(181b) On the Density and Stability of Crystal Structures of Chiral Molecules

In the pharmaceutical industry Active Pharmaceutical Ingredients (API's) are frequently chiral molecules and the enantiomers may have different pharmacological activity. FDA guidelines pay close attention to chirality in drug formulations, involving issues such as the enantiomeric composition of the drugs and pharmacological activity of the enantiomers. Production methods for API's as pure enantiomers by separation or asymmetric synthesis are of great interest [1]. A great majority of racemic mixtures of chiral molecules form solid phase racemic compounds that are more stable than the pure enantiomer solids and this complicates separation by crystallization. The stability of racemic compounds has been known for over a century but has yet to be completely understood [2].

In this paper we discuss the stability of racemic compounds from the perspective of molecular packing using an interaction site model of a chiral molecule with hard sphere sites [3]. Over the parameter space of the model we explore the solid phase stability in two ways. We first determine the close packed density for pure enantiomers and racemic compounds using a simulated annealing method that searches the molecular configuration space for density maxima [4]. We supplement these calculations with Monte Carlo simulations to determine the phase diagram [3]. Our results show that for this model racemic compounds are generally denser and more stable than pure enantiomers. In those cases where the pure enantiomers are more dense and stable this is often for model parameters where the chirality is weak. Since both the pure enantiomers and racemic compounds can be prepared for our model we can make an unbiased test of Wallach's rule [5], which states that racemic compounds are always more dense than pure enantiomers.

1. Datta, S. and D.J.W. Grant, Crystal structures of drugs: Advances in determination, prediction and engineering. Nature Reviews Drug Discovery, 2004. 3(1): p. 42-57.

2. Jacques, J., A. Collet, and S.H. Wilen, Enantiomers, racemates, and resolutions. 1981, New York: Wiley.

3. Cao, M. and P.A. Monson, A study of the phase behavior of a simple model of chiral molecules and enantiomeric mixtures. Journal Of Chemical Physics, 2005. 122(5): p. 054505.

4. Malanoski, A.P. and P.A. Monson, Solid-fluid equilibrium in molecular models of n-alkanes. Journal Of Chemical Physics, 1999. 110(1): p. 664-675.

5. Brock, C.P., W.B. Schweizer, and J.D. Dunitz, On the Validity of Wallach Rule - on the Density and Stability of Racemic Crystals Compared with Their Chiral Counterparts. Journal of the American Chemical Society, 1991. 113(26): p. 9811-9820.