Although it may be true that the first pilot plant reaction in a process step development should be done as close as possible to the preferred laboratory protocol, it is not true that the sampling for this pilot plant run should be no more substantial than that in the lab. Because a pilot plant test is so expensive, provision should be made so that, if it results in unpleasant surprises, it makes the investigation easy by providing bountiful data to point unambiguously to a most probable cause for the deviation from the expected result.
It is fair to say that in the first pilot plant run, one needs a convincing reason for not taking a sample at each point in the process where the reactor contents are homogeneous- not just at the points where a regular in-process analysis is planned in the final batch sheet, after optimization.
These samples are of two types. One type is forensic samples.
These need only be examined when there is a deviation that needs to be investigated. The second type are samples that are used to simplify the process as for example to determine the most efficient number of washes, the best volumes of washes and to obtain a mass balance by determining in what discarded phases product was thrown away.
When samples are taken, some of these samples will be kinetically unstable-that is the reaction is continuing to proceed in them even after the sample is taken. For these kinetically ’live’ samples the best course is to take them on to final product in the laboratory. To do this the sample should have the reactants completely added and should be representative of the reaction mixture. Reaction mixtures that are heterogeneous should not generally be completed in the lab because a negative result will only raise the question, “Is the problem the reaction or the sampling?”
Most often samples of reaction mixtures will be treated with some reagent to stop further reaction and to preserve the stoichiometries present at the time the samples was removed from the bulk reaction.
Sometimes reaction mixtures that are intentionally not quenched even though they are known to be poorly stable are stored in very cold conditions to stabilize them and only used for forensic purposes if and when it is discovered that there was a deviation. If all runs smoothly, they can be discarded.
If the quenched reaction mixture is quite stable, samples should be taken for split run testing of varying work-up variants. Also running the work-up of a known fraction of the reaction mixture in the lab allows a quantitative and qualitative comparison of the yield and purity between lab and plant methods.
If multiple extractions are performed, samples of the discarded phases can be used to determine the mass balance and to predict the most efficient number and volumes for the extraction liquid phases. Because the point of maximum volume often occurs during one of the extraction stages, efficiencies in the extraction can increase the throughput and improve the costing of the process step.
Washing of crystals or of insoluble catalysts or by-products can be important for realizing a good yield. Samples of the filtrate at different points can provide information about the best wash quantities. The effectiveness of the washing of a filtered solid will almost always be very different with the plant equipment compared to the laboratory setup. If centrifugation is used in the pilot plant this is even more often true.
A pilot plant run should never be undertaken until a lab batch has been made and analyzed using the solvents, reagents, and substrates to be used in the pilot batch. That is: substrates, reagents, solvents and catalysts that are to go into the pilot plant batch should be use-tested in the laboratory. This the most fundamental rule of scale up, yet, it is the frequently violated. The reason is that sampling the pilot plant materials is tedious or faces bureaucratic documentation hurdles. One solution is to ask well in advance so that the process development use-test sample is taken when the analytical laboratory sample to verify the certificate of analysis is taken.
When samples are taken, some of these samples will be kinetically unstable-that is the reaction is continuing to proceed in them even after the sample is taken. For these kinetically ’live’ samples the best course is to take them on to final product in the laboratory. To do this the sample should have the reactants completely added and should be representative of the reaction mixture. Reaction mixtures that are heterogeneous should not generally be completed in the lab because a negative result will only raise the question, “Is the problem the reaction or the sampling?”
Most often samples of reaction mixtures will be treated with some reagent to stop further reaction and to preserve the stoichiometries present at the time the samples was removed from the bulk reaction.
Sometimes reaction mixtures that are intentionally not quenched even though they are known to be poorly stable are stored in very cold conditions to stabilize them and only used for forensic purposes if and when it is discovered that there was a deviation. If all runs smoothly, they can be discarded.
If the quenched reaction mixture is quite stable, samples should be taken for split run testing of varying work-up variants. Also running the work-up of a known fraction of the reaction mixture in the lab allows a quantitative and qualitative comparison of the yield and purity between lab and plant methods.
If multiple extractions are performed, samples of the discarded phases can be used to determine the mass balance and to predict the most efficient number and volumes for the extraction liquid phases. Because the point of maximum volume often occurs during one of the extraction stages, efficiencies in the extraction can increase the throughput and improve the costing of the process step.
Washing of crystals or of insoluble catalysts or by-products can be important for realizing a good yield. Samples of the filtrate at different points can provide information about the best wash quantities. The effectiveness of the washing of a filtered solid will almost always be very different with the plant equipment compared to the laboratory setup. If centrifugation is used in the pilot plant this is even more often true.
A pilot plant run should never be undertaken until a lab batch has been made and analyzed using the solvents, reagents, and substrates to be used in the pilot batch. That is: substrates, reagents, solvents and catalysts that are to go into the pilot plant batch should be use-tested in the laboratory. This the most fundamental rule of scale up, yet, it is the frequently violated. The reason is that sampling the pilot plant materials is tedious or faces bureaucratic documentation hurdles. One solution is to ask well in advance so that the process development use-test sample is taken when the analytical laboratory sample to verify the certificate of analysis is taken.
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