Applications of Supercritical Fluids to Pharmaceuticals: Controlled Drug Release Systems

  • I. Kikic
  • P. Sist
Part of the NATO Science Series book series (NSSE, volume 366)


Controlled drag delivery systems received considerable attention in the last years and they are providing in general a more controlled rate of uptake of the drag by the body. In this way their therapeutic action is prolonged without increasing the dosage. The common way of controlling the release is by incorporating the drug in a polymeric carrier: the active pharmaceutical is released in the affected site by way of diffusion or surface erosion.


Supercritical Fluid Supercritical Carbon Dioxide Supercritical Fluid Chromatography Control Release System Salmeterol Xinafoate 
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  1. 1.
    Grassi, M. (1989) Design of Drug Delivery Systems: Diffusion in Biopolymer Hydrogeis, University of Trieste.Google Scholar
  2. 2.
    Leong, K.W. and Langer, R. (1987) Polymeric Controlled Drag Delivery, Advanced Drug Delivery Release 1, 199–233.CrossRefGoogle Scholar
  3. 3.
    San Roman, J., Gallardo, A. and Levenfeld, B. (1994) New Polymers for Biomedical Applications: Synthesis and Characterization of Acrylic Systems with Pharmacological Activity, Macromoiecular Symposia 84, 145–158.CrossRefGoogle Scholar
  4. 4.
    Robinson, R.J. and Lee, H.L.V. (1987) Controlled Drug Delivery:Fundamentals and Applications, Marcel Dckker, Inc., New York and Basel.Google Scholar
  5. 5.
    Kojima, S. (1997) Guidelines for Residual Solvents, Fourth International Conference on Harmonisation (ICH4), Bruxelles, July, Step 4 Draft.Google Scholar
  6. 6.
    Alessi, P., CortesI, A., Kikic, I., Colombo, I. Solvent Removal from Pharmaceutical Products, Proc, 4th Italian Conference on “Supercritical fluids and their Applications”, Capri, September, 115–120.Google Scholar
  7. 7.
    Matson, D.W., Petersen, C.R. and Smith, D.R. (1987) Production of Powders and Films by the Rapid Expansion of Supercritical Solutions, J. Materials Sci. 22, 1919–1928.CrossRefGoogle Scholar
  8. 8.
    Maison, D.W., Fulton, J.L., Petersen, R.C. and Smith, R.D. (1987) Rapid Expansion of Supercritical Fluid Solution: Solyte Formation of Powders, Thin Finis, and Fibers, Ind. Eng. Chem. Res. 26, 2298–2306.CrossRefGoogle Scholar
  9. 9.
    Kwauk, X. and Debenedetti, P.G. (1993) Mathematical Modeling of Aerosol Formation by rapid Expansion of Supercritical Solutions in a Convergence Nozzle, J. Aerosol. Sci. 34, 445–469.CrossRefGoogle Scholar
  10. 10.
    Mohamed, R.S., Halverson, D.S., Debenedetti, P.G. and Prud’homme, R.K. (1989) Solids Formation After the Expansion of Supercritical Mixtures, ACS Symposium Series 406, 355–378.CrossRefGoogle Scholar
  11. 11.
    Tom, J.W., Debenedetti, P.G. and Jerome, R. (1994) Precipitation of Poly(L-lactic acid) and Composite PoIy(L-Iactic acid)-Pyrene Particles by Rapid Expansion of Supercritical Solution, J. Supercrit. Fluids 7, 9–29.CrossRefGoogle Scholar
  12. 12.
    Mohamed, R.S., Debenedetti, P.G. and Prud’homme, R.K. (1989) Effects of Process Conditions on Crystals Obtained from Supercritical Mixtures, A.I.Ch.E. J. 35, 325–328.CrossRefGoogle Scholar
  13. 13.
    Alessi, P., Cortesi, A., Kikic, I., Foster, N.R., Macnaughton, S.J. and Colombo, I. (1996) Particle Production of Steroid Drugs Using Supercritical Fluid Processing, Ind. Eng. Chem. Res. 35, 4718–4726.CrossRefGoogle Scholar
  14. 14.
    Krukonis, V. (1984) Supercritical Fluid Nucieation of Difficult to Comminute Solids, A.I.Ch.E. Meeting, San Francisco, November, Papa- 140f.Google Scholar
  15. 15.
    Loth, H., Hemgesberg, E. (1986) Properties and Dissolution of Drugs Micronizcd by Cry stall ration from Supercritical Gases, Int. J. Pharm. 32, 265–267.CrossRefGoogle Scholar
  16. 16.
    Larson, K.A., King, M.L. (1986) Evaluation of Supercritical Fluid Extraction in the Pharmaceutical Industry, Biotech. Prog. 2, 73–82.CrossRefGoogle Scholar
  17. 17.
    Chang, C.J. and Randolph, A.D. (1989) Precipitation of Microsize Organic Particles from Supercritical Fluids, A.I.Ch.E. J. 35, 1876–1882.CrossRefGoogle Scholar
  18. 18.
    Tavana, A. and Randolph, A.D. (1989) Manipulating Solids CSD in a Supercritical Fluid Crystallizer: CO2 — Benzole Acid, A.I.Ch.E. J. 35, 1625–1630.CrossRefGoogle Scholar
  19. 19.
    Berends, E.M., Bruinsma, O.S.L. and van Rosmalen, G.M. (1993) Nudeation and Growth of Fine Crystals from Supercritical Carbon Dioxide, J. Crystal Growth 128, 50–56.CrossRefGoogle Scholar
  20. 20.
    Furuta, S., Rousseau, R.W., Teja, A.S. (1992) Production of Fine particles by Rapid Expansion of Amino Acid Solutions at High Temperatures and Pressures, A.I.Ch.E. Annual Meeting, Miami, 706.Google Scholar
  21. 21.
    Ohgaki, K., Kobayashi, H., Katayama, T. and Hirokawa, N. (1990) Whisker Formation from Jet of Supercritical Fluid Solution, J. Supercrit. Fluids 3, 103–107.CrossRefGoogle Scholar
  22. 22.
    Reverchon, E., Donsi, G. and Gorgoglione, D. (1993) Salicylic Acid Solubilization in Supercritical CO2 and Its Micronizatlon by RESS, J. Supercrit. Fluids 6, 241–248.CrossRefGoogle Scholar
  23. 23.
    Tom, J.V., Lim, G.-B., Debenoktti, P.G. and Prud’homme, R.K. (1993) Applications of Supercritical Fluids in Controlled Release of Drags. In Supercritical Fluid Engineering Science, Kiran, E., Brenmeclce, J.F., Eds., ACS Symp. Series 514; American Chemical Society: Washington, D.C., 238–257.Google Scholar
  24. 24.
    Revereiton, E., Delia Porte, G., Taddeo, R., Pailado, P. and Siassi, A. (1995) Solubility and Mlcroniation of Griseofulvin In Supercritical CHF3, Ind. Eng. Chem. Res. 34, 4087–4091.CrossRefGoogle Scholar
  25. 25.
    Gerard, D. and Quirin, K.-W. (1987) Private communication of FLAVEX Naturoctraktc GmbH, In Stahl E., Quirk K.-W., Gerard D., Dense Gases for Extraction and Refining, Springer Verlag Ed.Google Scholar
  26. 26.
    Best, W., Muller, F.J., Schmieder, K., Frank, R. and Paust, J. Germ Pat. Appl. 29 43 267 (BASF AG); filed 1979. (As reported in Steh!, E.; Quirin, K.-W.; Gerard, D.; Dense Gases for Extraction and Refining, Springe- Vertag Ed. 1987 )Google Scholar
  27. 27.
    Subra, P. and Debenedetti P.G. (1996) Application of RESS to Several Low Molecular Weight Compounds, High Pressure Chemical Engineering, Edited by Ph. RudoIf von Rohr and Ch.Trepp, Elsevier, Amsterdam, pp. 49–54.Google Scholar
  28. 28.
    Tom, W.J. and Debenedetti, P.G. (1991) Formation of Biocrodible Polymeric Microspheres and Microparticles by Rapid Expansion of Supercritical Solutions, Biotechnology Progress 7, 403–411.CrossRefGoogle Scholar
  29. 29.
    Kim, J.-H., Paxton, T.E. and Tomasko, D.L. (1996) Microemcapsufation of Nap-oxen Using Rapid Expansion of Supercritical Solutions, Biotechnology Progress 12, 650–661.CrossRefGoogle Scholar
  30. 30.
    Mfshfma, K., Matsuyama, K., Uchiyama, H., Ide, M., Shim, J.-J. and Bac, H.-K. (1997) Microcoating of Flavone and 3-Hydroxyflavone with Polymer Using Supercritical Carbon Dioxide, The 4* International Symposium on Supercritical Fluids, Sendai, Japan, 267–270.Google Scholar
  31. 31.
    Debenedetti, P.G., Torn, J.W., Yeo, S.-D. and Lim, G.-B. (1993) Application of Supercritical Fluids for the Production of Sustained Delivery Devices, Journal of Controlled Release 24, 27–44.CrossRefGoogle Scholar
  32. 32.
    Gallagher, P.M., Coffey, M.P., Krukonis, V.J. and Klasutis, N. (1989) Gas Antisolvent Recrystollization: New Process to Recrystollize Compounds Insoluble in Supercritical Fluids, in Supercritical Science and Technology, ACS Symposium Series 406, Johnson, K.P., Penninger, J.M.L., Eds., American Chemical Society: Washington D.C., pp. 334–354.Google Scholar
  33. 33.
    Dixon, D.J., Johnston, K.P. and Bodmeler, R.A. (1993) Polymeric Materials Formal by Precipitation with a Compressed Fluid Anttsofvent, A.I.Ch.E. J. 39, 127–139.CrossRefGoogle Scholar
  34. 34.
    Bleich, J., Müller, B.W. WaΩmus, W. (1993) Aerosol Solvent Extraction System: A New Microparticle Production Technique, Int. J. Pharm. 97, 111–117.Google Scholar
  35. 35.
    Yeo, S.-D., Debenedetti, P.G., Radosz, M. and Schmidt, H.-W. (1993) Supercritical Antisolveet Process for Substituted Para-IInked Aromatic Polyamides: Phase Equilibrium and Morphology Study. Macromokcules 26, 6207.CrossRefGoogle Scholar
  36. 36.
    Reverehon, E. (1998) Supercritical Antisoivent Precipitation: Its Application to Microparticle Generation and Products Fractionation, Proceedings of the 5th Meeting on Supercritical Fluids, Nice, 221–236.Google Scholar
  37. 37.
    Dixon, D. and Johnston, K.P. (1991) Molecular Thcrmodymmics of Solubilities in Gas-Antisolvent Crystallization., A.I.Ch.E. J. 37, 1441.CrossRefGoogle Scholar
  38. 38.
    Kick, I., Lora, M. and Bertucco, A. (1997) A Thermodynamic Analysis of Three-Phase Equilibria in Binary and Ternary Systems for Applications in Rapid Expansion of a Supercritical Solution (RESS), Particles from Gas-Saturated Solutions (PGSS), and Supercritical Antisolvent (SAS), Ind. Eng. Chem. Res. 36, 5507–5515.CrossRefGoogle Scholar
  39. 39.
    Kikic, I., Bertocco, A. and Lora, M. (1997) Thermodynamic Description of Systems Involved in Supercritical Anti-Solvent Processes, The 4 th International Symposium on Supercritical Fluids, Sendai, Japan, pp. 39–42.Google Scholar
  40. 40.
    Kikic, I., Bertucco, A. and Lora, M. (1997) Thermodynamic and Mass Transfer for the Simulation of Recrysiallization Processes with a Supercritical Antisolveet, Fourth Italian Conference on Supercritical Fluids and their Applications, Capri, Italy, pp. 299–306.Google Scholar
  41. 41.
    Yeo, S.-D., Lim, G.-B., Debenedetti P.G. and Bernstein H. (1993) Formation of Microparticulate Protein Powders Using a Supercritical Fluid Antisoivent, Biotechnol and Bioeng. 41, 341.CrossRefGoogle Scholar
  42. 42.
    Bleich, J. and Muller, B.W. (1996) Production of Drug loaded micraparticles by the Use of Supercritical Gases with the Aerosol Solvent Extraction System (ASES) Process, Microencapsulation 13, 131–139.CrossRefGoogle Scholar
  43. 43.
    Subramaniam, B., Rajewski, R.A. and Snavely, K. (1996) Pharmaceutical processing with Supercritical carbon Dioxide, J. Pharm. Sci. 86, 885–890.CrossRefGoogle Scholar
  44. 44.
    Schmitt, W.J., Salada, M.C., Shook, G.G. and Speaker III, S.M. (1995) Finely-Divided Powders by Carrier Solution Injection into a Near or Supercritical Fluid, A.I.Ch.E. J. 41, 2476–2486.Google Scholar
  45. 45.
    Hanna, M. H., York, P., Shekunov, B. Yu. (1998) Control of the Polymorphic Forms of a Drag Substance by Solution Enhanced Dispersion by Supercritical Fluids (SEDS) Proceedings of the 5th Meeting on Supercritical Fluids, Nice, pp. 325–330.Google Scholar
  46. 46.
    Winters, M.A., Knutson, B.A., Debeeedetti, P.G., Sparks, H.G., Pnybycien, T.M., Stevenson, C.L. and Prestrelski, S.J. (1996) Precipitation of Proteins Supercritical Carbon Dioxide, J.Pharm.Sci. 85, 5S6–594.Google Scholar
  47. 47.
    Bodmeier, R., Wang, H., Dixon, D.J., Mawson, S. and Johnston, K.P. (1995) Polymeric Microspheres Prepared by Spraying into Compressed Carbon Dioxide, Pharm. Res. 12, 1211–1217.CrossRefGoogle Scholar
  48. 48.
    Randolph, T.W., Randolph, A.D., Mebes, M. and Yeung, S. (1993) Sub-micrometer-sized Biodegradable particles of PoIy(L-lactic acid) Via the Gas Antisolvent Spray Precipitation Process, Biotechnol. Prog. 9, 429–435.CrossRefGoogle Scholar
  49. 49.
    Knutson, B.L., Debenedetti, P.G. and Tom, J.W. (I996) In Microparticulate Systems for the Delivery of Proteins and Vaccines, Drags and the Pharmaceutical Sciences Series: Cohen S., Bernstein H., Eds., Mated Dekker, Inc: New York, 77, pp. 89–125.Google Scholar
  50. 50.
    Bertucco, A., Pallado, P. and Bcnedetti, L. (1996) Formation of Biocompatible Polymer Microsphcres for Controlled Drag Delivery by Supercritical Antisoivent Technique In High Pressure Chemical Engineering, Process Technology Proceedings, 12, von Rohr P.R., Trepp C., Eds, EIsevier, Amsterdam, 217–222.Google Scholar
  51. 51.
    Jaanno, S., Rantakyla, M. and Aaltonen, O. (1997) Particle Tailoring with Supercritical Fluids: Production of Amorphous Pharmaceutical Particles, The 4* International Symposium on Supercritical Fluids, Sendai, Japan, 263–266.Google Scholar
  52. 52.
    Shim, J.-J. and Johnston, K.P. (1989) Adjustable Solute Distribution Between Polymers and Supercritical Fluids, A.I.Ch.E. J. 35, 1097.CrossRefGoogle Scholar
  53. 53.
    Eckert, C.A., Kazariatt, S.G., West, B.L. and Brantley, N.N. (1998) Polymer Processing with Supercritical Fluids: Partitioning of Solutes and cosolvents between Supercritical Fluids and Polymer Matrices, Proceedings of the 5th Meeting on Supercritical Fluids, Mice, pp. 85–88.Google Scholar
  54. 54.
    Sand, M.L. (1987) Method for Impregnating a Thenroplastic Polymer, U.S. Patent, 4678684.Google Scholar
  55. 55.
    Berens, A.R. (1989) Process for Incorporating an additive info a Polymer and Product Produced Thereby, US. Patent, 4820752.Google Scholar
  56. 56.
    Penman, C.A. (1996) Method of Polymer Impregnation, U.S. Patent, 5508060.Google Scholar
  57. 57.
    Carli, F., Colombo, I., Alessi, P., Kikic, I. and Cortesi, A. (1997) Supercritical Process for Preparation of Pharmaceutical Formulations of Cross-linked Polymer Powders Loaded with Drugs, Patent Application N°MI 97A002571 of Nov. 19th, 1997.Google Scholar
  58. 58.
    Penman, C.A., Choi, H.-O. and Bartkus, J. (1998) Drug Loading of Polymer Substrates Using Supercritical Fluid Impregnation in an Aqueous Carrier Liquid, Proceedings of the 5th Meeting on Supercritical Fluids. Nice, pp. 379–385.Google Scholar
  59. 59.
    Alessi, P., Cortesi, A., Kikic, I. and Colombo, I. (1998) Effect of Operating Parameters on the Impregnation of Polymers with Drugs, Proceedings of the 5 th Meeting on Supercritical Fluids, Nice, pp. 373–378.Google Scholar
  60. 60.
    Condo, P.D., Sumpte, S.R., Lee, M.L. and Johnston, K.P. (1996) Partition Coefficients and Polymer-Solute Interaction Parameters by Irwerse Supercritical Fluid Chrematopapby, Ind. Eng. Chem. Res. 35, 1115–1123.CrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media Dordrecht 2000

Authors and Affiliations

  • I. Kikic
    • 1
  • P. Sist
    • 1
  1. 1.Department of Chemical, Environmental and Raw Materials Engineering (D.I.C.A.M.P.)University of TriesteTriesteItaly

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