Controlling the crystal size distribution (CSD) in the crystallization process is considered as key to the successful control of the process.The objective of this research is to perform a systematic study on how the cooling and anti-solvent addition should be combined using three open-loop conventional cooling policies and three feeding policies that are inspired by these well-known cooling policies. Specifically, we choose crystallization of L-asparagine monohydrate from its aqueous solution by cooling as well as using isopropyl alcohol as anti-solvent. First, the solubility of LAM in water-isopropanol mixture is determined gravimetrically as a function of temperature (25 to 45 °C) and weight fraction of isopropanol (0 to 80%). We conducted a series of combined cooling and antisolvent crystallization where a saturated aqueous solution of LAM at 45 °C is cooled using a given cooling policy from 45 to 25 °C in 2 h while isopropanol is added simultaneously with a given feeding policy such that its weight fraction changes from 0 to 40 wt% by the end of the experiment. For all the experiments, the final crystal size distribution was measured using both Mastersizer 2000 and a home-grown image analysis method. Enhanced yield was obtained for all the experiments by combining two modes of operation. The particle size distribution obtained from the combined approach is compared to the crystallization mode in which cooling or anti-solvent addition is used independently.The experiments conducted produce a good amount of data for developing a predictive model for the system. We first developed a 1-D population balance model considering both nucleation and growth phenomena. The nucleation and growth kinetics were determined simultaneously by a combination of population balance model and a nonlinear optimization technique which uses concentration data measured by HPLC and final number based CSD obtained from optical microscopic images. A high resolution finite volume discretization with a flux limiter was used to solve the population balance equation. The validated model was then used to determine the optimal cooling and anti-solvent addition profiles of the crystallization process using various objective function that characterizes product properties. Finally, we attempt to develop a 2-D population balance model for the system as several microscope images of LAM crystals show that they are better characterized by two internal coordinates, namely, length and width.

Study on combined cooling and antisolvent crystallization of L- asparagine monohydrate

253rd National Meeting (2017)

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