Nucleation of Conformational Polymorphs: A Computational Study of Tolfenamic Acid by Explicit Solvation

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• 作者：Alessandra Mattei ; Tonglei Li
• 刊名：Crystal Growth & Design
• 出版年：2014
• 出版时间：June 4, 2014
• 年：2014
• 卷：14
• 期：6
• 页码：2709-2713
• 全文大小：320K
• 年卷期：v.14,no.6(June 4, 2014)
• ISSN：1528-7505

文摘

The nucleation mechanism of polymorph formation remains poorly understood. For conformational polymorphism, the nature and strength of molecular interactions influence the conformation of a molecule, and such interplay between conformation and intermolecular interaction likely plays out through the self-assembling process of nucleation governing the outcome of resultant crystal structures. This study investigates molecular interactions and structural properties of a conformationally flexible molecule, tolfenamic acid, in explicit solvent by means of molecular dynamics and combined quantum mechanics and molecular mechanics methods. The results point out that tolfenamic acid prefers to take a relatively flat conformation, stabilized by intermolecular interactions between the solute and solvent molecules. Tolfenamic acid molecules can also adopt a more twisted conformation in a homodimeric state which exhibits lower solvation energy but greater stability. The computational work unravels the important influence by intermolecular interactions鈥攂etween the solute and solvent or between the solute and solute鈥攐n stabilizing the conformation of solute molecules and, thus, highlights the underlying cooperation between a molecule鈥檚 conformation and its intermolecular interaction leading to the nucleation of distinct polymorphic structures.