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Crystallization Behavior of Mannitol in Frozen Aqueous Solutions

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Abstract

Purpose. To study the effect of cooling rate, the influence of phosphate buffers and polyvinylpyrrolidone (PVP) on the crystallization behavior of mannitol in frozen aqueous solutions.

Methods. Low-temperature differential scanning calorimetry and powder X-ray diffractometry were used to characterize the frozen solutions.

Results. Rapid cooling (20°C/min) inhibited mannitol crystallization, whereas at slower cooling rates (10°C and 5°C/min) partial crystallization was observed. The amorphous freeze-concentrate was characterized by two glass transitions at -32°C and -25°C. When the frozen solutions were heated past the two glass transition temperatures, the solute crystallized as mannitol hydrate. An increase in the concentration of PVP increased the induction time for the crystallization of mannitol hydrate. At concentrations of ≥100 mM, the buffer salts significantly inhibited mannitol crystallization.

Conclusions. The crystallization behavior of mannitol in frozen solutions was influenced by the cooling rate and the presence of phosphate buffers and PVP.

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REFERENCES

  1. M. J. Pikal. Freeze-drying of proteins: Part I. Process design. Biopharm. 3:18–28 (1990).

    Google Scholar 

  2. E. Y. Shalaev and F. Franks. Changes in the physical state of model mixtures during freezing and drying: Impact on product quality. Cryobiology 33:14–26 (1996).

    Google Scholar 

  3. J. F. Carpenter, M. J. Pikal, B. S. Chang, and T. W. Randolph. Rational design of stable lyophilized protein formulations: Some practical advice. Pharm. Res. 14:969–975 (1997).

    Google Scholar 

  4. J. F. Carpenter and J. H. Crowe. An infrared spectroscopic study of the interactions of carbohydrates with dried proteins. Biochemistry 28:3916–3922 (1989).

    Google Scholar 

  5. K. Izutsu, S. Yoshioka, and T. Terao. Effect of mannitol crystallinity on the stabilization of enzymes during freeze-drying. Chem. Pharm. Bull. 42:5–8 (1994).

    Google Scholar 

  6. A. I. Kim, M. J. Akers, and S. L. Nail. The physical state of mannitol after freeze-drying: Effects of mannitol concentration, freezing rate, and a noncrystallizing cosolute. J. Pharm. Sci. 87: 931–935 (1998).

    Google Scholar 

  7. A. Burger, J. O. Henck, S. Hetz, J. M. Rollinger, A. A. Weissnicht, and H. Stottner. Energy/temperature diagram and compression behavior of the polymorphs of D-mannitol. J. Pharm. Sci. 89:457–468 (2000).

    Google Scholar 

  8. L. Yu, D. S. Mishra, and D. R. Rigsbee. Determination of the glass properties of D-mannitol using sorbitol as an impurity. J. Pharm. Sci. 87:774–777 (1998).

    Google Scholar 

  9. N. Murase and F. Franks. Salt precipitation during freezeconcentration of phosphate buffer solutions. Biophys. Chem. 34: 293–300 (1989).

    Google Scholar 

  10. L. Yu, N. Milton, E. G. Groleau, D. S. Mishra, and R. E. Vansickle. Existence of a mannitol hydrate during freeze-drying and practical implications. J. Pharm. Sci. 88:196–198 (1999).

    Google Scholar 

  11. R. K. Cavatur and R. Suryanarayanan. Characterization of phase transitions during freeze-drying by in situ X-ray powder diffractometry. Pharm. Dev. Technol. 3:579–586 (1998).

    Google Scholar 

  12. K.A. Pikal, and J.F. Carpenter. pH changes during freezing in sodium and potassium phosphate buffer systems in the presence of glycine: Effect on protein stability. PharmSci Suppl 1:S–544 (1998).

    Google Scholar 

  13. M. Yoshioka, B. C. Hancock, and G. Zografi. Inhibition of indomethacin crystallization in poly(vinylpyrrolidone) coprecipitates. J. Pharm. Sci. 84:983–986 (1995).

    Google Scholar 

  14. G. Van den Mooter, M. Wuyts, N. Blaton, R. Busson, P. Grobet, P. Augustijns, and R. Kinget. Physical stabilization of amorphous ketoconazole in solid dispersions with polyvinylpyrrolidone K25. Eur. J. Pharm. Sci. 12:261–269 (2001).

    Google Scholar 

  15. T. Matsumoto and G. Zografi. Physical properties of solid molecular dispersions of indomethacin with poly(vinylpyrrolidone) and poly(vinylpyrrolidone-co-vinylacetate) in relation to indomethacin crystallization. Pharm. Res. 16:1722–1728 (1999).

    Google Scholar 

  16. A. Martini, S. Kume, M. Crivellente, and R. Artico. Use of sub-ambient differential scanning calorimetry to monitor the frozenstate behavior of blends of excipients for freeze-drying. PDA J. Pharm. Sci. Technol. 51:62–67 (1997).

    Google Scholar 

  17. M. Reading, A. Luget, and R. Wilson. Modulated differential scanning calorimetry. Thermochim. Acta 238:295–307 (1994).

    Google Scholar 

  18. B. Luyet and D. Rasmussen. Study by differential thermal analysis of the temperature of instability of rapidly cooled solutions of glycerol, ethylene glycol, sucrose and glucose. Biodynamica 10: 1167–1191 (1968).

    Google Scholar 

  19. M. L. LeMeste and D. Simatos. Use of electron spin resonance for the study of “ante-melting” phenomenon observed in sugar solution by differential scanning calorimetry. Cryo Lett. 9:21–63 (1980).

    Google Scholar 

  20. S. Ablett, M. J. Izzard, and P. J. Lillford. Differential scanning calorimetric study of frozen sucrose and glycerol solutions. J. Chem. Soc. Faraday Trans. 88:789–794 (1992).

    Google Scholar 

  21. M. J. Izzard, S. Ablett, P. J. Lillford, V. L. Hill, and I. F. Groves. A modulated differential scanning calorimetric study: Glass transitions occurring in sucrose solutions. J. Therm. Anal. 47:1407–1418 (1996).

    Google Scholar 

  22. H. Levine and L. Slade. Thermomechanical properties of small-carbohydrate-water glasses and “rubbers”: Kinetically metastable systems at sub-zero temperatures. J. Chem. Soc. Faraday Trans. 84:2619–2633 (1988).

    Google Scholar 

  23. E. Y. Shalaev and F. Franks. Structural glass transitions and thermophysical processes in amorphous carbohydrates and their super-saturated solutions. J. Chem. Soc. Faraday Trans. 91:1511–1517 (1995).

    Google Scholar 

  24. L. Chang, X. Tang, M. J. Pikal, N. Milton, and L. Thomas. The origin of multiple glass transitions in frozen aqueous solutions. Proc. NATAS Annu. Conf. Therm. Anal. Appl. 27:624–628 (1999).

    Google Scholar 

  25. M. Yoshioka, B. C. Hancock, and G. Zografi. Crystallization of indomethacin from the amorphous state below and above its glass transition temperature. J. Pharm. Sci. 83:1700–1705 (1994).

    Google Scholar 

  26. A. Pyne, R. Surana, and R. Suryanarayanan. Crystallization of mannitol below Tg´ during freeze-drying in binary and ternary aqueous systems. Pharm. Res. 19:901–908 (2002).

    Google Scholar 

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Author notes

  1. Raghu K. Cavatur

    Present address: Aventis Pharmaceuticals, Bridgewater, New Jersey

  2. Abira Pyne

    Present address: Eli Lilly and Company, Indianapolis, Indiana

Authors and Affiliations

  1. Department of Pharmaceutics, University of Minnesota, 308 Harvard Street, S.E., Minneapolis, Minnesota, 55455

    Raghu K. Cavatur, Abira Pyne & Raj Suryanarayanan

  2. Aventis Pharmaceuticals, Bridgewater, New Jersey

    N. Murti Vemuri & Zofia Chrzan

  3. Merck and Company, West Point, Pennsylvania

    David Toledo-Velasquez

Authors
  1. Raghu K. Cavatur
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  2. N. Murti Vemuri
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  3. Abira Pyne
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  4. Zofia Chrzan
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  5. David Toledo-Velasquez
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  6. Raj Suryanarayanan
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Correspondence to Raj Suryanarayanan.

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Cavatur, R.K., Vemuri, N.M., Pyne, A. et al. Crystallization Behavior of Mannitol in Frozen Aqueous Solutions. Pharm Res 19, 894–900 (2002). https://doi.org/10.1023/A:1016177404647

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