270744 Design and Characterization of a Continuous Stirred Tank Crystallizer

Tuesday, October 30, 2012: 9:06 AM
Crawford West (Westin )
Gary Morris, Guangyang Hou, Mark Barrett and Brian Glennon, School of Chemical & Bioprocess Engineering, University College Dublin, Dublin 4, Ireland

Design and Characterisation of a Continuous Stirred Tank Crystallizer


G. Morris, G. Hou, M. Barrett, B. Glennon


Solid State Pharmaceutical Cluster, The School of Chemical and Bioprocess Engineering, University College Dublin, Belfield, Dublin 4, Ireland

Keywords: Mixed Suspension Mixed Product Removal, Benzoic Acid, Cooling Crystallization, Process Analytical Technology




This study presents the development of a continuous crystallization platform consisting of a single stirred tank Mixed Suspension Mixed Product Removal (MSMPR) crystallizer. A photo and schematic drawing of the MSMPR setup appear in Figures 1 and 2 respectively. A recirculation loop is incorporated such that the withdrawn product is recycled to a dissolution vessel which serves as the feed tank to the crystallizer. Two OptiMaxTM workstations (Mettler-Toledo) are used as both the feed/dissolution tank and the MSMPR crystallizer. Difficulties can often arise in the continuous removal of representative, non-classified product from lab-scale MSMPRs as a result of the relatively low volumes involved and consequently slow flowrates and removal velocities observed [1]. Intermittent withdrawal, whereby a certain percentage volume of the MSMPR is periodically removed at a high velocity so as to aid the potential for iso-kinetic removal and mitigate classification has been applied previously and is adopted in this work [2, 3]. This quasi-continuous transfer of the MSMPR product to the feed/dissolution vessel is achieved using vacuum with 7.1% of the suspension volume removed per transfer.


Figure 1: Image of the MSMPR setup showing feed/dissolution vessel on the left and MSMPR on the right with FBRM in-situ



Figure 2: Schematic drawing of the MSMPR setup showing application of vacuum in recycling material from MSMPR to feed/dissolution vessel

In-situ process analytical technologies (FBRM, PVM), together with periodic sampling of the withdrawn product at steady-state and during the dynamic period of the process, have been applied in order to characterize the continuous cooling crystallization of benzoic acid from water and ethanol. Comparison is drawn between high magma density crystallizations (feed saturated at 40oC with the crystallizer at 18oC) and low magma density crystallizations (feed saturated at 15oC with the crystallizer at 0oC). For the low magma density runs the influence of residence time on affecting the steady-state particle size was investigated. For each of these studies, continuous operation was started with a suspension in the MSMPR at time zero by first batch cooling the saturated feed to the desired MSMPR temperature. In addition, a further set of experiments was carried out to investigate whether the mode of start-up bears any influence on the final steady-state product obtained and the route to steady-state.



Characterization with FBRM and Periodic Sampling

The crystallization is monitored in-situ using FBRM and PVM. This allows real time tracking of the changes in the particle size distribution and attainment of steady-state. Figure 3 shows the dynamic response in the FBRM total counts and mean chord length trends for a high-magma density crystallization proceeding to steady-state.

Figure 3: Tracking MSMPR to steady-state with FBRM for a high magma density run of 60 minute residence time. Showing regions: (A) wash-out period, (B) nucleation response and (C) attainment of steady-state

Figure 4: MSMPR solute concentration and magma density trends from start-up to steady-state for a 15 minute residence time high magma density run

As the crystallization proceeds initially there is a wash-out period (A) where particles are withdrawn in the absence of nucleation as the supersaturation builds. Over this period crystal growth is observed which is confirmed by an increase in the FBRM size trends and in-situ PVM images (Figure 5). Supersaturation increases to a maximum just before region (B), where the kinetics of the system force a period of constant nucleation which steadily consumes some of the supersaturation and slightly shifts the CSD back towards the fine end. Eventually the rate at which new crystals are formed by nucleation balances the rate at which they are withdrawn from the MSMPR and the system tends towards a steady-state (C).

Figure 5: In-situ PVM images from a low magma density run of 15 minute residence time showing the change in particle size during MSMPR start-up. Taken at: (A) time zero after batch cooling at 1.5oC/min, (B) at 1 residence time, (C) at 2 residence times and (D) at 3 residence times

High & Low Magma Density Crystallizations

Comparing high and low magma density crystallizations it was observed that the level of the nucleation response in the dynamic route to steady-state is reduced when the slurry density in the crystallizer is relatively low (Figure 6), demonstrating the dependency of the nucleation rate on magma density. Consequently for the high magma density process the steady-state chord length distribution is shifted more towards the fine end (Figure 7).



Evolution of Particle Size with Increasing Residence Time

In an MSMPR, for a given temperature drop between feed and crystallizer, it is possible to access different positions on the phase diagram by varying the residence time and as a result manipulate the steady-state supersaturation. The speed of the crystallization kinetics and the meta-stable zone width will ultimately dictate the supersaturation range accessible, and whether changing residence time will be favourable in terms of manipulating particle size advantageously. The benzoic acid system used in this study has a small meta-stable zone width and is more growth dominated. Consequently, the accessible range of supersaturation is limited but particle size has been shown to grow with residence time (Figure 8). Figure 9 demonstrates that steady-state particle size increases whilst MSMPR solute concentration and hence supersaturation deceases with increasing residence time.

Figure 8: Steady-state CLDs (un-weighted) for low magma density runs of varying residence time













Figure 9: Demonstrating increase in particle size with residence time whilst solute concentration decreases



Influence of Start-Up Mode on Attainment of Steady-State

Several start-up regimes for running an MSMPR could potentially be employed. To examine whether particular choices in this area can have a significant bearing on the steady-state particle size obtained by the system, three methods of starting the MSMPR were investigated whilst keeping all other conditions the same:

(i) Batch cooling the saturated feed to the desired MSMPR operating temperature, therefore allowing continuous operation to be started with an equilibrium suspension in the MSMPR at time zero

(ii) Starting with a clear solution which is saturated at the MSMPR operating temperature

(iii) Seeding a solution that is saturated at the MSMPR operating temperature with isolated steady-state product from a previous run, therefore creating a suspension of the final product at time zero

All start-up methodologies were assessed through high magma density benzoic acid crystallizations, where the feed to the MSMPR is saturated at 40oC and the crystallizer is operated at 18oC. The resulting steady-state chord length distributions from each start-up regime are seen to be similar in all cases (Figure 10). This suggests that the final steady-state condition attained by the system is largely unaffected by the start-up methodology adopted.


Figure 10: Steady-state CLDs (un-weighted) for high magma density crystallizations with different start-up regimes

Comparison of the FBRM total counts trends during the dynamic route to steady-state suggests that starting with saturated solution that is seeded with final product material may offer the quickest route to steady-state (Figure 11). Unlike the equilibrium batch start-up, in this case the initial particle size distribution is the same as the final and as a result the system does not require periods of significant oscillation in the size distribution to develop the steady-state CSD for the continuous process. This therefore may represent an optimum start-up strategy for MSMPRs, as the time required to reach steady-state is reduced and hence wastage of material whilst the final product is potentially out of spec is minimised.



Figure 11: Comparison of the dynamic response in the FBRM total counts trends as the system proceeds to steady-state for all three start-up methodologies investigated



[1] A.D. Randolph, M.A. Larson, Theory of Particulate Processes, 2nd edition, Academic Press, New York, 1988.

[2] V.A. Chan, H.M. Ang, Journal of Crystal Growth 166 (1996) 1009-1014

[3] E. Kougoulos, A.G. Jones, K.H. Jennings, M.W. Wood-Kaczmar, Journal of Crystal Growth 273 (2005) 529534





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