Achieving desired attributes such as size, purity, polymorphic form, etc., in crystallization processes are generally difficult due to the stochastic nature of the nucleation event and the limited number of manipulated variables. In this context ultrasound can be used as an additional manipulated variable to control crystallization process.<br/>In this work, we develop a mathematical model based on population balance framework for ultrasound assisted crystallization of L-asparagine monohydrate (LAM) with an objective to perform particle engineering. The population balance model considered here includes nucleation, growth, and breakage phenomena. An additional kinetic expression is introduced for induced nucleation due to ultrasound irradiation. The kinetic parameters are determined by combining the population balance model with a nonlinear optimization technique that uses solute concentration data and information on final crystal size distribution. The concentration of LAM was measured using HPLC and the final crystal size distribution was measured using both Mastersizer 2000 and a home-grown image analysis method.<br/>Application of ultrasound induces energy into the system and this in turn leads to temperature rise of the crystallizer. Thus there is a non-coincidence of the target temperature profile fed to the refrigerated/heating circulator and the actual temperature profile implemented by the circulator. It is easy to handle this rise in temperature during parameter estimation stage. But for determination of optimal control profiles using dynamic optimization, it is necessary to consider the closed-loop control of the crystallizer in order to model this temperature rise.  We, therefore, consider the crystallizer temperature and jacket temperature; and model the control system of the circulator by a Generic Model Control algorithm. The results of closed-loop simulation clearly indicate that the model can represent the temperature rise due to sonication very well. The validated model is then used to determine the optimal cooling profile and sonication time for the crystallization process using various objective functions that specify product characteristics. Specifically, we first use the model to determine the region of attainable sizes for ultrasound assisted crystallization process by solving appropriate dynamic optimization problems. Then we use the model to determine optimal operating conditions for achieving a target crystal size distribution.

Modeling and optimization of ultrasound assisted crystallization of L asparagine monohydrate

253rd National Meeting (2017)

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