(744d) Mechanistic Model for the Effect of Molecular Imposters on the Shape of Molecular Organic Crystals

The large majority of active pharmaceutical ingredients (APIs) are separated by crystallization from solution and later formulated into tablets as crystals. One important physical property of the crystal is its shape, which can impact the crystal's dissolution rate in the gut, its tendency to agglomerate, and its ability to be compacted into tablets. APIs are formed through a series of reactions, so there are always by-products in solution during crystallization, and these by-products can be quite similar in structure to the API itself. The structurally-related by-products can be occluded in the API crystal during crystallization and exert conspicuous effects on crystal shape. For example, Hendriksen et al. (1998) report the effect of several structurally related molecules on the morphology of paracetamol.

Models of crystal growth shape have moved away from those depending only on crystal geometry or thermodynamics to incorporate mechanistic ideas such as the incorporation of solute at kink sites. In particular, there exists a class of kinetic models based on step flow and the spiral growth of crystal surfaces which are founded on the work of Burton, Cabrera, and Frank (1951) and Chernov (1961); solvent effects in these models have been accounted for by Winn and Doherty (1998).

We furnish an extension of these crystal growth models to capture the effect of structurally-related by-products (here termed ?imposters?) based on a mechanistic description of the way a molecular imposter impacts a growing crystal surface. We argue that the imposter has no net effect on these growth spirals except at the point where the first turn of a spiral occurs. The model is applied to alpha-glycine growing from water in the presence of L-alanine, and our shape predictions are compared to experimental results (Weissbuch et al., 1983).

Hendriksen, Barry.A., David J.W. Grant, Paul Meenan, and Daniel A. Green. Crystallisation of paracetamol (acetaminophen) in the presence of structurally related substances. Journal of Crystal Growth, 183: 629?640, 1998.

Burton, W.K., N. Cabrera, and F.C. Frank. The Growth of Crystals and the Equilibrium Structure of their Surfaces. Phil. Trans. R. Soc., 243: 299?358, 1951.

Chernov, A.A. The Spiral Growth of Crystals. Soviet Physics Uspekhi, 4: 117?145, 1961.

Weissbuch, I., L. Addadi, Z. Berkovitch-Yellin, E. Gati, S. Weinstein, M. Lahav, and L. Leiserowitz. Centrosymmetric crystals for the direct assignment of the absolute configuration of chiral molecules: Application to the alpha-amino acids by their effect on glycine crystals. J. Am. Chem. Soc., 105: 6615?6621, 1983.