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An Intelligent Continuous Collection Device for HighPressure Flow Synthesis: Design and Implementation Michael Tilley, GuanLong Li, Paul Savel, Debasis Mallik, and Michael G. Organ Org. Process Res. Dev., Just Accepted Manuscript • DOI: 10.1021/acs.oprd.5b00363 • Publication Date (Web): 20 Jan 2016 Downloaded from http://pubs.acs.org on January 27, 2016

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Organic Process Research & Development

An Intelligent Continuous Collection Device for High-Pressure Flow Synthesis: Design and Implementation Michael Tilley, Guanlong Li, Paul Savel, Debasis Mallik, Michael G. Organ* Department of Chemistry, York University, 4700 Keele St., Toronto, Ontario, Canada, M3J 1P3

ACS Paragon Plus Environment

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Table of Contents Graphic


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Abstract

An automated collection/diversion device for high-pressure continuous flow synthesis is introduced. Integration of sampling and collection functions with decision-making capabilities to handle process disruptions is detailed. A device to mitigate pressure swing effects of reciprocal pump systems is also described. System performance is evaluated by simulating fast and slow chemical processes and change of critical reaction parameters, including the ones that involve flow catalysis.

Key Words Continuous Flow, Organic Synthesis, High Pressure, Uninterrupted High Pressure Collection, Diversion of Non-Conforming Material


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Introduction Interest in flow chemistry has been driven by the promise of cost savings associated with efficient scale-up,1 increased processing safety with reactive intermediates,2 and discovery of new synthetic strategies.3,4,5 However, reaping the benefits of the flow format also means being able to reliably withdraw a high quality product at the end of a process run. In the past, we have demonstrated our ability to extract a sample (i.e., analyte) from a flow reactor without compromising any of the process parameters (e.g., flow-rate and pressure).6 The success of this strategy prompted us to integrate our reaction monitoring capability to a product collection device, which can guide a volume of material to flow into the subsequent process line, or to exit the process environment depending on the purity of the reactor output. Although there has been significant progress in the development of flow technology, the capacity to collect or divert a reactor output based on inline analyses has not been fully explored.7 The objective of our Microwave Assisted Continuous Organic Synthesis (MACOSTM) technology platform is to develop a range of equipment to facilitate flow processes for research-scale research and chemical manufacturing. Presently, we will communicate the development of an automated and intelligent product collection device capable of operating in all flow conditions, including the ones under high pressure. Historically, the single-vessel batch reactor has been the simplest path to ensure quality control. By closing the vessel, material properties are unified, if not homogenized,8 throughout the reactor. Quality control is achieved on a batch-by-batch basis. A batch of material in a tank reactor is uniquely characterized by the conditions of its manufacture. If those conditions produce an undesirable product, then that information is added to the batch report. In case the concentration of the contaminant is found to be beyond its threshold limits, the entire content of


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the batch is rejected. When the cost of the starting materials is significant, the batch reactor technology can lead to significant loss and potential delay in the manufacturing pipeline. In flow, this risk is substantially less especially when the reactor is equipped with technologies to continuously monitor the state of the flow-reactor (e.g., the MACOSTM platform) and transfer the analytical information to the collection device before an entire batch is contaminated with an undesired substance beyond its acceptable concentration limit. The salient principle of the batch concept is material traceability. Material is traceable if it is uniquely identifiable throughout its life cycle. For a batch this means that the quantity and characteristics of a material, as well as the parameters of its production, are known.9 This information allows chemists to build control strategies,10,11 create documentation12 and ensure quality control. In batch production, it is the physical limits of the reactor itself that provide this knowledge and define the control volume. We believe that the MACOSTM product collection technology can potentially increase the level of control available for the flow format. Progress in on-line monitoring has been demonstrated in flow using a variety of analytical technologies. Many of these technologies,13,14,15 including ours,6 demonstrated the importance of continuous monitoring in order to ensure that the process output meets certain standards. Of note, Jensen and collaborators reported an automated monitoring system with elaborate feedback control in the end-to-end synthesis of aliskiren hemifumarate.16 Although the authors made a significant advancement in this flow technology, there was no provision for the diversion of the deficient material. In our opinion, any disruption of the process parameters could contaminate the downstream material and require a system shutdown. Production of deficient material is endemic to continuous processing.17 Process disturbances, both planned, such as start-up, shut down, material replenishment, and unplanned, are part of this mode of manufacture. Monitoring


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alone without a means to remove non-conforming reactor output without interrupting the process or affecting critical process parameters eliminates the strategic advantage that flow format enjoys over batch production. Without a way to remove non-conforming reactor output, product of varied quality could accumulate and the scope of application of the flow format could become limited. We decided to address this by equipping our platform with a product collection/diversion device. A control strategy (i.e., the collection/diversion based on results) based on the operation of this device could prove useful for the future development of the flow technologies. In the present article, we will introduce an apparatus with a decision-based collection/diversion capability that can be used under high pressure and temperature and most importantly, that will not cause any interruption to the flow process during its operation. Further, this new methodology will be used to assess segments of reactor output (micro-lots) that are systematically isolated and individually analyzed without any interruption to the flow process (i.e., continuous). Purity of these "micro-lots" are to be evaluated for their inclusion into the overall growing pool of the flow output coming from one single continuous process. Results and Discussion System Architecture Smart diversion of material from a continuous process requires collection of volumes of material, when and as frequently as necessary, without disturbing process parameters, with the ability to discretely analyze and, if required, divert aliquots of material from the process line. Further, adding to this complexity, many flow reactors, including our MACOSTM system, can operate at


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high temperature and pressure. Therefore, the sampling and diversion solutions must avoid any perturbation of a reaction’s steady-state conditions. Figure 1 shows a schematic representation of the MACOSTM system. High pressure reciprocating syringe pumps (P1 and P2) deliver reagents to the microwave reaction chamber (Reactor). Heat exchangers on either side of the reactor (HE1 and HE2) ensure that heating is limited to the reactor. Sampling is performed immediately downstream of the reactor (V3) and back pressure is provided by the Back Pressure Creation Device (BPCD), (PB1), previously highlighted.18 Deficient material is removed by the Continuous Collection Device (CCD), consisting of a high pressure continuous collection valve (V3), a diversion valve (V4) that selects the destination of the fluid collected, and the auxiliary hardware and software to operate the valves. Valve V3 is plumbed with two collection loops, switching of the valve position isolates aliquots of product from the main process line by diverting the output into one of the two loops, without interrupting the flow or affecting the process pressure.


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Figure 1. The MACOSTM system with CCD components highlighted. syringe pump (P1 and P2), transfer solvent pump (P3 and P4), reagent holding loop (L1 and L2), reagent reservoir (R1), sample transfer solvent reservoir (R2), collection transfer solvent reservoir (R3), transfer solvent collection reservoir (R4), product collection reservoir (R5), waste collection reservoir (R6), continuous flow unit valve (V1), sampling valve (V2), continuous collection valve (V3), diversion valve (V4), manual pressure release valve (V5), manual gas shut off valve (V6), heat exchanger (HE1 and HE2), pressure ballast (PB1), system pressure indicator (PI1), gas pressure regulator (PR), sample transfer tube (TT). The main component of the CCD is the continuous collection valve, V3, an 8-port, 2-position high pressure valve (Figure 2, below). Reaction product flows in through Port 1, while port 5 is connected to the pressure ballast (PB1). Port 3 is the transfer solvent source, port 7 is the outlet to product collection. Two collection loops run from port 2 to port 6 (Loop 1) and port 8 to port 4 (Loop 2), respectively. The valve alternates between two positions, position “A,” (Figure 2a) in which Loop 1 intersects the high pressure line while loop 2 is connected to the transfer line, and position “B” (Figure 2b) in which the loop connections are reversed. Transfer solvent flushes reaction material from the loop and cleans the internals, and it is this solvent that flows through port 5 to the pressure ballast. Actuation of the valve depressurizes the fluid in Loop 1 and pressurizes the fluid in Loop 2, which was not found to cause significant pressure fluctuation.19


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a)

b)

Figure 2 Layout of CCD collection valve. a) Position “A.” b) Position “B.” The intelligent operation of the CCD depends upon coordination with the sampling valve (V2) and the analytical routine. As one loop of V3 fills with material, an aliquot (5µL) of material from the midpoint of the volume collecting in this loop is withdrawn by the sampling valve (V2). Fluid continues to collect in the loop until a metered amount is reached. The fluid volume is held in the loop awaiting the analytical result of the sample (i.e., the analyte) from V2. The analytical information is then interpreted by the MACOSTM software and a decision (i.e., diversion or collection) is made and the diversion valve (V4) is actuated accordingly. The arrangement and coordination of sampling and collection valve operations is illustrated in Figure 3.


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Figure 3. Work flow of CCD for sampling valve V2 and collection valve V3. Articulation of the CCD collection valve generates the micro-lots of process output. A lot is: “a batch, or a specific identified portion of a batch, having uniform character and quality within specified limits; or, in the case of a drug product produced by continuous process, it is a specific identified amount produced in a unit of time or quantity in a manner that assures its having


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uniform character and quality within specified limits.”9 In our design, the CCD compartmentalizes the downstream output into micro-lots and re-constitutes them in accordance with the process qualification parameters once the analysis of a specific micro-lot is complete. Although the definition of a batch in a dynamic environment such as the flow format may not be straight-forward, our ability to include or reject the micro-lots allows us to prevent the central pool of the reactor output going out of specifications before a breach in the critical process parameters is detected. Consequently, this enables MACOSTM to maintain the definition of a batch through high frequency quality assurance strategies during a flow operation. Depending on the setup, micro-lots may also be transferred to individual vials, with the use of a fraction collector or stream selection device as in the case of an optimization type run where the user may want to perform further analysis of the products. Collection of micro-lots enables our system to achieve a highly resolved quality control. As well as uninterrupted collection and diversion of micro-lots, the CCD also performs a substitution of reagent solution fluid for clean solvent. Process fluid is flushed from the loop during transfer to collection or waste. The action fills the loop with clean solvent. It is the clean solvent that continues onwards to the ballast (PB1) of the pressure source while depressurized product is removed from the pressurized process envelope. This substitution keeps reaction material from entering into the BPCD. Further, with the reagent/solvent substitution, the risk of fouling decreases and conventional mechanical flow control devices may be employed to enable the MACOSTM system to run indefinitely.


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Handling Pressure Effects While accurate metering of fluid is not critical for the product collection device, the same is essential for the MACOSTM reagent delivery system. High pressure delivery of material is perturbed by sudden pressure imbalances caused by the introduction of low pressure reagents to the high pressure process environment. In the MACOSTM system, continuous flow is provided by reciprocating syringe pumps alternately infusing and refilling with the aid of a high pressure 4port valve (V1, Figure 1). This Continuous Flow Unit (CFU) valve connects and disconnects the reagent delivery syringes from the high pressure process path. Fluid in the high pressure process line exposed to a newly refilled syringe (atmospheric pressure) flows upstream (backwards) as the pressure differential is balanced. Similarly, a syringe assembly under tension at high pressure experiences an elastic contraction when exposed to the atmospheric pressure of the reservoir line (see Figure 4a) squeezing out fluid. The net effect of this imbalance is backflow of material in the system, which results in volume loss of the product in the loops of the collection valve, V3, disruption of reactor steady state, and ultimately ejection of fluid backwards into the reservoir. Measurement at the reservoir of fluid ejected from a syringe depressurizing as a result of CFU actuation was plotted in Figure 4b. Approximately 8μL of fluid was ejected per 100psi of applied system pressure. Depending on system pressure and syringe volume,20 the net flow rate can be significantly affected by the pressure swing effect.


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a)

b)

Figure 4. a) High and low pressure zones of the MACOSTM synthesis unit at the CFU valve. b) Reservoir fluid ejection response to unmitigated pressure increase. This pressure swing affect from the actuation of the reciprocating syringe pump setup was addressed by creating a 4-port, 4-position valve. Specifically, a standard 4-port, 2-position, highpressure valve was fitted with a modified valve rotor designed with extended rotor channels (Figure 5b). This rotor design along with custom firmware circuitry and software control adds two intermediate positions, “I-1” and “I-2,” between the standard “A” and “B” of the twoposition valve (Figure 5c). In Position “A” ports 1 & 4 and 2 & 3 are connected. In position “I1,” the valve is rotated to dead end port 2, while ports 1 & 4 remain connected. In this position the syringe at port 2 may be advanced or retracted, “pre-positioned” to balance pressure. Position “I-2” connects ports 1 & 2 while isolating port 4, the syringe at port 4 may now be similarly balanced. Turning the valve to position “B” completes the actuation. Mitigation of pressure swings by use of the 4-port 4-position valve to pre-positioning the syringe (37µL at 1000psi) using the 4-port 4-position valve port virtually eliminated fluid ejection at the reservoir (Figure 5d).


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b)

a)

c)

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d)

Figure 5. a) Standard 4-port 2-position valve rotor design with 90° rotor channels. b) 4-port 4position rotor design with extended rotor channels. c) 4-port 4-position valve port alignment schematic. d) Pressure swing effect after mitigation. Comparing the accuracy of collected volumes at the CCD with and without pressure mitigation, shows a marked difference. In this test, the MACOSTM system was primed with pure solvent (accounting for the lower than expected micro-lot values in data points 1 &2 of both runs, as the system reached steady-state) and then charged to 1000psi via the BPCD. A known concentration of analyte was run through the system, sampled at the sampling valve (V2) and collected at the CCD. During the collection process, the CFU valve was actuated. Concentrations with and


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without mitigation were compared to those from the sampling valve, which, because it is overfilled with an unchanging concentration of test solution, does not feel the effects of the pressure fluctuation. Figure 6 shows that the mitigated collection was normally distributed around the average solution value with an average error of 2.7% and relative standard deviation (RSD) of 1.5%. By comparison, collections of the unmitigated run were distributed around a concentration 10% lower than the solution concentration, with an RSD of 2.6%, implying loss from back-flowing material.21

Figure 6. MACOSTM micro-lot collection with and without pressure mitigation. The blue line represents expected concentration. CCD Performance Tests Experiments were performed to demonstrate that the MACOSTM system with CCD and pressure mitigation can successfully accommodate system disruptions while mitigating effects on downstream product quality. Disruptions can result from a rapid change such as a stalled pump, a malfunctioning valve, loss of pressure, or a gradual degradation of a reagent or a catalyst.


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To simulate such conditions that would take the product material out of specification, the MACOSTM system was initially primed with pure solvent and the CFU inlet port was then connected to a stirred analyte solution. The solution was fed by a syringe pump programmed to dilute the solution by 5% at each syringe refill. The system was pressurized to 1000psi, and flow was set at 100µL/min. The process was sampled every 500µL, and 500µL micro-lot volumes of product were collected from the CCD.22 Immediately prior to each syringe refill stroke, a hand sample was taken from the supply reservoir solution to check the current new concentration. The increasingly dilute solution was analyzed after the run for precision between the sampling valve and CCD operations as well as for agreement with the reservoir material. The initial data points of the simulation (Figure 7, sample points 1-3) show priming with reagent solution. From the fourth data point onward precision between the sampling and collection values is 3.1% with 2.1% RSD. Accuracy to the hand sample was 6.0% with 1.8% RSD for the sample values, 3.1% with 1.5% RSD for the micro-lot collection values. Overall, variation was low and the system was able to follow a 5% decline of the solution concentration to half of the original concentration value. This experiment demonstrates that the system can provide validated, accurate, and constant in-line monitoring of isolated micro-lots to follow the gradual movement of a process out of the parameters of the desired reaction outcome. The result is that the loops of nonconforming material are to be diverted to waste so as not to negatively impact the previously pooled micro-lots (i.e., the growing production batch) until such time as the product becomes acceptable again, or to simply bring about the termination of the synthetic run at that point.


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Figure 7. Gradual degradation simulation. Data points 1-3 show system priming. The second simulation examined a scenario where a catastrophic loss of analyte could affect the detection and collection/diversion functions, in two parts. In the first part (Figure 8), the system was primed with an analyte solution and pressurized to 1000psi. Flow was initiated at 50µL/min. The collection loops dispensed 500µL micro-lots of product into separate vials. The process was sampled at the midpoint of the micro-lot volume. Analyte solution was substituted with pure solvent after the first 20 minutes, for a duration of 10 minutes, to simulate a precipitous drop in the product conversion. The system responded rapidly, identifying the out of specification condition within 500µL. Further, within 1000µL of replacing the analyte solution, sample values returned to their original levels. Frequent sampling limited waste to just two micro-lots: 3 and 4 (1000µL total). Observations suggest that a disruption shows greater deviation from the norm in the sample loop than in the collection loop. This high sensitivity to parametric changes provides a good basis for automated decision-making for the collection or diversion of the micro-lots.


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Figure 8. System response to substitution of analyte solution with pure solvent. The second part of the catastrophic loss experiment tested the intelligent diversion strategy (Figure 9). As above, a drop in analyte levels was simulated by substituting pure solvent for the analyte solution in a primed and pressurized system. Flow rate, sampling and collection parameters remained unchanged. Based on the previous experiments, a diversion decision criterion of 95% concentration value (relative to the concentration of the prepared solution) was pre-programed. The process qualifier was set such that the micro-lots with concentrations greater than 95% would be diverted into a product vial, otherwise they would be diverted to waste. Pure solvent was substituted after the first 10 minutes running for a duration of 10 minutes and again after 50 minutes for 20 minutes. Samples were collected every 10 minutes for 100 minutes. MACOSTM software analyzed all samples from the midpoints of the loop volumes and determined that the micro-lots 1, 4, 5, 9, 10 meet the qualification. The entire operation of sampling, analysis and the collection/diversion was executed by the software without any human intervention. After the run, the vial with collected “good” material, which met or exceeded the 95% concentration parameter, was tested and this value was found to be within 4% of any


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individual component value and within 1% of their average value. All non-conforming material (micro-lots 2, 3, 6, 7 & 8) was successfully diverted to waste.

Figure 9. Intelligent diversion with multiple substitutions. Conclusions A new flow technology capable of uninterrupted diversion and collection of product from a high pressure environment, without disturbing the process parameters, has been developed. Integration of the CCD with MACOSTM high pressure sampling and reaction monitoring technologies permits smart automated decision-making for selective removal of non-conforming material. Further technologies have been introduced to increase the reproducibility of this function, including a custom 4-position valve and pressure swing mitigation.


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These developments have facilitated the collection of high frequency micro-lots of product with concomitant on-line analysis and discrete diversion of every micro-lot, if desired. This potential for integrated monitoring and diversion will allow for the immediate recognition of product not conforming to specification and, if desired, the quarantining of this material from the growing pool of product. All of the above technology can be operated in a hand-free fashion using MACOSTM software that has been written for these purposes. Finally, one exciting and very practical application of this micro-lot collection with individual lot analysis would be in the production of precious materials that are perishable due to some form of instability. This instability is actually a key attribute in compounds containing unstable isotopes whose half-lives are on the order an hour or less, which are used, for example, in medical imaging and in cancer treatment. For example, targeted radio-conjugate therapies, in which radio-nuclides such as α-particle emitters

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Bi and

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At are bound to effector molecules that

guide them to the treatment area to release a higher specific radiation dose while reducing the overall radioactive load on the patient, show promise treating a variety of cancers.23 Once produced such molecules have very little time to be purified, quality assessed, and formulated into the appropriate vehicle for immediate patient injection. The above technology would allow for the rapid synthesis of the final isotope-containing target, which microwave heating could accelerate if necessary. Each patient could receive a tailored amount of the labeled product, which is simultaneously quality-assessed, such that a good product micro-lot can immediately be processed, reconstituted in saline, and injected directly into the patient, which has both significant positive impact on patient safety and business practicality.


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Experimental Section Flow reactions were performed using the MACOSTM synthesis platform, with custom control software developed in-house. High pressure syringe pumps and syringes were acquired from Harvard Apparatus. High pressure valves were purchased from the Cheminert line from Vici Valco Inc. A customized valve rotor was designed by MACOSTM and produced by Vici Valco Inc. (Part No. C2-20R4-YUT) to perform the pressure swing mitigation. Stainless Steel tubing and fittings were purchased from Vici Valco Inc. and Swagelok. On-line analysis was performed using an Agilent 1200 Infintiy HPLC, with a Gerstel MultiPurpose Sampler (MPS) performing the liquid handling. For validation experiments, analyte solutions were made from Allyl Phenyl Ether purchased from Sigma Aldrich, product number A35208, CAS 1746-13-0, along with an internal standard.


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Supporting Information Available Supporting information including results of device validation tests referred to in this manuscript has been included.

AUTHOR INFORMATION Corresponding Author *[email protected] Author Contributions The manuscript was written through contributions of all authors. All authors have given approval to the final version of the manuscript. Funding Sources This work was supported by NSERC (Canada). ABBREVIATIONS CCR2, CC chemokine receptor 2; CCL2, CC chemokine ligand 2; CCR5, CC chemokine receptor 5; TLC, thin layer chromatography.


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Nalivela, K. S.; Tilley, M.; McGuire, M. A.; Organ, M. G. Chem. Eur. J. 2014, 20, 6603-6607; b) Yu, Z.; Lv, Y.; Yu, C. Org. Proc. Res. Dev. 2012, 16, 1669-1672; c) Chernyak, N.; Buchwald, S. L. J. Am. Chem. Soc. 2012, 134, 12466-12469; d) Li, B.; Widlicka, D.; Boucher, S.; Hayward, C.; Lucas, J.; Murray, J. C.; O’Neil, B. T.; Pfisterer, D.; Samp, L.; VanAlsten, J.; Xiang, Y.; Young, J. Org. Proc. Res. Dev. 2012, 16, 2031-2035; e) Malet-Sanz, L.; Madrzak, J.; Ley, S. V.; Baxendale, I. R. Org. Biomol. Chem. 2010, 8, 5324-5332; f) Malet-Sanz, L.; Madrzak, J.; Holvey, R. S.; Underwood, T. Tetrahedron Lett. 2009, 50, 7263-7267; g) Fortt, R.; Wootton, R. C. R.; de Mello, A. J. Org. Proc. Res. Dev. 2003, 7, 762-768; h) Wootton, R. C. R.; Fortt, R.; de Mello, A. J. Lab Chip 2002, 2, 5-7. 5

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Thornton, P. D.; Orestano, M.; Santini, C.; Organ, M. G.; Aube, J. Chem. Eur. J. 2011, 17, 95959598; b) Baxendale, I. R.; Ley, S. V.; Mansfield, A. C.; Smith, C. D. Angew. Chem. Int. Ed. 2009, 48, 4017; c) Smith, C. D.; Baxendale, I. R.; Tranmer, G. K.; Baumann, M.; Smith, S. C.;


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Lewthwaite, R. A.; Ley, S. V. Org. Biomol. Chem. 2007, 5, 1562; d) Fuchs, M.; Goessler, W.; Pilger, C.; Kappe, C. O. Adv. Synth. Catal. 2010, 352, 323; e) Tinder, R.; Farr, R.; Heid, R.; Zhao, R.; Rarig, R. S.; Storz, T. Org. Process Res. Dev. 2009, 13, 1401. 6

Somerville, K.; Tilley, M.; Li, Guanlong; Mallik, D.; Organ, M. Org. Proc. Res. Dev. 2014,

18, 1315-1320. 7

a) McQuade, T., Seeberger, P. J. Org. Chem. 2013, 78, 6384-6389; for an industry perspective

on implementation of continuous processing see also b) Poechlauer, P.; Manley, J.; Broxterman, R.; Gregertsen, B.; Ridemark, M.; Org Process Res. Dev. 2012, 16, 1586-1590. 8

The uneven distribution of material and energy remains one of the most difficult problems of

batch reaction modelling. a) Danckwerts, P. Chem. Engng Sci 1958, 8, 93-99. b) Villermaux, J. Falk, L. Chem. Engng Sci. 1994, 49, 5127-5140. 9

21 Code of Federal Regulations, Section 210.3(b).

10

Lee, S., O’Connor, T., Yang, X., Cruz, C., Chatterjee, S., Madurawe, R., Moore, C., Yu, L.,

Woodcock, J. J. Pharm. Innov. 2015, 10, 191-199. 11

21 Code of Federal Regulations, Section 211.165(a):“appropriate laboratory determination

of satisfactory conformance to final specifications for the drug product… prior to release.” 12

21 Code of Federal Regulations, Section 211.188:“batch product and control records shall be

prepared for each batch of drug product produced.” 13

Welch, C., Gong, X., Cuff, J., Dolman, S., Nyrop, J., Lin, F., Rogers, H. Org. Proc. Res.

Dev. 2009, 13, 1022-1025.


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14

Browne, D., Wright, S., Deadman, B., Dunnage, S., Baxendale, I., Turner, R., Ley, S. Rapid

Commun. Mass Spectrom. 2012, 26, 1999-2010. 15

Bristow, T., Ray, A., O’Kearney McMullan, A., Lim, L., Mcullough, B., Zammataro, A. J.

Am. Soc. Mass Spectrom. 2014, 25, 1794-1802. 16

Mascia, S., Heider, P., Zhang, H., Lakerveld, R. Benyahia, B., Barton, P., Braatz, R.,

Cooney, C., Evans, J., Jamison, T., Jensen, K., Myerson, A., Trout, B. Angew. Chem. Int. Ed. 2013, 52, 12359-12363. 17

Demming, W. E. Mechanical Engineering, 1944, 66, 173-177.

18

Sauks, M., Mallik, D., Lawryshyn, Y., Bender, T., Organ, M. Org. Proc. Res. Dev. 2014,

18, 1310-1314. 19

Average pressure fluctuation observed over multiple valve actuations was 4psi at 1000psi.

20

There is an optimum infusion volume for any process dependent on such factors as reagent

waste and system stability. A small infusion volume means that less reagent is held in the syringe at any one time, changing reagents in this case would in less waste. A larger syringe volume will waste more unused reagents but will switch the CFU valve less frequently resulting in fewer pressure spikes. 21

The first and second data points in each run were not included in calculations.

22

Collection cycle times depend upon several factors including process flow rate, analytical

method, and rate of reaction. Cycle time for the current experiments was approximately 3 minutes, including 30s to transfer the sample to the liquid handler, 60s to prime the HPLC


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injection syringe, and 90s to run the analytical method. If necessary, a quench may be introduced to the process line downstream of the reactor (between the reactor and HE2) to eliminate further chemical activity. 23

Elgqvist, J., Frost, S., Pouget, J-P, Albertsson, P. Front Oncol, 2014, 3, 1-9.


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Intelligent Continuous Collection Device for High ... - ACS Publications

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