58 Chimica Oggi - Chemistry Today - vol. 33(3) May/June 2015

KEYWORDS:Process intensification, flow chemistry, continuous processing, online monitoring, flow reactors

Abstract Whilst continuous processing is a mainstream technique in the petrochemical and food industries as a tool for accessing highly productive and low cost production processes, until recently the

pharmaceutical, fine chemical and specialty chemical industries were still dominated by batch processes and segmented unit operations. Through multi-disciplinary consortia activities in Europe this is changing, with users, technology providers and solution developers coming together in a pre-competitive arena with the common goal of accelerating the development and uptake of continuous process technologies. We discuss herein the challenges at hand, the lessons learned and the developments that remain to be addressed following two successful public-private partnership projects (Action Plan Process Intensification & Institute for Sustainable Process Technology) in the Netherlands and Belgium called CoRIAC and Flow4API.

One solution fits all? A need for the benchmarking of continuous process technologies

INTRODUCTION

In the decade that followed the turn of the Century we saw a prolific uptake of continuous flow technology within academic and research environments, with focus on identifying the opportunities associated with this way of working in the higher added value chemical industry (1). At the start of the current decade, a significant shift in focus has been observed as industrialists from the fine and speciality chemicals industries looked to what this innovative technology could bring them in terms of securing competitiveness, increasing manufacturing sustainability (2,3), safety improvements (4) and cost reductions (5,6). Compared to the commodities industry, industrialists from these sectors predominately worked with traditional batch processing. One thought is that this could be due to the imbalance in the ratio between chemical engineers and chemists. In addition, it was viewed that the high costs associated with continuous processing could only be recovered in large scale production. However, scientific and technological breakthroughs have shifted the balance and have enabled technology transfer from commodities to specialties, from chemical engineers to chemists and from research to industry. In order to further facilitate this technology transfer, many public-private funded initiatives were started, such as Impulse (7) and the F3 Factory (8,9), whereby research institutes, technology developers and industrialists from a broad range of chemical sectors looked towards industrial production challenges and applications. Activities are further bolstered by industry driven

associations such as EFFRA (European Factories of the Future Research Association) (10) and Britest (Best Route Innovative Technology Evaluation and Selection Techniques) (11) which continue to promote the development of new and innovative production technologies. Herein we discuss the lessons learned within two public-private consortia that operated within the framework of the European Roadmap for Process Intensification (12) to address some of the challenges that were discussed in stakeholder consultations like the IPIT symposium (13). These projects are CoRIAC (Demonstration of a Continuous Reactor with In-line Analytics for Fine Chemical Production) and Flow4API (Flow Chemistry for Active Pharmaceutical Ingredients).

At the outset of the CoRIAC project, end user consortia members were selected to have a cross-sectorial make-up in order to facilitate transfer of technologies, ways-of-working and ideas. The goal was benchmarking of technologies to identify how flexible particular solutions could be. With this in mind, Janssen Pharmaceutica, DSM and Procter and Gamble provided access to the challenges encountered by pharmaceutical, life science, material science and consumer goods focused industries. Technology providers (3M (ESK), Mettler Toledo, Bronkhorst, Chemtrix and Zeton) partnered with Academic Institutes (Technical University of Eindhoven and Technical University of Delft) and Applied R&D (TNO) to perform theoretical modelling, proof of concept trials and demonstrator system production. The project was conducted over a period of 4 years and CoRIAC concluded in December 2014.

FLOW CHEMISTRY

CHARLOTTE WILES1, MARTIJN DE GRAAFF2 1. Chemtrix BV, Urmonderbaan 22, 6167 RD, Geleen, The Netherlands

2. TNO Sustainable Chemical Industry, Leeghwaterstraat 46, 2628 CA, Delft, The Netherlands

Martijn De GraaffCharlotte Wiles

Industry perspective

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FLEXIBLE OR DEDICATED? IT DEPENDS…

Following on from the reaction screening, three processes were selected for scale-up in the demonstrator pilot equipment. - Case 1: Chemical conversion of solids in an ATEX

environment – requiring Hastelloy MOC (Figure 2)- Case 2: Multiphase exothermic chemical conversions –

utilising SS MOC (Figure 3)- Case 3: Exothermic neutralisation with future heat

recovery potential (Figure 4)

In comparison, Flow4API was a small consortium comprising of three Dutch partners; Synthon, TNO and Chemtrix – with a more focused goal of assessing and overcoming the challenges associated with continuous operation of telescoped reactions that are frequently encountered within the pharmaceutical industry. This project ran for 2 years and also concluded in December 2014.

HOW TO START? MAKE THE RIGHT TECHNOLOGY CHOICES…

In order to gain benefit from a varied consortium, both CoRIAC and Flow4API started by benchmarking available technologies and assessing suitability towards a series of chemical cases. This is an approach that was described already at the start of CoRIAC (14) and which was also seen in other initiatives like F3 Factory (8). This enabled usage scenarios to be determined and any gaps in technology provision to be identified. When looking to the varied end user requirements in terms of production type (GMP, non-GMP, ATEX), production volume (kg/annum to kT/annum), reaction type (single/multi-step, organic/aqueous, liquid/liquid, solid/liquid, gas/liquid/solid, viscous/non-viscous, room temperature to exothermic systems) – a matrix of available technologies was drawn up and a series of theoretical and practical evaluations performed.

The reactor technologies assessed included glass and metal micro reactors, silicon carbide flow reactors, steel Helix reactors and Oscillatory Baffled Reactors (Figure 1). From this exercise we were, as a group, able to sort the reaction cases into those that:- Required continuous mixing;- Exhibited a high exotherm;- Had challenging changes in physical property – such as

shear thinning, solid-liquid, solid-liquid-gas and particle generating systems

Subsequently we determined whether a process would benefit and in what way from execution in the reactor portfolio available.

Figure 1. Examples of the reactor technologies assessed within CoRIAC and Flow4API (top left) silicon carbide flow reactors, (top right) steel tube reactors, (bottom left) oscillatory baffle reactor and (bottom right) glass micro reactor.

Figure 2. Illustration of the multipurpose Slurry Handling Unit (SHU) skid for the chemical conversion of suspensions.

Figure 3. Illustration of the Oscillating Flow Reactor (OFR) skid for multiphase exothermic chemical conversions.

Figure 4. Photograph of a custom multi-injection SiC flow reactor (MR8X260) for execution of highly exothermic flow reactions – within CoRIAC this was used for the neutralisation of concentrated acid streams.

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reactor, the consortia was able to demonstrate, at the bench-scale, productivities of 1 kg/h and subsequent scaling into a pilot unit. The reaction time was reduced to 30 min for 50 % conversion which exhibited a ten-fold reduction compared to batch and was later improved to >90 % in the pilot installation using reaction times of 1.5 h (Figure 2).

For Case 2, an emulsion polymerisation, process challenges included low productivity in batch due to poor exotherm management and sensitivity of the micelles to shear which resulted in aggregation, giving rise to an undesirable particle size distribution and sedimentation in the reactor. As it was desirable to operate at higher concentrations whilst maintaining process control, the emulsion polymerisation was trialled in a series of reactor types in the lab and scaled in a pilot reactor to afford throughputs in the range of 10 l/h (Figure 3). At this scale the reaction conditions were further tuned to assess the effect of flow rate, temperature, pressure and monomer dosing strategy – allowing a factor 100 increase in productivity to be achieved for an equivalent product quality.

In Case 3, a challenging neutralisation reaction was trialled whereby a high degree of thermal control was required in order to prevent degradation of the high value material contained within the acidic media. With the aim to harvest energy from the neutralisation, it was desirable to perform the neutralisation at an elevated temperature (200°C) whilst maintaining thermal control. Owing to the high corrosivity of the reaction mixture/reagent feeds and high exothermicity of the reaction, a multi-injection silicon carbide reactor was developed within the project by 3M (ESK) (Figure 4). Using this approach it was shown that it was possible to employ elevated reactor temperatures and reaction times in the range of seconds. Going forwards this reactors broad chemical compatibility has applicability towards the development of continuous strategies for many other exothermic processes.

ALL TOO EASY? ADDITIONAL CHALLENGES

Based on the early successes within CoRIAC, an additional project was started in 2012 called Flow4API which focused on addressing the challenges faced by the pharmaceutical industry in terms of process development and manufacturing strategies for multi-step syntheses in high value, low volume processes. Learning from CoRIAC, a similar approach of benchmarking was taken, with 16 reactions listed by the industrial partner Synthon based on their interest for up-scaling. From this long list, a short list was created and trails performed within glass micro reactors to assess the potential for process improvement compared to the existing batch protocols. On the basis of these trials, two processes were selected for up-scaling demonstration owing to the results obtained and the respective business cases. Unlike many reports in the literature, these transformations involved telescoping of reaction steps which were identified at the micro reactor level as requiring different thermal conditions for optimal material production. Using the set-up illustrated in Figure 5, a scale-up of x330 was demonstrated for the reaction depicted in Scheme 2, with an API intermediate yield of 99.4% obtained. Utilising process monitoring with a FlowIR (also illustrated in Figure 6) between the reaction steps enabled confirmation of optimal processing conditions for material production were maintained. Unlike the analogous

It was noted that at the lab-scale, significant flexibility is required in terms of chemical compatibility, flow rates, reaction times and temperatures, owing to the wide range of conditions and cases to be assessed. At a larger scale, it appears that such flexibility in the equipment is not affordable and also not needed. Within CoRIAC it was observed that a more dedicated set-up that ran under fixed conditions for a specified period of time was more desirable. A certain degree of flexibility was however maintained in order to ensure that that equipment is future proofed towards more than one process of a similar type. Consequently, continuous pilot equipment is often modular in nature enabling reactors to be changed with ease and additional dosing modules/feeds to be employed for example. With respect to process analytical tools (PAT), for process development an ‘all seeing eye’ is often requested, whilst for production process monitoring a more simplified marker of ‘has anything changed’ and ‘is the product quality acceptable’ is the approach of choice.

CONSTRUCTION OF DEMONSTRATORS, IT’S ALL ABOUT PERIPHERALS…

With the user cases selected and reactor technologies identified, the second phase of the CoRIAC project focused on the development of the necessary peripherals including; fluid handling, process monitoring, process controls and safety features. In all cases emphasis was put on ensuring correct reagent dosing through the selection of appropriate pump technologies and the use of flow meters and mass flow controllers. It should not be underestimated how important stable, precise, accurate flow is to a continuous production system. In the case of an exothermic neutralisation (Case 3), eight injection points were employed in a SiC flow reactor in order to maintain the desired product quality. As such, the demands for flow control and thus complexity of the system were increased 8-fold (Figure 4). In Case 1 which employed suspensions, a special feed handling system was developed to enable stable dosing of a solid substrate into a Helix reactor (Figure 3). Given the dramatically different requirements for the production equipment in terms of process materials and production rates, two multi-purpose demonstrator skids were developed, each for a specific class of reactions.

PROOF THROUGH DEMONSTRATORS

In Case 1, Janssen Pharmaceutica were interested in scaling a debromination reaction (Scheme 1) which was challenging as it employed a solid starting material and catalyst to generate a product which was also sparingly soluble in the reaction solvent. Exhibiting strong mass transfer limitations, a typical batch reaction took 17 h and CO2 evolution led to foaming of the reaction mixture. Employing a continuous Helix

Scheme 1. Illustration of the debromination reaction scaled in the multipurpose pilot reactor for the chemical conversion of suspensions.

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it is imperative that equipment developers take the time to characterise their technologies both in operational window and degree of flexibility, enabling potential users to select the most appropriate technology for their cases. Consequently as the title eludes, no one solution fits all! Through such initiatives and the sharing of pre-competitive information, it becomes clear where the benefits of one technology starts and another ends – theoretical modelling and practical evaluation/case studies with real industrial cases that can (at least partly) be shared in the public domain are therefore essential to the uptake of continuous manufacturing.

Partnering is also key - innovation is a multi-disciplinary activity and it is essential to draw together mixed teams of chemists, chemical engineers, engineers and regulators in order to effectively facilitate change and harness the full potential that innovation has to offer. Partnering also helps with viewing the whole process, not just your part. This is particularly important as what can be perceived as trivial or incremental change to a reaction step can have significant impact on the requirements, costs and efficiencies associated with both up and down stream transformations. Change therefore must consider the whole process otherwise there is a danger of simply moving the process bottleneck to a later step or even not realising the full potential that a change has to offer. Whilst technologies for downstream unit operations are being researched proactively, a need still exists for the development of scaled down systems to facilitate their evaluation at the lab-scale.

With that said, a significant challenge faced for this emerging technology is the quantity of ‘metal on the ground’ or existing batch capacity which can reduce the speed with which technological change is taken up – however the adoption of continuous manufacturing is entering an interesting time as it matures and we see Companies across the globe (and across

batch reaction, a significant reduction in anhydride precursor was possible in flow resulting in the elimination of a quench step, and simplification of downstream purification of the target compound.

WANT SUCCESS? TAKE YOUR TIME WHEN NEEDED…

One overwhelming observation made during both of these projects was the need to strike a balance between planning and execution of experimentation. At the lab-scale it can often be beneficial to perform several scouting experiments with which you develop more focused experimental strategies. When considering use of the technology at the pilot-scale and beyond, ensuring significant time is taken to understand the requirements for start-up and shutdown protocols in particular was found to be imperative.

Testament to the strides made within the projects and the successes for the partners is the afterlife plan that has been developed whereby retention of the skids by the end users is confirmed across the board, enabling further exploration at the Partner sites; Janssen Pharmaceutica, DSM, TNO, Synthon and Chemtrix.

PERSPECTIVE AND OUTLOOK

Whilst diverse in their nature, this and other consortium-led projects have served to demonstrate that modularity and flexibility are required when developing continuous manufacturing strategies as often equipment is intended for multiple uses. However, the degree of flexibility or modularity depends on the phase of the development as was exemplified in the projects described herein. With this in mind,

Figure 5. Illustration of the set-up used to scale-up the telescope reaction shown in Scheme 1.

Scheme 2. Schematic of a telescope reaction developed using Labtrix and scaled into KiloFlow – whereby two temperature zones were employed with no intermediate isolation required.

Figure 6. Illustration of a Plantrix MR260 silicon carbide reactor with inline process monitoring using a FlowIR – for exothermic, corrosive processes.

projects. Next to its technical role, TNO is thanked for its project coordination and ISPT for the financial and administrative support.

REFERENCES

1. Ley S. V., Fitzpatrick D. E., Ingham R. J., et al., Angew. Chem. Int. Ed., DOI: 10.1002/anie.201410744 in press.

2. Watson W., Chimica Oggi, 32(4), 14-15, 2014. 3. Domier R. C., Hartman R. L., Chimica Oggi, 32(4), 36-41, 2014.4. Brocklehurst C. E., La Vecchia L., Lehmann H., Chimica Oggi,

32(4), 30-32, 2014. 5. Poechlauer P., Braune S., Dielemens B., et al., Chimica Oggi,

30(4), 51-54, 2012. 6. Calabrese G. S., Pissavini S., AIChE J., 57(4), 828-834, 2011. 7. http://cordis.europa.eu/publication/rcn/10831_en.html 8. Bieringer T., Buchholz S., Kockmann N., Chem. Eng. Technol., 36(6),

900-910, 2013.9. www.f3factory.com10. www.effra.eu11. www.britest.co.uk12. http://www.efce.info/EUROPIN.html13. Duisterwinkel A., Bassett J.-M., Chimica Oggi, 29, 4, 2011.14. Lexmond A., Chimica Oggi, 28, 46-48, 2010.

chemical sectors) taking up the technology in earnest as they find new opportunities to manufacture previously problematic materials – with scales ranging from low kg’s to 1000’s tonnes/annum and strategies such as distributed manufacturing being adopted.

If you take home one message from these projects let it be, look not only to the solutions available within your given industry but also carefully to those available within other manufacturing sectors. There are many existing technologies in areas such as process control that are already implemented widely within industries such as electronics, automotive, petrochemical and food processing which have potential for application in the wider chemical industry. Again, interdisciplinary partnering will remain key to problem solving – consider not just the reaction, consider the process!

ACKNOWLEDGEMENTS

The twelve project partners and their representatives, from the CoRIAC and Flow4API consortia, are acknowledged for their support and contribution both within and outside of the

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63Chimica Oggi - Chemistry Today - vol. 33(3) May/June 2015