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.

Top Ten Kilomentor Chemical Process Development Blog Articles

The Kilomentor Blog has existed for seven years. It was originally hosted on Chemical Blogs but for the last three years, it has been a Google Blogspot tenant. Although, as the editor, I can see which of my blog articles has received the most readership, this is not available to readers.

Readers do have access to an in the blog search engine that can select articles pertinent to the keywords they select; however, I thought it might interest all readers to have links to the top 10 articles that have appeared these last three years. If this is of interest I can do the same for more top articles in another blog.

1. Pamoates and Embonate Salts

2. Preparation of Pharmaceutical Salts

3. Recycling Mother Liquors in Chemical Process Development to Raise Yields

4. Solvent Replacement in the Plant at Scale

5. Getting Better Recovery from Recrystallization

6. Claisen’s Alkali Reagent for separating very Weak Acids like Enols and Cryptophenols

7. The Problem of Oiling Out in chemical Process Development

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

9. The 1,2-Diol Functionality as a Phase Tag for Process Separation

10. 10. PEG 400 (polyethylene glycol liquid) as a Useful Organic Reaction     Solvent

How does one Produce the Most Likely Impurities in the Product from a Process Step?

In order to develop a good purity analysis for an organic substance, one needs to have some method to assess different methods. A better method separates and quantifies more impurities from the product. A better method increases the degree of separation between the closest impurity and the product without losing separation for any other impurity. A better method separates more cleanly an impurity designed to have a very minor structural difference from the product.

 

But is there a way to prepare a  resolution standard with larger amounts of the most likely potential impurities of the product? This becomes an important practical matter.

There are two types of impurities. Impurities that are derived from product degradation; that is, they come via the desired product and arise from reactions of the desired product occurring after it has been isolated and purified. A separate type of impurity is one that is formed at the time of the synthesis of the desired product and which is not completely removed by the isolation, separation, and purification processes performed before packaging the final product. Such impurities are characteristic of the process. 

It is this second type that is considered here. These impurities are produced in greater or lesser amounts by variations from the proper continuous variables controlling the process.

 

New previously unobserved impurities are usually created by changing the discontinuous variables of the process step, such as reagents, reagent purity, reagent/substrate ratio, solvent, solvent purity, substrate purity, processing chemicals…

The most significant continuous variables are time and temperature.

The one that can produce the most profound or substantial changes in chemical reactivity is temperature. The effect of time is usually more limited because if we are seeking a complete reaction it is likely that the transformation is self-terminating and will essentially stop when the correct time has expired with relatively less occurring after this required reaction time. Increasing the temperature by 10 C according to a rule of thumb should double the rate of reaction. This will also allow competing reactions that are limited under the most preferred conditions to compete and produce by-products.

Thus, an increase in the temperatures of each of the different stages of the reaction by 10C and a decrease in the time by half in each stage should produce more impurities in the final product and these impurities should reflect realistic possible impurities.   If possible the extent of disappearance of starting material should be kept about the same.

Product separated from a process step stressed in this way should show increased amounts of the most likely process impurities.

If it does not, this is important information for your determination of critical parameters that you will need to work on at some point. Tests that provide a resolution standard go hand-in-hand with examining critical parameters!

Uncommon Solvent Immiscibilities

 KiloMentor is always on the lookout for methods to separate components of a mixture by partitioning between immiscible liquids. Better known ones are methanol or acetonitrile with hydrocarbons. Many different solvent pairs may show immiscibility between ambient temperature and -20 C and this temperature range is easily accessible inside a jacketed reactor where liquid-liquid partitioning is done at scale. It is in the laboratory that this temperature range is inconvenient to achieve.

Below are listed some less-common immiscible pairs that may prove useful.

Dimethylsulfoxide - Xylene

Dimethylsulfoxide - Diethyl Ether

Dimethylformamide - Xylene

Dimethylformamide -Diisopropylether

Trichloroethylene - Xylene

Acetic acid - Hexane

Methyl t-Butyl Ether (TBME) -Sulfolane

The DMF /Diisopropyl ether immiscibility suggests that one look for an Upper Critical SolutionTemperature (UCST) between DMF and TBME at below room temperature. A small amount of water could be added to the DMF to raise the UCST.

Since DMSO and diethyl ether have immiscibility it suggests that one explore for a UCST between DMSO and TBME below ambient temperature.

What would the miscibility be between a mixture of xylene and diethyl ether with DMSO? Both xylene and diethyl ether are separately immiscible with DMSO.

To get rid of the diethyl ether suppose we try a mixture of xylene and TBME with DMSO?

How about a mixture of DMSO and trichloroethylene with xylene? Both DMSO and trichloroethylene are separately immiscible with xylene.

Dimethylsulfoxide or DMF reactions could be worked up by extraction into m-Xylene followed by azeotropically removing the xylene as an azeotrope with water after cold extracting the xylene to remove residual dipolar aprotic solvent.

Both m-xylene and isopropylbenzene form azeotropes with water that can be used to quickly remove the organic as a clean phase. Can either of these be useful for isolating organics formed in the solvents DMF or DMSO? You tell me- I’m retired; you have a lab.

Diphenylphosphine Oxide Containing Compounds: Intermediates almost guaranteed to be Crystalline

 

 Stuart Warren, in an article in Accounts of Chemical Research 11 (11) 401 (1978), wrote that almost all diphenylphosphine oxide-containing compounds are highly crystalline white solids. KiloMentor is, therefore, proposing the use of compounds containing the diphenylphosphine oxide substructure as one of the preferred intermediate types in ‘paper’ syntheses.

It is well known that the reaction of a primary alkyl halide with triphenylphosphine produces a quaternary phosphonium salt that is both an ionic salt and crystalline. Hydrolysis of such a compound in aqueous base liberates benzene and provides the phosphine oxides. These compounds in turn can be alkylated with other alkyl halides using butyllithium and TMEDA as co-solvent. [J. Chem. Soc. Perkin Trans. I, 550 (1977)] Warren predicts that these also will be highly crystalline solids.

The KiloMentor strategy for paper synthesis route design emphasizes the advantages of selecting a route that can easily be scaled up. To be preferred, intermediates need to have an increased likelihood of being easily separated and purified, preferably by acid-base extraction. This is proposed to be an overarching advantage over competing routes, whose intermediates almost always have to be purified by crystallization. The problem with these competing routes is that the crystallizability of an intermediate from a paper synthesis cannot be dependably predicted.  

Besides those intermediates, purifiable by extraction, other intermediates would also be preferred if, even when still unknown and existing only ‘on paper’, they contained a functional group that could pretty well guarantee they would be found to be crystalline. There are not many of these and they are not celebrated for this property. Usually, the ease of crystallization for a compound depends upon the entire molecular structure and cannot be predicted, but diphenylphosphine oxide appears to be one that should come with a guarantee.  

Tannic Acid Hydrotropes

Most hydrotropes are made by dissolving organic salts at a concentration of at least 1M in water. Covalently bonded materials do exist that form hydrotropes. The best known is urea. Another inexpensive, non-ionic organic material that is highly soluble in water and that can be expected to promote the dissolution of other organic substances is tannic acid.     
                 
Molecular Formula - C₇₆H₅₂O₄₆
Molecular Weight - 1700
Melting point - 218°C
Water solubility - 1g/ 0.35 ml

Speaking roughly, to produce a hydrotrope a chemical must dissolve in water to give a 1M solution. A 1M solution of tannic acid would contain 1700g of organic solid per liter of water. That would be 1.7 gm per milliliter. The solubility of tannic acid in water is 4.88 gm per milliliter. One could achieve a solubility of 2.87M if required in a saturated solution. Tannic acid is a material available in industrial quantities at a practical price. Sigma-Aldrich sells 500 grams for less than $100.00. Considering that only 60 g of urea are needed to produce a 1M aqueous solution that would give an effective hydrotrope and supposing that we provide three times as much tannic acid by weight, that would just be 180 g per liter that would not cost more than $75.00!

The molecule shown in the figure is only one representative (perhaps the major one) of the constituents of the organic mixture called ‘tannic acid’ but if we accept that it is typical, then each molecule can be approximated as containing about 25 phenolic groups and 10 ester linkages. The phenolic groups alone would comprise over 15 hydrogen bond acceptors and 25 hydrogen bond donors. Certainly these can be counted on to increase the solubility of many organic solutes in the tannic acid/water phase.

Diisopropyl Ether (DIPE) Solvent Can be Safely Used in Industry

 

Diisopropyl ether also trivially called isopropyl ether (analogous with ethyl ether) is an important anti-knock additive for gasoline. It is an important coproduct in the preparation of isopropanol by the hydration of propylene. As a result, it is reasonably priced.

In the Research Laboratory

In the laboratory setting, diisopropyl ether must be treated with great caution because, more than almost any prospective solvent, it readily forms explosive peroxides when exposed to atmospheric oxygen. Bottles of old solvent that are left in a laboratory or storeroom slowly evaporate through inadequately seals and the peroxides concentrate. Sometimes the peroxides even crystallize. Such residues or concentrates are extremely dangerous. If one of these concentrates is discovered, it must be handled by trained personnel with special safety equipment.

The consequence is this useful solvent does not get incorporated into scaled-up processes. This is unfortunate because at scale the dangers of the solvent are drastically mitigated. 

The Difference In the Plant At-Scale

In the plant, all process operations are executed under an inert atmosphere. This is part of standard operating procedures (SOPs). Vessels are closed. Transfers are made by piping liquids, solutions, or slurries. There is no pouring through the air! The possibility of exposure to oxygen in the air is remote. 

In addition, in the laboratory the formation of peroxides in diisopropyl ether is made more likely because exposure to light is increased and light can catalyze peroxide formation. In the plant light is blocked by working in drums, closed metal reactors, piping, and pumps. Reactions and processing involving DIPE occur either in subdued lighting or in the dark. There is no photocatalysis possible.

Finally, at scale, batch sheets require that all chemical inputs be tested to be sure they meet their specifications and one of the requirements for DIPE use is that it passes its requirement with regard to peroxide impurities. So unlike the situation in a laboratory where an old bottle of solvent might be used in an experiment, all the inputs for working in the kilo lab or pilot plant are rigorously tested. Furthermore, the capacity for the analytical testing laboratory to do retesting for peroxides during processing is also available.

So as we can show, unlike other materials, the higher danger point using diisopropyl ether occurs in the research laboratory during process research and development. Yes- special precautions need to be implemented -in the laboratory!

These laboratory dangers can be stymied a number of ways:

• Store in the dark 
• Keep bottle sealed
• Stabilize with butylated hydroxytoluene (BHT) or NaOH  
• Remove peroxides by acidic iron(II) sulfate wash
• Pass through alumina (does not destroy the peroxides; merely traps them)
• A more drastic method that also removes water/oxygen is to distill from sodium/benzophenone

But Why Bother Taking Any Risk?

DIPE readily separates from water-free sulfolane.

 

DIPE won’t separate from totally anhydrous DMF, but adding  a little water gives two layers.

 

DIPE does give phase separation from anhydrous DMSO. So you can do a reaction in dry DMSO and repeatedly extract the product into DIPE. 

A biphasic/phase transfer catalyzed reaction can be conducted using the DIPE/DMSO system. 

Diisopropyl ether (DIPE) is a clear liquid that is immiscible with water. It smells like decomposing green tea. MP: -60 °C; BP: 69 °C; Density: 0.725 g/mL . It has a reputation as a go-to solvent for recrystallizations that have failed with other solvents.

In addition to what has been established for sure, DIPE is promising in other ways. Reactions performed in dipolar aprotic solvents such as N-methylpyrollidone, dimethylformamide, N-methylformamide, dimethylacetamide and dimethylsulfoxide are often drowned out with water and then extracted to isolate organic products.  No cheap and convenient method has been worked out to separate these polar organics from the bulk of the water and return the dipolar aprotic to an anhydrous condition suitable for reuse.

On the basis of the physical properties of the chemicals, the following might be workable but KiloMentor has seen no experiment to substantiate it. 

Diisopropyl ether (DIPE) forms an azeotrope with water that is reported to boil at 62.2 C. This is a heteroazeotrope.  The designation means that this azeotrope’s vapor is in equilibrium with two immiscible liquid phases. According to the Chemical Rubber Handbook, DIPE and water form an azeotrope that on condensation splits into a water-poor DIPE-rich upper phase and a water-rich lower phase. Thus, addition of DIPE to a mixture of one of these higher boiling solvents and water, and boiling of the ternary mixture under a Dean-Stark trap with continuous return of the top DIPE phase could be expected to gradually separate a lower water-rich phase which could be periodically drained away. The high boiling solvent that is being dried would theoretically be retained throughout in the still pot.

In the real laboratory situation, however, a small amount of the high boiling solvent as vapor entrained in the reflux stream that one is trying to free from water could be all that is needed to prevent the distillate from separating into two phases in the trap and this would scupper the procedure so this concept would need to be tested. Nevertheless, if it works and your facility has unused distillation capacity, solvent recovery could be profitably practiced.

 It is crucial for a practical process that the DIPE be recycled since the distillate is 97% DIPE and only 3% water. Recycling is essential to be able to remove a large amount of water using only a small amount of DIPE. 

Before recovering the DIPE by distillation in the plant it should be tested for peroxides and washed with aq. acidic iron (II) sulfate if the peroxide test is positive.

Other solvents that boil above 100 C that can potentially be separated from water and dried using DIPE are nitromethane, acetic acid, dioxane, ethylenediamine, sulfolane, and isoamyl alcohol.

After the water has been completely removed continued distillation will drive over the DIPE itself. Even if small amounts of DIPE remained in a recovered dipolar aprotic solvent it is usually unreactive. Of particular importance… it is inert towards organometallic reagents.