RAPID DETERMINATION OF A NEAR-OPTIMAL SEEDING PROCEDURE AT AN INDUSTRIAL SCALE BATCH CRYSTALLIZER

Somnath S. Kadam1, Jochem A. W. Vissers2, Marco Forgione3, Rob M. Geertman4,

Peter J. Daudey5, Herman J.M. Kramer1.

1IRSS, Delft University of Technology, The Netherlands. (s.s.kadam@tudelft.nl) 2Dept. Electrical Engineering, Control Systems, Eindhoven University of Technology, The Netherlands. 3DCSC, Delft University of Technology, The Netherlands. 4MSD, Oss, The Netherlands. 5Albemarle, Amsterdam, The Netherlands. Keywords: Seeding, Batch cooling crystallization, Industrial scale. 1. Introduction: Seeding of batch crystallisation processes has received much attention in literature.[1] Experimental and modeling results of various crystallization systems with different seeding objectives have been presented. It appears that the crystal size distribution (CSD) of the final crystalline product of a seeded batch crystallization process is not only a function of the parameters of the seeding procedure (seed size, seed mass, supersaturation) at the seed point, but also of the seed preparation methods, batch trajectory (temperature and supersaturation profile), the crystallization system, the scale and geometry of the crystallizer and the mixing. As a result of this complex interaction, the outcome of seeding procedure at lab scale has little predictive value for larger scale. It would therefore be of great advantage if the seeding procedure is rapidly determined directly on an industrial scale setup for the intended crystallizing system. 2. Variable-Space Search (VSS) seeding approach: Here we propose a Variable-Space Search (VSS) seeding approach which is rapid, model-free and implementable directly on industrial setups. The intent is to explore the n-dimensional space of n-seeding variables and to monitor the extent to which the seeding objective is met. Although the approach is compatible with common seeding objectives, here we introduce another objective which is to reduce the supersaturation peak which arises when we start cooling after seeding. The advantage of this objective would be to reduce the cause (supersaturation) of the unwanted crystallization phenomena and the expected effect would be a better crystal quality.

Figure 1. Schematics of the VSS seeding approach in 3-D

For practical purposes it may not always be possible to work with all the seeding variables. Also the variables must be varied with certain practical limits. Examples of boundaries on some of the variables are listed in Table 1. Table 1: Boundaries for seed variables Variable Lower boundary Upper boundary Seed size Agglomeration size Attrition size Seed mass Mass of a single crystal Mass allowed by the size of

dosing device. Initial supersaturation 0 Metastable limit Dosing devices, if present at industrial crystallizers, are usually small. A small amount of seeds is in all cases sufficient to trigger secondary nucleation which prohibits extensive optimization of the seeding strategy. 3. Experimental: To investigate the applicability of VSS seeding on industrial scale, experiments were performed with a pharmaceutical compound, Androsta-1,4-diene-3,17-dione, cyclic 17-(2,2-dimethyltrimethylene acetal), abbreviated as ADD-NEOP. A mixture of pure ethanol (99.5% v/v) and triethyl amine (0.5% v/v) was used as the solvent. A curved cooling profile was mimicked by using different linear cooling rates. In our case, the number of seeding variables was limited to two (seed mass and initial supersaturation) due to practical limitations. As the mean size of the ungrinded ADD-NEOP was already very small (30 microns) it was not used as a seeding variable. Experiments were performed in a 1000l stainless steel industrial crystallizer (Merck Sharp and Dohme, Apeldoorn) which was agitated by a four blade propeller. With a traced DIN25 line, the crystallizer was connected to the instrument skid which housed four in-situ measurement instruments viz. attenuated total reflectance Fourier transform infrared, (MATRIX-MF, Bruker Optics, Germany), Refractive index sensor (PR-23-C, K-Patents, Finland), Insitu particle viewer (ISPV) (Perdix Analytical System, The Netherlands) and OPUS (Sympatec, Germany). The slurry was circulated through the instrument skid and back to the crystallizer with the help of a lobe pump present in the pump skid. The schematic of the setup is shown in Figure 2.

Figure 2. a. Schematic of the skids connected to the crystallizer b. Image of the skids.

During experiments, the crystallizer was maintained at a constant seeding temperature for approximately one hour (seed adaption stage) before cooling. This was done to promote Ostwald’s ripening and to have a stable number of crystals before cooling. In this abstract the results of the supersaturation measurements done with the K-Patents refractive index sensor are reported. 4. Results: The experiments performed to reduce the supersaturation peak are summarized in Table 2. Table 2: Experimental conditions during dry seeding. Expt Code

Initial Conc. [mg/ml]

Sat. Temp.[oC]

Seeding Temp [oC]

Seed mass [g]

Supersat. peak [mg/ml]

Supersat. before cooling [mg/ml]

D 168.20 39.60 37.90 1500 12 13 E 169.80 39.80 39.60 1500 27 7 G 171.45 40.01 39.60 200 25 5 H 171.68 40.04 36.60 200 7 15 L 168.60 39.64 35.00 5 7 15 M 168.65 39.65 39.60 3000 18 5 As can be seen from Figure 3, equilibrium was not always reached during the seed adaption stage in the beginning of the batch.

Figure 3. Supersaturation peak of 12 mg/ml ( Experiment D). Variables - 1. Seed mass: 1500 g, 2. Initial supersaturation: 12.5mg/ml. A maximum of only 9 g/s.kg seeds mass growth rate is reached. This is due to the growth behaviour demonstrated by the available seed material of ADD-NEOP: seed consume significant saturation only above supersaturation of approximately 20 mg/ml. This could be due to the effect of impurities present with the seed material which prevent crystal growth at low supersaturations. The effect of seed poisoning is also reflected in a very small mass growth rates throughout the batch as seen in Figure 3. It is suspected that seed poisoning may be more general at industrial scales than assumed. In

future the effect of seed poisoning will be investigated by doing experiments with poisoned and unpoisoned ADD-NEOP seeds in a growth cell. Due to small mass growth rates it is expected during cooling that the supersaturation will first increase, go through a maximum and subsequently decrease as a result of a) seeds starting to grow and b) secondary nucleation. If the supersaturation peak is reduced by choosing the seeding variables appropriately, a better crystalline product quality might result. The validity of the approach can be examined when the final product for experiments E (largest supersaturation peak) and H (smallest supersaturation peak) are compared.

Figure 4. SEM images of final product obtained from experiments E and H Experiment H was performed at relatively higher initial supersaturation compared to experiment E and also with a relatively lower amount of seeds. The higher initial supersaturation in experiment H might have resulted in secondary nucleation resulting into formation of fresh crystal surface. As this crystal surface is not poisoned, it is able to consume supersaturation at a much faster rate leading to a small supersaturation peak. On the other hand experiment E was performed with a larger amount of seeds but since its initial supersaturation was lower, significant generation of fresh crystal surface might not have occurred. As a result, during cooling the supersaturation went on increasing to a relatively higher value before its consumption started. Surprisingly, the differences between the final crystal size distributions measured offline with a laser diffraction instrument of the product obtained from experiments E and H were minimal. But SEM pictures shown in Figure 4 show that the crystals obtained from experiment E display wider variations in crystal dimensions than those in experiment H as expected by the VSS. The experiments reported here allow rapid determination of a near-optimal seeding profile on industrial scale. The general applicability of the VSS seeding approach will be examined in future. 5. Acknowledgement: The authors acknowledge Dutch Separation Technology Institute for supporting the experiments financially. The authors also thank the staff at MSD Apeldoorn and Oss for their support during the experiments. Reference: [1] Chung, S. H., Ma, D. L.Braatz, R. D.,1999. Optimal seeding in batch crystallization. The Canadian Journal of Chemical Engineering 77(3), 590-596