Br Batch : HN R
20h , 125 º C , EtOH , 2 bar
+ R NH 2
+ HBr
Substrate Reagent Product By-product
Figure 2 – Nucleophilic aromatic substitution reaction
In terms of assessment , Hovione identifies the business drivers and objectives for the specific project . These are a combination of one or more of the following :
• Safety ( reduced working volume & inventory ; improved control )
• Efficiency ( improved mass & heat transfer ; intensification ; no headspace )
• Quality ( process control & reduced batch-to-batch variations )
• Environmental impact ( process intensification ; less waste )
• Time-to-market ( faster scaleup ; greater adaptability to market demands )
• Costs ( reduced non-quality costs ; reduced footprint ; higher productivity ; being faster to market ) Next , there is a checklist of 18 simple yes-no questions to identify the process drivers ( Figure 1 ) that relate to the business drivers in different ways . This gives a good indication of whether or not flow will be beneficial . In some cases , a simple economic analysis is also made to highlight any potential reduction in the cost of goods , particularly if a business case is needed for a secondgeneration process . The parameter review , said Oliveira , starts with proof of concept in “ a meaningful feasibility study of the process in flow for a data-driven go / no-go decision ”. The basic chemistry is defined in detail , then a laboratory set-up is assembled and any available batch data are examined , particularly with regard to early kinetics and solubility . Failing that , Hovione will try to extract this data as soon as possible , in order to guide the assembly of the system . Next a series of experiments is run . This is done to take advantage of the fast reaction times obtainable in continuous flow . It covers the ‘ usual suspects ’ of temperature , residence time , pressure and reagent equivalents . If the results indicate that flow is probably the best option , the group moves on to the development phase . This involves :
• Modelling & simulation , i . e . kinetic modelling and computational fluid dynamics
• An internal technology & applications database , which is used to find solutions to technical challenges encountered
• Design-of-experiments
Once the process is developed , it can move on to the last stages of scale-up studies and engineering . One of the first deliverables here is the user requirement specifications for the set-up , essentially ensuring that what was used in the development stages can be replicated at larger scale . This stage also involves a risk assessment for the process and establishing a control strategy . The process can then move on to industrialisation .
Case studies
Oliveira went on to share a case study from Hovione ’ s experience that showed how these principles were applied . The chemistry , he said , “ was quite simple ”: a nucleophilic and aromatic substitution reaction that releases hydrogen bromide as a byproduct . No side reactions needed to be considered ( Figure 2 ). The key driver for moving to flow was safety because the reaction had the potential for a significant exotherm at temperatures above 150 ° C . It needed to be run at 125 ° C for 20 hours in flow , conditions which were not very different to the runaway conditions . In addition , the solvent was ethanol , whose boiling point is below 125 ° C , and some pressure was built into the reaction . These were significant challenges , considering the scale at which Hovione wanted to carry out the reaction . For this reason and also because of the opportunity flow conditions offered to reduce the excess of reagent required in batch , efficiency was another , secondary driver . The company then ran through its checklist , answering yes to three of the 18 questions : ‘ Is the reaction highly exothermic ?’, ‘ Does the reaction require pressure ?’ and Does the reaction require temperature control ?’ The outcome was a decision to move it to flow . Before taking the reaction into the lab , Hovione used its existing knowledge from carrying it out in
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