23rd Congress Montreal, 5th to 12th August 2014
MS107.P09.B629 - Redefining Solution-Mediated Transformations: Pharmaceutical
Systems
M. O'Mahony1,2, A. Maher2, D. Croker2, A. Rasmuson2, B. Hodnett2
1
Massachusetts Institute of Technology, Chemical Engineering, Cambridge, USA, 2University
of Limerick, Chemical and Environmental Science, Limerick, Ireland
Engineering the isolation of a metastable or stable crystalline phase of an active
pharmaceutical ingredient (API) is of critical importance when crystallizing from solution as
an uncontrolled outcome can directly affect API manufacture and performance. The
theoretical framework for understanding solution-mediated crystal phase or polymorphic
transformation (SMPT) was first established by Cardew & Davey.[1] The process is defined
to consist of a metastable phase that dissolves and a stable phase that nucleates and grows
independently from the solution. That paper also identified that in terms of a reaction
pathway, SMPT could be controlled in either of two ways: by growth of the stable phase or
dissolution the metastable phase. Studies concerning SMPT since then have brought the
definition and those conclusions into question. Firstly, the recent case of the SMPT from FI
to FIII carbamazepine and FII to FIII piractem were studied separately where data on both the
solid state composition and solution concentration were collected during the transformation
using powder X-ray diffraction and in situ infra-red spectroscopy, respectively. These studies,
in combination with a brief review of the literature, reveal that SMPT can be controlled not
only in the two ways described by Cardew & Davey but rather in 4 principal ways (Figure
1).[2] Secondly, many studies now identify that nucleation of the stable phase often occurs on
the surface of the metastable phase during SMPT [3] and not independently from solution.
Again when the literature is examined, this surface supported nucleation event is identified as
being either epitaxial in nature or having no or inconclusive evidence of epitaxy. It is
concluded that the term “independently” in the definition by Cardew & Davey be redefined to
recognize that the crystallization of the stable phase during SMPT is often dependent on the
surface of the metastable phase in solution.
References:
[1] [1] P. T. Cardew, R. J. Davey, Proc. Royal. Soc. A 1985, 398, 415.
[2] [2] M. O’Mahony, A. Maher, D. M. Croker et al. Cryst. Growth & Des. 2012, 12, 1925.
[3] [3] D. Croker, B. K. Hodnett, Cryst. Growth & Des. 2010, 10, 2806.
MS43.P26.A450 - Anisotropic crystal growth of carbamazepine form I and a
hydroxysulfonamide
N. Walshe1, A. Erxleben1, P. McArdle1
1
National University of Ireland, School of Chemistry, Galway, Ireland
Carbamazepine form I, CBZ, and 4-hydroxy-N-phenylbenzenesulfonamide, HPS, both
exhibit highly anisotropic needle-like crystal growth. CBZ has been observed to have a
corresponding anisotropy in its dissolution. Using the assumption that crystal growth and
dissolution have reciprocal mechanisms[1] molecular dynamics, MD, simulations of CBZ
and HPS crystal dissolution have been used to examine the mechanism of the needle
growth/dissolution. MD simulations of CBZ dissolution using AMBER[2] reproduce the
highly anisotropic crystal dissolution. Blocks containing between 48 and 256 molecules in 50
to 90 Å3 boxes of solvent show rapid loss of molecules from the a face. Simulation of HPS
crystal dissolution also shows high anisotropy however the dissolution of HPS is much
slower than that of CBZ due to the presence of hydrogen bonding chains in the structure. A
two unit cell molecule centroid distance matrix analysis was used to detect molecular
stacking in both structures. The direction of the hydrogen bonding in HPS is normal to the
direction of growth. However the relatively rapid dissolution is in the stacking direction in
both crystal structures and is attributed to the higher relative energy of surface molecules at
the ends of the stacks that have a higher fraction of exposed atoms. A related analysis has
been applied to flat molecule structures which are stacked. [3] If flat molecule stacks can be
compared to stacks of pizza boxes then the non-flat molecules described here can be
compared to stacked chairs.
References:
[1] P. M. Dove, N. Han and J. J. De Yoreo, Proceedings of the National Academy of Sciences
of the United States of America, 2005, 102, 15357-15362.
[2] Y. Duan, C. Wu, S. Chowdhury, M. C. Lee, G. M. Xiong, W. Zhang, R. Yang, P. Cieplak,
R. Luo, T. Lee, J. Caldwell, J. M. Wang and P. Kollman, J. Comput. Chem., 2003, 24, 19992012.
[3] N. Panina, R. van de Ven, F. F. B. J. Janssen, H. Meekes, E. Vlieg and G. Deroover,
Cryst. Growth Des., 2008, 9, 840-847