Continuous Crystallization and Polymorph Dynamics in the l -Glutamic Acid System

Polymorph dynamics of l -glutamic acid were examined during continuous mixed suspension mixed product removal (MSMPR) crystallization as a function of residence time and temperature. Results indicate that it is possible to selectively produce metastable or stable polymorphs via a kinetically controlled crystallization in an MSMPR crystallizer by manipulating the crystallizer temperature and residence time. Additionally, on the basis of experimental and modeling studies, it was found that seeding is not necessarily sufficient to alter polymorphism at a given steady state, indicating that this traditional polymorph control strategy may not be applicable in MSMPR systems. The competition between nucleation and growth kinetics of the metastable α form and the stable β form is the major factor in determining the polymorphic outcome at particular steady state conditions. A metastable steady state with a population of the stable β polymorphic was experimentally obtained at 25 °C and 120 min residence time where a small perturbation from the α form could induce a change in the steady state polymorphism. This “polymorphic transformation”, unlike the traditional solvent-mediated transformation, is a result of the interplay of kinetic driving forces. In addition, our dynamic simulation suggests that long residence times (>17.4 h) are required to obtain a steady state of the stable β form when operating at temperatures of 25 °C. Our studies indicate one challenge for designing a MSMPR crystallization will be the interplay of growth and nucleation kinetics of the various forms at conditions which produce the desired yield and polymorph.