Polymorph Formation and Nucleation Mechanism of Tolfenamic Acid in Solution: An Investigation of Pre-nucleation Solute Association
- 705 Downloads
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.
KEY WORDSdimer nucleation polymorph self-association supersaturation
ACKNOWLEDGMENTS & DISCLOSURES
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).
- 1.Byrn SR, Pfeiffer RR, Stowell JG. Solid state chemistry of drugs. West Lafayette: SSCI, Inc.; 1999.Google Scholar
- 19.Volmer M. Kinetik der phasenbildung. Dresden: Steinkopf; 1939.Google Scholar
- 23.Ostwald W. Studien über die Bildung und Umwandlung fester Körper. Z Phys Chem. 1897;22:289–330.Google Scholar
- 24.Haisa M, Kashino S, Kawai R, Maeda H. Monoclinic form of para-hydroxyacetanilide. Acta Crystallogr. 1976;B32:1283–5.Google Scholar
- 46.Frisch MJ, Trucks GW, Schlegel HB, Scuseria GE, Robb MA, Cheeseman JR, et al. Gaussian 03, Revision C.02. Wallingford: Gaussian Inc.; 2004.Google Scholar
- 56.Dovesi R, Saunders VR, Roetti C, Orlando R, Zicovich-Wilson CM, Pascale F, et al. Crystal06 User’s Manual. Torino: Universita’ di Torino; 2006.Google Scholar
- 57.Cardew PT, Davey RJ. The kinetics of solvent-mediated phase-transformations. Proc R Soc London. 1985;A398:415–28.Google Scholar
- 60.Rao CNR. Ultra-violet and visible spectroscopy. London: Butterworths; 1961.Google Scholar
- 62.Surov AO, Szterner P, Zielenkiewicz W, Perlovich GL. Thermodynamic and structural study of tolfenamic acid polymorphs. J Pharm Biom Anal. 2009;50:831–40. The sublimation enthalpies of TFA forms I and II were experimentally determined as 128.4 and 135.1 kJ/mol at 298 K, respectively. Note that the experimental value of sublimation enthalpy of form I was directly determined, but that of form II was estimated based on solution calorimetry data. Their claim of phase transition from form I to II in solution contradicts our observation.CrossRefGoogle Scholar