(287g) Kinetic Assessment for Continuous Crystallization Process Development of an Early Development Compound

Acquisition of reliable kinetic correlations that describe how rates of nucleation and growth vary over the crystallization design space is necessary for enabling robust prediction of crystallizer performance. The aim of this study was to generate a standardised workflow approach for the generation of crystallization kinetics data using population balance modelling (PBM), and to assess the batch crystallization process for feasibility of continuous processing for an early development compound. Initially, the crystallization growth kinetics were estimated by means of seeded isothermal desupersaturation experiments in a batch reactor. PAT tools such as Attenuated Total Reflectance-Fourier Infrared (ATR-FTIR) spectroscopy and Focused Beam Reflectance Measurement (FBRM) were utilised for in situ measurement of solute concentration and for detection of occurrence of nucleation events, respectively. The initial crystal size distributions (CSDs) and desupersaturation profiles were used to estimate the growth kinetics as a function of temperature and supersaturation. Two solvent systems were tested to extract growth kinetics and were used for comparison. Activity coefficients as a function of temperature and composition were considered in the kinetic model, which enabled to directly evaluate the solvent dependency effect. Next, a continuously operated single-stage mixed suspension mixed product removal (MSMPR) crystallizer was used to extract the secondary nucleation kinetics. During the continuous crystallization study, a recycling system was employed to significantly reduce the waste of raw materials during the MSMPR study prior to the onset of steady state, which can be very useful during the early stages of process development where limited amount of product is available. Furthermore, problems such as blocking of transfer line and feed inlet were eliminated, by applying a rapid intermittent withdrawal of slurry via dipped pipe¹, and by using a tube-in-tube configuration to insulate the feed inlet line. Finally, a novel 3D printed jacketed nozzle was attached at the end of the feed inlet line to avoid the saturated solution from crystallizing which can lead to blockage. Based on PBM and utilisation of the kinetic data², CSD was simulated and residence time distribution, operating temperature and productivity of the MSMPR were optimised and finally experimentally verified. Overall, a standardised workflow was developed for the kinetic assessment of an early development compound for continuous crystallization.

1. Hou, G., Power, G., Barrett, M., Glennon, B., Morris, G. & Zhao, Y. (2014) 'Development and Characterization of a Single Stage Mixed-Suspension, Mixed-Product-Removal Crystallization Process with a Novel Transfer Unit', Crystal Growth & Design, 14(4), pp. 1782-1793.
2. Power, G., Hou, G., Kamaraju, V. K., Morris, G., Zhao, Y. and Glennon, B. (2015) 'Design and optimization of a multistage continuous cooling mixed suspension, mixed product removal crystallizer', Chemical Engineering Science, 133, pp. 125-139.