(586c) Selection of Polymorphic Forms Via Continuous Kinetically Controlled Msmpr Crystallization

This work presents the first study of the mechanism controlling crystallization of polymorphs in continuous MSMPR type crystallizers. Crystallization is the dominant purification and separation technique used in the pharmaceutical industry, with more than 90% of small molecule pharmaceutical products utilizing a crystallization step in their production [1]. For this reason the understanding of polymorphism in continuous crystallization is vital for the future implementation of continuous processing in pharmaceutical manufacturing. It was found that if the MSMPR crystallization used in this study was operated at a steady state so that supersaturation exists with respect to both the metastable (alpha) and stable (beta) polymorphs for L-glutamic acid (a model monotropic organic system). The controlling mechanism as to which polymorph was produced was the relative rates of secondary nucleation of the two polymorphs.

This is due to the fact that when solution mediated polymorphic transformation is eliminated, the ability to sustain the number of particles in the crystallizer at a given residence time becomes the controlling factor as to which polymorph or the relative amount of each that are produced. This enabled selective crystallization of either the meta-stable or stable form by a purely kinetically controlled crystallization, and may provide the first robust and scalable method for isolation of metastable forms on an industrial scale. The use of mother liquor recycle enabled the yield in either of these scenarios to at least match that of the equivalent batch crystallization [2].

[1]        Variankaval, N., Cote, A. S., Doherty, M. F. (2008). From Form to Function: Crystallization of Active Pharmaceutical Ingredients.  AIChE Journal 54(7): 1682-1688.

[2]        Wong, S.Y., Tatusko, A.P., Trout, B.L., Myerson, A.S. (2012). Development of Continuous Crystallization Processes. Using a Single-Stage, Mixed-Suspension, Mixed-Product Removal Crystallizer with Recycle. Cryst. Growth & Des. 12(11), 5701-5707.