Cell and Cell Constituent Freeze-Drying: Fundamentals and Principles

  • P. J. M. Salemink
Part of the Developments in Hematology and Immunology book series (DIHI, volume 24)


The freeze-drying technique can be applied for preservation, when a compound or a product appears to be chemically, biologically or thermally unstable in solution or when different components in solution are mutually incompatible. Increasingly, guarding and control of the freeze-drying process becomes important to obtain a lyophilized product, from which the original form/structure can be recovered optimally.


Cholesterol Entropy Cellulose Crystallization Glycerol 


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  1. 1.
    Bensley RR, Gersh I. Studies on cell structure by the freeze-drying method. I. Introduction. Anatom Record 1933; 57: 205–15.CrossRefGoogle Scholar
  2. 2.
    Elser WJ, Thomas RA, Steffen GI. The desiccation of sera and other biological products in the frozen state with the preservation of the original qualities of products so treated. J Immunol 1935; 28: 433–73.Google Scholar
  3. 3.
    Draper N, Smith H. Applied regression analysis. New York: Wiley J and Sons, 1966;chap 10.Google Scholar
  4. 4.
    Jordan-Engeln G, Reutter F. Formelsammlung zur Numerischen Mathematik mit Fortran IV Programmen Hochschultaschenbucher. Bibliographisches Institut Mannheim 1974; Bd 106; 49: 247–9.Google Scholar
  5. 5.
    Van Gorp JA, Salemink PJM, Vermeulen M, Banken P. Evaluation of electrical conductivity-temperature curves using a mathematical model: temperature-dependent changes during thawing of frozen aqueous pharmaceuticals. J Pharm Pharmacol 1987; 39: 73–8.PubMedCrossRefGoogle Scholar
  6. 6.
    Fransen GJ, Salemink PJM, Crommelin DJA. Critical parameters in freezing of liposomes. IntJ Pharmaceutics 1986; 33: 27–35.CrossRefGoogle Scholar
  7. 7.
    Fiske CH, Subbarow Y. The colorimetric determination of phosphorous. J Biol Chem 1925; 66: 375–400.Google Scholar
  8. 8.
    Lelkes PI. Methodological aspects dealing with stability measurements of liposomes in vitro using the carboxyfluorescein-assay. In: Gregoriades G (ed). Liposome technology, Volume III. Boca Raton, FL: CRC Press, 1984: 225–46.Google Scholar
  9. 9.
    Salemink PJM. Thesis at the University of Nijmegen 1980. Nijmegen, the Netherlands.Google Scholar
  10. 10.
    Mackenzie AP. International Symposium on Freeze-Drying of Biological Products. 1976; 36: 51–67.Google Scholar
  11. 11.
    Gatlin L, Deluca P. A study of the phase transitions in frozen antibiotic solutions by DSC. J Parentral Drug Ass 1980; 34: 398–408.Google Scholar
  12. 12.
    Campbell AN, Smith NO. The phase rule and its applications, 9th ed. Dover Publishing Co 1951;chap 8.Google Scholar
  13. 13.
    Ito K. Chem Pharm Bull 1971; 19: 1095–102.Google Scholar
  14. 14.
    Salemink PJM, Banken P, Vermeulen M, van Gorp JA. Structure-property relationships in freeze-drying. In: Abstracts of the 43rd International Congress of Pharmaceutical Sciences. Montreux 1983:abstract 41.Google Scholar
  15. 15.
    Van Gorp JA, Salemink PJM, Vermeulen M, Kolkman L. Phase transitions in freeze-drying, 1st International Symposium on Drug Analysis, Brussels 1983;abstract:727.Google Scholar
  16. 16.
    Salemink PJM, Gribnau TCJ. Applications of freeze-drying in the pharmaceutical industry. Chemisch Magazine 1984; 5: 97–9.Google Scholar
  17. 17.
    Manual of Leybold-Heraeus GmbH. Freeze-drying plants. Cologne, FRG (1982).Google Scholar
  18. 18.
    Ishibashi N, Tatematsu T, Shimamura S, Tomita M, Okonogi S. Effect of water activity on the viability of freeze-dried bifidobacteria and lactic acid bacteria. In: IIR Commission Cl Meeting on freeze-drying. Tokyo 1985: Session 5. 1.Google Scholar
  19. 19.
    Loncin M. Basic principles of moisture equilibria. In: Goldblith SA, Rey L, Rothmayer WW (eds). Freeze-drying and advanced food technology. London, New York and San Francisco: Academic Press 1975: 599–615.Google Scholar
  20. 20.
    Lewin B. Gene expression-I. New York: Wiley J and Sons, 1974.Google Scholar
  21. 21.
    Sundaralingam M, Rao St (eds). Structure and conformation of nucleic acids and protein-nucleic acid interactions. Baltimore, London and Tokyo: University Park Press, 1975.Google Scholar
  22. 22.
    Katchalsky A, Curran PF. Nonequilibrium thermodynamics in biophysics. Cambridge: Harvard University Press, 1974.Google Scholar
  23. 23.
    Abu-Zaid SS, Morii M, Takeguchi N. Effects of freezing, freeze-drying and cold storage on the size and membrane permeability of multilamellar liposomes. Membrane 1984; 9: 43–8.Google Scholar
  24. 24.
    Ashwood-Smith MJ, Farrant J. Low temperature preservation in medicine and biology. Kent: Pitman Medical Ltd, 1980.Google Scholar
  25. 25.
    Crommelin DJA, van Bommel EMG. Stability of liposomes on storage: freeze dried, frozen or as an aqueous dispersion. Pharm Res 1984; 1: 159–64.CrossRefGoogle Scholar
  26. 26.
    Crowe JH, Crowe LM, Mouradian R. Stabilization of biological membranes at low water activities. Cryobiology 1983; 20: 346–56.PubMedCrossRefGoogle Scholar
  27. 27.
    Gordon RE, Mayer PR, Kildsig DO. Lyophilization-a means of increasing shelf-life of phospholipid bilayer vesicles. Drug Dev Ind Pharm 1982; 8: 465–73.CrossRefGoogle Scholar
  28. 28.
    Henry-Michelland S, Ter-Minassian-Saraga L, Poly PA, Delattre J, Puisieux F. Lyophilization and rehydration of liposomes. Colloids and Surfaces 1985; 14: 269–76.Google Scholar
  29. 29.
    Huggins CE, Blood freezing. In: Goldblith SA, Rey L, Rothmayer WW (eds). Free-drying and advanced food technology. Londen, New York and San Francisco: Academic Press, 1975: 51–60.Google Scholar
  30. 30.
    Machy P, Leserman LD. Freezing of liposomes. In: Gregoriades G (ed). Liposome technology, Vol 1. Boca Raton, FL: CRC Press, 1984: 221–33.Google Scholar
  31. 31.
    Mazur P. Cryobiology: the freezing of biological systems. Science 1970; 168: 939–49.PubMedCrossRefGoogle Scholar
  32. 32.
    Mazur P. The role of intracellular freezing in the death of cells cooled at supraoptimal rates. Cryobiology 1977; 14: 251–72.PubMedCrossRefGoogle Scholar
  33. 33.
    McGrath JJ. Cryomicroscopy of liposome systems as simple models to study cellular freezing response. Cryobiology 1984; 21: 81–92.CrossRefGoogle Scholar
  34. 34.
    Michelmore RW, Franks F. Nucleation rates of ice in undercooled water and aqueous solutions of polyethylene glycol. Cryobiology 1982; 19: 163–71.PubMedCrossRefGoogle Scholar
  35. 35.
    Morris GJ, McGrath JJ. The response of multilamellar liposomes to freezing and thawing. Cryobiology 1981; 18: 390–8.PubMedCrossRefGoogle Scholar
  36. 36.
    Morris GJ. The response of liposomes to various rates of cooling to -196°C: effect of phospholipid:cholesterol ratio. Cryobiology 1982; 19: 215–8.PubMedCrossRefGoogle Scholar
  37. 37.
    Rendi R. Water extrusion in isolated subcellular fractions VI. Osmotic properties of swollen phospholipid suspensions. Biochim Biophys Acta 1967; 135: 333–46.PubMedCrossRefGoogle Scholar
  38. 38.
    Shulkin PM, Seltzer SE, Davis MA, Adams DF. Lyophilized liposomes: a new method for long-term vesicular storage. J Microencaps 1984; 1: 73–80.CrossRefGoogle Scholar
  39. 39.
    Siminovitch D, Chapman D. Liposome bilayer model systems of freezing living cells. FEBS Letters 1971; 16: 207–12.PubMedCrossRefGoogle Scholar
  40. 40.
    Strauss G, Ingenito EP. Stabilization of liposome bilayers to freezing and thawing: effects of cryoprotective agents and membrane proteins. Cryobiology 1980; 17: 508–15.PubMedCrossRefGoogle Scholar
  41. 41.
    Van Bommel EMG, Crommelin DJA. Stability of doxorubicin-liposomes on storage: as an aqueous dispersion, frozen or freeze dried. Int J Pharm 1984; 22: 299–310.CrossRefGoogle Scholar
  42. 42.
    Crowe LM, Womersley C, Crowe JH, Reid D, Appel L, Rudolph A. Prevention of fusion and leakage in freeze-dried liposomes by carbohydrates. Biochim Biophys Acta 1986; 861: 131–40.Google Scholar
  43. 43.
    RajBhandary UL, Chang SH. Yeast tRNAPe: partial digestion with RNASE Tl and derivation of the total primary structure. J Biol Chem 1968; 243: 589–608.Google Scholar
  44. 44.
    Jack A, Ladner J, Klug A. Crystallographic refinement of yeast tRNAPhe at 2.5. A resolution. J Mol Biol 1976; 108: 619–49.PubMedCrossRefGoogle Scholar

Copyright information

© Kluwer Academic Publishers, Boston 1990

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  • P. J. M. Salemink

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