Pharmaceutical Research

, Volume 28, Issue 2, pp 364–373 | Cite as

Influence of Temperature on Solvent-Mediated Anhydrate-to-Hydrate Transformation Kinetics

  • Haiyan Qu
  • Tommy Munk
  • Claus Cornett
  • Jian X. Wu
  • Johan P. Bøtker
  • Lars P. Christensen
  • Jukka Rantanen
  • Fang Tian
Research Paper



To achieve an in-depth understanding of the underlying mechanism of the acceleration or deceleration effect of temperature on solvent-mediated anhydrate-to-hydrate phase transformation.


The effect of temperature on the phase transformation rate and onset time of two model compounds was investigated using in situ Raman spectroscopy. The thermodynamic driving force of the phase transformation (e.g. supersaturation) at different temperatures was determined by measuring the solubility of the anhydrate and the hydrate.


Both acceleration and deceleration effects of temperature on the phase transformation were observed. The mechanism of these temperature effects was studied by exploring the influence of temperature on supersaturation level and crystallization kinetics. Increasing temperature usually leads to accelerated phase transformation kinetics, but it simultaneously decreases supersaturation, which has the opposite effect on the kinetics of the phase transformation. The overall effect of temperature on the phase transformation is therefore determined by the combined effects of supersaturation and temperature on the nucleation and crystal growth kinetics of the hydrate.


By differentiating and comparing the effects of temperature and supersaturation on the anhydrate-to-hydrate phase transformation, a deeper understanding of the underlying principle of the acceleration and deceleration effects of temperature on the phase transformation has been achieved.


anhydrate-to-hydrate crystallization phase transformation supersaturation 



Financial support from the Danish Council for Independent Research, Technology and Production Sciences (Project No. 274-09-0028) is acknowledged. Lundbeckfonden (Denmark, project No. 479/06) is acknowledged for the financial support of XRPD instrument.


  1. 1.
    Morris KR. Structural aspects of hydrates and solvates. In: Brittain HG, editor. Polymorphism in pharmaceutical solids. New York: Marcel Dekker, Inc; 1999. p. 125–81.Google Scholar
  2. 2.
    Kobayashi Y, Ito S, Itai S, Yamamoto K. Physicochemical properties and bioavailability of carbamazepine polymorphs and dihydrate. Int J Pharm. 2000;193:137–45.CrossRefPubMedGoogle Scholar
  3. 3.
    Grant DJW, Higuchi T. Solubility behavior of organic compounds. New York: Willey; 1990.Google Scholar
  4. 4.
    Qu H, Louhi-Kultanen M, Rantanen J, Kallas J. Solvent-mediated phase transformation kinetics of an anhydrate/hydrate system. Cryst Growth Des. 2006;6:2053–60.CrossRefGoogle Scholar
  5. 5.
    Chiarella RA, Gillon AL, Burton RC, Davey RJ, Sadiq G, Auffret A, et al. The nucleation of inosine: the impact of solution chemistry on the appearance of polymorphic and hydrated crystal forms. Faraday Discuss. 2007;136:179–93.CrossRefPubMedGoogle Scholar
  6. 6.
    Luk C-WJ, Rousseau RW. Solubilities of and transformations between the anhydrous and hydrated forms of L-serine in water-methanol solutions. Cryst Growth Des. 2006;6:1808–12.CrossRefGoogle Scholar
  7. 7.
    Cardewand PT, Davey RJ. The kinetics of solvent-mediated phase transformations. Proc R Soc Lond A. 1985;398:415–28.CrossRefGoogle Scholar
  8. 8.
    Daveyand RJ, Cardew PT. Rate controlling processes in solvent-mediated phase transformations. J Cryst Growth. 1986;79:648–53.CrossRefGoogle Scholar
  9. 9.
    Wikström H, Kakidas C, Taylor LS. Determination of hydrate transition temperature using transformation kinetics obtained by Raman spectroscopoy. J Pharm Biomed Anal. 2009;49:247–52.CrossRefPubMedGoogle Scholar
  10. 10.
    Krahn FU, Mielck JB. Relations between several polymorphic forms and the dihydrate of carbamazepine. Pharm Acta Hel. 1987;62:247–54.Google Scholar
  11. 11.
    Rustichelli C, Gamberini G, Ferioli V, Gamberini MC, Ficarra R, Tommasini S. Solid-state study of polymorphic drugs: carbamazepine. J Pharm Biomed Anal. 2000;23:41–54.CrossRefPubMedGoogle Scholar
  12. 12.
    Reboul PJ, Cristau B, Soyfer JC. 5H-Dibenz[b, f]azepine-5-carboxamide (carbamazepine). Acta Crystallogr. 1981;B37:1844–8.Google Scholar
  13. 13.
    Mihalic M, Hofman H, Kajfez F, Kuftinec J, Blazvic N, Zinic M. Physico-chemical and analytical characteristics of piroxicam. Acta Pharm Jugosl. 1982;32:13–20.Google Scholar
  14. 14.
    Vrecer F, Vrbinc M, Meden A. Characterization of piroxicam crystal modifications. Int J Pharm. 2003;256:3–15.CrossRefPubMedGoogle Scholar
  15. 15.
    Reck G, Dietz G, Laban G, Günther W, Bannier G, Höhne E. X-ray studies on piroxicam modifications. Pharmazie. 1988;43:477–81.PubMedGoogle Scholar
  16. 16.
    Qu H, Louhi-Kultanen M, Kallas J. Solubility and stability of anhydrate/hydrate in solvent mixtures. Int J Pharm. 2006;321:101–7.CrossRefPubMedGoogle Scholar
  17. 17.
    Reck G, Dietz G. The order-disorder structure of carbamazepine dihydrate: 5H-dibenz [b, f] azepine-5-carboxamide dihydrate, C15H12N2O. Cryst Res Technol. 1986;21:1463–8.CrossRefGoogle Scholar
  18. 18.
    Wu JX, Tian F, Cornett C, Munk T, Savolainen M, Rantanen J. Building a robust quantitative model for process monitoring of solid state transformation AAPS Annual meeting Nov 8–12. USA: Los Angeles; 2009.Google Scholar
  19. 19.
    Jennrich RI, Ralston ML. Fitting nonlinear models to data. Ann Rev Biophys Bioeng. 1979;8:195–238.CrossRefGoogle Scholar
  20. 20.
    Draper NR, Smith H. Applied regression analysis, Wiley, ISBN: 0-471-02995-5, 1981.Google Scholar
  21. 21.
    Shefter E, Higuchi T. Dissolution behavior of crystalline solvated and nonsolvated forms of some pharmaceuticals. J Pharm Sci. 1963;52:781–91.CrossRefPubMedGoogle Scholar
  22. 22.
    Grant DJW, Mehdizadeh M, Chow AHL, Fairbrother JE. Non-linear van’t Hoff solubility-temperature plots and their pharmaceutical interpretation. Int J Pharm. 1984;18:25–38.CrossRefGoogle Scholar
  23. 23.
    Otsuka M, Teraoka R, Matsuda Y. Rotating-disk dissolution kinetics of nitrofurantoin anhydrate and monohydrate at various temperatures. Pharm Res. 1992;9:307–11.CrossRefPubMedGoogle Scholar
  24. 24.
    Gu C-H, Grant DJW. Estimating the relative stability of polymorphs and hydrates from heats of solution and solubility data. J Pharm Sci. 2001;90:1277–87.CrossRefPubMedGoogle Scholar
  25. 25.
    Wikström H, Rantanen J, Gift AD, Taylor LS. Towards an understanding of the factors influencing anhydrate-to-hydrate transformation kinetics in aqueous environments. Cryst Growth Des. 2008;8:2684–93.CrossRefGoogle Scholar
  26. 26.
    Davey RJ, Blagden N, Righini S, Alison H, Ferrari ES. Nucleation control in solution mediated polymorphic phase transformations: the case of 2, 6-Dihydroxybenzoic acid. J Phys Chem B. 2002;106:1954–9.CrossRefGoogle Scholar
  27. 27.
    Mullin JW. Crystallization. Oxford: Butterworth-Heinemann; 2001.Google Scholar
  28. 28.
    Mersmann A. Crystallization technology handbook. New York: Marcel Dekker; 2001.CrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2010

Authors and Affiliations

  • Haiyan Qu
    • 1
    • 2
  • Tommy Munk
    • 1
  • Claus Cornett
    • 1
  • Jian X. Wu
    • 1
  • Johan P. Bøtker
    • 1
  • Lars P. Christensen
    • 2
  • Jukka Rantanen
    • 1
  • Fang Tian
    • 1
  1. 1.Department of Pharmaceutics and Analytical ChemistryFaculty of Pharmaceutical Sciences, University of CopenhagenCopenhagen ØDenmark
  2. 2.Institute of Chemical Engineering Biotechnology and Environmental Technology, Faculty of EngineeringUniversity of Southern DenmarkOdense MDenmark

Personalised recommendations