Optimal Control of Polymorphic Transformation in Batch Pharmaceutical Crystallization

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. This paper explores the optimal batch control of the polymorphic transformation of L-glutamic acid from the metastable alpha-form to the stable beta-form, 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 non-robust or resulted in long batch times. The results indicate that the proposed approach should be incorporated in the design of operating procedures for polymorphic batch crystallizations.