CONTINUOUS ANTISOLVENT PLUG-FLOW CRYSTALLIZATION OF A FAST GROWING API L. L. Simona, A. S. Myersonb a
Illinois Institute of Technology, Chicago, USA Department of Chemical Engineering, Massachusetts Institute of Technology, USA, (
[email protected])
b
Keywords: continuous manufacturing, static mixer, process analytical technologies 1. Introduction and project aim Continuous crystallization is a promising option for the elimination of batch-to-batch variability typical to batch processes. It is also characterized by shorter downtimes and scale-up is more robust. Recently, continuous crystallization has been implemented in oscillatory baffled units [1], in tubes [2] and in static mixers [3]. The main aim of this project is to produce Butamben crystals in the 1-10 micron range with narrow particle size distribution (PSD) by anti-solvent precipitation. Since the PSD width is influenced by the plug-flow like behaviour the first sub goal is to investigate the flow regime. Another important process which influences the crystal properties is micromixing, which is enhanced by turbulent conditions. Furthermore, the on-line use of the FBRM sensor for crystal size monitoring is also evaluated. 2. Experimental setup and data analysis methods The experimental setup is described in detail in a recent work by Alvarez and Myerson[3]. The crystallizer is a Kenics static mixer which has three inlets: solvent, antisolvent and the tracer injection port. In order to monitor the plug-like behavior a tracer suspension of non-soluble black copper-hydroxide particles in paracetamol slurry is used as shown in Figure 1. Ideally, the size of the tracer plug should be constant which means that back-mixing is minimized. The size of the tracer is evaluated by recording video data of the experiments using a high definition Sony video camera with a 25 frames/sec sampling rate. The individual pictures are retrieved from the movie and imported in Corel Photopaint where the plug size is measured manually. The experimental conditions are as follows: water flow rate 1250 mL/min, Butamben in ethanol solution (24 mg/mL concentration) flow rate 363 mL/min; residence time 2.3 s. The feasibility of the FBRM probe use for continuous on-line application is tested by placing it perpendicular to the flow direction as shown in Figure 2. 3. Results & discussion The results of the plug-like behaviour investigation for a low liquid flow rate are shown in Figure 1 where it is observed that significant plug enlargement takes place. In
contrast to this the results obtained for significantly higher flow rates indicate that the enlargement is less. The values in Table 1 are normalized to the initial plug size. According to these results it is concluded that the process should be operated at high velocities in order to ensure a narrow particle size distribution. Since Butamben is a fast growing substance and the supersaturation is high a short residence time is desired. Note that operating at high flow rates is beneficial for the production of small crystals (Figure 3), size distribution width, production rate and micromixing at the liquid inlets. An upper limit on the total liquid flow rate was found at about 3600 mL/min where a significant pressure drop occurred and the peristaltic pumps were not able to ensure good micromixing. Related to the feasibility of the FBRM probe it is concluded that it is a valuable tool for the in-situ monitoring of continuous processes. Figure 4 shows the unweighted chord length distribution evolution in time. Nucleation takes place at around 40 s after which it takes about 12 s until the process reaches steady state. Note that in steady-state conditions the distribution is shifted toward small particles. a)
b)
c)
Figure 1. Length of the copper-hydroxide tracer. The slurry is pumped at 550 ml/min flow rate, Reynolds number (Re) = 916.
Table 1 Copper-hydroxide tracer plug size in a paracetamol slurry, horizontal position. The plug size has normalized values.
Inlet section
Middle section
End of mixer section
Flow rate [ml/min]: 550, Re: 916 Plug Size [-]
Plug Size [-]
Plug Size [-]
1
1.4
1.7
Flow rate [mL/min]: 3000, Re: 4994 1
1.3
1.3
1
1.1
1.3
1
1.1
1.2
Kenics mixer
FBRM probe
Figure 2. The on-line FBRM sensor placed at the end of the Kenics mixer.
38 s, m :5.2, m :5.7 15
Figure 3. Butamben crystals obtained using the continuous crystallizer.
40 s, m :5.7, m :7.3
50
15
42 s, m :6.3, m :7.7
50
15
44 s, m :6.3, m :7.8
50
15
400
2000
4000
4000
200
1000
2000
2000
0 0
50
4000
0 0 0 0 5 10 15 0 5 10 15 0 5 10 15 48 s, m :5.9, m :6.8 50 s, m :5.2, m :5.6 52 s, m :4.6, m :4.9 15 50 15 50 15 50 4000 4000 2000
2000
2000
5 10 15 46 s, m :6.1, m :7.2 15
0 0
50
2000
1000
2000
0 0 0 0 5 10 15 0 5 10 15 0 5 10 15 56 s, m :4.8, m :5.2 58 s, m :4.9, m :5.2 60 s, m :4.8, m :5.3 15 50 15 50 15 50 2000 2000 2000
1000
1000
5 10 15 54 s, m :4.7, m :5.1 15
0 0
50
1000
1000
2000
0 0 0 0 5 10 15 0 5 10 15 0 5 10 15 64 s, m :4.8, m :5.3 66 s, m :4.8, m :5.4 68 s, m :4.8, m :5.5 15 50 15 50 15 50 2000 2000 2000
1000
1000
5 10 15 62 s, m :4.8, m :5.3 15
0 0
5
50
10
15
0 0
1000 5
10
15
0 0
1000 5
10
15
0 0
5
10
15
Figure 4. No weight CLDs before and after nucleation; x: cld size, y: counts/s. Nucleation detected at 40 s. m15 is the mean CLD size, no weight, on the 1-15 micron interval; m50 refers to the mean on the 1-50 micron range.
Acknowledgements The authors are grateful to Dr. A. Alvarez for stimulating discussions. References [1]
Lawton, S.; Steele, G.; Shering, P.; Zhao, L.; Laird, I.; Ni, X.-W. Continuous Crystallization of Pharmaceuticals Using a Continuous Oscillatory Baffled Crystallizer. Org. Process Res. Dev. 2009, 13, 1357. [2] Eder, R. J. P.; Radl, S.; Schmitt, E.; Innerhofer, S.; Maier, M.; Gruber-Woelfler, H.; Khinast, J. G. Continuously Seeded, Continuously Operated Tubular Crystallizer for the Production of Active Pharmaceutical Ingredients. Cryst. Growth Des. 2010, 10, 2247. [3] Alvarez, A. J.; Myerson, A. S. Continuous Plug Flow Crystallization of Pharmaceutical Compounds. Cryst. Growth Des. 2010, 10, 2219.
