Supercritical Antisolvent Process: PVP/Nimesulide Coprecipitates

  • Iolanda De MarcoEmail author
  • Valentina Prosapio
  • Ernesto Reverchon
Part of the Lecture Notes in Bioengineering book series (LNBE)


Nimesulide (NIM) is an anti-inflammatory drug, widely used in the treatment of acute pain associated with different diseases. A major limitation in its usage is due to its reduced solubility in water; therefore, large doses are required to reach the therapeutic level, with consequent undesired effects on patient’s health. In order to improve NIM dissolution rate, a possible solution is represented by its micronization. Traditional micronization techniques show several drawbacks: lack of control over the particle morphology and particle size distribution, large solvent residues and use of high temperatures. An alternative to conventional techniques is represented by supercritical carbon dioxide (scCO2) based processes. In particular, nanoparticles and microparticles of different kind of materials were successfully obtained by supercritical antisolvent (SAS) precipitation. However, when processed using SAS, nimesulide precipitated in form of large crystals or it is completely extracted by the mixture solvent/antisolvent. A solution to this problem can be the production of drug-polymer composite microspheres, using a water soluble polymer in which the drug is entrapped. In this work, NIM coprecipitation with polyvinylpyrrolidone (PVP) is proposed on pilot scale. The effects of polymer/drug ratio, concentration, pressure and temperature were investigated to identify successful operating conditions for SAS coprecipitation. Microparticles with a mean diameter ranging between 1.6 and 4.1 µm were successfully produced. Drug release analyses revealed that NIM dissolution rate from PVP/NIM microparticles was 2.5 times faster with respect to unprocessed drug. The possible precipitation mechanisms involved in the process were discussed.


Nanocomposite microparticles Coprecipitation Nimesulide Polyvinylpyrrolidone Supercritical antisolvent process Precipitation mechanisms 


  1. 1.
    Pouchain, E.C., Costa, F.W.G., Bezerra, T.P., Soares, E.C.S.: Comparative efficacy of nimesulide and ketoprofen on inflammatory events in third molar surgery: a split-mouth, prospective, randomized, double-blind study. International Journal of Oral and Maxillofacial Surgery 44(7), 876–884 (2015). doi: 10.1016/j.ijom.2014.10.026
  2. 2.
    Dashora, K., Saraf, S., Saraf, S.: Effect of processing variables and in-vitro study of microparticulate system of nimesulide. Revista Brasileira de Ciências Farmacêuticas 43, 555–562 (2007)CrossRefGoogle Scholar
  3. 3.
    Saffari, M., Ebrahimi, A., Langrish, T.: A novel formulation for solubility and content uniformity enhancement of poorly water-soluble drugs using highly-porous mannitol. Eur J Pharm Sci 83, 52–61 (2016). doi: 10.1016/j.ejps.2015.12.016
  4. 4.
    Wang, W., Liu, G., Wu, J., Jiang, Y.: Co-precipitation of 10-hydroxycamptothecin and poly (l-lactic acid) by supercritical CO2 anti-solvent process using dichloromethane/ethanol co-solvent. The Journal of Supercritical Fluids 74, 137–144 (2013). doi: 10.1016/j.supflu.2012.11.022
  5. 5.
    Couto, R., Alvarez, V., Temelli, F.: Encapsulation of Vitamin B2 in solid lipid nanoparticles using supercritical CO2. J. Supercrit. Fluids 120, Part 2, 432–442 (2017). doi: 10.1016/j.supflu.2016.05.036
  6. 6.
    Prosapio, V., Reverchon, E., De Marco, I.: Antisolvent micronization of BSA using supercritical mixtures carbon dioxide + organic solvent. J. Supercrit. Fluids 94, 189–197 (2014)CrossRefGoogle Scholar
  7. 7.
    Reverchon, E., Adami, R., De Marco, I., Laudani, C.G., Spada, A.: Pigment Red 60 micronization using supercritical fluids based techniques. J. Supercrit. Fluids 35(1), 76–82 (2005)CrossRefGoogle Scholar
  8. 8.
    Campardelli, R., Trucillo, P., Reverchon, E.: A supercritical fluid-based process for the production of fluorescein-loaded liposomes. Ind. Eng. Chem. Res. 55(18), 5359–5365 (2016). doi: 10.1021/acs.iecr.5b04885 CrossRefGoogle Scholar
  9. 9.
    Hossain, M.S., Norulaini, N.A.N., Naim, A.Y.A., Zulkhairi, A.R.M., Bennama, M.M., Omar, A.K.M.: Utilization of the supercritical carbon dioxide extraction technology for the production of deoiled palm kernel cake. J. CO2 Util. 16, 121–129 (2016). doi: 10.1016/j.jcou.2016.06.010
  10. 10.
    Smirnova, I., Mamic, J., Arlt, W.: Adsorption of drugs on silica aerogels. Langmuir 19(20), 8521–8525 (2003)CrossRefGoogle Scholar
  11. 11.
    Baldino, L., Concilio, S., Cardea, S., De Marco, I., Reverchon, E.: Complete glutaraldehyde elimination during chitosan hydrogel drying by SC-CO2 processing. J. Supercrit. Fluids 103, 70–76 (2015). doi: 10.1016/j.supflu.2015.04.020 CrossRefGoogle Scholar
  12. 12.
    Baldino, L., Concilio, S., Cardea, S., Reverchon, E.: Interpenetration of natural polymer aerogels by supercritical drying. Polymers 8(4), 106 (2016). doi: 10.3390/polym8040106 CrossRefGoogle Scholar
  13. 13.
    Badens, E., Majerik, V., Horváth, G., Szokonya, L., Bosc, N., Teillaud, E., Charbit, G.: Comparison of solid dispersions produced by supercritical antisolvent and spray-freezing technologies. Int. J. Pharm. 377(1), 25–34 (2009)CrossRefGoogle Scholar
  14. 14.
    De Marco, I., Reverchon, E.: Supercritical carbon dioxide + ethanol mixtures for the antisolvent micronization of hydrosoluble materials. Chem. Eng. J. 187, 401–409 (2012). doi:  10.1016/j.cej.2012.01.135
  15. 15.
    Rueda, M., Sanz-Moral, L.M., Segovia, J.J., Martín, Á.: Enhancement of hydrogen release kinetics from ethane 1,2 diamineborane (EDAB) by micronization using Supercritical Antisolvent (SAS) precipitation. Chem. Eng. J. 306, 164–173 (2016). doi: 10.1016/j.cej.2016.07.052 CrossRefGoogle Scholar
  16. 16.
    Moneghini, M., Perissutti, B., Vecchione, F., Kikic, I., Alessi, P., Cortesi, A., Princivalle, F.: Supercritical antisolvent precipitation of nimesulide: preliminary experiments. Curr. Drug Deliv. 4(3), 241–248 (2007). doi: 10.2174/156720107781023901
  17. 17.
    Montes, A., Gordillo, M.D., Pereyra, C., Martínez de la Ossa, E.J.: Co-precipitation of amoxicillin and ethyl cellulose microparticles by supercritical antisolvent process. J. Supercrit. Fluids 60, 75–80 (2011). doi: 10.1016/j.supflu.2011.05.002
  18. 18.
    Kurniawansyah, F., Mammucari, R., Foster, N.R.: Inhalable curcumin formulations by supercritical technology. Powder Technol. 284, 289–298 (2015). doi: 10.1016/j.powtec.2015.04.083 CrossRefGoogle Scholar
  19. 19.
    Jin, H.Y., Xia, F., Zhao, Y.P.: Preparation of hydroxypropyl methyl cellulose phthalate nanoparticles with mixed solvent using supercritical antisolvent process and its application in co-precipitation of insulin. Adv. Pow. Tech. 23(2), 157–163 (2012). doi: 10.1016/j.apt.2011.01.007
  20. 20.
    Franceschi, E., De Cezaro, A., Ferreira, S.R.S., Kunita, M.H., Muniz, E.C., Rubira, A.F., Oliveira, J.V.: Co-precipitation of beta-carotene and bio-polymer using supercritical carbon dioxide as antisolvent. Open Chem. Eng. J. 5(1), 11–20 (2011)CrossRefGoogle Scholar
  21. 21.
    Prosapio, V., Reverchon, E., De Marco, I.: Incorporation of liposoluble vitamins within PVP microparticles using supercritical antisolvent precipitation. J. CO2 Util. 19, 230–237 (2017)Google Scholar
  22. 22.
    Prosapio, V., Reverchon, E., De Marco, I.: Coprecipitation of Polyvinylpyrrolidone/β-Carotene by supercritical antisolvent processing. Ind. Eng. Chem. Res. 54(46), 11568–11575 (2015). doi: 10.1021/acs.iecr.5b03504 CrossRefGoogle Scholar
  23. 23.
    Prosapio, V., De Marco, I., Reverchon, E.: PVP/corticosteroid microspheres produced by supercritical antisolvent coprecipitation. Chem. Eng. J. 292, 264–275 (2016). doi: 10.1016/j.cej.2016.02.041
  24. 24.
    Ledet, G.A., Graves, R.A., Glotser, E.Y., Mandal, T.K., Bostanian, L.A.: Preparation and in vitro evaluation of hydrophilic fenretinide nanoparticles. Int. J. Pharm. 479(2), 329–337 (2015). doi: 10.1016/j.ijpharm.2014.12.052
  25. 25.
    Prosapio, V., Reverchon, E., De Marco, I.: Formation of PVP/nimesulide microspheres by supercritical antisolvent coprecipitation. J. Supercrit. Fluids 118, 19–26 (2016)CrossRefGoogle Scholar
  26. 26.
    Andreatta, A.E., Florusse, L.J., Bottini, S.B., Peters, C.J.: Phase equilibria of dimethyl sulfoxide (DMSO) + carbon dioxide, and DMSO + carbon dioxide + water mixtures. J. Supercrit. Fluids 42(1), 60–68 (2007). doi: 10.1016/j.supflu.2006.12.015
  27. 27.
    De Marco, I., Rossmann, M., Prosapio, V., Reverchon, E., Braeuer, A.: Control of particle size, at micrometric and nanometric range, using supercritical antisolvent precipitation from solvent mixtures: application to PVP. Chem. Eng. J. 273, 344–352 (2015)CrossRefGoogle Scholar

Copyright information

© Springer International Publishing AG 2018

Authors and Affiliations

  • Iolanda De Marco
    • 1
    Email author
  • Valentina Prosapio
    • 1
  • Ernesto Reverchon
    • 1
  1. 1.Department of Industrial EngineeringUniversity of SalernoFiscianoItaly

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