4. Results and discussion
4.5 Experiments in two coupled fluidized beds
4.5.2 Continuous crystallization of asparagine enantiomers
Results and discussion Ch. 4
4.5.2 Continuous crystallization of asparagine enantiomers
Ch. 4 Results and discussion
- Continuous selective preferential crystallization of asparagine monohydrate enantiomers
Continuous preferential crystallization of L-asn.H2O and D-asn.H2O from an aqueous solution of DL-asn.H2O in coupled fluidized bed crystallizers setup was conducted. The start parameters of the process are given in Table 4.10 and the results from the experiments are summarized in Table 4.11. The trajectories of the solution concentration and relative optical rotation in both crystallizers are presented in Figure 4.31. The analytical equipment (densitometer and polarimeter) was calibrated prior to the experiments. The measured optical rotation is relative to the initial value, which for DL-asn.H2O is equal to zero. The time, shown in Fig. 4.31 is relative to the start of the crystallization process (time
= 0) by adding seeds to both fluidized bed crystallizers.
Table 4.10 Experimental conditions for the preferential crystallization process.
Saturation temperature Crystallization temperature Solution concentration Supersaturation
Mass of seed crystals
Seed d50 (both enantiomers) Feed flow rate
Suspension flow rate
Excess of solid DL-asn.H2O in tank Solution density at 35 °C
Solution viscosityat 35 °C[Seebach2011]
Growth rate of L-asn.H2O[Seebach2011]
35°C 27 °C 8.76 wt.%
1.37 4 g 55 µm 9 l/h 4 l/h 80 g
1031 kg/m3 8.5*10-4 Pa.s 1.117*10-6 m/s Table 4.11 Results from the preferential crystallization experiments.
Total product recovery L-asn.H2O / D-asn.H2O Product d50 (both enantiomers)
Enantiomer purity L-asn.H2O / D-asn.H2O
46.2 / 49 g 184 µm 97 / 97.9 %
After addition of 4 g of seed crystals of the pure enantiomers in the respected crystallizer, the crystallization process was initiated, indicated by a small change in the solution density (i.e. concentration) values, detected in both crystallizers.
Afterwords, a steady state operation was observed confirmed by both analytical circles, which show nearly the same values for the solution concentration.
Results and discussion Ch. 4
Fig. 4.31 Trajectories of the total solution concentration and relative optical rotation with time for the preferential crystallization experiment. Solution measurements, done in the crystallizer, where L-asn.H2O crystallized are shown in blue color and solution measurements, done in the crystallizer, where D-asn.H2O crystallized are shown in red color. Time axle is zeroed at the point, when respected seeds are added to respected crystallizer.
The constancy of the solution concentration shows that the dissolution rate of the excess solid DL-asparagine monohydrate in the feed tank is equal to the crystallization rate in the crystallizers. The two absolute values for the optical rotation are very close, just with the opposite sign. This means that a very small excess of the counter enantiomer is detected in the mother liquor. The almost constant optical rotation values show that the enantiomer ratio remains stable with the time. The two asparagine enantiomers clearly possess equal crystallization kinetics. Every hour a 150 ml fraction of the crystallization suspension was collected from the product outlets of the crystallizers. After 220 min the excess racemic solid in the feed tank was completely depleted and the supersaturation started to decrease, thus lowering the crystallization rate. After further 60 min the crystallization process was stopped (at 4.7 h in Fig. 4.31) and residual product crystals were collected. The crystallized product recovery was in total 95.2 g (46,2 g of L-asn.H2O and 49 g of D-asn.H2O). The mean enantiomer purity of the product enantiomer crystals exceeded 97% (measured by HPLC). A productivity of 28 g/(l.h) (or 14 g/(l.h) per enantiomer) was calculated by taking
consumption of solid racemic feed (steady state production) seeding and
start of the process
end of the steady state production
Ch. 4 Results and discussion
collected mass of enantiomer crystals at the end of the experiment divided the total time the process was in steady state of 3.67 h or 220 min). A comparison with the calculated theoretical yield, based on the solubility data of DL-asn.H2O for 35°C (8.76 wt.%) and 27°C (6.324 wt.%), shows that about 24.4 g/kg of DL-asn.H2O can be crystallized (yield is equal to the concentration difference multiplied by a 1 kg solvent). Recalculated for the amount of solvent used (7700 g) plus the excess solid in the feed tank (80 g), gives a total mass of 267.6 g of DL-asn.H2O, or ~ 133.8 g of each enantiomer at the end of the process (enantiomer yield = (80 + 7700 * (0.0876-0.06324)) / 2). As already mentioned, the possible crystal mass recovery of each substance is less than the theoretical yield. The reason for this was already elucidated in the discussion of the preferential crystallization of ABA. Nevertheless, the residual crystal mass can be calculated by applying eq. 4.19 and taking into account the substance respected parameters. The calculated value of 76 g (εus = 0.8) of the nonrecoverable enantiomer crystals is in fair agreement with the theoretical yield of 87.6 g of the remaining amount of crystals (total theoretical yield of 133.8 g substracted with 46.2 g experimental recovery) for L-asn.H2O.
From table 4.10 can be seen, that suspension flow rate is relatively low, compared to the one used for preferential crystallization of ABA stereomers (4 l/h in comparison with 18 l/h, respectively). In this case almost no agglomerates were formed and no crystal settling was detected in the tubing. Thus, the residence time of the bigger crystals and agglomerates in the US bad is sufficient with respect to seed generation.
Microscopic photographs of the collected L-asn.H2O product crystals as well as the experimental crystal size distributions for the L-asn.H2O seeds, L-asn.H2O / D-asn.H2O product crystals are shown in Fig. 4.32 together with their calculated cumulative CSDs. Again, the calculated CSDs are derived from the calculated mean product size, Lp. Obviously besides product crystals, a small portion of seed crystals can be noticed as already shown in previous chapter (Fig. 4.28). A possible reason for the presence of the seeds generated by ultrasonic attenuation is when floating from the bottom of the crystallizer through the crystal bed to its top, they were partly captured by the product separation process. The
Results and discussion Ch. 4
CSD of the product crystals shows that crystals with mean size of ~180 µm are collected.
Fig. 4.32 Left: Experimental (solid line) and calculated (dashed line) cumulative CSDs for L-asn.H2O seed (blue color), L-asn.H2O / D-asn.H2O product crystals (red / violet color respectively). Right: Microscopic photographs of the L-asn.H2O product crystals.
In Figure 4.33 are shown the predicted solution concentration development with time and compared with the experimentally measured one. The measurement of the solution concentration during the process was done through a densitometer.
The collected density values are then converted to weight percent. For the prediction of the solution concentration, the simplified dynamical model presented in chapter 4.1 was used with process parameters given in Table 4.10. As already elucidated by the disscussion of the preferential crystallization of OABA and PABA, the calculated predictions for the preferential crystallization of L- and D-asn.H2O could be seen as a validation of the mathematical method introduced.
The predicted solution concentration development is in good agreement with the experimentally measured one, as both curves show almost the same behavior.
From the beginning of the process until about 3.5 hours both show straight line, as the excess of solids in feed tank are not dissolved. After this time the concentration values start to decrease, after depletion of the excess solids in the feed tank. After ~ 5 hours the crystallization process is over with only fluidization process running.
Ch. 4 Results and discussion
Fig. 4.33 Experimental and calculated (model described in section 4.1) solution concentration development in the fluidized bed crystallizer for the DL-asparagine monohydrate solution with time. Conditions are shown in Table 4.10.