(214e) Ultrasound-Assisted Crystallization in a Two-Stage Continuous Msmpr Crystallizer System
Zhenguo Gao 1,2※ Dan Zhu 1,2※ Yuanyi Wu 1 Sohrab Rohani 1* Junbo Gong 2, Jingkang Wang 2
1. The University
of Western Ontario, Department of Chemical and Biochemical Engineering, London,
Ontario N6A 5B9, Canada
Tianjin University, School of Chemical Engineering and Technology, Tianjin,
300072, P. R. China
* Corresponding author. Email: email@example.com
Ultrasonic irradiation, Continuous crystallization, Crystal size distribution
Continuous pharmaceuticals manufacturing is an attractive method
to improve product quality, consistency and also process efficiency and
robustness. Since the promotion proposed by U.S. Food and Drug Administration
(FDA) to integrate continuous manufacturing into pharmaceutical production
and the practices implemented by leading pharmaceutical companies e.g. Vertex
and Novartis, there has been a growing interest in transforming a batch
production plant into a continuous process
in pharmaceutical industry (Adamo et al., 2016;
Mascia et al., 2013). Compared
with a batch process, which contains many intermittent steps, a continuous
process shows its advantages in better product quality and consistency, greater
process robustness and safety, lower cost and higher efficiency. Continuous
crystallization as a key unit operation to optimize solid product quality e.g.
purity, polymorphism, size/size distribution and stability, has been attempted
in several geometries. Sigle stage or multistage mixed suspension mixed product
removal (MSMPR) crystallizers have been studied to optimize the process
efficiency and product quality (Alvarez et al., 2011; Wong et al., 2012). A continuous tubular
crystallizer has shown potential application because of optimizing mixing
performance, supersaturation profile and diminishing shear force. Oscillatory
baffled crystallizer (OBC) has been successfully commercialized and various
strategies such as seeded, self-seeded, laminar, plug flow etc., have been
studied (Besenhard et al., 2015; McGlone et al., 2015).
Studies have proven that ultrasonic irradiation affects nucleation
and growth during crystallization process (Castro and Priego-Capote, 2007;
Bhangu et al., 2016). The
shock wave caused by cavitation of ultrasonic irradiation can promote
nucleation at a lower supersaturation level and a shortened induction time.
This promotes nucleation, which would result in a smaller size crystal. The
ultrasonic irradiation would also help to separate crystals at high surface
tension to prevent agglomeration (Narducci et al., 2011). Thus, with the help
of ultrasound, a smaller crystal size and a narrower crystal size distribution
(CSD) would result in a short time. In general, bigger crystals with narrower CSD are preferred considering
purity and downstream processing in pharmaceutical industry. Therefore, in this
study, a two-stage continuous MSMPR crystallizer series is used in which uniform
small crystals are produced in the first stage and further grow in the second
stage. In the present study, large α-form L-glutamic acid crystals around
150 μm were obtained with a narrow CSD and a higher process efficiency.
Experiments and Discussions
The two-stage continuous MSMPR crystallizer series was built to
optimized the CSD of α-form L-glutamic acid (Alfa Aesar, USA) in this
study. The schematic of experimental setup is shown in Figure 1. The first step
was to prepare the saturated solution (3.0 g/L) in the feed tank, and then
flowed through (50 mL/min) the two-stage MSMPR crystallizers with the help of
pumps. The first stage MSMPR crystallizer was coupled with an ultrasonic processor
(20KHz, 14-30W, VCX 500, Sonic & Materials Inc., USA) to promote
nucleation and also to optimize the size and population of crystals by tuning
the residence time and the intensity of ultrasonic irradiation (with and
without pause). A magnetic stirrer (200 rpm, Cimarec+TM,
Thermo Fisher Scientific, USA) was used to provide moderate mixing to
keep the crystals suspended. In-situ
focused beam reflectance measurement (FBRM, S400, Mettler Toledo, USA) was
used to measure the size/chord length and population/FBRM counts per sec to characterize the
crystal slurry in the two-stage MSMPR crystallizers. There was a moderate mechanical stirring (200 rpm, a
four-bladed stirrer, 45° blade angle) in the second stage MMSPR
crystallizer. Further characterizations like scanning electron microscope,
laser scattering crystal size measurement etc., were conducted to characterize
the crystalline product and optimize the performance of the system.
1. Schematic of experimental setup of two-stage ultrasound assisted MSMPR
With the help of ultrasonic irradiation, the nucleation occurs
easily (short induction time and lower supersaturation level required). As
shown in Figure 2, there are four lines that indicate the free energy required
by primary nucleation, secondary nucleation, nucleation under ultrasonic
irradiation and crystal growth, respectively. The primary nucleation requires
the highest free energy in contrast to crystal growth which requires the least
free energy. This shows that primary nuclei are difficult to generate as well
as hard to control. Crystals grow in any supersaturated solution. In this
system, the ultrasound-assisted nucleation occurred in the first stage MSMPR
crystallizer, which required lower free energy compared with primary and
secondary nucleation (Jiang, 2012). In
the second stage MSMPR crystallizer, secondary nucleation will not occur in the
crystal slurry since the free energy required was not sufficient. In the
presence of moderate mechanical stirring in the second stage, there is a
difference of required free energy for nucleation between those two stages, as
shown in Figure 2. Thus, the transferred crystal slurry from first stage to
second would not generate secondary nucleation appreciably because of higher free energy required with
the moderate mechanical mixing. The crystals from the first stage with narrow
distribution would further grow in the second stage without significant
breakage. The inserted images (a) and (b) are micrographs of the crystals at the
outlet of the two stages. Uniform crystals around 35µm were obtained under paused ultrasonic
irradiation (15s on, 10s off, 15W, residence time one minute) in the first
stage, and the crystals grew to 150 µm without obvious breakage and
Figure 2. Schematic analysis of free energy required by different
kinds of nucleation processes and corresponding operation point in the
two-stage MSMPR crystallizer system. Image (a) and (b) are crystals at the
outlet of the first stage and the second stage MSMPR crystallizer. The scale
bar is 200 microns.
In this study, a two-stage continuous MSMPR crystallizer system
was used to optimize the CSD of α-form L-glutamic acid and to improve the
process efficiency with the help of ultrasonic irradiation. The final product
crystals around 150 µm were obtained with a narrow crystal size distribution.
The total residence time in this system was 5 to 15 minutes, which is an
obvious improvement of process efficiency with the help of ultrasonic irradiation.
With the improved crystal qualities and process efficiency, challenges still
exist in continuous crystallization process: i) a long time may be required to
reach steady state; ii) any unexpected process malfunction may cause the shut down of the whole production process; iii) there is
a limited application in small scale, low output systems, especially for newly
released drugs. The properties of model compound are highly dependent on the
design of continuous crystallization process and operation recipe.
authors acknowledge the ﬁnancial support provided by the Natural Science
and Engineering Research Council (NSERC) of Canada and the China Scholarship
A., Beingessner, R.L., Behnam, M., Chen, J., Jamison, T.F., Jensen, K.F.,
Monbaliu, J.-C.M.C., Myerson, A.S., Revalor, E.M., Snead, D.R., Stelzer, T.,
Weeranoppanant, N., Wong, S.Y., Zhang, P., 2016. On-demand continuous-flow
production of pharmaceuticals in a compact, reconfigurable system. Science 352,
A., Singh, A., Myerson, A., 2011. Crystallization of Cyclosporine in a
Multistage Continuous MSMPR Crystallizer. Cryst Growth Des 11, 43924400.
M., Neugebauer, P., Ho, C.-D., Khinast, J., 2015. Crystal Size Control in a
Continuous Tubular Crystallizer. Crystal Growth & Design 15, 16831691.
S., Ashokkumar, M., Lee, J., 2016. Ultrasound Assisted Crystallization of
Paracetamol: Crystal Size Distribution and Polymorph Control. Cryst Growth Des
M.D., Priego-Capote, F., 2007. Ultrasound-assisted crystallization
(sonocrystallization). Ultrason Sonochem 14, 717724.
S., 2012. An Examination of Sonocrystallization Kinetics of L-Glutamic Acid.
University of Leeds.
S., Heider, P.L., Zhang, H., Lakerveld, R., Benyahia, B., Barton, P.I., Braatz,
R.D., Cooney, C.L., Evans, J.M., Jamison, T.F., Jensen, K.F., Myerson, A.S.,
Trout, B.L., 2013. End-to-end continuous manufacturing of pharmaceuticals:
integrated synthesis, purification, and final dosage formation. Angew. Chem.
Int. Ed. Engl. 52, 1235963.
T., Briggs, N., Clark, C., Brown, C., Sefcik, J., Florence, A., 2015.
Oscillatory Flow Reactors (OFRs) for Continuous Manufacturing and
Crystallization. Organic Process Research & Development 19, 11861202.
O., Jones, A.G., Kougoulos, E., 2011. Continuous crystallization of adipic acid
with ultrasound. Chem Eng Sci 66, 10691076.
S., Tatusko, A., Trout, B., Myerson, A., 2012. Development of Continuous
Crystallization Processes Using a Single-Stage Mixed-Suspension, Mixed-Product
Removal Crystallizer with Recycle. Cryst Growth Des 12, 57015707.