Research Articles
Evaluating Computational Predictions of the Relative Stabilities of Polymorphic Pharmaceuticals

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Abstract

The ability of computational methods to describe the relative energies of polymorphic pharmaceuticals is investigated for a diverse array of compounds. The initial molecular geometries were taken from crystal structures, and energy differences between polymorphic pairs were calculated with various geometry optimization methods. Results using molecular mechanics were compared to experimental calorimetric data and periodic density functional theory (DFT) calculations. The best agreement with experimental heats of transition was shown with energies calculated from geometry optimizations using the Compass force field. Calculations that optimized atomic positions with the Compass force field gave correct energy rankings for all 11 polymorphic pairs studied, with an average deviation of 0.61 kcal/mol from experimental results. These findings suggest that computational methods are poised to predict enthalpy differences between polymorphic forms with levels of accuracy that are quite acceptable when proper approaches are employed.

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.

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