Pharmaceutical Research

, Volume 25, Issue 4, pp 969–978 | Cite as

Ability of Different Polymers to Inhibit the Crystallization of Amorphous Felodipine in the Presence of Moisture

  • Hajime Konno
  • Lynne S. Taylor
Research Paper



To investigate the ability of various polymers to inhibit the crystallization of amorphous felodipine from amorphous molecular dispersions in the presence of absorbed moisture.


Spin coated films of felodipine with poly(vinylpyrrolidone) (PVP), hydroxypropylmethylcellulose acetate succinate (HPMCAS) and hydroxypropylmethylcellulose (HPMC) were exposed to different storage relative humidities and nucleation rates were measured using polarized light microscopy. Solid dispersions were further characterized using differential scanning calorimetry, infrared spectroscopy and gravimetric measurement of water vapor sorption.


It was found that the polymer additive reduced nucleation rates whereas absorbed water enhanced the nucleation rate as anticipated. When both polymer and water were present, nucleation rates were reduced relative to those of the pure amorphous drug stored at the same relative humidity, despite the fact that the polymer containing systems absorbed more water. Differences between the stabilizing abilities of the various polymers were observed and these were explained by the variations in the moisture contents of the solid dispersions caused by the different hygroscopicities of the component polymers. No correlations could be drawn between nucleation rates and the glass transition temperature (T g) of the system. PVP containing solid dispersions appeared to undergo molecular level changes on exposure to moisture which may be indicative of phase separation.


In conclusion, it was found that for a given storage relative humidity, although the addition of a polymer increases the moisture content of the system relative to that of the pure amorphous drug, the crystallization tendency was still reduced.

Key words

amorphous crystallization FTIR solid dispersion water sorption 



Professor George Zografi is thanked for many enlightening discussions about this research. The authors are grateful to Dr. Sheri L. Shamblin for helpful comments. LST thanks AFPE/AACP for a New Investigator Award. HK acknowledges Astellas Pharma Inc. for granting him a leave of absence to undertake this work.


  1. 1.
    W. L. Chiou and S. Riegelman. Pharmaceutical applications of solid dispersion systems. J. Pharm. Sci. 60:1281–1302 (1971).PubMedCrossRefGoogle Scholar
  2. 2.
    J. L. Ford. The current status of solid dispersions. Pharm. Acta Helv. 61:69–88 (1986).PubMedGoogle Scholar
  3. 3.
    A. T. M. Serajuddin. Solid dispersions of poorly water-soluble drugs: early promises, subsequent problems and recent breakthroughs. J. Pharm. Sci. 88:1058–1066 (1999).PubMedCrossRefGoogle Scholar
  4. 4.
    C. Leuner and J. Dressman. Improving drug solubility for oral delivery using solid dispersions. Eur. J. Pharm. Biopharm. 50:47–60 (2000).PubMedCrossRefGoogle Scholar
  5. 5.
    M. Yoshioka, B. C. Hancock, and G. Zografi. Inhibition of indomethacin crystallization in poly(vinylpyrrolidone). J. Pharm. Sci. 84:983–986 (1995).PubMedCrossRefGoogle Scholar
  6. 6.
    L. S. Taylor and G. Zografi. Spectroscopic characterization of interactions between PVP and indomethacin in amorphous molecular dispersions. Pharm. Res. 14:1691–1698 (1997).PubMedCrossRefGoogle Scholar
  7. 7.
    T. Hino and J. L. Ford. Characterization of the hydroxypropylmethylcellulose–nicontinamide binary system. Int. J. Pharm. 219:39–49 (2001).PubMedCrossRefGoogle Scholar
  8. 8.
    K. Yamashita, T. Nakate, K. Okimoto, A. Ohike, Y. Tokunaga, R. Ibuki, K. Higaki, and T. Kimura. Establishment of new preparation method for solid dispersion formulation of tacrolimus. Int. J. Pharm. 267:79–91 (2003).PubMedCrossRefGoogle Scholar
  9. 9.
    T. Matsumoto and G. Zografi. Physical properties of solid dispersions of indomethacin with poly(vinylpyrrolidone) and poly(vinylpyrrolidone-co-vinyl acetate) in relation to indomethacin crystallization. Pharm. Res. 16:1722–1728 (1999).PubMedCrossRefGoogle Scholar
  10. 10.
    T. Miyazaki, S. Yoshioka, Y. Aso, and S. Kojima. Ability of poly(vinylpyrrolidone) and polyacrylic acid to inhibit the crystallization of amorphous acetaminophen. J. Pharm. Sci. 93:2710–2717 (2004).PubMedCrossRefGoogle Scholar
  11. 11.
    H. Konno and L. S. Taylor. Influence of different polymers on the crystallization tendency of molecularly dispersed amorphous felodipine. J. Pharm. Sci. 95:2692–2705 (2006).PubMedCrossRefGoogle Scholar
  12. 12.
    G. Zografi. States of water associated with solids. Drug Dev. Ind. Pharm. 14:1905–1926 (1988).CrossRefGoogle Scholar
  13. 13.
    C. Ahlneck and G. Zografi. The molecular basis of moisture effects on the physical and chemical stability of drugs in the solid state. Int. J. Pharm. 62:87–95 (1990).CrossRefGoogle Scholar
  14. 14.
    S. L. Shamblin and G. Zografi. The effects of absorbed water on the properties of amorphous mixtures containing sucrose. Pharm. Res. 16:1119–1124 (1999).PubMedCrossRefGoogle Scholar
  15. 15.
    C. A. Oksanen and G. Zografi. The relationship between the glass transition temperature and water vapor absorption by poly(vinylpyrrolidone). Pharm. Res. 7:654–657 (1990).PubMedCrossRefGoogle Scholar
  16. 16.
    L. S. Taylor, F. W. Langkilde, and G. Zografi. Fourier transform Raman spectroscopic study of the interaction of water vapor with amorphous polymers. J. Pharm. Sci. 90:888–901 (2001).PubMedCrossRefGoogle Scholar
  17. 17.
    V. Andronis and G. Zografi. Crystal nucleation and growth of indomethacin polymorphs from the amorphous state. J. Non-Cryst. Solids 271:236–248 (2000).CrossRefGoogle Scholar
  18. 18.
    S. Inoue and R. Oldenbourg. Microscopes. Handbook of Optics, Volume II, Bass, M. (ed), McGraw-Hill, New York, 1995.Google Scholar
  19. 19.
    L. S. Taylor and G. Zografi. Sugar–polymer hydrogen bond interactions in lyophilized amorphous mixtures. J. Pharm. Sci. 87:1615–1621 (1998).PubMedCrossRefGoogle Scholar
  20. 20.
    B. C. Hancock and G. Zografi. Characteristics and significance of amorphous state in pharmaceutical systems. J. Pharm. Sci. 86:1–12 (1997).PubMedCrossRefGoogle Scholar
  21. 21.
    B. Makower and W. C. Dye. Equilibrium moisture content and crystallization of amorphous sucrose and glucose. J. Agric. Food Chem. 4:72–77 (1956).CrossRefGoogle Scholar
  22. 22.
    H. Imaizumi, N. Nambu and T. Nagai. Stability and several physical properties of amorphous and crystalline forms of indomethacin. Chem. Pharm. Bull. 28:2565–2569 (1980).PubMedGoogle Scholar
  23. 23.
    C. Schimitt, C. W. Davis, and S. T. Long. Moisture-dependent crystallization of amorphous lamotrigine mesylate. J. Pharm. Sci. 85:1215–1219 (1996).CrossRefGoogle Scholar
  24. 24.
    V. Andronis, M. Yoshioka, and G. Zografi. Effects of sorbed water on the crystallization of indomethacin from the amorphous state. J. Pharm. Sci. 86:346–351 (1997).PubMedCrossRefGoogle Scholar
  25. 25.
    F. Tanno, Y. Nishiyama, H. Kokubo and S. Obara. Evaluation of hypromellose acetate succinate (HPMCAS) as a carrier in solid dispersions. Drug Dev. Ind. Pharm. 30:9–17 (2004).PubMedCrossRefGoogle Scholar
  26. 26.
    A. Saleki-Gerhard and G. Zografi. Non-isothermal and isothermal crystallization of amorphous state. Pharm. Res. 11:1166–1173 (1994).CrossRefGoogle Scholar
  27. 27.
    B. C. Hancock and G. Zografi. The relationship between glass transition temperature and water content of amorphous pharmaceutical solids. Pharm. Res. 11:471–477 (1994).PubMedCrossRefGoogle Scholar
  28. 28.
    G. Van den Mooter, M. Wuyts, N. Blaton, R. Busson, P. Grobet, P. Augustijns, and R. Kinget. Physical stabi-lisation of amorphous ketoconazole in solid dispersions with polyvinylpyrrolidone K25. Eur. J. Pharm. Sci. 12:261–269 (2001).PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2007

Authors and Affiliations

  1. 1.Department of Industrial and Physical Pharmacy, School of PharmacyPurdue UniversityWest LafayetteUSA
  2. 2.Astellas Pharma Inc.YaizuJapan

Personalised recommendations