. 7.LASEFI/DEA, School of Food EngineeringUniversity of Campinas—UNICAMPCampinasBrazil
  8. 8.LASEFI/DEA, School of Food EngineeringUniversity of Campinas—UNICAMPCampinasBrazil
  9. 9.LASEFI/DEA, School of Food EngineeringUniversity of Campinas—UNICAMPCampinasBrazil
  10. 10.LASEFI/DEA, School of Food EngineeringUniversity of Campinas—UNICAMPCampinasBrazil

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