The AAPS Journal

, Volume 14, Issue 3, pp 380–388 | Cite as

Stability of Amorphous Pharmaceutical Solids: Crystal Growth Mechanisms and Effect of Polymer Additives

  • Ye Sun
  • Lei Zhu
  • Tian Wu
  • Ting Cai
  • Erica M. Gunn
  • Lian Yu
Review Article Theme: Develop Enabling Technologies for Delivering Poorly Water Soluble Drugs: Current Status and Future Perspectives


We review recent progress toward understanding and enhancing the stability of amorphous pharmaceutical solids against crystallization. As organic liquids are cooled to become glasses, fast modes of crystal growth can emerge. One such growth mode, the glass-to-crystal or GC mode, occurs in the bulk, and another exists at the free surface, both leading to crystal growth much faster than predicted by theories that assume diffusion defines the kinetic barrier of crystallization. These phenomena have received different explanations, and we propose that GC growth is a solid-state transformation enabled by local mobility in glasses and that fast surface crystal growth is facilitated by surface molecular mobility. In the second part, we review recent findings concerning the effect of polymer additives on crystallization in organic glasses. Low-concentration polymer additives can strongly inhibit crystal growth in the bulk of organic glasses, while having weaker effect on surface crystal growth. Ultra-thin polymer coatings can inhibit surface crystallization. Recent work has shown the importance of molecular weight for crystallization inhibitors of organic glasses, besides “direct intermolecular interactions” such as hydrogen bonding. Relative to polyvinylpyrrolidone, the VP dimer is far less effective in inhibiting crystal growth in amorphous nifedipine. Further work is suggested for better understanding of crystallization of amorphous organic solids and the prediction of their stability.

Key words

amorphous solid crystal growth crystallization crystallization inhibitor glass glass transition polymer additive surface molecular mobility 



This work was supported in part by NSF (DMR-0804786 and DMR-0907031), the American Chemical Society Petroleum Research Funds (43809-AC10), Abbott Laboratories, AstraZeneca, Bristol-Myers Squibb, and the PhRMA Foundation.


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Copyright information

© American Association of Pharmaceutical Scientists 2012

Authors and Affiliations

  1. 1.School of PharmacyUniversity of Wisconsin—MadisonMadisonUSA
  2. 2.Department of ChemistryUniversity of Wisconsin—MadisonMadisonUSA
  3. 3.Department of Chemical EngineeringMassachusetts Institute of TechnologyCambridgeUSA
  4. 4.Pharmaceutical Sciences and Clinical SupplyMerck & Co., Inc.SummitUSA
  5. 5.Small Molecule Process and Product DevelopmentAmgen Inc.Thousand OaksUSA

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