Continuous Plug Flow Crystallization of Pharmaceutical Compounds

Abstract

Crystallization processes in the pharmaceutical industry are usually designed to obtain crystals with controlled size, shape, purity, and polymorphic form. Knowledge of the process conditions required to fabricate crystals with controlled characteristics is critical during process development. In this work, continuous crystallization of ketoconazole, flufenamic acid, and L-glutamic acid in a nonconventional plug flow crystallizer was investigated. Kenics type static mixers were used to promote homogeneous mixing of active pharmaceutical ingredient solution and antisolvent. A strategy of multiple points of addition of antisolvent along the crystallizer was evaluated to control the size of the crystals. Interestingly, it was found that crystal size can be increased or decreased with an increased number of antisolvent addition points, depending on the kinetics of the system. It was also found that smaller crystals with a narrower size distribution can be obtained with the static mixers. A model to describe the continuous crystallization process was developed through the simultaneous solution of a population balance equation, kinetics expressions for crystal growth and nucleation, and a mass balance. The comparison of experimental and calculated values for crystal size distribution revealed that a growth rate dispersion model could describe accurately the continuous crystallization process. Collision of crystals with each other and with mixing elements inside the crystallizer may be the source of random fluctuation of the growth rate in the nonconventional plug flow crystallizer with static mixers.

Mathematical modelling and experimental validation of a novel periodic flow crystallization using MSMPR crystallizers

“…However, rising market competitiveness due to patent expiration and the need to reduce manufacturing costs have now driven the future of pharmaceutical industries towards continuous manufacturing, which have potentials for improvements in quality control, equipment footprint, and energy and labour costs, and so on. 1,2 In the past decade, continuous manufacturing and crystallization has been a highly active research field, as part of the campaign aimed at developing the next generation technologies for the pharmaceutical and fine chemical industries. 3,4 Generally, there are two types of continuous crystallizers that are most investigated, viz., the tubular and the stirred-tank designs.…”

Measurement, modelling, and closed-loop control of crystal shape distribution: Literature review and future perspectives

“…Crystal morphology has been a very important research area, but the focus has been on shape prediction for single crystals [10,[75][76][77][78][79][80] rather than for all the crystal population within a crystalliser. On the other hand, although population balance (PB) modeling for crystallisation processes is for all crystals in a crystalliser, crystal shape was often ignored with an over-simplified crystal-size definition, i.e., the volume equivalent diameter of spheres (see for example [54,[81][82][83][84][85][86][87][88]). The difference between morphological PB model and multi-dimensional (multi size dimensional) PB models for crystallisation in the published literature differs mainly in how the size dimensions are defined.…”

Advancing Product Quality: a Summary of the Inaugural FDA/PQRI Conference

“…Several model-based approaches for design and control of continuous crystallizers for manufacturing APIs have been described, for example, to predict how temperature variation and processing time of each stage may affect purity and yield (18,19). Flowsheet models, which represent a sequence of unit operations, can be applied to pharmaceutical processes in order to conduct preliminary design evaluation, identify potential bottlenecks, compare control strategies, identify potential critical process parameters, explore design space, and enhance process understanding (20).…”