(468b) A Novel Mode of Supersaturation Feedback Control: Semi-Batch Cooling Crystallization By Feeding Flow Rate Profiles

Zhang, T., Tianjin University
Szilagyi, B., Purdue University
Nagy, B., Budapest University of Technology and Economics
Gong, J., Tianjin University
Nagy, Z. K., Purdue University
Concentration Feedback Control (CFC) approaches, based on ATR-FTIR, ATR-UV/Vis or Raman spectroscopy coupled with chemometrics, have been widely applied in cooling and antisolvent crystallization systems at laboratory as well as industrial scales, by which the improved product quality have been extensively demonstrated [1]. In the feedback loop, traditionally the supersaturation is controlled to an optimal set point by manipulating the solution or cooling jacket temperature. However, the traditional batch cooling crystallization is limited by the temperature dependency and has limited applicability in some specific, but often encountering situations like crystallization of heat sensitive materials or polymorphic crystallization systems.

In this work, we propose a novel CFC implementation of semi-batch mode (feed hot saturated solution into lower temperature saturated solution), which can achieve the feedback control of supersaturation by manipulating the feeding flow rate rather than the temperature. In such, the crystallization temperature can be fixed throughout the process and thus eliminate the temperature dependence of the system. The semi-batch mode complements the classical mode in CFC implementation to some crystallization systems, such as enantiotropic polymorphic system, heat sensitive system, temperature dependent reversible reaction-crystallization and also could be designed as a start-up strategy for continuous MSMPR crystallizers [2].

Using the proposed operational method for enantiotropic polymorphic system, in the feeding step the process temperature is fixed or varied in a narrow range. This is advantageous over the cooling crystallization of much more stable polymorphic form, because the polymorph stability order is a function of temperature for enantiotropic polymorphic system. For instance, the transition temperature of α and β form of para-amino benzoic acid (pABA) in pure ethanol [3], is 13.8 ℃ (β form is stable under 13.8 ℃). Therefore, it is difficult to obtain pure β form with CFC in batch cooling mode because the operating temperature range was limited by this transition point. Whereas the crystallization temperature is fixed in the proposed CFC with semi-batch mode, which can be flexible for crystallization of easily design for each polymorphic form. In this context, the semi-batch operation to generate different polymorphic forms combines the advantages of batch and continuous crystallization: applicable to small scale production and stably produces one or the other pure polymorphic forms.

We modelled, simulated and evaluated three supersaturation control procedures for cooling crystallization processes: batch crystallization (T-SSC), semi-batch crystallization (F-SSC) and combined cooling and semi-batch crystallization (TF-SSC). For this, the monovariate population balance equation was used, involving nucleation and growth, solved by the method of moments and extended with the solute mass balance equation [4]. In this work, the comparison of these three scenarios will be presented through numerical simulations, which enables the identification of optimal operation modes of cooling crystallizers for various types of crystallization systems. Proof of concept experimental demonstrations for cooling and semi-bath crystallization will be also presented to support the numerical results followed by the implementation of T-SSC and F-SSC for enantiotropic polymorphic system (o-ABA) to achieve the efficient crystallization of both polymorphic forms.


[1] Nagy Z K, Braatz R D. Advances and new directions in crystallization control[J]. Annual Review of Chemical & Biomolecular Engineering, 2012, 3(5):55.

[2] Su Q, Nagy Z K, Rielly C D. Pharmaceutical crystallisation processes from batch to continuous operation using MSMPR stages: Modelling, design, and control[J]. Chemical Engineering & Processing Process Intensification, 2015, 89:41-53.

[3] Hao H, Barrett M, Hu Y, et al. The Use of in Situ Tools To Monitor the Enantiotropic Transformation of p-Aminobenzoic Acid Polymorphs[J]. Organic Process Research & Development, 2012, 16(16):35-41

[4] Poehlein G W, Wenzel L A. Theory of particulate processes-analysis and techniques of continuous crystallization: By Alan D. Randolph and Maurice A. Larson, Academic Press, New York, Journal of Colloid & Interface Science, 1972, 40(1):130-130.