Custom-Built Miniature Continuous Crystallization System with

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Custom-Built Miniature Continuous Crystallization System with Pressure-Driven Suspension Transfer Yuqing Cui, Marcus O'Mahony, Juan J. Jaramillo, Torsten Stelzer, and Allan S. Myerson Org. Process Res. Dev., Just Accepted Manuscript • DOI: 10.1021/acs.oprd.6b00113 • Publication Date (Web): 13 Jun 2016 Downloaded from http://pubs.acs.org on June 15, 2016

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Organic Process Research & Development

Custom-Built Miniature Continuous Crystallization System with Pressure-Driven Suspension Transfer Yuqing Cui†, Marcus O’Mahony†‡, Juan J. Jaramillo, Torsten Stelzer§, Allan S. Myerson* Department of Chemical Engineering, Massachusetts Institute of Technology, 77 Massachusetts Avenue, Cambridge, Massachusetts 02139, United States † These authors contributed equally to this work * To whom correspondence should be addressed. Email: [email protected].

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Abstract At the bench scale, transfer of solid-liquid streams between reaction vessels or crystallizers that operate continuously poses a significant problem. Reduced equipment size of pumps and valves (i.e. approaching that on the microfluidic scale) means even further reduced orifices in which suspensions must attempt to flow. It forces bridging of solids and leads to blockages in flow. This study presents a new pressure-driven flow crystallizer (PDFC) with a custom-built suspension transfer pumping system. In the system, a dip tube is used to carry suspension between crystallizers by controlling the pressure differences of the crystallizers. This novel system has a small footprint on the scale of similar bench-top flow synthesis systems, and has been demonstrated to operate continuously with intermittent withdrawal for at least 24 hours. The system accommodates both cooling and antisolvent crystallization. It is compatible with a variety of solvents, can handle crystals with large and small aspect ratios, and it can also handle a large range of crystal sizes and suspension density. The miniature design of the system requires as little as 0.36 psig (0.025 bar(g)) pressure to operate and a design equation can be used to guide the estimation of the minimum pressure needed for the transfer of suspensions at larger scales. Keywords Suspension transfer, benchtop-scale crystallizers, continuous crystallization, multi-stage MSMPR Introduction Continuous flow synthesis of high value active pharmaceutical ingredient (API) is becoming a priority area of research and development for today’s process chemistry and engineering. This trend is highlighted by the recent collaborative work on continuous flow production of 3 ACS Paragon Plus Environment


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pharmaceuticals in a small-scale system.1 A crucial part of such synthesis is continuous crystallization, and the work presented here aims to solve the issue of suspension transfer in small-scale continuous crystallization. Developments in continuous crystallization are key to maintaining the integrated chain of continuous manufacturing from synthesized molecules to crystalline drug substances and formulated drug products.2,3 Continuous crystallizers have been in operation in many large-scale, high volume non-pharmaceutical settings for many decades.4 Recent continuous crystallizer developments, aimed at the pharmaceutical industry include the oscillatory baffled crystallizer5 and novel plug-flow crystallizers6,7. Unfortunately, all of these crystallizer designs can suffer from fouling and sedimentation. In contrast the traditional continuous stirred-tank reactor (CSTR) or mixed suspension, mixed product removal (MSMPR) crystallizers generally operate efficiently without fouling. They are also well-characterized to enable crystal nucleation and growth rate to be determined4 and have been used to crystallize many APIs3,8. Multistage MSMPR with crystallizers in series have many advantages over a single stage MSMPR crystallizers, such as greater throughput9, increased mean crystal size10,11, and improved crystal purity12. Multistage MSMPR systems often rely on peristaltic or centrifugal pumps to withdraw the product suspension from the crystallizers and these pumps are often effective at removing suspensions from continuous crystallizers. However, they are not ideal and suffer from drawbacks. In fact, they can directly impact the product crystals flowing through them. Collisions between the peristaltic pump rollers and product crystals can lead to fragmentation and generation of secondary nuclei.13 Bennet et al. discovered that there was significant rounding of large salt particles at high pump speeds.14 Crystal breakage through peristaltic 4 ACS Paragon Plus Environment

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pumps is still an issue that needs to be monitored,15 and is an area in which researchers have dedicated efforts to study.16 Another issue with pumping suspensions with peristaltic or centrifugal pumps is their large footprint. While MSMPR crystallizers can be scaled down to a working volume as little as 20 ml,17 the size of pumps that handle suspensions is still typically greater than or at best equal to the size of the crystallizer. These drawbacks demand a more effective approach for crystallization suspension transfer, particularly, on the lab-scale and in the case of miniaturized desk-top scale production systems (which are currently in development within our research group). Some suspension transfer techniques from crystallizers at lab-scale and pilot plant scale have been developed in the past where the footprint of such systems typically exceeds bench top scale. These include the use of an overflow tube18 (does not operate robustly in all cases), or a combined vacuum/pressure transfer system that requires the need for an additional transfer/holding zone (a separate vessel) and facilitates only a single MSMPR that cannot be used in series19,20. Our transfer scheme presented here does not require such transfer/holding vessels and can operate MSMPRs in series. This paper presents a simple, robust and flexible Pressure-Driven Flow Crystallizer (PDFC) based on the traditional MSMPR design that can handle a variety of crystallization methods, solvents, crystal sizes, shapes and suspension density. Critically, the PDFC is desk-top scale with a similar footprint to other flow synthesis systems. The PDFC design does not require suspension to pass through pumps or valves that are used within the system and multiple PDFCs can operate in series as a multistage MSMPR. To the best of our knowledge, desktop-scale technology capable of handling milliliter to liter scale suspension pumping and transfer for crystallizers does not exist. Experimental 5 ACS Paragon Plus Environment


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Description of Continuous Transfer Scheme PDFC as a Single-Stage MSMPR. Feed streams are continuously delivered into the first stage of the MSMPR with a diaphragm dosing pump (Model PML-9431-FMM20 manufactured by KNF Flodos AG). The resulting suspension is then transferred out of the MSMPR via a dip tube through the generation of head pressure within the MSMPR vessel. This transfer occurs on an intermittent basis, i.e. transferring 5-10% of the volume build-up within the MSMPR at repeating time intervals.21 Rapid intermittent withdrawal has proved to be capable of largely negating the problem of blocking of transfer lines, especially when under a differential pressure between inlet and outlet22, as is the case in this system. Custom-made crystallizers were devised to achieve such a transfer scheme at the target processing scale (40 ml). The feed streams can be an API dissolved in solvent which crystallizes in the single-stage of the MSMPR due to cooling from the cooling jacket surrounding the crystallizer. The feed streams could also consist of an API solution and an antisolvent stream. The crystallizers used in this study are made of polypropylene and high density polyethylene (HDPE), and have the dimensions of 6 x 7 x 7 cm for 40 ml volume. They are stirred to keep solids suspended – this can be achieved by a regular magnetic stir bar or a magnetic agitator with marine impeller blades coated with Teflon (from HEL Inc.). A dip tube is inserted into the crystallizer and acts as the transfer line to move suspension out of the crystallizer into downstream processes. Adjustment of the dip tube length submerged in the reactor allows adjustment of working volumes in a single reactor. A three-way valve (type 0127 3/2-way Rocker-Solenoid Valve manufactured by Burkert GmbH & Co. KG) is connected to the first stage. The purpose of the three-way valve is to (1) allow the crystallizer to vent thus preventing unwanted pressure build up in the crystallizer as feed streams are added, and (2) facilitate pressure build-up during the pressure-driven flow transfer. A solenoid dosing 6 ACS Paragon Plus Environment

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pump to generate pressure within the crystallizer is attached at the normally closed side of the three-way valve. See Figure 1 for illustration of the setup for the single stage crystallizer.

Figure 1. Piping and instrumentation diagram to illustrate the setup required to achieve pressure-driven transfer within a continuously operated process. No = normally open, Nc = normally closed and refers to the different ports on the three-way valve. L1 is the liquid height bordering the tip of the dip tube while L2 is the highest level attained before pressure-driven transfer. Figure 2 shows a schematic of the custom-made crystallizer with 40 ml working volume. The design is shown from top, side section view and isometric view in perspectives I, II and III respectively with each component labelled. In Figure 2-IV, an image is shown of the actual crystallizer with magnetic PTFE impeller and hastelloy shaft.



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Figure 2. Custom designed pressure driven flow crystallizer (PDFC) with magnetic impeller for both rotational and axial mixing. I – top view, II- side section view and III- isometric section view of the design. IV- image of the actual crystallizer with PTFE coated magnetic impeller and hastelloy shaft. The design is shown for a 40 ml working volume PDFC vessel. PFDC as a Multi-stage MSMPR. The single-stage MSMPR system can be extended to include N crystallization stages. Figure 3 shows the arrangement required for such a system. In the case of antisolvent crystallization, antisolvent addition ports may be incorporated into each stage in order to increase the driving force for crystallization in successive stages.


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The transferring of slurry forward from stage to stage + 1 is best understood with reference to Figure 3. In order to transfer slurry out of stage to stage + 1, the transfer pump and three-way valve connected to stage are actuated. This displaces air into stage , but head pressure buildup can be lost in stage through transfer line − 1. In order to prevent such loss, the three-way valve connected with − 1 (TV1) is actuated and any pressure loss is sealed against the two-way valve (V1) which remains closed. This allows the air originally displaced into stage to build head pressure within stage and subsequently transfer slurry from stage to stage + 1 via transfer line + 1 (provided the slurry level is above L1b in stage ). Multi-stage transfer proceeds in this way, that is, by ensuring that stage , stage -1 and any more preceding stages are sealed against pressure losses when pressurizing the head pressure in stage to transfer to stage +1. The collection vessel following stage can be connected to a vacuum, making the last slurry transfer vacuum-driven. The transfer process to coordinate the operation of the pumps and valves was automated with LabView (National Instruments). Typically, no more than 5-10% of the total volume is withdrawn for every transfer.21 Under this condition, the system behaves just as if there was continuous withdrawal and steady state can be established.22–26



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Figure 3. Schematic for an N-stage continuous MSMPR with the PDFC transfer scheme. Note that stage − and stage may, in most cases but not all, be labeled as stage 1 and stage 2 of an MSMPR cascade. Mean Residence time (MRT). The mean residence time for stage can be determined by the following equation:

Here, represents the mean volume of stage and is the volumetric flowrate of the combined reagents going into stage . During an operation, when the total volume of suspension is 10% larger than the minimum volume of the crystallizer, the excess content is withdrawn through the 10 ACS Paragon Plus Environment

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dipping tube. Thus the mean volume of each crystallizer stage is the average of its maximum and minimum volume. The minimum volume can be controlled by altering the position of the dipping tube or installing crystallizers with different total volume. This design allows every stage to host a different working volume, making individual stage mean residence times flexible. The transfer time is short compared to the mean residence time (

Custom-Built Miniature Continuous Crystallization System with

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