Document Detail


Polymorph Formation and Nucleation Mechanism of Tolfenamic Acid in Solution: An Investigation of Pre-nucleation Solute Association.
MedLine Citation:
PMID:  21879384     Owner:  NLM     Status:  Publisher    
Abstract/OtherAbstract:
PURPOSE: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.
Authors:
Alessandra Mattei; Tonglei Li
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Publication Detail:
Type:  JOURNAL ARTICLE     Date:  2011-8-31
Journal Detail:
Title:  Pharmaceutical research     Volume:  -     ISSN:  1573-904X     ISO Abbreviation:  -     Publication Date:  2011 Aug 
Date Detail:
Created Date:  2011-8-31     Completed Date:  -     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  8406521     Medline TA:  Pharm Res     Country:  -    
Other Details:
Languages:  ENG     Pagination:  -     Citation Subset:  -    
Affiliation:
Department of Pharmaceutical Sciences, University of Kentucky, Lexington, Kentucky, USA.
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