(744c) Polymorph Selection In Solution Crystallization: Is Kinetics the Primary Determinant?

In determining the structural outcome of a solution crystallization process, there is a delicate interplay between the kinetics and thermodynamics controlling crystal nucleation. As a result, many a times, the stable crystalline form of an organic compound as predicted using lattice energy minimization approach may not be obtained experimentally. This was best illustrated by the case study of glycine, wherein it was shown that the thermodynamically stable g-form grows 500 times slower than the metastable a-form at the same supersaturation, and hence, is difficult to crystallize from pure aqueous solution (Chew et al., CrystEngComm, 2007, 9, 128). Nevertheless, g-glycine could be obtained from aqueous solutions at high or low pH conditions, as well as in the presence of certain salts and ‘tailor-made' additives. Given this, we are confronted with the fundamental question - is kinetics or thermodynamics the primary determinant of polymorph selection?

In this work, the influence of tailor-made additives on the relative nucleation and growth behavior of the individual glycine polymorphs were studied. The observed changes in metastable zone widths and crystal morphology indicated growth inhibition of the metastable a-glycine by the additives (Poornachary et al., Cryst. Growth Des., 2008, 8(1), 179). On the basis of the ‘self-poisoning' (Towler et al., J. Am. Chem. Soc., 2004, 126, 13347) and ‘stereoselective nucleation inhibition' (Weissbuch et al., Cryst. Growth Des., 2003, 3(2), 125) mechanisms, we rationalize that kinetics controls the appearance of g-glycine. Furthermore, our data showed that NaCl and NH₄NO₃ can remarkably enhance g-glycine growth, providing additional evidence that the g-polymorph is kinetically favored in the presence of these salts (Han et al., 17th International Symposium on Industrial Crystallization, Maastricht, The Netherlands, 2008). As an outcome of this investigation, we could conclude that the appearance of both the glycine polymorphs under these operating conditions is kinetically controlled.