Robust optimal control of polymorphic transformation in batch crystallization

Abstract

in Wiley InterScience (www.interscience.wiley.com).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 a-form to the stable b-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

Problems, potentials and future of industrial crystallization

“…Therefore, novel control approaches that incorporate robustness in the crystallization process control [60,61] and include the application to the control of polymorphic transformations [62] need to be applied [56]. Nonetheless, all simulated crystallization systems need to be supported by results from experimental work which illustrates the importance of an intelligent combination of state-of-the-art instrumentation (PAT tools) and efficient optimization algorithms.…”

Crystal Shape Engineering

“…In another study by Yang et al, 212 the effects of different cooling modes were investigated for a batch cooling crystallization by using the supersaturation as the manipulated variable to control the shape of KDP crystals; this can be beneficial in selecting an optimal cooling profile for a desired product shape. Ultimately, if shape and size can be effectively controlled then there is also the possibility of controlling polymorphic transformations as demonstrated by the C-control strategies implemented by Hermanto et al 213 for the transformation of L-glutamic acid from the metastable α form to the stable β form. Braatz and co-workers 214 have recently reviewed the advances in the direct design and control of pharmaceutical crystallization processes and discuss the possible applications to more complicated tasks such as polymorph control and protein crystallization.…”

Closed‐Loop Control of Reactive Crystallization. Part I: Supersaturation‐Controlled Crystallization of L‐Glutamic Acid

“…Hermanto et al [16], Woo et al [17] Ferrari and Davey [18] focused on controlling a-to b-polymorph transformation to produce a needle-like b-polymorph with model-based T and/or concentration control of cooling crystallization and antisolvent crystallization. Schöll et al [19,20] studied solvent-mediated polymorphic transformation of L-glutamic acid and determined nucleation kinetics for pH-shift precipitation of L-glutamic acid for a reactive aqueous solution of monosodium glutamate and hydrochloric acid.…”