Research ArticlesEvaluating Computational Predictions of the Relative Stabilities of Polymorphic Pharmaceuticals
Section snippets
INTRODUCTION
An important prerequisite for crystal structure prediction is the ability of a computational method to correctly rank the relative energies of different polymorphic packing structures. The correct energy ranking of polymorphs is also important to describe hypothetical or newly discovered polymorphic systems, which are sometimes energetically characterized by computational methods in lieu of calorimetric data. While many computational methods have been validated through comparisons with
METHODS
The data set was chosen to contain pharmaceuticals with high quality structural and calorimetric characterization, such that direct comparison could be made between experimental and computational results. If multiple crystal structures were available for a given pharmaceutical, structures acquired at low temperature or with lower R-values were selected. Specific compounds were chosen to create a set of pharmaceuticals with a variety of functional groups and hydrogen bonding motifs. Although the
RESULTS AND DISCUSSION
A number of computational approaches were explored for the set of polymorphs. The simplest calculation that can be employed is a single point energy, in which the energy for a crystal structure is directly calculated. Other strategies include constrained geometry optimizations, in which some atomic positions are allowed to vary, and full geometry optimizations with all atomic positions and cell parameters unconstrained. Figure 2 presents the geometry optimizations used in this study. For each
CONCLUSIONS
Because of the low computational expense of molecular mechanics methods and good agreement with experimental results using the Compass force field, such methods for geometry minimizations of known crystal structures have been shown to be the best computational approach to describe the energetics of polymorphic pharmaceutical compounds in this survey. Table 2 summarizes how well each method agrees with experimental data. Quantitative agreement was rarely seen with Dreiding force field
Acknowledgements
This work was supported by the National Science Foundation under grant CHE-0316250. K. M. K. gratefully acknowledges the support by the Fannie and John Hertz Foundation.
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Tables with calculated energies, calculated transition energies, and experimental heats of transition. This material is available free of charge via the Internet (http://www.interscience.wiley.com/).
Katie R. Mitchell-Koch’s present address is Department of Chemistry, University of Kansas, 1251 Wescoe Hall Drive, 2010 Malott Hall, Lawrence, Kansas 66045.