(580c) Towards Modelling Facet-Specific Impurity Incorporation Rates Using Molecular Dynamics Simulations – a Case Study on the Urea/Biuret/Water System

Crystallization is one of the most widely used separation technologies for the purification of fine chemicals, agrochemicals, and pharmaceuticals. In the pharmaceutical industry, as demands on product purity can be extremely high (up to 99.9%)¹, it is of vital importance to minimize impurity incorporation during the crystallization process. To this end, this study is aimed towards a better understanding of the molecular mechanisms underpinning impurity incorporation into organic crystals.

Crystals grown from solution expose multiple facets, where each facet is a cessation of the crystal structure. The unique arrangement of host molecules and hence functional groups on a developing crystal face leads to varying affinities for the solute and impurity molecules present in solution. This, in turn, results in facet-specific growth rates and inherently anisotropic impurity distribution in the crystal lattice.

This work has quantitatively investigated impurity incorporation into an organic crystal using the classical example of urea crystal growth from aqueous solution, with biuret (a reaction by-product) present as an impurity. Molecular dynamics (MD) simulations were performed in GROMACS to determine incorporation of biuret on the (001) and (110) facets respectively. Keeping the initial supersaturation constant among the different cases, we have varied the concentration of the biuret impurity present in the solution. The computational method developed previously by Salvalaglio et al.² to quantify the ‘crystallinity’ of urea molecules (the ‘crystallinity’ parameter was calculated by taking into consideration the C=O bond angles between a urea/biuret molecule incorporated from solution and that of neighboring urea molecules in the crystal lattice) was adapted to allow quantifying the number of biuret molecules incorporated during the growth of different crystal facets.

It was previously shown experimentally and from simulation work^2,3 that the growth rate of the {001} facet is strongly affected by the presence of biuret in the solution, while the growth rate of the {110} facet is largely unaffected. However, an analysis of the number of biuret molecules incorporated during crystal growth is to date absent from the literature.

References:

[1] “FDA Guidance for Industry Drug Substance Chemistry, Manufacturing, and Controls Information,” Structure no. Cvm, 2004.

[2] M. Salvalaglio, T. Vetter, F. Giberti, M. Mazzotti, and M. Parrinello, “Uncovering Molecular Details of Urea Crystal Growth in the Presence of Additives,” J. Am. Chem. Soc., 134 (41), 17221–17233, 2012.

[3] M. K. Singh, V. S. Tiwari. “Uncovering the Mode of Action of Solvent and Additive Controlled Crystallization of Urea Crystal: A Molecular-Scale Study”, Cryst. Growth Des. 15(7), 3220–3234. 2015.