(509d) Application of PAT to the Design and Optimization of Plug Flow Crystallization Systems

Traditionally batch processing has been the dominant mode of pharmaceutical production. However in recent years the potential to reduce costs and improve product quality have sparked renewed interest in continuous production within the industry. Since crystallization is the most common purification technique used in pharmaceutical production, the development and characterization of small intensive continuous crystallizers such as a plug flow crystallizer could be extremely valuable.

This study applies in situ and at line PAT (FBRM, FT-IR and PVM) to investigate the applicability of plug flow crystallization systems to pharmaceutical production and furthermore develop a standard design and optimization methodology. To this end the anti solvent crystallization of benzoic acid (a model organic compound) was characterized in a plug flow crystallizer consisting of a Roughton Vortex mixer combined with tubular reactor via the application of a novel flow cell design allowing for the simultaneous in-situ observation of the crystallization using both FBRM and FT-IR.

The results of this characterization indicate that Plug Flow Crystallizers provide a robust and impressively productive crystallization methodology. Supersaturation was found to be depleted extremely rapidly within the reactor volume allowing for the maximum potential system yield for a purely anti-solvent crystallization to be obtained. This meant that despite the small size of the crystallizer (~40 ml) it was capable of producing approximately 50 kg of product per day. The crystal population produced was found to consist of a small and narrowly distributed crystal population relative to the corresponding batch crystallization resulting in an increase in the isolation time. However in the case of many products this could eliminate the need for milling operations resulting in significant reduction in production costs.