AAPS PharmSciTech

, Volume 15, Issue 6, pp 1516–1526 | Cite as

A Method to Evaluate the Effect of Contact with Excipients on the Surface Crystallization of Amorphous Drugs

  • Si-Wei Zhang
  • Lian Yu
  • Jun Huang
  • Munir A. Hussain
  • Lotfi Derdour
  • Feng Qian
  • Melgardt M. de Villiers
Research Article


Amorphous drugs are used to improve the solubility, dissolution, and bioavailability of drugs. However, these metastable forms of drugs can transform into more stable, less soluble, crystalline counterparts. This study reports a method for evaluating the effect of commonly used excipients on the surface crystallization of amorphous drugs and its application to two model amorphous compounds, nifedipine and indomethacin. In this method, amorphous samples of the drugs were covered by excipients and stored in controlled environments. An inverted light microscope was used to measure in real time the rates of surface crystal nucleation and growth. For nifedipine, vacuum-dried microcrystalline cellulose and lactose monohydrate increased the nucleation rate of the β polymorph from two to five times when samples were stored in a desiccator, while d-mannitol and magnesium stearate increased the nucleation rate 50 times. At 50% relative humidity, the nucleation rates were further increased, suggesting that moisture played an important role in the crystallization caused by the excipients. The effect of excipients on the crystal growth rate was not significant, suggesting that contact with excipients influences the physical stability of amorphous nifedipine mainly through the effect on crystal nucleation. This effect seems to be drug specific because for two polymorphs of indomethacin, no significant change in the nucleation rate was observed under the excipients.


amorphous drugs growth rate nucleation rate tablet excipients 



We thank Bristol-Myers Squibb Co. for supporting this work.


  1. 1.
    Yu L. Amorphous pharmaceutical solids: preparation, characterization and stabilization. Adv Drug Deliv Rev. 2001;48(1):27–42.PubMedCrossRefGoogle Scholar
  2. 2.
    Hikima T, Adachi Y, Hanaya M, Oguni M. Determination of potentially homogeneous-nucleation-based crystallization in o-terphernyl and an interpretation of the nucleation-enhancement mechanism. Phys Rev B. 1995;52(6):3900–8.CrossRefGoogle Scholar
  3. 3.
    Hatase M, Hanaya M, Oguni M. Studies of homogeneous-nucleation-based crystal growth: significant role of phenyl ring in the structure formation. J Non-Cryst Solids. 2004;333(2):129–36.CrossRefGoogle Scholar
  4. 4.
    Sun Y, Xi HM, Chen S, Ediger MD, Yu L. Crystallization near glass transition: transition from diffusion-controlled to diffusionless crystal growth studied with seven polymorphs. J Phys Chem B. 2008;112(18):5594–601.PubMedCrossRefGoogle Scholar
  5. 5.
    Xi HM, Sun Y, Yu L. Diffusion-controlled and diffusionless crystal growth in liquid o-terphenyl near its glass transition temperature. J Chem Phys. 2009;130:094508.PubMedCrossRefGoogle Scholar
  6. 6.
    Wu T, Yu L. Surface crystallization of indomethacin below T-g. Pharm Res. 2006;23(10):2350–5.PubMedCrossRefGoogle Scholar
  7. 7.
    Zhu L, Wong L, Yu L. Surface-enhanced crystallization of amorphous nifedipine. Mol Pharm. 2008;5(6):921–6.PubMedCrossRefGoogle Scholar
  8. 8.
    Sun Y, Zhu L, Kearns KL, Ediger MD, Yu L. Glasses crystallize rapidly at free surfaces by growing crystals upward. PNAS. 2011;108(15):5990–5.PubMedCentralPubMedCrossRefGoogle Scholar
  9. 9.
    Zhu L, Brian CW, Swallen SF, Straus PT, Ediger MD, Yu L. Surface self-diffusion of an organic glass. Phys Rev Lett. 2011;106(25):256103.PubMedCrossRefGoogle Scholar
  10. 10.
    Brian CW, Yu L. Surface self-diffusion of organic glasses. J Phys Chem A. 2013;117(50):13303–9.PubMedCrossRefGoogle Scholar
  11. 11.
    Wu T, Sun Y, Li N, de Villiers MM, Yu L. Inhibiting surface crystallization of amorphous indomethacin by nanocoating. Langmuir. 2007;23(9):5148–53.PubMedCrossRefGoogle Scholar
  12. 12.
    Marsac PJ, Konno H, Taylor LS. A comparison of the physical stability of amorphous felodipine and nifedipine systems. Pharm Res. 2006;23(10):2306–16.PubMedCrossRefGoogle Scholar
  13. 13.
    Ishida H, Wu T, Yu L. A sudden rise of crystal growth rate of nifedipine near t-g without and with polyvinylpyrrolidone. J Pharm Sci. 2007;96(5):1131–8.PubMedCrossRefGoogle Scholar
  14. 14.
    Kestur US, Lee H, Santiago D, Rinaldi C, Won Y-Y, Taylor LS. Effects of the molecular weight and concentration of polymer additives, and temperature on the melt crystallization kinetics of a small drug molecule. Cryst Growth Des. 2010;10(8):3585–95.CrossRefGoogle Scholar
  15. 15.
    Cai T, Zhu L, Yu L. Crystallization of organic glasses: effects of polymer additives on bulk and surface crystal growth in amorphous nifedipine. Pharm Res. 2011;28(10):2458–66.PubMedCrossRefGoogle Scholar
  16. 16.
    Powell CT, Cai T, Hasebe M, Gunn EM, Gao P, Zhang G, et al. Low-concentration polymers inhibit and accelerate crystal growth in organic glasses in correlation with segmental mobility. J Phys Chem B. 2013;117(35):10334–41.PubMedCrossRefGoogle Scholar
  17. 17.
    Malan CEP, de Villiers MM, Lotter AP. Application of differential scanning calorimetry and high performance liquid chromatography to determine the effects of mixture composition and preparation during the evaluation of niclosamide-excipient compatibility. J Pharm Biomed Anal. 1997;15(4):549–57.PubMedCrossRefGoogle Scholar
  18. 18.
    Narang AS, Desai D, Badawy S. Impact of excipient interactions on solid dosage form stability. Pharm Res. 2012;29(10):2660–83.PubMedCrossRefGoogle Scholar
  19. 19.
    Chadha R, Bhandari S. Drug-excipient compatibility screening—role of thermoanalytical and spectroscopic techniques. J Pharm Biomed Anal. 2014;87:82–97.PubMedCrossRefGoogle Scholar
  20. 20.
    Simmons DL, Chen WS, Frechett M, Ranz RJ, Patel NK. Rotating compartmentalized disk for dissolution rate determinations. Can J Pharm Sci. 1972;7(2):62–5.Google Scholar
  21. 21.
    Gunn E, Guzei IA, Cai T, Yu L. Polymorphism of nifedipine: crystal structure and reversible transition of the metastable beta polymorph. Cryst Growth Des. 2012;12(4):2037–43.CrossRefGoogle Scholar
  22. 22.
    Kibbe AH. Handbook of pharmaceutical excipients. 3rd ed. London: American Pharmaceutical Association and Pharmaceutical Press; 2000.Google Scholar
  23. 23.
    Yoshioka M, Hancock BC, Zografi G. Crystallization of indomethacin from the amorphous state below and above its glass-transition temperature. J Pharm Sci. 1994;83(12):1700–5.PubMedCrossRefGoogle Scholar
  24. 24.
    Baird JA, Van Eerdenbrugh B, Taylor LS. A classification system to assess the crystallization tendency of organic molecules from undercooled melts. J Pharm Sci. 2010;99(9):3787–806.PubMedGoogle Scholar
  25. 25.
    Stieger N, Aucamp M, Zhang SW, de Villiers MM. Hot-stage optical microscopy as an analytical tool to understand solid-state changes in pharmaceutical materials. Am Pharm Rev. 2012;15(2):32–6.Google Scholar

Copyright information

© American Association of Pharmaceutical Scientists 2014

Authors and Affiliations

  • Si-Wei Zhang
    • 1
  • Lian Yu
    • 1
    • 2
  • Jun Huang
    • 3
  • Munir A. Hussain
    • 3
  • Lotfi Derdour
    • 3
  • Feng Qian
    • 4
  • Melgardt M. de Villiers
    • 1
  1. 1.School of PharmacyUniversity of Wisconsin-MadisonMadisonUSA
  2. 2.Department of ChemistryUniversity of Wisconsin-MadisonMadisonUSA
  3. 3.Bristol-Myers Squibb CompanyNew BrunswickUSA
  4. 4.School of MedicineTsinghua UniversityBeijingChina

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