(410d) Growth Prediction For Molecular Crystals Of Api-Complexity

Modeling crystal growth of organic compounds is of paramount interest to the pharmaceutical, dyes and food products industries. Crystal growth plays an important role in both crystal morphology and polymorph transformations. Steady state and dynamic crystal morphology affect down stream processes such as filtering, washing and drying as well as particle flowability and agglomeration. Furthermore, the quality and efficacy of these materials are affected by crystal shape and polymorph. The shape affects which surface structures are present and their relative sizes. The polymorph can affect the solubility, color, bioavailability, stability and patentability of a crystalline product. Polymorphic phase transformations often take place by a solution mediated mechanism, which is characterized by the growth of a more stable polymorph and the simultaneous dissolution of a less stable polymorph. Thus, predicting growth of the stable polymorph facilitates the calculation of a polymorphic phase transformation rate. The abilities to predict crystal shapes and polymorphic phase transformations enable both process and product improvments.

Models of crystal growth shape have evolved from those that depend purely on crystal structure and thermodynamics to those that incorporate mechanistic phenomena such as the incorporation of solute at kinks on steps flowing across surfaces. We have focused on a class of these kinetic models and the development of steps on crystal faces through the spiral growth mechanism that was pioneered by Burton, Cabrera and Frank (1951) and further developed by Chernov (1984). Winn and Doherty (1998) further enabled the models to account for the effect of solvent. However, these models have primarily focused on systems where the molecules and crystal interactions are highly symmetric. On the other hand, pharmaceutical level molecular organic and biological crystals have complex bonding structures, molecular arrangements and energetic interactions.

We have developed a spiral growth model to incorporate these important quantities, which result in numerous complicated microscopic features such as non-isotropic spiral shapes, non-uniform velocity distributions and spirals of alternating step height. Some of these features (for example non-isotropic spiral shapes) have previously been measured by experiment; however, existing models do not account for their influence. In addition, for these complex systems, classical kinks (i.e. half crystal positions) do not exist since there are many locations where the interactions at a site cannot be divided in half. Thus, the velocity for each side of a spiral cannot be determined as being proportional to the probability of finding a kink site. Rather, the probability of a molecule attaching to each of the different sites must be enumerated. In this talk, key modeling details will be presented alongside examples of complex crystal systems where each of the new modeling concepts is needed. Finally, the results for growth shape predictions are compared to experiment.

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

Chernov, A.A., Modern Crystallography III: Crystal Growth, Berlin: Springer-Verlag (1984).

Winn, D. and M.F. Doherty, ?A New Technique for Predicting the Shape of Solutions-Grown Organic Systems,? AIChE J., 44 (11), 2501 (1998).