Research Articles
Molecular Modeling Study Of Chiral Drug Crystals: Lattice Energy Calculations

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ABSTRACT

The lattice energies of a number of chiral drugs with known crystal structures were calculated using Dreiding II force field. The lattice energies, including van der Waals, Coulombic, and hydrogen‐bonding energies, of homochiral and racemic crystals of some ephedrine derivatives and of several other chiral drugs, are compared. The calculated energies are correlated with experimental data to probe the underlying intermolecular forces responsible for the formation of racemic species, racemic conglomerates, or racemic compounds, termed chiral discrimination. Comparison of the calculated energies among ephedrine derivatives reveals that a greater Coulombic energy corresponds to a higher melting temperature, while a greater van der Waals energy corresponds to a larger enthalpy of fusion. For seven pairs of homochiral and racemic compounds, correlation of the differences between the two forms in the calculated energies and experimental enthalpy of fusion suggests that the van der Waals interactions play a key role in the chiral discrimination in the crystalline state. For salts of the chiral drugs, the counter ions diminish chiral discrimination by increasing the Coulombic interactions. This result may explain why salt forms favor the formation of racemic conglomerates, thereby facilitating the resolution of racemates. © 2001 Wiley‐Liss, Inc. and the American Pharmaceutical Association J Pharm Sci 90:1523–1539, 2001

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INTRODUCTION

Molecular modeling uses computational methods to study various chemical and biological systems. In recent years this technique has emerged as an important tool for predicting and correlating the energies and properties of molecules of known and unknown structures in chemical, biological, and pharmaceutical research.1,2 One of the major advantages of computer modeling over experiment is that the interaction energy and its variation with structure may be investigated at the atomic and molecular

EXPERIMENTAL SECTION

The model compounds used in this work were selected based on the availability of crystal structural data, and are listed in Table 1 together with the acronyms that are employed in this report.

RESULTS AND DISCUSSION

The crystal structures of a number of homochiral and racemic crystals are available either through structural determination reported in this work or through a search of the CSD (Table 1). Ephedrine and its N‐methyl derivatives and their salts were used as structurally related model compounds, collectively termed ephedrine derivatives. Although the crystal structures of many chiral compounds are available, few have known structures for both the homochiral and racemic crystals, and even fewer for

CONCLUSION

The contributions of the individual energy components, namely van der Waals interactions, electrostatic interactions, and hydrogen bonding, to the total lattice energy were calculated for a number of organic pharmaceutical crystals, and the individual correlations with their physical properties were investigated. Among the ephedrine bases and their salts, the electrostatic interaction correlates with the relatively large increases of melting temperatures of the salts, while the van der Waals

ACKNOWLEDGEMENTS

The authors thank the following: Dr. William B. Gleason, Department of Laboratory Medicine and Pathology, University of Minnesota, for advice on crystal structure analysis of several compounds; Ms. Shuxuan Chao of 3M Pharmaceuticals for statistical analysis; the Pharmaceutical Research and Manufacturers of America Foundation for an Advanced Predoctoral Fellowship for Z. J. Li; and the Supercomputer Institute of the University of Minnesota for supporting our use of the Medicinal

REFERENCES (40)

  • J. Jacques et al.

    Enantiomers, Racemates and Resolutions

    (1981)
  • F.J.J. Leusen

    Rationalization of Racemate Resolution

    (1993)
  • H. Lopez de Diego

    1‐Phenylethylammonium Mandelates, a Structural and Physico‐chemical Investigation of a Complicated System of Diastereomers

    (1995)
  • T. Clark

    A Handbook of Computational Chemistry, A Practical Guide to Chemical Structure and Energy Calculations

    (1985)
  • S.L. Mayo et al.

    Dreiding: a generic force field for molecular simulation

    J Phys Chem

    (1990)
  • A.J. Pertsin et al.

    The Atom‐Atom Potential Method: Application to Organic Solids

    (1987)
  • J.E. Lennard‐Jones

    On the determination of molecular fields

    II. Proc R Soc London, Ser A

    (1924)
  • G.A. Jeffrey et al.

    Hydrogen Bonding in Biological Structures

    (1991)
  • A.I. Kitaigorodski

    Molecular Crystals and Molecules

    (1973)
  • A. Gavezzotti

    Molecular packing and correlations between molecular and crystal properties

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