Robust optimal control of polymorphic transformation in batch crystallization

AIChE Journal (Impact Factor: 2.75). 10/2007; 53(10):2643 - 2650. DOI: 10.1002/aic.11266


One of the most important problems that can arise in the development of a pharmaceutical crystallization process is the control of polymorphism, in which there exist different crystal forms for the same chemical compound. Different polymorphs can have very different properties, such as bioavailability, which motivates the design of controlled processes to ensure consistent production of the desired polymorph to produce reliable therapeutic benefits upon delivery. The optimal batch control of the polymorphic transformation of L-glutamic acid from the metastable α-form to the stable β-form is studied, with the goal of optimizing batch productivity, while providing robustness to variations in the physicochemical parameters that can occur in practice due to variations in contaminant profiles in the feedstocks. A nonlinear state feedback controller designed to follow an optimal setpoint trajectory defined in the crystallization phase diagram simultaneously provided high-batch productivity and robustness, in contrast to optimal temperature control strategies that were either nonrobust or resulted in long-batch times. The results motivate the incorporation of the proposed approach into the design of operating procedures for polymorphic batch crystallizations. © 2007 American Institute of Chemical Engineers AIChE J, 2007

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    • "The underlying principle is that changing the global properties can change the dynamic pathways of assembly. For example, during crystallization, optimized temperature control can improve the yield of one particular crystal polymorph over another [33] [34]. The number of such global variables that can be useful for altering the state of assembly are somewhat limited, which often includes temperature, pressure, concentration, composition, and, for some systems, external fields such as electric and magnetic fields. "
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    • "Polymorphic transformations lead to variations in physical properties (e.g., shape, solubility, and chemical reactivity) of crystals, and, therefore, can be detrimental to their performance. The problem of controlling polymorphic transformations consists of ensuring consistent production of the desired polymorph in a stochastic environment [38]. The batch polymorphic crystallization of L-glutamic acid is investigated using the kinetic model developed in [39] for polymorphic transformations of metastable α-form and stable β-form L-glutamic acid crystals. "
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