Characterization of the anti-solvent batch, plug flow and MSMPR crystallization of benzoic acid

Abstract Continuous operation allows process conditions that are not attainable within batch crystallizers to be utilized. This in turn allows for product crystal attributes that are not possible in the equivalent batch crystallizations to be produced. In this study, the product crystal size distributions attainable from the anti-solvent crystallization of benzoic acid in plug flow, MSMPR and the equivalent fed batch and batch reverse addition crystallizations, were characterized. It was found that the continuous plug flow and MSMPR crystallizers were able to access crystal size distributions that are both smaller and larger than could be produced via the equivalent batch crystallizations, in addition to providing huge increases in productivity. In-situ process analytical techniques (FBRM, ATR-FTIR) were employed to characterize each of these processes, including a calibration-free ATR-FTIR technique. Furthermore, a novel intermittent pneumatic MSMPR withdrawal method, which negated clogging/fouling of transfer lines, is demonstrated. It is hoped that the use of such techniques may facilitate the uptake of continuous processes in pharmaceutical crystallization where limitations on development time and concerns about slurry transport are perceived to be barriers to the implementation of this technology.