Pharmaceutical Research

, Volume 29, Issue 2, pp 460–470 | Cite as

Polymorph Formation and Nucleation Mechanism of Tolfenamic Acid in Solution: An Investigation of Pre-nucleation Solute Association

Research Paper



Crystallization from solution involves nucleation and growth; growth conditions greatly influence self-association behaviors of solute molecules in these steps, affecting crystal packing of organic molecules. We examined the role of pre-nucleation association to provide insights into the mutual influence between molecular conformation in solution and packing in the solid state.


Crystallization experiments of tolfenamic acid were conducted in ethanol under different supersaturation conditions. UV spectroscopy was performed to study self-association of solute molecules in ethanol as a function of concentration. Intermolecular interaction energies of tolfenamic acid dimers were calculated with quantum mechanical methods.


As supersaturation increased, growth of the most stable polymorph outpaced the metastable one, contradicting Ostwald’s Rule of Stages. UV spectroscopy measurement suggests solute molecules exist as hydrogen-bonded dimers and more dimers form as total concentration increases. Hydrogen bonding in the most stable form is significantly stronger than that in the metastable form.


With the fact that molecular conformation is different in the two polymorphs, as concentration increases, solute molecules rearrange their conformations to form stronger hydrogen-bonded dimers in solution, resulting in nucleation of the most stable form.


dimer nucleation polymorph self-association supersaturation 



The authors recognize Dr. Roger Zanon from Upsher-Smith Laboratories for his suggestion of the seeding experiment and thank Profs. B. D. Anderson, Z. J. Hilt, and S. Van Lanen for their advices and instrument support. The study was supported by NSF (DMR-0449633 and DMR-1006364).


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© Springer Science+Business Media, LLC 2011

Authors and Affiliations

  1. 1.Department of Pharmaceutical SciencesUniversity of KentuckyLexingtonUSA

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