(14g) Process Optimization of an Integrated Chemical Reactor and Crystallization System for Higher Product Quality

Crystallization as a purification and separation process is often used unit operation in the pharmaceutical and fine chemical industries. The properties of the produced crystals such as purity or size and shape distribution have strong impact on the downstream processes as well as on the end usage such as bioavailability or toxicity in the case when products are active pharmaceutical ingredients (APIs) [1, 2].

There are different methods for crystal size and shape control, including supersaturation control or direct nucleation control, however these techniques provide narrow window for shape manipulation [3-5]. Additional unit operations such as milling is also often used as post process treatment, but additional operation is not recommended because it increases the complexity of the process and production cost [6]. Additives or growth modifiers can be used to control crystal size and shape distribution [7, 8]. Upstream processes have strong impact on the product quality and also on the effectiveness of the crystallization process especially on the purity. In the present work, investigation of the integrated reaction-crystallization process is performed to evaluate how the process properties of the chemical reactor and crystallizer impact the final product properties. Mathematical model is developed for both processes. Two chemical reactions are considered in the reactor model. The first produces the reaction product which needs to be crystallized, while the second leads to a trace amount of byproduct which is crystal growth modifier. The products from the reactor are fed to the crystallizer. It is considered that the byproduct is an impurity in the system and its concentration can be changed by modifying the process parameters such as residence time in the units or the concentrations in the input. The sensitivity study indicated that the residence time has strong impact on all of the investigated product properties (particle number, mean crystal size, crystal shape, solid concentration and product purity). The results also show that increasing residence time leads to decreased productivity in the reactor and also in the crystallizer. While the size, shape and purity strongly depends on the kinetic properties of the adsorption, nucleation and growth. The interactions between the purity, crystal shape and the productivity in the investigated system provides opportunity for optimization. Hence, integrated optimization can be used for purity and/or shape control of crystal product. The results show that the optimized process provided less productivity, but higher product quality while no additional unit operation is needed.

Acknowledgment: Financial support provided by the European Research Council grant no. [280106-CrySys] is gratefully acknowledged.

References:

[1] Z.K., Nagy, R.D., Braatz, 2012. Advances and New Directions in Crystallization Control. Annual Review of Chemical and Bimolecular Engineering, 3, 55-75.

[2] Z.K., Nagy, G., Fevotte, H., Kramer, L.L., Simon, 2013. Recent advantages in the monitoring, modeling and control of crystallization systems. Chemical Engineering Research and Design, 91, 1903-1922.

[3] G., Yang, N., Kubota, Z., Sha, M., Louhi-Kultanen, J., Wang, 2006. Crystal shape control by manipulating supersaturation in batch cooling crystallization. Crystal Growth and Design, 6, 2799-2803.

[4] M.A., Lovette, A.R., Browning, D.W., Griffin, J.P., Sizemore, R.C., Snyder, M.F., Doherty, 2008. Crystal shape engineering. Industrial & Engineering Chemistry Research, 47, 9812-9833.

[5] A., Borsos, B.G., Lakatos, 2013. Investigation and simulation of crystallization of high aspect ratio crystals with fragmentation. Chemical Engineering Research and Design, 92, 1133-1141.

[6] Ho, R.; Naderi, M.; Heng, J.Y.Y.; Williams, D.R.; Thielmann, F.; Buaza, P.; Keith, A.R.; Thiele, G.; Burnett, D.J. Effect of milling on the particle shape and surface energy heterogeneity of needle-shape crystals. Pharmaceutical Research 2012, 29, 2806-2816.

[7] A., Majumder, Z.K., Nagy, 2013. Prediction and control of crystal shape distribution in the presence of crystal growth modifiers. Chemical Engineering Science, 101, 598-602.

[8] A., Borsos, A., Majumder, Z. K., Nagy, 2014a. Model development and experimental validation for crystal shape control by using tailored mixtures of growth modifiers. Computer Aided Chemical Engineering, 33, 781-786.