(189e) Directing the Crystallization of a Desired Polymorph through Secondary Nucleation (Seeding)

Prasanna, P. R. M., Tufts Univeristy
Botsaris, G. D., Tufts Univeristy

            A large number of substances, including
high-value added pharmaceutical products, crystallize in more than one distinct
crystal structures.  These structures termed polymorphs, display different
physical properties (solubility, crystal form, density, compressibility, etc.)
and consequently pharmacological activities.  Regulatory pressure for the
development of consistent production processes, dictate the need for a better
understanding of all the crystallization steps involved in the process.

            The outcome at the primary nucleation step is
described by the Ostwald's ?Rule of Stages,? which states that the stable
polymorph has the lowest solubility and yet the metastable form of higher
solubility nucleates first.

            It appears, however, that things are much more
complex in the case of secondary nucleation.  Recent studies1, 2 involved the crystallization of L-glutamic acid which has two polymorphs: the stable beta-form and the metastable alpha-form.  Seeds of the latter polymorph were used but the resulting secondary nuclei were not necessarily alpha polymorph. For instance, at a certain supersaturation beta-polymorph was obtained while at another a mixture of alpha and beta was produced.  The case of epitaxial growth of beta on alpha was also reported.

            This paper describes a systematic investigation
of secondary nucleation in the crystallization of L-glutamic acid.  Seeds of
both polymorphs are used at different supersaturations and temperatures.  The
crystals resulting from the secondary nuclei are collected and their
crystalline structure is obtained by melting point measurements and an x-ray
diffraction technique.

            The interpretation of the results is based on
the solubility data of the two polymorphs and two mechanisms of secondary
nucleation: the Contact Secondary Nucleation (CSN) and the Embryos-Coagulation
Secondary Nucleation (ESCN) model.

The ESCN model wad developed by Qian and Botsaris3, 4 and was successfully used to direct the crystallization of crystals of a desired chirality in the cases of sodium chlorate and threonine.


1.         Cashell C, Corcoran D, Hodnett BK. Secondary nucleation of the b-polymorph of the L-glutamic acid on the
surface of a-form crystals. Chem

2.         Ferrari
ES, Davey RJ. Solution-mediated transformation of a to b L-glutamic acid:
Rate enhancement due to secondary nucleation. Cryst Growth Des. Sep-Oct

3.         Qian
R-Y, Botsaris GD. A new mechanism for nuclei formation in suspension
crystallizers: the role of interparticle forces. Chem Eng Sci. 1997;52(20):3429-3440.

4.         Qian
R-Y, Botsaris GD. The effect of seed preparation on the chirality of the
secondary nuclei. Chem Eng Sci. 2004;59:2841-2852.