Population Balance Model-Based Multiobjective Optimization of a Multisegment Multiaddition (MSMA) Continuous Plug-Flow Antisolvent Crystallizer

Abstract

Crystallization is a major separation process in the pharmaceutical industry. Most crystallizations are performed batchwise, but there is great incentive for converting them to continuous operations. This paper investigates the modeling, simulation, and optimization of a special antisolvent plug-flow crystallizer: the multisegmented, multiaddition plug-flow crystallizer (MSMA-PFC). The MSMA-PFC accepts multiple antisolvent flows along its length, permitting finer control of supersaturation. A steady-state population balance equation was applied for tracking the crystal size distribution, and a mass balance equation was used to track the depletion of dissolved solute (flufenamic acid). A multiobjective optimization framework was applied to determine the antisolvent flow rates into each segment that simultaneously maximize the average crystal size, and minimize the coefficient of variation. The set of coupled differential equations was solved, depending on circumstance, with either the method-of-moments (MO...