No abstract

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.

Control of polymorphism of the enantiotropic p-aminobenzoic acid at either the α or β polymorph while maintaining high yield was achieved by mixed suspension mixed product removal (MSMPR) cascade design. A systematic approach was developed to identify the operational window of the process variables, stage temperature and residence time, in which the stringent polymorph purity criterion (>95 wt %) and high yield were met. The comprehensive understanding of the polymorphism of the model compound, p-aminobenzoic acid, was the key for the identification of the operational window. On the basis of single-stage MSMPR experiments, three temperature regimes thermodynamic control, energy barrier control, and kinetic competitionwere identified, and the interplay between the crystallization kinetics and the thermodynamics in each regime was elucidated. Experimental studies also demonstrated the first polymorph specific MSMPR for enantiotropic systems. Single-stage MSMPRs at low temperature, e.g., 5°C, were found to be β polymorph-specific at steady states across multiple operating conditions. Two-stage MSMPR was designed to alter the polymorphism at the 5°C stage from β polymorph-specific to α polymorph-specific. The first stage temperature was selected in the thermodynamic control regime (30°C) at which the steady state polymorphism was α-specific. Feeding continuously to the second stage, the α crystals generated at the first stage increased the total surface area and thereby the secondary nucleation and mass deposition rates of the α polymorph in the 5°C stage. This in turn increased the α polymorph from 0 wt % to at least 75 wt %, proving that it is feasible to control the polymorphism via design of the MSMPR cascade.