Practical Assessment Methodology for Converting Fine Chemicals

Article pubs.acs.org/OPRD

Practical Assessment Methodology for Converting Fine Chemicals Processes from Batch to Continuous Soo Khean Teoh,*,† Chetankumar Rathi,‡ and Paul Sharratt† †

Institute of Chemical and Engineering Sciences (ICES), A*STAR, 1, Pesek Road, Jurong Island, Singapore 627833 GEA Pharma Systems (India) Private Limited, Block No. 8, Phase B, Village Dumad, Savli Road, Vadodara, 391740 Gujarat India

‡

ABSTRACT: A practical methodology is proposed to assess the feasibility of converting a batch process into a continuous one. Simple guidelines are illustrated to facilitate decision making at different stages of the evaluation, in particular the swift first decision either to proceed with or kill the idea at the early evaluation stage to avoid wasted effort. The ordered approach also provides a whole process assessment and decision making for the appropriate choice of continuous or hybrid processing mode. Three multistep processes that have been operated at kilogram scale are presented to demonstrate the application of this methodology.

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INTRODUCTION Fine and specialty chemicals industries are looking into new ways/technologies for step-change improvements in process performance to sustain their businesses in the face of global competition, tighter safety and environmental regulations, as well as growing demands in product quality and cost efficiency. Batch and fed-batch (semibatch) processing are widely used in manufacturing because of their flexibility1 and easy reconfigurability for multiple different sequential operations. In the pharmaceutical sector, due in part to tight regulatory control on the product and process after it is licensed, the industry tends to stick to the batch mode with reluctance to change.2 The batch manufacturing chain consisting of multiple consecutive processes is normally contracted or segmented and carried out in different facilities. This raises the issue of quality guarantee and management of the process. Complex scheduling and sequencing of operations3 may result in inefficient utilisation of equipment. In addition, the equipment used in batch processes is itself often inefficient; for example, stirred tank reactors suffer from mixing and heat transfer limitations. Continuous processing has been claimed to enable a promising new business model that could radically improve quality control, decrease scale-up issues and cycle time, allow for faster release of new products, increase energy efficiency, reduce waste and process inventories, develop a safer process and provide better process control.4−8 Studies have shown that perhaps 30−50%1,9 of the current batch processes can be operated in continuous mode and offer worthwhile benefits over the batch mode. The technology has matured as a tool that is now routinely used by many chemical synthesis laboratories and increasingly in process development and scale-up.10 Regulators have also been encouraging the use of this technology to improve manufacturing efficiencies.11 While isolated examples8 have been visible for a long time, overall the implementation has been slow.12 The industry is cautious in adopting this technology unless they can see clear techno-economic benefits.13 The starting point for the process design in this low tonnage sector (pharmaceutical and speciality chemicals) is the presumption of a batch process. Development laboratories and protocols © XXXX American Chemical Society

are usually predicated on this. A company may wish to explore a continuous process as an option to improve efficiency for their existing batch process. However, not all the batch processes are viable for continuous processing in the aspect of technical feasibility and business benefits. A methodology to evaluate such processes is important to the industry, especially in making a high level swift early decision to gauge if it is worthwhile to invest significant effort to investigate the idea. Process design/synthesis methods can be broadly classified into heuristic/rule-based, optimisation-based, or combinations of these as hybrid methods. In heuristic-based methods, the approach is typically a hierarchical decision making procedure based on engineering knowledge and physical principles in developing process flow sheets. Examples are the unit operationbased methods devised by Douglas14 or Smith and Linnhoff.15 These methods rely on the existence of equipment or welldefined operations, and it is impossible to manage the interactions between different design levels.16,17 Douglas’ hierarchical design procedure decides batch or continuous operation mode up-front and continuous process is considered as a means to develop the equivalent batch process.18,19 The conventional rule-of-thumb for designing processes suggests batch processes at low production rates and continuous processes at high production rates. High pressures and safety and toxicity concerns also favor continuous processing. Optimisation approaches attempt to generate all conceivable unit operations and connected in all possible ways into a superstructure where a large mathematical model is used to search for optimum equipment and conditions under certain constraint criteria.20−22 Other approaches integrate both the heuristic and optimisation-based methods.23−25 However, these methods are complex and need a huge computational effort16 and the feasibility of practical implementation is a question. Traditional chemical engineering tools commonly applied to continuous bulk processes are not widely used in designing Special Issue: Continuous Processing, Microreactors and Flow Chemistry Received: January 2, 2015

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DOI: 10.1021/acs.oprd.5b00001 Org. Process Res. Dev. XXXX, XXX, XXX−XXX

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a continuous fine chemicals process from its batch equivalent for a number of reasons: chemistries and molecules involved are complex, solids are present, and physicochemical data of the complex molecules are often not available for standard modelling tools. There are ongoing attempts to rectify that with increasing capabilities being developed in more complex operations like crystallization26 and formulation.27,28 Direct adaptation of processes to conventional unit operations is not appropriate because the inherent inefficiencies of the associated equipment might not deliver the process requirements. A number of design concepts were developed to facilitate innovative process design. For example, equipment-independent approaches,29 methodological tools to capture process knowledge (rate processes and phase behaviour) in an equipment-independent way,30 define process task/functions to enable integration of unit operations,31 task integration using conventional unit operation concepts32 or considered process requirements prior to task integration,33 describing processes in terms of fundamental phenomena/process functions to allow manipulating individual component flows or rate-limiting phenomena,34,17,35−37 and various associated modelling approaches.36,38,39 Concepts such as process intensification (PI)40,41 and multiscale design17,42 require understanding of process phenomena and their inter-relationships. Process (equipment) is designed to perform at the appropriate length scale and time scale according to ideal requirements at a close-to-molecular level without the spatial constraints of conventional unit operation models and associated equipment.43 Novel technology44 and tools should be considered at the early stages of design in order to achieve a paradigm shift.42 However, new technological tools are useful only if they can be used beneficially in a whole process. It is believed that the technological advances from PI and multiscale design can be used to deliver continuous processing in low tonnage sectors. Recently, Cervera-Padrell et al. proposed a systematic design framework that exploits the synergic combination of continuous flow technologies (esp. microfluidic techniques) and process systems engineering (PSE) methods and tools.45 Similar to other methodologies, it is comprehensive and thus might not be practical when a swift decision is required especially at the early stage of assessment. There is no high level evaluation which could give a simple guideline on the techno-economic benefits and feasibility of converting a batch to continuous process for stakeholders to quickly decide whether it is worthwhile going into detailed analysis. Drawn on our experience in assessing the conversion of a number of batch processes to continuous processes and all the way to feasibility demonstration at pilot scale, we have developed a practical methodology that enables a process development team to evaluate their existing batch process holistically. The aim was not to develop an “optimal” process from the first-principles, but rather to identify efficiently a suitable process that meets the business need. This is a realistic position for many in the fine chemicals and pharmaceuticals industry, where the opportunity to obtain step change improvements in an existing process might be considered to address cost or regulatory concerns. Our work is complementary to other methodologies, especially where a swift first decision is required to either proceed with or kill the idea at the very early stage of the assessment for an existing batch process. The proposed methodology is illustrated along with three processes that have been investigated at kilogram scale in our institute.

In what follows we consider our methodology practicable, as it has been applied to three reactions with reasonably complex molecules that have been physically operated in our laboratories at both small laboratory scale (batch-wise) and continuously at fume hood or pilot scale. The reactions are synthesis of β-hydroxyester via the Reformatsky route (Figure 1a),46 synthesis of 4,D-erythronolactone (Figure 1b),47 and phase transfer catalysis of O-alkylation of 3-phenyl-1-propanol (Figure 1c).48

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METHODOLOGY The conventional typical manufacturing process in batch mode is to react the raw materials, followed by workup (e.g., evaporation, solvent swap, filtration, etc.), often in the reactor vessel, and purification (e.g., crystallization) to afford specified products (Figure 2). In our methodology, we assume the same broad processing order, though it may turn out that significant changes in the workup and isolation are needed. It is also assumed that the reaction chemistry is fixed but there is sufficient flexibility to allow ancillary reagents to be changed (e.g., selection and change of solvent49). This is a realistic assumption for traditional batch sectors, where it is often impracticable to alter the reaction chemistry within the time frame available for process development or modification.50 The proposed methodology (Figure 3) consists of three stages: initial screening, extended evaluation, and process execution. If desired, the initial screening can be skipped, depending on the available information and the level of commitment to explore continuous options. Stage 1: Initial Screening. First and foremost, it is important to capture the definition of a project purpose, i.e. new capacity, cost reduction, or product quality, etc. The process requirements need to be understood, including the required production capacity, any quality constraints, and a broad idea of where the costs of operating the current process lie, as well as the business drivers for change. The first step in assessing an existing batch process is to evaluate its characteristics using the available batch development data, literature information, simple predictions, or experimental data. The initial assessment of the physicochemical characteristics and behaviour of a process allows a rough gauge of whether continuous operation potentially brings benefit. In parallel, the potential stopper(s) for continuous mode should be identified as well as process issues which are different for the continuous process. This will enable a swift and justified decision (based on potential techno-economic benefits) in either proceeding with or killing the idea. Given existing batch process understanding and/or development information, the initial evaluation should arrive at a decision without substantial effort. Otherwise, the initial evaluation would require more effort to generate the required information. A typical batch process development activity includes verification or screening tests in the laboratory based on an established procedure/recipe, hazard assessment, identification of critical process parameters, identification of potential issues for scale-up, kinetics (at least at a basic level) and thermal measurements, analytical development (including PAT), and predictions of process behaviours in up-scale. Reactions are usefully classified in terms of kinetics and mass and heat transfer demands.9 Besides these inherent reaction characteristics, potential side reaction formation, safety, phase complexity, and behaviour and workup requirements, should also be considered to have a holistic view of the whole process scenario. The basic physical behaviour51 of the materials, which includes boiling and melting points, and where relevant heat B



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Figure 1. Example reactions used to illustrate our methodology.

has a number of characteristics and behaviours that are likely to give benefits if operated continuously. The associated reactions are fast, highly exothermic, prone to run-away as a result of accumulation of unreacted material if oxide coats the zinc, use hazardous chemicals, and have a number of side reactions. In the synthesis of 4,D-erythronolactone (Process 2), there are fast reaction steps and a potential runaway, which indicate the potential advantages of continuous processing. In many cases, continuous operations are inherently more efficient that the batch equivalent−for example the small size of continuous reactors makes higher mixing rates possible;52 counter-current operations use driving forces more efficiently and can reduce solvent or energy use; the mass transfer intensity of a mechanically agitated liquid−liquid contactor is typically higher than a baffled agitated tank53 leading to lower consumption of solvent. This will be beneficial for multiphase reaction (e.g., Process 3) or workups which require extractions (e.g., Processes 2 and 3). On the other hand, systems which consist of significant free solids (e.g., Processes 1, 2) in general are not favorable for continuous processing if the solids could cause potential blockages. The presence of sticky solid which is not readily transferrable in Process 2 would pose a concern for continuous operation. High residence time for continuous processing (beyond a few hours) can only be achieved with a series of

Figure 2. Conventional batch processing methods in a primary manufacturing process.

sensitivity, relative solubility, phase behaviour, and other characteristics such as settling behaviour, stickiness, etc., should be available to assess the workup requirements/issues and possibility of continuous operation. Table 1 lists the characteristics and an assessment of those characteristics for the 3 test processes. Some operations bear characteristics that cannot be run efficiently batch-wise: for example, fast or complex reactions that require more effective mixing and/or mass transfer than what can be achieved in jacketed stirred vessels; thermally hazardous reactions where minimization of reaction volume is required for safety; some crystallization operations that require the control of particle size within tight limits. In general, reactions which are intrinsically fast, highly exothermic/ endothermic, hazardous (requiring containment), dirty (require tight control of by or side product), mainly in liquid phase, or strongly dependent on mixing are favorable for continuous processing. For instance, a Reformatsky reaction (Process 1) C



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Figure 3. Methodology of converting pharmaceutical/specialty chemical processes from batch to continuous or hybrid.

It is also important to assess what will not or might not work well with continuous processing. This includes process requirements or issues like long reaction or residence time for multiphase systems, presence of high loading of solids, sticky materials, or any complex processing issues that require specialized equipment. We can then map the process characteristics/requirements/issues to the techno-economic drivers associated with the ways to achieve them to elucidate the potential benefits and also map the same to the barriers to identify the potential hindrances (Tables 3, 4 and 5). We recommend a simple qualitative rating of 3 levels with wordings, i.e. “major”, “likely/maybe”, “no” for the potential technoeconomic benefits and “yes”, “maybe”, “no” for the barriers to continuous processing. The final go/no go criterion to pursue further evaluation depend on the situation and risk appetite of the operator, but they could sensibly be based on seeing a potentially major benefit in at least one category of the business drivers and no obvious barrier to continuous processing. Ultimately, the stakeholders should assess their individual situation to define their own rating and final decision criterion. As an illustration, operating Process 1 continuously would give a potential major benefit in safety enabled by a smaller in-process inventory (Table 3). There are also other potential benefits in terms of cleaner product, better product quality, reduced waste generation, and savings in CAPEX (capital expenditures) and OPEX (operational expenditures) if operated in a small set up in a fume hood. The time to market can be shortened if a standard, commercially available, and flexible setup (e.g., glassware, flexible tubing, easily run pipework, etc.) is

continuous stirred tanks, and may be uneconomical. Batch equipment becomes relatively more cost-effective for long duration process steps. Nevertheless, some long residence time examples for continuous processing are known.54 At this initial assessment stage, it is difficult to put down some absolute quantitative measurements to compare the benefits between batch and continuous processing. However, a quick qualitative guide on the potential benefits and hindrances of converting a batch process to continuous is very useful for swift decision making. The impact on broad cost profile and business drivers can be used to support the high level decision as in whether it is worthwhile to proceed further or kill the idea. Table 2 shows typical business drivers for continuous processing,7 which might include safety or license to operate, cost, quality, efficiency, environmental impact, and time to market. They can each be addressed in a number of ways, and often the same approach can deliver other business benefits simultaneously. Take safety as an example; a process can be made safer by reducing the in-process inventory and/or with good control of mixing and heat management. With good mixing and heat management, side reactions, if any, might be circumvented, leading to a cleaner process and possibly reducing the need for separations. To have a better idea on time to market, some basic information on commercially proven equipment/technology, their availability, and lead time is useful for decision making. Information of some established flow equipment (e.g., static mixer, oscillatory baffled reactor, agitated liquid−liquid extractor, centrifugal contactor, wiped film evaporator, etc.) is helpful in assessing other business drivers like cost and efficiency. D


E

Significant, i.e. a number of competing side reactions (contact between starting material and product) -High risk of runaway due to unpredictable zinc activation (delayed initiation) in reagent formation stage. -Highly flammable chemicals (starting material, substrates, solvents). Reactive compound (DIBAH) which may ignite in air/ water. Two phase mixture, i.e. excess Zn solids to provide enough specific surface area in reagent formation step. Zn solids settled readily.

No

Side reaction(s)

Viscous/sticky material Workup

Phase complexity

Hazards

Crude product mixture was obtained after the quench step. No further purification was explored.

Significant at reagent formation, coupling and quench steps from risk assessment. Typically manufacture in small batches with high solvent content as heat sink Not really

Heat generation

Mass transfer limited

Reagent formationFast but slowed down by addition rate control due to high exothermicity. Very long cycle time batch-wise. Reformatsky coupling reactionFast QuenchFast

3

Inefficient batch-wise due to multiple extractions in removing the catalyst from crude product mixture

No

Organic and aqueous phases with some solids formation (3% v/v). NaBr solids tend to settle.

Solid precipitate at high concentration during dissolution Gas formation at a number of steps Organic and aqueous phases at cyclisation step Precipitation of a sticky intermediate product obtained during concentration if pH is incorrect at cyclisation step. -Product and byproduct has similar high miscibility with water. Unwieldy separation due to multiple solvent extractions to obtain final products in solid form. -Crude product and byproduct mixture tend to form sticky solids, which are not readily transferrable. -Product starts to polymerise when exposed to heat.

Allyl bromide is highly flammable and poses potential health threat

Insignificant

Interfacial mass transfer limited and strong dependency on mixing

Moderate (≈104 kJ/mol)

Slow (≈3 h)

Phase transfer catalysed O-alkylation of 3-phenyl-1-propanol48

Potential oxidation reaction runaway if addition control fails

Salt formation & Cyclisation reaction rates are controlled by mixing No

Dissolution of reagentsSlow (hrs)

OxidationModerately fast (≈1 h) Excess H2O2 removalModerately fast (≈1 h) CyclisationInstantaneous (secs) Significant exotherm at oxidation step (≈760 kJ/mol). Controlled dosing of H2O2 batch-wise.

Salt formationInstantaneous (secs)

Synthesis of 4,D-erythronolactone47

Reformatsky46

Reaction rate

Characteristics

2

Process 1

Table 1. Initial Evaluation of the Characteristics of Batch Chemical Systems

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Table 2. High Level Business Drivers and How They Might Be Addressed Business driver How business driver might be addressed? Reduced process inventory Operation with no vapour space Good control of mixing, heat transfer, temperature and timing Reduced equipment size Increased reaction selectivity and yield Reduced downstream processing Increased separation efficiency Reduced wastes and emissions Effective use of raw materials Effective use of utilities, e.g. load smoothing and averaging Energy integration and reuse Speed of development and implementation Speed of building/assembling a plant Commercially proven technology Flexible & reconfigurable plant

Safety (license to operate)

Cost Quality

X X X

X X X X X X X X X

X X

Efficiency

Environmental impact

X

X X

X X X X X X X

Time to market

X X X X X X X X X X X

used for small tonnage production. However, the first step of the process, i.e. reagent formation, requires excess Zn solids to provide enough specific surface area for activation. The Zn solids readily settle, and this will pose a big challenge to continuous processing. Nevertheless, the potential benefit in safety is significant enough to make a strong case to carry on with further evaluation and find potential solutions to the barriers. For Process 2, there could be major benefits in safety if there is a suitable continuous reactor to operate the oxidation reaction (Table 5). There are some potential local economic benefits in terms of reducing the equipment size for the two instantaneous reaction steps and also the OPEX. The unwieldy batch isolation process suggests that efficient continuous processing might provide potential benefits in separation efficiency, product quality, operating cost, reduced emissions, and equipment footprint. However, the continuous separation equipment must be able to handle the sticky solids. The overall potential benefits are less apparent than Process 1, and the barrier to continuous processing is obvious for workup. As such, it makes a case to evaluate further the front end of the process but not the workup. For Process 3, the ability to run the long reaction in a continuous equipment that can provide higher mixing efficiency could reduce the equipment footprint and in-process inventory benefiting safety (Table 5). Continuous extraction, which increases the driving force, may intensify the separation steps to give potential benefits in separation efficiency, product quality, operating cost, reduced emissions, and equipment footprint. However, there may be some problems with solids accumulation over time for continuous processing. Although the overall potential benefits are less apparent than Process 1, it makes a marginal case to study further. Stage 2: Extended Evaluation. If the decision from Stage 1 is positive, the evaluation is extended to determine in detail the technical feasibility and economics of the continuous operation based on a whole process view. It is essential to consider the whole process to be clear on the overall economic benefit. The work at this stage will include identification and resolution of the key processing issues for continuous operation, selection of suitable equipment, development of plausible

process schemes, and demonstration of chosen parts of the process at a credible scale to reduce technical risk. Where feasible and cost-effective, modelling is also used both to enhance understanding and allow exploration of system-level trade-offs and synergies. Economic analysis can be carried out to compare between the batch and the sections converted to continuous process(s) at the required manufacturing scale. Such a techno-economic evaluation would provide justifications for further business decisions. This stage involves more detailed thinking and work, which generally takes a longer duration than Stage 1. The methodologies already reported in the literature mainly focus on this level of evaluation. Step-wise Evaluation. The batch process should be evaluated step by step based on the processing functions. A team effort is required to analyze every single reaction and processing task for the whole process to establish coherent understanding.6 Sufficient process understanding is important not only for the design of efficient processes, but also as a means to demonstrate that the risk of producing off-specification product is minimal. Knowledge capture tools, e.g. BRITEST’s Process Definition Diagram (PDD),29 could be used to abstract and document the key features of the process (examples for Processes 1, 2, and 3 are shown in Figure 4). A PDD is an equipment-independent representation which is also independent of the processing modes (batch or continuous) and is used to represent key features of each processing step, especially the contacting and phase behaviour. Issue Resolution with Possible Equipment Identification. The key issues which are different for the continuous process should be identified and resolved.55 Process issues which can vary include changes in phase behaviour (phase ratio, which is continuous or dispersed phase, phase separation rates, etc.), contacting pattern of the phases, temperature control/heat transfer intensity, mass transfer intensity, or residence time. The step by step approach (PDD or equivalent) helps to elucidate the critical issues identified from Stage 1. Any additional concerns might surface during this stepwise evaluation. The issue(s) will define the critical process requirements at or between the relevant step(s). Based on the process requirements from one processing step to another, possible approaches that address the relevant concern can be developed. The spontaneous F


G


Phase complexity

Hazards

Crude product mixture was obtained after the quench step. No further purification was explored.

-Highly flammable chemicals (starting material, substrates, solvents). Reactive compound (DIBAH) which may ignite in air/water. Two phase mixture, i.e. excess Zn solids to provide enough specific surface area in reagent formation step. Zn solids settled readily. No

Major The in-process inventory in continuous process is much lower than batch.

Likely Fast mixing and short contact time in continuous processing potentially alleviate formation of side products, leading to cleaner product, reduced downstream processing and cost, increased efficiency, and reduced waste generation.

No

Yes

No

No

No

No

Time to market Maybe If standard, commercially available and flexible setup is used for small tonnage production, the development and implementation time can be shortened.

Significant, i.e. a number of competing side reactions (contact between starting material and product) -High risk of runaway due to unpredictable zinc activation (delayed initiation) in reagent formation stage.

Efficiency

No

Quality

Not really

Cost Maybe For small tonnage, setup with costeffective glass ware and Swagelok fittings can be accommodated in fume hood. Potential savings in OPEX with continuous operation.

Mass transfer limited Side reaction(s)

Heat generation

Major Continuous reactor typically has a higher specific heat transfer area than batch reactor.

Safety

Barriers to continuous processing

Reagent formationFast but slowed down by addition rate control due to high exothermicity. Very long cycle time batch-wise. Reformatsky coupling reactionFast QuenchFast Significant at reagent formation, coupling and quench steps from risk assessment. Typically manufacture in small batches with high solvent content as heat sink.


Reaction rate

Process Characteristics

Business benefits

Table 3. High Level Potential Benefits and Barriers to Continuous Processing for Process 1



Process characteristics

Cost


H

Organic and aqueous phases at cyclisation step Precipitation of a sticky intermediate product obtained during concentration if pH is incorrect at cyclisation step. -Product and byproduct have similar high miscibility with water. Unwieldy separation due to multiple solvent extractions to obtain final products in solid form. -Crude product and byproduct mixture tend to form sticky solids, which are not readily transferrable. -Product starts to polymerise when exposed to heat.

Solids precipitate at high concentration during dissolution Gas formation at a number of steps

Phase complexity


No Potential oxidation reaction runaway if addition control fails

Side reaction(s) Hazards Major If suitable continuous equipment is available

Maybe Potential benefits for these categories if a suitable continuous separation equipment that increases the driving force and able to handle the sticky solids is available.

Yes

Yes Yes Gas bubbles will affect process measurement and control if it is not vented adequately No Yes

No. But limited by long residence time.

No

No. But limited by long residence time.

Maybe Not many continuous reactors provide long residence time No

No

Salt formation & Cyclisation reaction rates are controlled by mixing

Efficiency

Yes

Quality

Dissolution of reagentsSlow (hrs) Maybe Cost-effective continuous reactor, such as static mixer can be used. Potential savings in footprint and OPEX.

Maybe Cost-effective continuous reactor, such as static mixer can be used. Potential savings in footprint and OPEX.

Maybe Cost-effective continuous reactor, such as static mixer can be used. Potential savings in footprint and OPEX.

Mass transfer limited

Major If suitable continuous equipment is available

Safety

Time to market

Significant exotherm at oxidation step (≈760 kJ/mol). Controlled dosing of H2O2 batch-wise.

CyclisationInstantaneous (secs)

OxidationModerate (≈1 h) Excess H2O2 removalModerate (≈1 h)

Salt formationInstantaneous (secs)


Heat generation

Reaction rate

Business benefits

Table 4. High Level Potential Benefits and Barriers to Continuous Processing for Process 2



Slow (≈3 h)

Process characteristics


Phase complexity

Inefficient batch-wise due to multiple extractions in removing the catalyst from crude product mixture

Organic and aqueous phases with some solids formation (3% v/v). NaBr solids tend to settle. No

Side reaction(s) Insignificant Hazards Allyl bromide is highly flammable and pose potential health threat

Heat generation Moderate (≈104 kJ/mol) Mass transfer Interfacial mass transfer limited and limited strong dependency on mixing

Reaction rate

Major Continuous processing reduces the in-process inventory

No Mild reaction

Safety

Business benefits

Quality

Efficiency

Likely Since it is highly mixingdependent, continuous processing potentially shorten the reaction time.

Likely Since it is highly mixingdependent, continuous processing potentially shorten the reaction time.


Likely Continuous extraction which increases the driving force may intensify the separation steps to give these benefits.

Maybe Potential savings in OPEX and equipment footprint if continuous processing is feasible.

Cost

Table 5. High Level Potential Benefits and Barriers to Continuous Processing for Process 3 Time to market


Maybe The solids tend to settle. Small quantity is not an immediate threat but accumulation will occur over time. No

No

No No

Maybe


I



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Figure 4. continued

J



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Figure 4. Process definition diagram (PDD) for Processes 1, 2, and 3.

Identification of suitable equipment will depend on the process engineers’ experience and access to knowledge of the capabilities/characteristics of the relevant equipment. In the course of equipment selection, one should consider both conventional and intensified technology (innovative devices) based on the required processing duties (heat transfer, mass transfer, mixing time, residence time, etc.) and availability of the device at the desired scale. It is also feasible to develop new equipment specific to the requirements of a reaction or separation if no equipment is available to fulfill the required duties. It is also useful to identify where the change from batch to continuous would significantly alter the contacting pattern or the experience of the process fluid. This will lead to the selection of a suitable operating mode, whether in batch, semibatch or continuous. The heat and mass transfer duty in batch is often concentrated to a restricted period, and the corresponding equipment must accept the peak batch load. In flow the respective steady state heat and mass transfer rates are much less and automatically can use smaller equipment.58 In a batch process, solid is often the preferred product because of both the relative ease of isolation to high purity through crystallization, and the higher stability of solid in

processes (reaction, heat transfer, mass transfer, etc.) occur at rates determined by the local conditions (composition, temperature, interfacial area, etc.). To achieve the best process outcome, it is necessary to deliver conditions that maximize the rates of desired processes. In this way, the process design seeks sets of conditions that should deliver the best process performance, rather than accepting the limitations that are inherent in the equipment.51 Identification of possible equipment and its set up is an integral part of this activity. The determination of suitable equipment is important because many processes are scale- and equipment-sensitive and work may be needed to confirm scalability. They are affected by physical and chemical interactions such as kinetics, heat transfer, mass transfer, off-gas/foaming, emulsions and phase separation, power input, mixing and solids suspension, processing time, and physical property changes.56 Knowledge of the physical and chemical properties of the species involved is useful to tailor possible options for a continuous separation process;57 for example, boiling point and polarity differences influence strongly the suitability of separation methods such as distillation or extraction so as to deliver the intended purification downstream. K



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Isolation for Process 2 remains an issue for both batch and continuous operation. Both the product and byproducts have similar and high solubility, leading to a lengthy and solventintensive extraction. A solvent exchange into ethyl acetate is required, resulting in the simultaneous precipitation of byproducts and some products. The process requires an approach that could deliver a combination of mixing, liquid extraction, and solids suspension/separation. An additional issue that arises during batch scale-up for this reaction is that the product tends to polymerize when exposed to heat during the concentration step. It must be kept in short contact with heat to avoid the formation of sticky materials. Residence time or the rate of reaction is less significant in batch compared to continuous. Process 3 (Table 5) is mixing sensitive and requires a relatively long time (about 3 h) to achieve the intended conversion. This challenges the use of a conventional intensive flow device such as a static mixer. A continuous oscillatory baffled reactor (COBR) or continuous counter-current extractor might be feasible solutions. Develop Options of Process Scheme for the Whole Process. Conversion of the batch steps to a sequence of continuous steps can be achieved by direct replacement of the batch processing steps from the batch recipe. The advantage of one to one mapping is reducing or eliminating the need for additional process development studies beyond the batch method, which in our experience reduces development time. For example, there are no issues with over-reaction or change in temperature for the instantaneous salt formation step (Process 2), so a simple static mixer for continuous processing could be used to replace a batch reactor. However, direct swapping of batch operations with continuous operations might not always be practicable and technically feasible; for example, filtering catalyst continuously after a reaction step or carrying out catalyst filtration and a reaction step simultaneously would be difficult. Another downside of one to one mapping is it reduces the chance of identifying significantly different or better processing options. In our methodology, the order of processing steps as captured previously (PDD in Figure 4) is used at a block level to explore the opportunities and benefits of batch to continuous mapping with any of removal, addition (if required), or combination of processing steps. We call this (BatCoM or Batch to Continuous Mapping). One should look beyond the traditional design approach to identify any opportunities for better process options, e.g. integrating the processing steps so that a single equipment can be used to fulfill a few requirements simultaneously62 and continuously. If one to one mapping leads to multiple continuous process steps, one should explore replacing the multiple steps with one or lesser steps. This exercise draws on an existing core process assessment tool, i.e. equipment/technology knowledge, to fulfill the process requirements, as well as concepts such as process intensification (PI), task integration, and novel devices (e.g., microreactors) to open up new process options. Using the representation of continuous steps in Figure 5, matching of the process steps to continuous-oriented equipment/technology can be carried out leveraging on the knowledge/experience of a multidisciplinary team, and/or methods and tools45 available in the literature (where applicable). Continuous processing opens up opportunities for process integration (e.g., heat integration and direct recycles) and probably new reaction conditions (e.g., higher temperatures and pressures to increase the reaction rates). Combination of

storage. However, it remains a challenge to process effectively solids-containing fluid continuously despite recent progress in solids management.59 Equipment selection tools consisting of an equipment knowledge base60 could be deployed to screen and match the time and length scales of the required process phenomena. Table 6 provides a possible continuous equipment option for some typical batch process tasks. Table 6. Some Possible Equipment Options To Achieve Continuous Processing from a Batch Process Step Current batch process step Crystallization

Free catalyst removal by filtration

Large size batch reactor required to give long reaction time (mins and greater) Requirements of more intense micromixing (e.g., injection of reactant near impeller)

Equipment options for continuous process Mixer-settler chain Liquid−liquid extractor Wiped film evaporator (as evaporative precipitator) Catalyst bed Membrane filter Membrane and catalyst in single unit Membrane filter (membrane as catalyst) Simulated moving bed reactor Oscillatory baffled reactor Several small reactors in series (CSTR) Intensive reactors such as static mixer, microreactors, etc.

A number of processing tasks in Process 1 (Figure 4a) involved both liquid and solid phases. At the reagent formation step, the requirement is both to have the reaction complete and to avoid solids transfer downstream. The possible approaches to this requirement are the use of a continuous stirred tank reactor (CSTR) with liquid overflow, or flow through a packed bed or fluidized bed. Similarly, if the process involves dissolution of solid (e.g., Process 2, Table 1), it is important in many continuous processes that solids are completely dissolved before passing onto the next stage. In batch processes, modifications to the batch plant in the event of incorrect process design are often less serious than continuous process;61 for example, undissolved solids caused by under-design of a process step could be simply left for longer until they have fully dissolved. In a continuous process, incorrect design will result in a more significant impact on the overall plant productivity. To avoid potential problems of precipitation in a continuous system, the reaction mixture must be maintained in solution (or at least mobile) at an appropriate concentration. However, the necessary concentration to achieve this is often lower than that used in the batch process. This is a drawback which can compromise volume efficiency. Other ways to maintain homogeneity and keep the mixture in solution could be changing the solvents or the base (but these would likely require more significant modification to and testing of the process). Another issue is gas evolution. For example, in Process 2 (Figure 4b), this occurred at a number of processing steps (salt formation, H2O2 decomposition, cyclization), or at incorrect pH (oxidation step). Gas evolution in the liquid phase may cause surges which can lead to problems in maintaining steady flow and thus upset the composition and mass balance control. It is important to maintain control of the phase ratios in multiphase flow, which would require understanding of the cause of the gas evolution. L



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Figure 5. BatCoM (Batch to Continuous Mapping) for Processes 1, 2, and 3.

processing steps or task integration could be achieved by identifying the requirements of the individual tasks and then combining the tasks within their feasible operating windows

based on criteria such as consistencies or commonalities of operating conditions and material compatibility, without compromising the performance or creating additional complexity M



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(phase behaviour, fluid mechanics, etc.). In batch, solvent swap is done by producing slurry or concentrated solution and then rediluting in different solvent whereas, in continuous, solvent swap may be achieved by multistep extraction or distillation. The constraints of function integration, e.g. relatively small operation window, control, and simulation,63 should be avoided or resolved during design to enable practical implementation. Figure 5 shows some opportunities for combination of sequential steps (dotted boxes) for Processes 1, 2, and 3. A single batch vessel may carry out a series of processing operations (e.g., dissolution, reaction and batch distillation) which makes it attractive for saving CAPEX. The processing tasks which have been conducted one after another in batch may be integrated into one step in flow. For example, the tasks of heating, maintaining the temperature, and oxidation the reaction itself in Process 2 (tasks 30−40 in Figure 4b) could be performed continuously (dotted box A, Figure 5b) in the same jacketed equipment which has multiple inlet ports along the reactor for the injection of H2O2 as well as Na2CO3 to control the exotherm and pH, respectively. In principle, the task of residual H2O2 decomposition (task 50) with gas removal via an appropriate gas−liquid separator at the high point of the system and cooling (task 60) could also be accomplished in the same COBR which has multiple temperature control zones. For the workup, extraction and concentration (task 80−100 from PDD, Figure 4b) could be carried out simultaneously (dotted box B, Figure 5b) and continuously in a flow equipment such as a wiped film evaporator. This will also provide the advantages of excellent heat transfer with shorter residence time to overcome the issue of polymerization, as highlighted earlier. In Process 3, all the four reagents are typically charged one after another and mixed before reaction could occur in one batch reactor. If flow equipment is used, the reagents could be introduced, mixed and reacted continuously (tasks 10−50 in dotted Box C, Figure 5c). The reaction is liquid−liquid multiphase in nature, which requires good mixing. In this case, a continuous counter-current flow equipment may well be selected over a CSTR to give better mixing, reaction and volume efficiencies. For the workup, the 2-step extraction of phase transfer catalyst into wash water (tasks 90−120 Figure 4c) could be intensified to one-step continuous counter-current extraction or centrifugal extraction (dotted Box D, Figure 5c). Some steps that have been carried out in a batch process, e.g. waiting between steps and intermediate storage, can often be eliminated unless needed as a means to allow some decoupling between adjacent stages. If there are known hold points in a batch process, they can be a useful indication of a potential location for buffers in a continuous process. In general, a N2 blanket is only required at the headspace of the contained liquid to keep an inert atmosphere and must be prevented in the flow to avoid the problem of flow ratio control. In batch, the solid product is often redissolved in a solvent at the subsequent step for further processing. Solid production generally involves Crystallization, Filtration, Cake wash, and Drying (CFCD) operations. These CFCD operations may be eliminated by using liquid-phase purification methods (if feasible) and transferring a product solution directly to the next step. This liquid-phase approach is much more amenable to continuous operation, though continuous crystallization is often feasible. Decision on Continuous or Batch-Continuous Hybrid for the Whole Process. For each of the process requirements, one or a number of possible technical solutions or approaches (batch, semibatch or continuous) could have been identified.

Some form of decision would then be required to be taken on the whole process (from raw material to product) whether it is more worthwhile to convert entirely to continuous process or just convert partially to flow (batch-continuous hybrid mode). We suggest a decision making matrix based on the technical difficulties and qualitative benefits (including crude cost) of the identified continuous technology (Table 7) with additional Table 7. Proposed Decision Matrix for Converting Batch to Continuous Step

considerations on the practical constraints faced, e.g. availability of equipment/technology, lack of experience or resources. The level of technical difficulties and benefits are ranked as Low or none (L), Medium (M), and High (H). The rating assigned to each step is based on analysis of prior experiences and information gathered along the assessment. Clearly for H benefit and L technical difficulty areas, it will be considered as worthwhile to convert from batch to continuous and vice versa. The combined assessment for the whole process will enable the stakeholders to form an overall decision. Inevitably, such a decision will depend on the real constraints faced by the stakeholders. Table 8 shows an example of the matrix for decision making on Process 2. In some cases, fully continuous processing might be impracticable with the existing plant. For instance in Process 2 (Table 8), because of the difficulty in carrying out a multiphase isolation step continuously in the available plant, a hybrid batch− continuous option was adopted, with the front end reactions running continuously and workup batch-wise. Although step 110, i.e. continuous cooling with a flow heat exchanger, is worth doing, it is not advisible to be implemented in between the batch processes because that will complicate the control and operation of the whole process. Demonstration/Verification of Critical Process Change. Any part of the process converted to continuous should be sufficiently checked for potential technical risk at large scale. Before demonstration at a credible scale, a feasible process flow scheme (flow sheet or process flow diagram [PFD])64 is required. The process scheme should be further modified if there are necessary changes to be made upon the physical verification in pilot scale. Additional work (experimental and/or simulation) might be required. The additional work required could be to provide data to support the design or to test the modified process concept directly. For example, the state of the materials in the system (solid or liquid) is assumed to be unchanged while moving from batch to continuous mode. This is clearly an assumption that its practicality has to be validated with further work. The nature of the work could be experimental to determine the solubility and stability (if not already known) of the product in the intended solvent. In the physical demonstration of continuous processing of Process 1 at scale, ZnBr2 precipitated at a high mixture concentration. N


Process step

DIAA Dissolution

Salt formation

Heat to 40 °C

Oxidation H2O2 decomposition Cool to 20−30 °C Cyclization

Evaporation Hot extraction Evaporation

Cooling

Filter & Dry

Step ID

10

20

30

40 50

60 70

80 90 100

110

O

120

A flow heat exchanger will provide a better heat transfer compared to a batch stirred tank. Continuous filter drying could provide consistent particle properties, higher efficiency and smaller equipment footprint. However, there will be challenges in moving semidry or wet solids.

same as above Static mixer can be used to run this instantaneous reaction continuously. It is relatively smaller and cheaper than stirred tank. Wiped film evaporator (WFE) could provide a better heat transfer and shorter contact time compared to a batch extractor

Solids can be fed into a stirred buffer tank continuously with a screw feeder. The buffer tank will be relatively smaller. However, there could be challenges with moisturesensitive materials. Static mixer can be used to run this instantaneous reaction continuously. Static mixer is relatively smaller and cheaper than stirred tank at the equivalent throughput. COBR or CSTR can be used to provide the required retention time. COBR with multiple injection ports and different temperature contol segments provides additional benefits of operating process steps 30−60 in one equipment. same as above same as above

Equipment/approach identified for continuous processing

Table 8. Example of Decision Making Matrix for Process 2

H H

H

H

H

L

H

L

H

H

L

L (batch reactor) M (COBR)

L

Benefits of converting to Continuous

M

Technical difficulties for continuous mode

Stay in batch since more effort is required to overcome the technical difficulty where low pH required by the chemistry poses a problem to material compatibility. Worth converting

WFE is ≈9 times cheaper than stirred tank at the equivalent throughput.

Stay in batch

Worth getting one and convert to continuous

Continuous mode could be achieved using the existing batch reactor as a CSTR. However, a COBR will provide additional intensification benefits but some challenges in control.

COBR is ≈3 times cheaper than stirred tank reactor at the equivalent throughput.

Static mixer is ≈300 times cheaper than stirred tank at the equivalent throughput.

Worth getting one and convert to continuous

Stay in batch since the benefit is low and there could be challenges with sticky solids.

Assessment

Static mixer is ≈300 times cheaper than stirred tank at the equivalent throughput.

Crude costing

Due to the constraint in Step 100, the subsequent process was kept in batch mode to ease the entire operation.

Batch

Continuous Continuous

Continuous Continuous

Continuous

Continuous

Purchased DIAA in ready solution. Pumped it out continuously to the next step.

Final decision based on real constraints (in our case)




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Figure 6. Example of process scheme (Process 1).

Additional investigation was required to tackle this issue. When the same flow ratio obtained from batch process development of Process 2 was used in the flow-controlled continuous process operated at scale, the resultant pH was lower than the specification. Some detailed modelling showed that the retention of the carbon dioxide in the continuous system was sufficient to explain the difference in pH. Equipment selection, sizing, together with the process step requirements should be considered simultaneously and iterated (if unsuitable) during the development of the flow sheet. The sizing and rating of the equipment are established from the material and energy balances based on the standard design approach. For instance, in Process 1, in order to avoid the carryover of large zinc particles downstream, a tube is sized with a large internal diameter to ensure that the linear velocity in the tube is below the settling velocity of the particle. Kinetic and thermal measurements are used to support sizing and/or rating of equipment, and where practicable the ones used are those that had already been carried out for development of the batch process. Detailed equipment specifications are not necessary at this stage, as long as credible continuous equivalents that can deliver the continuous process and which are commercially available are selected. Detailed kinetic modeling is not needed unless oversizing of the continuous reactor would lead to reduced performance or high cost which is beyond batch experimentation assessment and prior knowledge. More than often, due to the inherent process complexity and cost and time constraints, a predictive model that could capture various forms of process understanding rather than a detailed mathematical model is adequate. Risk and hazard assessment (e.g., HAZOP level 1) should be carried out at this flow sheet level to include the safety measures. For example, the temperature excursion at the entrance of the continuous reactor for the reformatsky reaction (Process 1) raised a concern during the HAZOP study. As such, changes were made so that the two static mixers are in series with split benzaldehyde flow (Figure 6) to provide a better heat distribution and control. The reconfiguration also prevented side reactions which might have occurred during the temperature

excursion. Necessary control & PAT measures should also be incorporated in the flow sheet. If there is no existing plant, a brand new plant will be built from scratch. If there are existing batch facilities, they could be retrofitted to suit the needs. For example, a jacketed stirred tank used as a batch reactor could also be used as a continuous stirred tank reactor (CSTR) in a continuous process. For hybrid processing, the existing batch facilities will be used in conjunction with the continuous facilities. As such, the continuous facilities should be designed to be compatible and comparable with the existing batch facilities and infrastructures, flexible, and reconfigurable.65 Detailed Economic Analysis Leading to Final Decision. The final flow sheet (incorporated with any changes resulting from the up-scale verification) could then be used to detail the economic analysis on the section(s) of the process converted from batch to continuous. Figure 6 shows an example of the final selected flow sheet for Process 1. This would support a decision to implement the retrofitted process on a plant based on their overall business drivers (Table 2) and other considerations, such as acceptable risk (e.g., scale-up risks), availability of technical resources, and capability, training needs, etc. Table 9 shows the comparison of measurable business drivers between the batch and continuous processes using Process 3 as an example. For this process at the design scale of 100 te/a product throughput, the synergy of phase transfer catalysis and continuous processing provides a number of safety, efficiency, and environmental benefits, especially in smaller processing inventory, better volume efficiency, higher energy efficiency, smaller equipment footprint, lower VOC emission, and lower operating cost. However, the overall CAPEX is ≈50% higher than the batch equivalent. In this case, despite a higher CAPEX, the continuous process offers a slightly lower operating cost (≈ 6% lower) than the batch equivalent. It would be attractive when return on CAPEX investment is achieved. Some of the business drivers, such as time to market and cost, may influence the final decision despite appealing technical benefits. Even for the same process, there is no clear-cut P



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Table 9. Comparison of Business Benefits between Batch and Continuous Processes for Process 3 Business drivers Safety Cost

Eff iciency


Max. processing inventory at any point of time Ratio of CAPEX OPEX Ratio of Process equipment footprint Volume efficiency (reaction + separation) Material or mass efficiency Energy efficiency E factor Loss of product through the waste VOC emission

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CONCLUSIONS The proposed methodology provides an ordered and practical approach to a quick and early evaluation of whether a batch process is feasible and beneficial to be converted to a continuous process. The methodology also helps in systematically identifying the nature and extent of the work required to convert batch to continuous if initial screening leads to benefits of batch to continuous mode. The thinking is useful in the early stages of developing a new process where the batch−continuous decision is being made . The proposed methodology consists of three stages: initial screening, extended evaluation, and process execution. Three chemical processes were used to exemplify this methodology, especially the determining initial screening stage. AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected]. Notes

The authors declare no competing financial interest.

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Batch process

Continuous process

64 0.39 9.9 0.2 10.8 4.5 1051 3.5 0.4 0.007

20 0.60 9.3 0.1 34.0 4.5 923 3.5 0.03 0.001

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decision across the board, as it is really dependent on the individual organization who determines its own key decision driver. In our example for Process 2, a hybrid process was chosen with a continuous front end of the process feeding a batch process for product recovery. The key driver was to demonstrate technically the conversion of a batch to continuous process, and the performance benefits of the hybrid process over the batch were found to be commercially insignificant for this system. Final Stage: Process Execution. From Stage 2, a decision should have been made on the mode of processing for the whole process. The work involved in Stage 3 uses the flow sheet developed in Stage 2 to do all the standard detailed process design and plant layout, final equipment specifications, sizing and rating, material of construction (MOC), risk and hazard assessment (e.g., HAZOP level 2), and control and instrumentation with/without PAT to arrive at the final Piping and Instrumentation Diagram (P&ID). Design of a continuous plant usually requires more accurate experimental data and more careful design compared to a batch plant.61

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Unit m3/(ton product/h) USD/kg product (kg product/h)/m3 reagent/product (mass/mass) MJ/ton product waste/product (mass/mass) % (mass/mass) emission/product (mass/mass)

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Practical Assessment Methodology for Converting Fine Chemicals

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