Second Crops of Crystals are Easily Available from a Gas-Expanded, Mixed-Solvent System

 One of the advantages of performing crystallization of a substrate from a single solvent by cooling as opposed to causing crystallization by diluting a first solvent with a miscible anti-solvent is that one can try for a second crop simply by reducing the volume of the filtrate, recool the reduced volume to yield more solid. One can do this because the solvent composition isn't being modified. This advantage would be retained if the crystallizing solvent is a lower-boiling binary azeotrope.

In the alternative, where an anti-solvent is being mixed in to create the required supersaturation considerable tedious work is required to remove all the anti-solvent and concentrate that first pure solvent before a second crop can be attempted.

But if the anti-solvent is a gas under plant conditions, this re-establishment of a single solvent and its concentration is simple. Take for example a mixed-solvent recrystallization that was originally being performed by dissolving the substrate in toluene and then decreasing the overall solubility by adding hexane and then cooling. Suppose instead one dissolves the substrate in toluene cools the solution but instead now bubbles in butane gas. The butane will dissolve in the toluene but the solubility of the substrate will decline in just the same fashion that occurs by adding hexane. The product will crystallize. You cannot filter using a vacuum since this would drive off the butane. Filtration must instead be done by pushing the slurry through the filter cloth with pressure. When the crystallized substrate has been caught on a filter, evacuating the system will easily remove the butane from the filtrate leaving the toluene which can be further concentrated. A second crop can be isolated by repeating the gas expansion with butane.

Furthermore, although mixed solvents are not normally recycled and reused in multi-purpose fine chemical plants, Gas-expanded liquids are an exception since simple distillation rather than fractional distillation is sufficient to do the job.

Any mixed solvent recrystallization that uses cyclohexane, hexane, heptane or petroleum ether can be rejigged as a gas-expanded liquid mixed solvent recrystallization using butane thereby enabling taking a second crop of crystals to raise the yield.

Increasing Throughput in Chemical Process Development by Reducing Cycle Time

 

 Reducing Cycle Time

Often the easiest way to improve throughput is to reduce cycle time and this can be done just as often working on the work-up, isolation, or purification sequences as changing the actual chemical reactions. 

By cycle time, I mean the time it takes to run a batch when the reactor, reactor accessories, and peripheral equipment, such as centrifuges, filters, driers etc. are deployed as continuously as possible making the end product of that step. This includes cleaning, verifying, noting the results of the previous run …everything that must be done. The goal of reducing cycle time is to compress more process step runs into the same amount of time.

Some chemical process steps contain operations in which solution or slurried reactor contents are concentrated by removing some volatiles. If this concentrating consumes a significant amount of time, making it more efficient might go a long way or even all the way towards increasing throughput by reducing the cycle time. 

In the fine chemical industry most evaporations are either semi- or fully batch. While the product from the evaporation step can either be the overhead or the pot contents, the liquid to be separated is usually either wide-boiling or has a non-ideal vapour/liquid equilibrium (such as an azeotrope), which results in a more discreet separation between mixture components. 

Processes where liquid concentration is a predominant aspect actually use special equipment to remove unwanted fluid. A typical industrial evaporator has tubular heating surfaces, a vessel to hold the charge and sweep away vapour from liquid, and a condenser (heat exchanger) to condense the lighter overhead fraction. These units can operate at atmospheric or elevated pressures, but are often run under vacuum to reduce the system temperature. This unit operation can be run continuously, semi-batch-wise, or fully batch-wise. 

Most multi-purpose plants do not have access to such equipment; however, even in a process that is predominantly chemical reactions, getting access to such specialized but common equipment may be advantageous if part of a workup or isolation is a laborious concentration.

In batch chemical reactors commonly encountered in the typical multipurpose fine chemical plant heating is commonly simply coming from the reactor walls. 

Still even here the operation of concentrating solutions or slurries by batch distillation, can often be shortened. In most cases, these practical approaches are applicable to both vacuum and atmospheric evaporators. With respect to the evaporation the question needs to be asked, “Where are we with respect to this system’s capacity?” 

If an important element of the problem is the rate of heat transfer from a jacketed reactor’s walls, injecting live steam into the reactor is another way to supply heat. By using what is rudimentary steam distillation the vapour fraction of the organic volatile which you are trying to remove is reduced-yes- but the actual rate of heat transfer and hence mass vaporized per unit time may more than compensate for that. So long as your condenser can handle it, steam distillation can be combined with reduced pressure to give vacuum steam distillation. Contrary to what you might think, distilling with steam may actually cause less degradation than ordinary distillation because the temperature of the steam may be much less than the temperature of the jacket’s walls.

Even if water has deleterious effects on the charge you are trying to concentrate, inert gas sparging can still speed up an operation. We know this because there are anecdotal reports that reactions that use volatile catalysts can stall on scale-up because the higher rate of inert gas sparging provided in the pilot plant unexpectedly reduced the charge of catalyst.

If the process is currently set up as atmospheric evaporation, the obvious change would modify the process train such that it can become a vacuum operation. The first and hopefully most obvious issue here is to ensure that all equipment in the evaporator train is rated for vacuum service. If not, this option may require a substantial capital investment and other means of achieving desired capacity may need to be investigated first. However, if the process is already configured for vacuum evaporation, it can simply be run at lower pressures, thus allowing the system to operate at lower temperatures, keeping the product cooler. 

Take into consideration that running at lower pressure may mean a decrease in vapour density and, thus, an increase in vapour loading to the condenser to achieve the increase! Ensure that the condenser and utility streams are capable of handling such an increase. 

Temperature Sensitivity Issues 

When the product is a solute, one needs to know the yield/product losses due to the heat-treatment of temperature-sensitive materials. Perhaps the recovery-yield can be improved by more precise temperature control and throughput increased just by raising the overall yield. Even if the system’s overall temperature is not deleterious to the product, ensure that local hot spots in the base heater are not degrading some material. One way to resolve this is to ask: "Can we run the process at a lower temperature (which usually means running at lower pressure), such that we can keep the product cooler?" Again, this may extend the cycle time, but if yield improvements are large enough to counteract those losses, this could be an elegantly simple change which alters throughput in the right direction. 

More Precise Heating with a Tempered Loop

An option that provides benefits both in temperature control and heat-transfer efficiency is to install what is called a tempered loop feeding your base heater on the liquid-service side of the heat exchanger. In a tempered loop, a pump re-circulates the bulk of the heat-transfer fluid through the reactor jacket at an increased rate, with a small bleed-in of cold or hot utilities to achieve accurate temperature control. The increased mass of re-circulating fluid buffers the temperature, improving temperature control, which, in turn, permits running a little closer to any limiting temperature values (examples might be the freezing point of the condensate mixture or degradation of a heat-sensitive material due to a minor control upset on the base-heater service fluid). Higher fluid velocities and a higher corresponding Reynolds number positively affect the fouling resistance, as well as the overall heat-transfer coefficients and, thus, the heat exchanger efficiency. 

However, with the tempered loop, as with all changes, there are checks that need to be made to ensure that the system works properly. Be careful that the heat exchanger is sized to handle increased flow rates, velocities, pressures and pressure drops. This is something where you need the input of a chemical engineer. It can be problematic, and maybe dangerous, that after changing to a tempered loop, the heat exchanger's pressure-relief setting and system pressure are too close, causing the system to relieve the pressure with any pressure spike. 

Accurate temperature control is an area to look at early on in evaluating capacity increases or when troubleshooting temperature problems (such as freezing condensate) in heat-transfer systems. For a relatively small investment, the reward can be large in terms of condenser freeze protection, additional heat duties and overheat protection needed for temperature-sensitive materials. 

Cleaning

In cleaning, some of the desired material is removed from the equipment and ends up in the waste. In flushing (treated further below) residual desired material is removed from the equipment and combined with the major recovered amount. 

Another area often overlooked when searching for more capacity, perhaps more related to specific process materials than the unit operation itself, is the cleaning cycle time. Assess the impact the cleaning cycle has on the overall cycle time and then investigate what changes can be made to simply reduce this time. Assess the appropriateness of the cleaning agents, analyze the cleaning sequence, the quantities used, etc. Optimize the water flush/rinse times or volumes to achieve more production time. Reducing the amount of idle time increases the number of lots processed.

When repeating certain steps with identical runs one after the other only a partial cleaning may be needed and only a visual inspection rather than the more thorough swabbing and chemical analysis. This saves a lot of time that was being taken into account measuring throughput.

Product Flushing

Particularly for batch or semi-batch processes, eliminating or minimizing physical product losses in between batches from inadequate flushing of precipitated materials can increase the recovery yield. Changing flushing techniques or solvents can do this. 

Whereas extending flush time may cut some capacity by extending cycle time, it may still be justified if there is sufficient increased recovery. 

Look closely at the product/solute properties. If the product is sticky, look for a flushing agent that is compatible with downstream processes but will aid in removing such particles prior to their transfer to the next process step. 

Another example where extra flushing may pay dividends is recovering residual products from charcoaling and other solid adsorbent treatments.

Continuous Chemical Flow Reactors that Scale Well are not New

Even back in 2013 when this blog was first written, continuous flow reactors were increasingly popular. They have been available commercially for many years. They have become mechanically sophisticated in their pumping and controls. But even in Organic Synthesis Coll. Vol. III pg. 172 the synthesis of Carboxymethoxyamine Hydrochloride is described and it uses a continuous flow reactor in the first step.

The reactor works by gravity flow and is made from simple glassware and operates at 100 C using steam heating.

The procedure can be expected to work for reactions that are slow at room temperature or below but procedure rapidly at 100 C. The Organic Synthesis procedure combines acetone oxime with bromoacetic acid using an aqueous base:

“A mixture of 612 g. (4.4 moles) of bromoacetic acid and 500 g. of crushed ice is chilled in an ice-salt bath and made distinctly alkaline to litmus with sodium hydroxide ( about 440 g. of a 40% solution). During the neutralization, an additional 500 g. of ice is added. To the solution are then added 292 g. (4.0 moles) of acetoxime and 440 g. of 40% sodium hydroxide (4.4 moles), the temperature being held below 20 C during the addition of the alkali. The mixture is then allowed to flow dropwise, during 3-4 hours, through the inner tube of a steam-heated Liebig condenser (jacket 75 cm. long; inner tube 10-mm diameter; angle of inclination about 20 degrees) into a 5-l. round-bottomed flask cooled with running water (Note 2).”

Note 2 says that “[b]y this procedure, the reaction takes place in a few seconds, and the formation of by-products is minimized. If the solution of the reactants is heated in bulk, the reaction temperature cannot be controlled and a lower yield is obtained of a dark product which, however, can be purified by distillation under reduced pressure.”

The total throughput can be calculated to be 2784 g of solution which passes, in we can approximate, about 3.5 hours. That is 13.3 g. per minute. The actual duration that material is heated within the steam-heated 100 C zone is determined by the angle of declination of the condenser tube. One can imagine that using instead of a Liebig condenser an Allihn condenser,  that has a series of bulbs through which the liquid must pass, would imitate the effect of a series of continuously stirred tank reactors and the condenser would not need to be so long to have the heat contact time.

Reactor Cleaning: Where Organic Process Chemists Can Help Chemical Engineers in Process Development

For simplification in the operation of the plant, chemical engineers prefer a standard cleaning protocol no matter what process step has preceded it. This is often possible but for it to be workable without exception is wishful thinking. A standard protocol cannot take into account different substrates, different products, different processing conditions, different materials of construction, and the variety of different pieces of equipment in the reaction/isolation/purification train.

Because chemical engineers cannot as easily detect strongly adhering contamination in the larger equipment, they often learn about a problem far along in the development. The process chemists, in contrast, often working in transparent equipment that they clean themselves can be aware at an early stage when a cleaning difficulty is likely. Furthermore, so long as they know the standard cleaning protocol in the plant they are in a perfect position to know that it is likely to be seriously challenging.

Discovering an optimized reactor cleaning protocol can be regarded as unsophisticated stuff but it makes nonsense of our efforts to improve throughput with optimal processing conditions if, in fact, the reactor cleaning takes an order of magnitude more time to perform than the entire process! It very often can be easier and cheaper to improve throughput by reducing cleaning time by improving the cleaning protocol.

Reactor cleaning in API production is the most obvious situation where the process chemist can alert the engineers. It is in the reaction zone where highly insoluble, often polymeric, often baked or charred materials can become attached to the equipment. It is such impurities that provide the greatest challenge to cleaning methods because they cannot usually be treated by the physical abrasion of scrubbing. If an impurity can transfer either in solution or as a particulate downstream into the isolation/purification equipment that ability to migrate suggests an upper limit to the cleaning difficulty. Since it could be moved down the equipment chain it should be able to be moved out of the equipment entirely!

Neil G. Anderson in his monograph, Practical Process Research & Development, says nothing about reactor cleaning other than providing a reference to the article by I.I. Valvis, W.L. Champion Jr. “Cleaning and Decontamination of Potent Compounds in the Pharmaceutical Industry.”

Org. Process Res. Dev. 1999, 3, 44.  This latter article pertains to cleaning the residues from final products of known activity rather than unknown mixtures of compounds of unknown but probably low activity. Although the gunk that is tenaciously retained in the reactor zone is physically intractable it is likely not bioavailable.

The process chemist can do laboratory experiments in a fashion that will be more likely to show up such a gunking problem at an early stage. These difficult contaminants are often created when the reactor contents splash onto the vessel walls above the surface covered by solvent. This occurs in the plant because the entire wall of the reactor is heated not just up to the level of the reaction solvent. If in the laboratory the reaction flask is only lowered into the oil bath up to the solvent line, there will be no corresponding surface for this gunking to occur on and it might not be observed. To mimic more closely the process reactor both portions of the flask below and above the solvent line need to be heated.

When at the end of the reaction period the reaction vessel is visibly contaminated to an extent where hot reaction solvent will not make it visually clean, a scale-up problem is possible and potential solutions need to be considered in advance.

At the very least the process chemist should record and retain information about what was tried and what seemed useful in removing the visible impurities. It would also be useful to know at what point the impurities became apparent, whether they were deposited above the solvent level, below it, or in both places. Sometimes the gunk is more concentrated near the point of addition of some reagent or it may accumulate on the stirring paddle or the stirring shaft to a greater extent. 

The chemist may be able to make some useful guesses about the mechanism for producing the impurities and whether, for example, the impurities derive from a co-product (which will not be reduced in the optimization) or from a byproduct that could be reduced by optimizing. Since very often these dark-colored, low solubility substances are polymeric, consideration might be given to how a radical chain inhibitor might change things.

Polymers can also often be reduced by technologies that create an environment of high dilution for one or more of the reactants.

Definitions

Full cleaning is the more thorough cleaning protocol used when a different process step or a different product is going to be produced next in the reactor being cleaned. This is also referred to as decommissioning cleaning.

Partial cleaning is the less thorough cleaning protocol that is applied when the same process step is to be repeated next in the equipment. Some residual detectable contaminants are acceptable since they are the same as will be produced by the repetition of the step.

Boil outs, rinses, and swabs are three different methods for obtaining a sample to analyze to determine the extent of the cleaning.

A boil out is performed by refluxing a solvent in a closed reaction system in order to clean its interior surfaces and provide a sample of the residues in solution. The cleaning effectiveness of a boil out is a function of dissolution, mixing shear, and vapor extraction all resulting in an exponential dilution cleaning profile.

A rinse sample is performed using spraying or misting nozzles to send solvent where boil out would typically be impossible as for example in piping or portable equipment.

A swab sample is obtained by wiping a surface with solvent-moistened cotton gauze and it is used to grossly quantify the presence or absence of a contaminant.

Since boil outs result in exponential dilution profiles, equal results from two consecutive boil outs are sufficient to validate cleanliness.

The most common solvent to use in boil outs is methanol. Because it is miscible with water it does not form two phases even if the reactor is a bit wet. Although it is a good cleaning solvent for drugs since to be bioavailable they must have some solubility in water and hence likely some in polar organics, it is not necessarily good for process intermediates that may be very hydrophobic.

Acetamide is a solid at normal pressure mp 81℃ but it is liquid under reduced pressures: bp₇₆₀ 222℃; bp₁₀₀ 158℃; bp₄₀ 136℃; bp₂₀ 120℃ ; bp₁₀ 105℃ ; or bp₅ 92℃ . According to the Merck Index, 1 gram of acetamide dissolves in 0.4 ml of water, 2 ml of alcohol, or 6 ml of pyridine. It is also soluble in chloroform, glycerol, and hot benzene. Merck reports molten acetamide is reported to be an excellent solvent for many organic and inorganic compounds. It has been reported to be the most universal of all solvents. The high temperature required for melting and vaporizing the material will increase the dissolution. Under vacuum, the conditions for a boil-out are obtained in the reactor. Molten acetamide or condensing acetamide vapor can be expected to dissolve both organic and inorganic compounds.

Another idea for removing gunk would be to reflux the azeotropic mixture of diisobutylketone (isovalerone) and water. The minimum azeotrope boils at 97.0 C. When the azeotropic composition condenses it splits into two immiscible phases: 53.4% relative volume of >99% diisobutylketone and 46.6% of >99% water. Thus it is possible to boil out with a constant boiling mixture that applies a pure organic liquid of low surface tension to all the equipment surfaces.

Alternatively, using the azeotropic composition of the diisobutylketone reduction product, 2,6-dimethyl-4-heptanol and water (29.6% alcohol and 70.4% water) a constant boiling azeotrope can be boiled out in the system that upon condensation returns to immiscible alcohol and water phases. 

Shortening the Reaction Time of a Process Step At-Scale

Many synthetic reactions are second or higher kinetic order. Once initiated in a particular reactor at a particular concentration (solvent volume), they proceed most rapidly in the initial stage and then slow down as the starting materials are consumed and their concentrations decline. As a consequence, the major portion of reaction time is spent waiting for the last small part of the reacting to finish because the concentrations of agents in these multi-order kinetics have become relatively low.

From these same considerations when a reaction is exothermic, the larger part of the exotherm occurs in the early stage when concentrations are highest. It is for this reason that process chemists religiously avoid mixing the full stoichiometric quantities of all the reactants together first and then initiating the reaction (say by heating). The reason: this is a recipe for a disastrous runaway reaction. Instead, in the preferred approach, one essential reactant is added gradually to a mixture of the other chemicals at the reaction temperature. Operating this way, any unwanted exotherm above what can be balanced by cooling, can be choked off by stopping the addition.

The question considered here is whether, after the faster part of the reaction has passed, anything can be done to accelerate the later slower stage of the reaction so that the overall reaction time can be reduced? If the reaction is being conducted at the reflux temperature of a single pure solvent, the reaction can in principle be accelerated, without changing the steady reaction temperature, by distilling away part of this reaction solvent. In this situation the reaction temperature is the boiling temperature of the solvent and such distillation removes solvent and increases starting material concentrations without changing the reaction temperature. Because removing solvent increases the concentrations of all the solutes including all the starting materials, the rate of their consumption will increase and the point of effective disappearance of starting materials will arrive quicker. For example, if the volume for a bimolecular reaction is reduced in half, the concentrations are doubled and the rate of reaction will be increased by a factor of four.

Of course there is a limit to how low the volume can be taken in a standard reactor. The volume cannot practically be reduced below where the reactor contents can be effectively stirred (the minimum stirrable volume). Also the volume must not be reduced below the level at which the reacting materials begin to precipitate because the reaction’s kinetics are almost certainly dependent upon a homogeneous solution.

Another advantage for the process of concentrating the reaction mixture is that the volume at the point of maximum volume is likely to be lowered. This will result in a higher product throughput; that is, more kilograms can be synthesized in fewer batch repeats. If the volume at the point of maximum volume can be reduced in half (for the sake of simplicity of example) you would only need half as many repeats of that process step to transform the same amount of starting materials. 

A potential difficulty with such a concentrating procedure as I am describing can arise if some important element of the process co-distils with the solvent and is so removed. Again for example a volatile catalyst co-distilled when the solvent was being reduced this would slow down or stop the desired reaction despite the increased concentrating of the co-reactants. Although some reaction ingredients may not be blown out of a reaction mixture when distilled in the lab, distilling in the plant can have substantially different characteristics and one needs to be aware of the possible loss of even quite non-volatile materials via an aerosol. There are physical traps (called impingers) that can capture aerosol droplets and return them to the reactor to overcome this.

Resort to this concentration strategy described above is only needed when an unacceptably long time is required to get complete reaction at an acceptably low temperature. Of course it can only be practiced if a solvent is found that facilitates the desired reaction at the solvent’s boiling point.

Alternately the pressure in the reactor can be controlled so that the solvent that is most desirable for the reaction boils at the desired temperature.

Reactions that are bimolecular but exhibit pseudo-first order kinetics because one reactant is present in large excess can also be accelerated by this strategy.

This strategy could also be applied to a reaction conducted at the azeotropic boiling point of a binary solvent mixture.

What can Limit Throughput at Scale?

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.

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.  

Chemical Process Strategies to Increase Product Throughput

A distinction needs to be made between improving the quality of the product produced by a particular chemical process and the simpler need to improve the throughput from a particular plant using the same reaction steps. When questions of throughput are directed back to process chemists, they often, improperly, think about changes in the chemical process. It is efficiencies in the unit operations that need to be looked at first and usually exclusively. The most common places to save time and increase throughput accordingly are:

1.     Reactor preparation time

2.     Partial cleaning vs full cleaning

3.     Vacuum concentration vs atmospheric distillation

4.     Modified intermediate washing to reduce drier time

5.     Modifying isolation to reduce point of maximum volume

6.     Eliminate a charcoaling

7.     Eliminate a solution drying

8.     Improved reactor cleaning protocols

9.     Add peripheral equipment to debottle-neck an operation

10.    Remove in-process checks where procedure is under control.

What Might be the Best Cleaning Solvent for Cleaning the Reactor Walls of a Plant Reactor

acetamide model

The walls of a large-scale reactor can sometimes be difficult to clean.  The problem is compounded because they are not easily accessible and cannot be inspected closely. Methods that can be applied in the laboratory for many reasons are off-limits. Scrubbing is impractical, dangerous, and potentially damaging to the equipment. What is needed is a powerful but innocuous solvent that can work by vapor condensation not just below the surface of the refluxing liquid cleaner but above the surface and on the reactor walls where the reaction mixture may have splashed, caked, and baked.

In the very old literature, a common, inexpensive, and innocuous compound was claimed to be the best solvent known and one that would dissolve both organic and inorganic materials; salts as well as uncharged covalent molecules: molten boiling acetamide.  Acetamide can be synthesized in situ in the reactor by heating ammonium carbonate and acetic acid and distilling out water. This in fact is the first preparation in the First Collective Volume of Organic Synthesis. 
Acetamide has bp (760 mm) 222.0 C ; bp (100 mm) 158 C; bp (40 mm) 136 C;  bp (20 mm) 120 C; bp (10 mm) 105 C; or bp (5 mm) 92 C. 
As a white solid, it has mp 82.3 C. 
The solubility is 2 grams per ml of water. 
Acetamide has been advocated as a “green” solvent [http://acs.confex.com/acs/green07/techprogram/S3384.HTM]
The ninth edition of the Merck Index describes it as:
 “Solvent; molten acetamide is an excellent solvent for many organic and inorganic compounds. Solubilizer; renders sparingly soluble substances more soluble in water by mere addition or by fusion.”  Way back in 1933, Professor O.F. Stafford of the University of Oregon wrote that acetamide dissolved more different chemicals than any other known solvent. [J. Am. Chem. Soc., 1933, 55 (10), pp 3987–3988].

Process chemists sometimes forget that their responsibility is for the minimized overall cost of the process and this is much more than the chemicals only cost. The throughput per unit of time is a major factor in the overall cost. That time includes the equipment cleaning time required between batch runs and between the end of one campaign and a new one for another product that is to be run with the same equipment. It makes little sense to invest extensive research efforts in reducing processing time when the same throughput efficiencies can be more easily achieved by reducing cleaning time between runs.

Many plants use a standard cleaning protocol implemented as an SOP.  Special cleaning procedures are resorted to only when it fails to remove all the contamination. In some cases, the standard cleaning or rinsing will even exaggerate a problem. For example, in the synthesis of adamantane described in Organic  Synthesis Coll. Vol. III pg. 16-19, specific instructions are provided to avoid treating the vessel with water until acetone is used first to completely remove the tar.

Development chemists are the first to get an indication that special cleaning problems could arise after certain processing. Giving the plant scale-up people a heads-up and some suggestions will improve both teamwork and overall efficiency.

Since acetamide is Ames negative it is a moot point as to whether it should be considered as a “genotoxic impurity”; it is, however, a modest-potency carcinogen with a TD50 value of 180 mg/kg/day.