(83c) Optimal Control of Antisolvent and Cooling Crystallization

Quality requirements for crystallization products in the pharmaceutical industry are specified by the demands of the drug administration (e.g., bioavailability, size uniformity, and polymorphic form) and manufacturing considerations for downstream processes such as filtration, drying, and flowability. The large effect of the crystal size distribution (CSD) on crystal properties motivates the design of processes with reproducible and optimal control of the CSD [1-6].

This study investigates a new process for CSD control that combines antisolvent crystallization in a dual impinging jet crystallizer with cooling crystallization in a mixing tank, which is an extension of an idea published in an earlier theoretical investigation [7-9]. Specification of the inlet velocities to the dual impinging jet crystallizer as a function of time enables the controlled variation of the size distribution of seed crystals continually added to the mixing tank (that is, control of the crystal nucleation). Operation of the cooling crystallization under closed-loop feedback control of the solute concentration enables the specification of the supersaturation in the mixing tank as a function of time, which is equivalent to control of the crystal growth due to the direct algebraic relationship between supersatuation and crystal growth. This proposed semi-continuous process provides a higher degree of control of the CSD than has been obtainable with past crystallizer designs. The proposed approach uses the same equipment as described in Ref. [9], but with the extension that the supersaturation is time-varying instead of specified at a constant controlled value.

The ATR-FTIR spectra are first collected to construct a calibration model, which was used along with the infrared spectra to measure the solubility of paracetamol in isopropanol-water solution at various temperatures and solvent ratios, in a similar manner as earlier studies [1, 4, 10-12]. This information was used in subsequent simulations of open and closed-loop controls for the integrated crystallization process. Various time variations for the continual seeding produced by real-time antisolvent crystallization to various time variations in the supersaturation profile in the well-mixed cooling tank were simulated, to demonstrate the rate of product crystal size distributions that can be manufactured using this system. The design provides a higher degree of control of the CSD by decoupling crystal nucleation and crystal growth throughout the crystallization process. Optimization of the temperature profiles to achieve targeted crystal size distributions is presented. The simulation results motivate future experimental implementations.

[1]     M. Fujiwara, P. Chow, D. Ma, and R. Braatz, “Paracetamol crystallization using laser backscattering and ATR-FTIR spectroscopy: Metastability, agglomeration, and control,” Crystal Growth & Design, vol. 2, pp. 363–370, 2002.

[2]     H. Gron, A. Borissova, and K. Roberts, “In-process ATR-FTIR spectroscopy for closed-loop supersaturation control of a batch crystallizer producing monosodium glutamate crystals of defined size,” Industrial & Engineering Chemistry Research, vol. 42, pp. 198–206, 2003.

[3]     V. Liotta and V. Sabesan, “Monitoring and feedback control of supersaturation using ATR-FTIR to produce an active pharmaceutical ingredient of a desired crystal size,” Organic Process Research & Development, vol. 8, pp. 488–494, 2004.

[4]     G. Zhou, M. Fujiwara, X. Woo, E. Rusli, H. Tung, C. Starbuck, O. Davidson, Z. Ge, and R. Braatz, “Direct design of pharmaceutical antisolvent crystallization through concentration control,” Crystal Growth & Design, vol. 6, pp. 892–898, 2006.

[5]     C. Lindenberg, M. Kraettli, J. Cornel, M. Mazzotti, and J. Brozio, “Design and optimization of a combined cooling/antisolvent crystallization process,” Crystal Growth & Design, vol. 9, pp. 1124–1136, 2009.

[6]     N. C. S. Kee, R. B. H. Tan, and R. D. Braatz, “Selective crystallization of the metastable alpha-form of L-glutamic acid using concentration feedback control,” Crystal Growth & Design, vol. 9, pp. 3044–3051, 2009.

[7]     X. Y. Woo, R. B. H. Tan, and R. D. Braatz, “Precise tailoring of the crystal size distribution by controlled growth and continuous seeding from impinging jet crystallizers,” CrystEngComm, vol. 13, no. 6, pp. 2006–2014, 2011.

[8]     X. Y. Woo, Z. K. Nagy, R. B. H. Tan, and R. D. Braatz, “Adaptive concentration control of cooling and antisolvent crystallization with laser backscattering measurement,” Crystal Growth & Design, vol. 9, pp. 182–191, 2009.

[9]     X. Y. Woo, Modeling and simulation of antisolvent crystallization mixing and control. PhD thesis, University of Illinois at Urbana - Champaign and National University of Singapore, 2007.

[10] T. Togkalidou, M. Fujiwara, S. Patel, and R. Braatz, “Solute concentration prediction using chemometrics and ATR-FTIR spectroscopy,” Journal of Crystal Growth, vol. 231, pp. 534–543, 2001.

[11]   Z. Q. Yu, P. S. Chow, and R. B. H. Tan, “Application of attenuated total reflectance-Fourier transform infrared (ATR-FTIR) technique in the monitoring and control of anti-solvent crystallization,” Industrial & Engineering Chemistry Research, vol. 45, no. 1, pp. 438–444, 2006.

[12]   Z. K. Nagy, M. Fujiwara, and R. D. Braatz, “Modelling and control of combined cooling and antisolvent crystallization processes,” Journal of Process Control, vol. 18, pp. 856–864, 2008.