Pharmaceutical Research

, 35:23 | Cite as

Gelatin Nano-coating for Inhibiting Surface Crystallization of Amorphous Drugs

  • Rattavut Teerakapibal
  • Yue Gui
  • Lian YuEmail author
Research Paper Theme: Formulation and Manufacturing of Solid Dosage Forms
Part of the following topical collections:
  1. Formulation and Manufacturing of Solid Dosage Forms



Inhibit the fast surface crystallization of amorphous drugs with gelatin nano-coatings.


The free surface of amorphous films of indomethacin or nifedipine was coated by a gelatin solution (type A or B) and dried. The coating’s effect on surface crystallization was evaluated. Coating thickness was estimated from mass change after coating.


For indomethacin (weak acid, pKa = 4.5), a gelatin coating of either type deposited at pH 5 and 10 inhibited its fast surface crystal growth. The coating thickness was 20 ± 10 nm. A gelatin coating deposited at pH 3, however, provided no protective effect. These results suggest that an effective gelatin coating does not require that the drug and the polymer have opposite charges. The ineffective pH 3 coating might reflect the poor wetting of indomethacin’s neutral, hydrophobic surface by the coating solution. For nifedipine (weak base, pKa = 2.6), a gelatin coating of either type deposited at pH 5 inhibited its fast surface crystal growth.


Gelatin nano-coatings can be conveniently applied to amorphous drugs from solution to inhibit fast surface crystallization. Unlike strong polyelectrolyte coatings, a protective gelatin coating does not require strict pairing of opposite charges. This could make gelatin coating a versatile, pharmaceutically acceptable coating for stabilizing amorphous drugs.


amorphous crystallization gelatin indomethacin nano-coating nifedipine surface 







Poly(dimethyldiallyl ammonium chloride)


Sodium poly(styrenesulfonate)



We thank the Bill and Melinda Gates Foundation for financial support and Melgardt de Villiers, Ed Elders, Mark Sacchetti, Niya Bowers, Phil Goliber, and Ellen Harrington for helpful discussions.


  1. 1.
    Hasebe M, Musumeci D, Powell CT, Cai T, Gunn E, Zhu L, et al. Fast surface crystal growth on molecular glasses and its termination by the onset of fluidity. J Phys Chem B. 2014;118:7638–46.CrossRefPubMedGoogle Scholar
  2. 2.
    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;28:2458–66.CrossRefPubMedGoogle Scholar
  3. 3.
    Wu T, Yu L. Surface crystallization of indomethacin below T g. Pharm Res. 2006;23:2350–5.Google Scholar
  4. 4.
    Zhu L, Wong L, Yu L. Surface-enhanced crystallization of amorphous nifedipine. Mol Pharm. 2008;5:921–6.CrossRefPubMedGoogle Scholar
  5. 5.
    Sun Y, Zhu L, Kearns KL, Ediger MD, Yu L. Glasses crystallize rapidly at surfaces by growing crystals upward. Proc Natl Acad Sci U S A. 2011;108:5990–5.CrossRefPubMedPubMedCentralGoogle Scholar
  6. 6.
    Zhang W, Brian CW, Yu L. Fast surface diffusion of amorphous o-terphenyl and its competition with viscous flow in surface evolution. J Phys Chem B. 2015;119:5071–8.CrossRefPubMedGoogle Scholar
  7. 7.
    Yu L. Surface mobility of molecular glasses and its importance in physical stability. Adv Drug Deliv Rev. 2016;100:3–9.CrossRefPubMedGoogle Scholar
  8. 8.
    Wu T, Sun Y, Li N, de Villiers MM, Yu L. Inhibiting surface crystallization of amorphous indomethacin by nanocoating. Langmuir. 2007;23:5148–53.CrossRefPubMedGoogle Scholar
  9. 9.
    Baghel S, Cathcart H, O’Reilly NJ. Polymeric amorphous solid dispersions: a review of amorphization crystallization, stabilization, solid-state characterization, and aqueous solubilization of biopharmaceutical classification system class II drugs. J Pharm Sci. 2016;105:2527–44.CrossRefPubMedGoogle Scholar
  10. 10.
    Theil F, Anantharaman S, Kyeremateng SO, van Lishaut H, Dreis-Kuhne SH, Rosenberg J, et al. Frozen in time: kinetically stabilized amorphous solid dispersions of nifedipine stable after a quarter century of storage. Mol Pharm. 2017;14:183–92.CrossRefPubMedGoogle Scholar
  11. 11.
    Barbara F, Merkley VF, Ingar N. Reducing pill burden and helping with medication awareness to improve adherence. Can Pharm J. 2013;146:262–9.CrossRefGoogle Scholar
  12. 12.
    Roew RC, Sheskey PJ, Owem SC. Handbook of pharmaceutical excipients, fifth edition. Great Britain: Pharmaceutical Press; 2006. PrintGoogle Scholar
  13. 13.
    Miller JM, Blackburn AC, Shi Y, Melzak AJ, Ando HY. semi-empirical relationships between effective mobility, charge, and molecular weight of pharmaceuticals by pressure-assisted capillary electrophoresis: applications in drug discovery. Electrophoresis. 2002;23:2833–41.CrossRefPubMedGoogle Scholar
  14. 14.
    Ai H, Jones SA, de Villiers MM, Lvov YM. Nano-encapsulation of furosemide microcrystals for controlled drug release. J Control Release. 2003;86:59–68.CrossRefPubMedGoogle Scholar
  15. 15.
    Pargaonkar N, Lvov YM, Li N, Steenekamp JH, de Villiers MM. Controlled release of dexamethasone from microcapsules produced by polyelectrolyte layer-by-layer nanoassembly. Pharm Res. 2005;22:826–35.CrossRefPubMedGoogle Scholar
  16. 16.
    Holmes-Farley SR, Bain CD, Whitesides GM. Wetting of functionalized polyethylene film having ionizable organic acids and bases at the polymer-water interface: relations between functional group polarity, extent of ionization, and contact angle with water. Langmuir. 1988;4:921–37.CrossRefGoogle Scholar
  17. 17.
    Bain CD, Whitesides GMA. Study by contact angle of the acid-base behavior of monolayers containing ω-mercaptocarboxylic acids adsorbed on gold: an example of reactive spreading. Langmuir. 1989;5:1370–7.CrossRefGoogle Scholar
  18. 18.
    Whitesides GM, Biebuyck HA, Folkers JP, Prime KL. Acid-base interactions in wetting. J Adhes Sci Technol. 1991;5:57–69.Google Scholar
  19. 19.
    McDaid DM, Deasy PB. An investigation into the transdermal delivery of nifedipine. Pharm Acta Helv. 1996;71:253–8.CrossRefPubMedGoogle Scholar
  20. 20.
    Inagi T, Muramatsu T, Nagni H, Terada H. mechanism of indomethacin partition between n-octanol and water. Chem Pharm Bull. 1981;29:2330–7.CrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2018

Authors and Affiliations

  1. 1.School of PharmacyUniversity of Wisconsin-MadisonMadisonUSA
  2. 2.Department of ChemistryUniversity of Wisconsin-MadisonMadisonUSA

Personalised recommendations