When conducting organic synthesis on a large scale in a kilolab, pilot plant or plant, a key factor that effects cost is the throughput of the equipment; that is, how much product can be produced how rapidly. Since most new organic chemicals are produced in employer’s semi-continuous batch reactors whose sizes are fixed, more production cannot be achieved just by using more or bigger reactor units and their peripherals. More material must be squeezed out of each run and/or the speed of iterations increased. Consequently, it is wise to think at the very outset about what factors in each process step limit its increase. What factors can limit the throughput of a reaction step with fixed plant equipment?
1. Risk of a Catastrophic Loss
Sometimes there is a scale of reaction that involves such a large commitment of expensive materials that your organization would not be ready to risk everything in a single reaction. This arises most frequently when the process is just being developed. At least with two or more small runs, they argue, we will deliver some product. It is less likely that everything will be completely lost. This situation most often arises towards the end of a long unbranched sequence of reaction steps.
2. Exothermicity of Concentrated Solutions or Large Volumes
For larger volumes or concentrated reaction mixtures, cooling becomes increasingly difficult as scale increases. How much can be loaded in a reactor may be limited by the cooling or heating capacity of the reactor.
3. Viscosity/Stirrability of Concentrated Solutions
The concentration of the reactants in homogeneous solution can sometimes be increased by reducing the amount of solvent, but this must stop when the mixture becomes impossible to adequately stir even if this thickening is only a transient event in the procedure. I once had a reaction that worked well except that at scale during the quench the mixture became so thick that it set and stopped the agitator. In the lab, the speed of the quench addition was so rapid we never saw the thickening.
Sometimes there is a scale of reaction that involves such a large commitment of expensive materials that your organization would not be ready to risk everything in a single reaction. This arises most frequently when the process is just being developed. At least with two or more small runs, they argue, we will deliver some product. It is less likely that everything will be completely lost. This situation most often arises towards the end of a long unbranched sequence of reaction steps.
2. Exothermicity of Concentrated Solutions or Large Volumes
For larger volumes or concentrated reaction mixtures, cooling becomes increasingly difficult as scale increases. How much can be loaded in a reactor may be limited by the cooling or heating capacity of the reactor.
3. Viscosity/Stirrability of Concentrated Solutions
The concentration of the reactants in homogeneous solution can sometimes be increased by reducing the amount of solvent, but this must stop when the mixture becomes impossible to adequately stir even if this thickening is only a transient event in the procedure. I once had a reaction that worked well except that at scale during the quench the mixture became so thick that it set and stopped the agitator. In the lab, the speed of the quench addition was so rapid we never saw the thickening.
4. The Ability to Sample Dependably for an IPC
It is possible that a reaction could be concentrated by reducing solvent without affecting yield or purity even beyond the point where it becomes heterogeneous, but the question must be asked, "Will sampling using the technology available to me at scale (for example by sucking up a sample through a dip tube), be able to accurately identify the correct stopping point for the reaction? Getting a representative sample for analysis from a heterogeneous reaction mixture is difficult. It may be even more difficult, even for practical purposes impossible, using the different sampling equipment available at scale. Incidentally, a reaction in the plant should not be so fast that product is destroyed by over-reaction before the result of an IPC for reaction completion is returned to the plant from the analysts.
5. The Size of the Equipment Needed for the Workup, Isolation and Purification
It is not just the maximum stirrable volume in the reactor that limits how big one can go. It is the ancillary equipment. An obvious exemplary case here is when steam distillation is needed in the work-up. The volume of water mixed with volatiles that needs to be collected in steam distillation is routinely much, much, larger than the reactor volume. If you are going to do it you need to have planned how you will handle the volume of water mixed with product that distils.
6. Storage Stability of an Isolated Intermediate
Using semi-continuous reactors, product made by a sequence of chemical steps is normally produced ‘campaign style’. This means that the first step is done batch after batch in the reactor and the first intermediate accumulated, analyzed, and stored temporarily. Then the second reaction step is performed over and over until the first intermediate is completely processed; and so on and so on until the desired final product is complete. This campaign style method has the advantage that the reactors and peripheral equipment do not need to be as thoroughly cleaned between uses as they would need to be if a different reaction were being performed next. (This is because the trace chemicals that could be left in the reactor and reactor train from any one of the reaction repeats are always the same).There are also advantages relating to the familiarity gained by the operators with repetition.
You would not be able to accumulate as much material before you use it, if an intermediate has limited storage stability and that might limit the extent to which that intermediate can be accumulated and hence the scale at which you can operate.
7. Addition time required (for reagents or quench or work-up)
If, when you double the scale or double the concentration, the overall run time of a batch also doubles, you have not increased your throughput, since you could have done two batches at half the scale in the same time. This increase in duration of a batch as the scale increases is most likely to occur when there is a long addition, a long filtration or a long drying in the process step. In effect the process time is no longer proportional to the reaction time. Some other unit operation is limiting.
8. Maximum Stirrable Volume
This is the usual limiting factor in the laboratory. It is determined by how much volume is needed in the reactor at the point in the procedure when the volume is at its highest. For large scale reactions without other complicating factors this limitation also holds.
9. Scrubbing Capacity
If your reaction involves evolving gaseous materials that cannot be let out into the atmosphere, the off gases must be scrubbed. With a large throughput of material a large quantity of gases can be produced quickly. The reactor’s ancillary scrubbing system must be insufficient to treat them.
10. Foaming Tendency
You may think that the volume of your reactor is sufficient to contain a particular scale but what if there is vigorous foaming at some point? You need to make allowance for this foaming or make process changes to control it before you reach scale.
11. Production Scaled to Sensitive Reagent Packages
Some reactions, such as LiAlH4 reductions, use sealed prepackaged reagent sold in a particular molar amount. The package is placed into the reactor and when the appropriate solvent is added the package dissolves in the solvent freeing the reagent for reaction. The prepackaging avoids handling of dangerous materials by workers, avoids degradation of the reagent during measurement and does not leave partial packages of unstable reagent to be stored for later use. The method does limit the throughput to what can be obtained using an integral number of packages of reagent.
12. Rate of Gas Addition
For reactions that have a constituent that is gaseous, the reaction rate may be controlled by mass transfer of that gas into the liquid phase where reaction occurs. High throughput procedures because the reactor is usually more completely filled characteristically have less gas-liquid interface. This is because the liquid in the reactor is not as deep when the reactor is only partially filled yet the surface area of the liquid even without stirring is the same. Stirring less liquid can be done more vigorously introducing more bubbles than can be done in a filled reactor.
13. Rate of Solid Addition
At scale, most preferably, solids are added in total, then the reactor is closed, inerted, then solvent is added and then liquid or gaseous components. Sometimes, however, the addition of a solid must be done later in the process. Solid can be pumped in as a slurry in a solvent or dissolved in a solvent and added as a liquid solution. Thus, the solid addition suffers from the restrictions on adding liquids; that is, because of restrictions of the piping, the addition may be of longer duration when the concentrations and scales increase because mass transfer is not as simple.
It is possible that a reaction could be concentrated by reducing solvent without affecting yield or purity even beyond the point where it becomes heterogeneous, but the question must be asked, "Will sampling using the technology available to me at scale (for example by sucking up a sample through a dip tube), be able to accurately identify the correct stopping point for the reaction? Getting a representative sample for analysis from a heterogeneous reaction mixture is difficult. It may be even more difficult, even for practical purposes impossible, using the different sampling equipment available at scale. Incidentally, a reaction in the plant should not be so fast that product is destroyed by over-reaction before the result of an IPC for reaction completion is returned to the plant from the analysts.
5. The Size of the Equipment Needed for the Workup, Isolation and Purification
It is not just the maximum stirrable volume in the reactor that limits how big one can go. It is the ancillary equipment. An obvious exemplary case here is when steam distillation is needed in the work-up. The volume of water mixed with volatiles that needs to be collected in steam distillation is routinely much, much, larger than the reactor volume. If you are going to do it you need to have planned how you will handle the volume of water mixed with product that distils.
6. Storage Stability of an Isolated Intermediate
Using semi-continuous reactors, product made by a sequence of chemical steps is normally produced ‘campaign style’. This means that the first step is done batch after batch in the reactor and the first intermediate accumulated, analyzed, and stored temporarily. Then the second reaction step is performed over and over until the first intermediate is completely processed; and so on and so on until the desired final product is complete. This campaign style method has the advantage that the reactors and peripheral equipment do not need to be as thoroughly cleaned between uses as they would need to be if a different reaction were being performed next. (This is because the trace chemicals that could be left in the reactor and reactor train from any one of the reaction repeats are always the same).There are also advantages relating to the familiarity gained by the operators with repetition.
You would not be able to accumulate as much material before you use it, if an intermediate has limited storage stability and that might limit the extent to which that intermediate can be accumulated and hence the scale at which you can operate.
7. Addition time required (for reagents or quench or work-up)
If, when you double the scale or double the concentration, the overall run time of a batch also doubles, you have not increased your throughput, since you could have done two batches at half the scale in the same time. This increase in duration of a batch as the scale increases is most likely to occur when there is a long addition, a long filtration or a long drying in the process step. In effect the process time is no longer proportional to the reaction time. Some other unit operation is limiting.
8. Maximum Stirrable Volume
This is the usual limiting factor in the laboratory. It is determined by how much volume is needed in the reactor at the point in the procedure when the volume is at its highest. For large scale reactions without other complicating factors this limitation also holds.
9. Scrubbing Capacity
If your reaction involves evolving gaseous materials that cannot be let out into the atmosphere, the off gases must be scrubbed. With a large throughput of material a large quantity of gases can be produced quickly. The reactor’s ancillary scrubbing system must be insufficient to treat them.
10. Foaming Tendency
You may think that the volume of your reactor is sufficient to contain a particular scale but what if there is vigorous foaming at some point? You need to make allowance for this foaming or make process changes to control it before you reach scale.
11. Production Scaled to Sensitive Reagent Packages
Some reactions, such as LiAlH4 reductions, use sealed prepackaged reagent sold in a particular molar amount. The package is placed into the reactor and when the appropriate solvent is added the package dissolves in the solvent freeing the reagent for reaction. The prepackaging avoids handling of dangerous materials by workers, avoids degradation of the reagent during measurement and does not leave partial packages of unstable reagent to be stored for later use. The method does limit the throughput to what can be obtained using an integral number of packages of reagent.
12. Rate of Gas Addition
For reactions that have a constituent that is gaseous, the reaction rate may be controlled by mass transfer of that gas into the liquid phase where reaction occurs. High throughput procedures because the reactor is usually more completely filled characteristically have less gas-liquid interface. This is because the liquid in the reactor is not as deep when the reactor is only partially filled yet the surface area of the liquid even without stirring is the same. Stirring less liquid can be done more vigorously introducing more bubbles than can be done in a filled reactor.
13. Rate of Solid Addition
At scale, most preferably, solids are added in total, then the reactor is closed, inerted, then solvent is added and then liquid or gaseous components. Sometimes, however, the addition of a solid must be done later in the process. Solid can be pumped in as a slurry in a solvent or dissolved in a solvent and added as a liquid solution. Thus, the solid addition suffers from the restrictions on adding liquids; that is, because of restrictions of the piping, the addition may be of longer duration when the concentrations and scales increase because mass transfer is not as simple.
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