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Chemical Product Design
Specialty Chemicals
Chemical Products
Chemical Products can be convenientlyseparated into three categories (according toCussler and Moggridge)
- Micro- andmacrostructuredproducts
- Specialty chemicals- Devices for chemical
changes
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What is different in specialty design?
Microstructured Products- The design of microstructured
products usually depends onphysical operations and physical
chemistry
- The design of structured productsrequires knowledge about
operations that create and controlmicrostructural development
- Microstructured products oftenstart from several pure
components
Specialty Chemicals- The design of a specialty
chemical usually starts with aknown reaction
- The design process involves
then first the verification of thesynthesis
- The second design step is thento develop the reaction
engineering needed
- Separation techniques in relation
to the involved costs are a keyelement of specialty chemical
design
What is a Specialty Chemical?
Specialty Chemicals have a high added value
Specialty chemicals are produced in smalleramounts
Antibiotics,Selling at 10/kg
Toluene,Selling at 0.20/kg
Source:Agricultural waste at
0.01/kg
Source:Alkanes at 0.15/kg
Specialty chemicals< 106 kg/yr
Commodity chemicals> 107 kg/yr
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What is a Specialty Chemical?
Specialty Chemicals are regularly produced inbatch processes
The reactors used are normally not optimizedfor one process, but designed to be flexiblyused for different products
Scale-up of chemical products needs to be fastas the time-to-market is critical for specialtychemicals with a short life cycle
- Scale-up needs to be robust. For product designsincluding clinical trials the final process must be thesame as for the products tested clinically
What is a Specialty Chemical?
The idea selection is regularly relatively simple(it is just a chemical to choose)
The establishment of the final productspecifications is for speciality chemicals oftenthe time consuming (and expensive) step
In the following we will focus on these finalsteps of the chemical design process, as theseare for speciality chemicals the important ones!
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Extending Laboratory Results (overheard from dialogue between a chemist and an engineer doing
product design of a specialty chemical, a steroid that can be used in
birth control pils)
Chemist: This is an easy reaction which anyone intelligent should be ableto run. I just dissolve the crude steroid in methylene chloride and then add
n-butyllithium. The reaction is ... Wait, let me put it in terms you'll
understand. At -40C,
A + B AB.
You cannot run too long because there is a side reaction:
AB +B AB2.
I then add acetone, which knocks out the product (i.e., causes it to
precipitate). I decant the solvents and add DMF (dimethylformamide) toredissolve it. Then I add water to make the alcohol:
AB +H2O AOH + BH.
Extending Laboratory Results Chemist: All these reactions are pretty exothermic. Still, they run easily,
though the overall selectivity is often low, around 40%. You shouldn't have
any trouble getting that higher.
Engineer: Why is the selectivity so low?
Chemist: I don't know. It often is in reactions like these.
Engineer: How much does the temperature increase?
Chemist: Quite a lot. Even at -40C, you can see the temperature jumpwhen you add the n-butyllithium. However, I've kept the temperature rise
small by running the reaction in an acetone-CO2 bath. Sometimes, I've kept
it from jumping too much by turning off the stirrer for a while.
Engineer: Can you use any different solvents? Chemist: I don't know. You probably can't replace methylene chloride; it
really is the best for these reactions.
Engineer: You remember that it's viewed as a dangerous carcinogen.
Chemist: Yeah, but lots of chemicals are dangerous.
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Extending Laboratory Results Engineer: Could methylene chloride be replaced with butyl acetate?
Chemist: I don't know. Look: I really like methylene chloride. It works really
well and I think you'll have trouble replacing it.
Engineer: Did you ever check for the maximum temperature rise in this
reaction?
Chemist: No, but it could be big, enough to boil the solvent. But you can slow
the reaction by shutting down the stirring. .
Engineer: Does that work if the reaction mixture starts to boil?
Chemist: I don't know. My experiments never boiled.
Engineer: Why do you always run in a round-bottom flask? You could get
faster conversion in a tubular reactor.
Chemist: Look, I need to slow the reaction down, not speed it up. When it
runs too fast, it makes too much by-product. Then the product goes brown, notwhite, like it probably should be.
Extending Laboratory Results Engineer: How can you remove the color?
Chemist: I don't know. Sometimes activated carbon works on problems like
these.
Engineer: Can you try to get any purification when you make the acetone
knock-out?
Chemist: You mean add the acetone slowly so that you get purer crystals?
That's a good direction to go, though it's hard at -40C. I didn't do it,because I was just trying to rough out the process chemistry.
Engineer: Did you measure the purity of that intermediate precipitate?
Chemist: No. I don't think it is that important.
Engineer: How did you separate the product? The one after hydrolysis. Chemist: Actually I didn't. I just ran the solids that were knocked out and
hydrolyzed through the HPLC. I knew where the peaks should be because
of earlier experiments using combinatorial chemistry.
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Extending Laboratory Results Engineer: Do you know how to purify the product?
Chemist: Sure.
Engineer: I mean at large scale.
Chemist: But that's your job. I finished this one, and I did it right. I've got
other reactions to run. Come back and see me if you need help. This isn'thard. See you later.
(this ended the discussion)
What can theEngineer learn from this conversation?
He must scale up a highly exothermic reaction whoseselectivity is strongly temperature dependent.
The reaction is possibly mass transfer controlled,because its rate depends on stirring.
The separation of the reaction products will include rawmaterials and the results of side reactions. Separation byadsorption (the basis of chromatography) works, at least
on a small scale.
Solvents are important, but largely uninvestigated.
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What to do next for the Engineer? In a case like this, the engineer must first check the
chemist's results.
- He must repeat the reactions in round-bottom flasks, carefully
watching the temperature versus time.
- He should imitate the way that the chemist combines the reagents
- He should use the same solvents, even the methylene chloride.
- He should separate the products by HPLC.
In most cases, he will not initially get results that are asgood as the chemist's, a result of the chemist's greater skilland of the inadvertent omission of nuances of chemical
technique. But eventually, he should equal or surpass the chemist's
laboratory results. He is then ready for the reactionengineering.
Reaction Engineering
We have duplicated the chemist's results
We now need to consider the speed and theselectivity of the chemical reaction.
The chemist has shown that this synthetic routeis possible. We need to discover how much it canmake
We begin by seeking the rate-limiting steps of
the various reactions. In many cases, the limiting reagent will be the most
expensive material, and the excess reagents will be cheaper.
However, in some cases we may use the expensive reagentin excess to minimize the side reaction
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Reaction Engineering Determining the rate-limiting step is detailed in
texts on chemical kinetics!
- Normally, we will want to know the effect of changingthe concentration of the limiting reagent (in order todetermine the order of the reaction)
- We then measure how the rate changes withtemperature and with stirring.
Separations for Specialty Chemicals
Separating and purifying are often complicated by thetendency of specialty chemicals to be produced at highdilution
Separations of mixtures of dilute chemicals usuallyinvolve two groups of problems:
- First, we must plan in what sequence we intend to separate thevarious compounds in our reacted mixture.
- Second, we should review the types of separation processes
that are most likely to be useful for these products. (Attractiveprocesses usually do not include distillation, which is a major
difference from commodity chemicals)
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Separations for Specialty Chemicals
Separating specialty chemicals will normally begin withthe contents of a batch reactor. These contents will befed to generic separation equipment to produce perhaps10-100 kg of product.
The following heuristics can guide how to proceed (givenin their approximate order of importance):- Concentrate the product before purifying.
- Remove the most plentiful products early.
- Do the hardest separations last.
- Remove any hazardous materials early.
- Avoid adding new species during the separation. If you must add them,remove them promptly.
- Try to avoid extreme temperatures by using different solvents.
Concentrate The Product Before Purifying
The first step in any separation train shouldfocus on taking the dilute feed and concentratingboth the product and the principal impurities
This heuristic gains considerable support from a
graph of product concentration in the feedversus product selling price (the Sherwood plot).
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TheSherwood
Plot
The Sherwood Plot
The implications of the Sherwood plot are that
- the volume of a specialty chemical reactant solutionhas roughly a constant value, independent of thevalue of the contained chemical
- concentrating the product is probably more important
than separating it from the solution.
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Remove the most plentiful products early
Do the hardest separations lastRemove any hazardous materials early
These three heuristics (also often given forcommodity chemical separation!), are bestunderstood by imagining the sorting of tablewareremoved from a big dishwasher:- We separate the sharp knives first because they can cut us; they
are a potential hazard.
- We sort the forks and spoons early, because there are a lot of
each and because the separation is easy.
- We separate Aunt Evetta's spoons last because they look similarto some of the other spoons.
Avoid adding new species
We will need to add new species in many specialtychemical separations.
- We will add solvents to extract many fine chemicals from the
original extraction mixture.
- We will use adsorbants, especially ion exchangers, forpurification.
- We will add detergents to lyse cell walls and hence release
precipitated proteins that are of therapeutic value.
However, the caution that we remove these addedspecies quickly is the real message of the heuristic.These added species will be much harder to remove themore we close onto the final product.
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Try to avoid extreme temperatures
by using different solvents High temperatures can decompose many specialty
chemicals, but low temperatures can be expensive.
In many cases, we can avoid these challenges byswitching solvents.
In doing so, we will have trouble getting help from thesynthetic chemists, who will normally have identified afew that work well and will not be sympathetic with ourefforts to change reaction conditions in order to make the
purification easier. In addition, we must remember that our choice of
solvents is more binding than normal, for it may violatethe manufacturing procedure approved by clinical trials
The most useful Separations
Fractional distillation is usually not important for speciality chemicalsbecause these tend to have low volatility and to be thermally unstable.
(However, it is the most important separation process for commoditychemicals. This process is basic to the estimated 40,000 columns thatconsume about 6% of the energy used in the USA!).
Fractional distillation will be important to many peripheralsteps in specialtymanufacture, including the recycle and reuse of solvents.
One method of distillation that is quite common for specialty chemicals issteam distillation
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Steam Destillation In this method a temperature-sensitive organic that is only partially
miscible in water is distilled from a two-phase liquid mixture.
The presence of the aqueous rich phase lowers the boiling point andallows distillation of the organic phase (with a high boiling point) without
its decomposition.
Steam distillation is the most common method of obtaining extracts fromplants.
The vapour pressure for two liquids can be approximated as:
Because the boiling point is the temperature at which the total vapor
pressure equals the external applied pressure, this implies that theboiling point of the two-phase mixture is lower than both the boilingpoints of the individual components.
(single phase system)(two-phase system)
Thus even relatively nonvolatile species can be steam
distilled at a temperature lower than the boiling point ofwater.
Moreover, once the distillate is condensed, the twoliquids separate out again and so the removal of theadded water is easy.
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Extraction In extraction, we begin with the dilute solution containing the
specialty product produced by our batch reactor.
We contact the solution with samples of solvent in which the product
is more soluble (we thus concentrate the product, not necessarilyselectively).
If the relative solubility (the solubility of the product in the original
solution relative to that in the extraction solvent) is small, then thatsolvent (extractant) is a good choice
For the product 1 in equilibrium between solvent and feed we have
And the partition coeffiecient:
Extraction
To identify mwe recognize that for saturation in the feedand solution we have
and therefore for the partition coefficient:
In order to seek for efficient extraction we should look forlow relative solubility
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Extraction The second key to extraction is to estimate how much separation we
can get in a single batch:
Combining with the partition coefficient, m, we find the fraction
extracted, f, is given by
Again, it should be noted that a small value of mwill give a large
fraction extracted
Feed volume
Initial feed solute concentration
Feed solute concentration
Solvent solute concentration
Solvent volume
The Soxhlet Extractor
Multiple batchextractions and up-concentration in a singledestillation unit
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Extraction Extraction can also be used as a means of purification
This commonly makes use of mixer-settlers, consists of one stirred tank, calledthe mixer, into which both phases are pumped. The resulting emulsion of the
feed and solvent phases is then pumped to a second unstirred tank, called the
settler, where the two phases are allowed to separate.
When used for purification, the mixer-settlers are often arranged in a staged
cascade (for simplicity, we assume an aqueous feed and an organic solvent).
Stages 2 and 3 concentrate the product, removing it from the aqueous stream
into the organic extract.
Stage 1, however, dilutes the product because of washing the feed with the pure
solvent. But, although Stage 1 dilutes the product, it also purifies it, preferentiallywashing away impurities.
The price of this purification is dilution.
Adsorption In adsorption, a feed containing the product is contacted
with a solid adsorbent.
Because the adsorbent is usually micro-porous, it has alarge surface area on which it can adsorb the product.
These solute-surface interactions are frequently moreselective than the solute-solvent interactions that occurin extraction. Thus adsorption is especially effective forproduct purification, though it can also be used forproduct concentration.
Like extraction, adsorption is conveniently discussed asthree topics:
- how we choose the adsorbent,
- how it will work in batch, and
- how we will use it to purify the product.
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Adsorption
There are three common classes of adsorbents:- Carbons have non-polar surfaces that adsorb non-polar solutes.
They are manufactured from a variety of sources, including coke,wood, and coconut shells (Carbons made from a mixture of
sawdust and pumice are often used to remove color from finechemical solutions).
- Inorganic adsorbents center on activated alumina and silica
gels, both of which are used as dessicants. These materialshave polar surfaces, and so tend to be more effective for polar
solutes.
- Synthetic polymers including ion exchangers. Although ionexchangers are most often designed to capture multivalent ions
in exchange for monovalent ones, they are often remarkablyeffective for selectively adsorbing high value-added solutes suchas drugs and pigments (Often, the desorption to regenerate the
ion exchanger can be more selective than the originaladsorption).
Adsorption
The choice of the adsorbentdepends on experimentalmeasurements of theequilibrium between productadsorbed versus product insolution.
These experimental results,called isotherms, are oftenpresented graphically.
Isotherms are often nonlinear,implying that thethermodynamics is morecomplex than that responsiblefor the partition coefficient usedin extraction.
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Adsorption Isotherms give the solute volume per volume of adsorbent, q1, as a
function of the final solute concentrations in the solution, y1. This means for a batch absorption with a mass balance
where Vis the volume of liquid solution and W is the volume of
adsorbent, that at equilibrium the solute concentration is lower thanthe initial feed concentration y10
A simple way to describe the isotherm mathematically is for example
the Freundlich isotherm,
where Kis an equilibrium constant and the exponent nis less than
one for a favorable isotherm. In practice such batch adsorptions are uncommon.
- One case in which batch adsorption is used concerns the recovery ofextracellular products such as antibiotics from a fermentation broth. By droppingthe adsorbent directly into the broth, we can adsorb the product directly andavoid the sometimes difficult filtration of the broth.
Adsorption A more common way to do adsorptions is to put the adsorbent in apacked bed, and to pour the feed solution through the bed.
In this way the adsorbent is in equilibrium with the feed concentration and
not with the smaller depleted batch concentration (this means that we arehigher up the isotherm and the adsorbent adsorbs more).
If we feed the product solution into a packed bed, in an ideal case the
product will always adsorb until the adsorbent is saturated. This results ina zone of the bed, fully saturated with solute, which grows with time.
When the bed is totally saturated, the exiting concentration will jump from
zero to the feed concentration ("breakthrough curve)
time when the solute starts
to flow out of the bed
time when the bed isfully saturated(exhausted)
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Adsorption
Unfortunately, packed beds do not show these ideal stepchanges in their output. Instead, the concentration profile withinthe bed is dispersed, caused by
- non-instaneous absorption that is in competition with transportthrough the bed
- inhomogeneities in packing
- Taylor dispersion
- axial diffusion.
Because the breakthrough is not a step function, we will need to
use more adsorbent than the ideal minimum needed. One approximate way to estimate this amount is as a "length of
unused bed l',"which can be described as
Adsorption Interestingly, l'is independent of the length of the bed l
This is counterintuitive, as we would expect the concentration profileto spread more the longer the bed and therefore the longer theresidence time in the bed is
However, most isotherms are favorable; they adsorb more stronglyin dilute solution than in concentrated solution (the bent shape of theisotherms)
Any solute that strays ahead of the profile is more likely to be
adsorbed and thus retarded, and any solute that lags behind tends
to flow ahead more quickly. The result is a concentration profile thatis self-sharpening and tends to become more like a step function.
This tendency of adsorption to correct its own dispersion, makes itone of the key separation processes for specialty products
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Crystallization and Precipitation
The third important separation process forspecialty chemicals is crystallization, and itsbastard cousin, precipitation.
- Precipitation is usually a poorly controlled process,done quickly to concentrate the product, to facilitateits isolation.
- Crystallization is done much more slowly, and aims atdramatic purification. It is often the penultimate step in
specialty separation, followed only by drying.
Precipitation Precipitation is triggered by adding a nonsolvent to the solution. The nonsolvent is misciblein the solution, but causes the product to
precipitate because its free energy in solution is increased above that
of the solid product.
Nonsolvents normally have a very different polarity to that of theproduct, resulting in some general heuristics:
- if the feed is aqueous, the nonsolvent may be acetone or t-butanol
- the feed has a solvent such as ethanol, the nonsolvent is usually water
- If the feed is potentially ionic, the precipitation can be effected by excesssalt
Furthermore:
- Precipitation increases as temperature decreases.
- Precipitation of high molecular weight products is easier than of lowmolecular weight ones.
- Precipitation tends to be easier if many solutes are present.
- Precipitation from water is easier when the ionic strength is around 0.1 M.
For more exact results, we must depend on experiment.
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Crystallization
Crystallization tries to purifythe product, not just toconcentrate it, and is therefore one of the most importantseparation processes for specialty chemicals
Crystallization aims at large crystals, that are easier towash and filter (normally the next steps in the separation).
Crystallization depends on three key factors:
- Solubility variation with temperature and solvent composition (an
equilibrium factor parallel to the partition coefficient for extractionand the isotherm for adsorption).
- Second, crystallization depends on the crystal growth rate.
- Third, crystallization depends on the "cooling curve."
Solubility Variation
Usually, the solubility increases as temperature increases.
By reducing the temperature or changing the solventconcentration, we can potentially initiate crystal formation.
Solutions can often contain more solute than that presentat saturation. Such supersaturated solutions arethermodynamically unstable, however, they can bemetastable, a result of the surface energy of small crystals
To overcome the thermodynamic barrier of metastability,larger seed crystals can be added to start the crystalsgrowing in the supersaturated solution. Ideally, theseseeds will be of pure product.
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Crystal Growth Rate The crystal growth rate is, in many instances, controlled by diffusion,
and is described by
where Mis the crystal mass, A is the total crystal surface area, kis a
mass transfer coefficient, and c and c* are the solute concentrationactually in the solution and at saturation, respectively.
The crystal area, A, varies with the crystal mass, M. Assuming
(simplified) spherical crystals we obtain the growth rate of a singlecrystal G, that is independent of crystal size and linearly dependent
on the degree of super saturation.
The Cooling Curve
In order to control the size and purity of product crystalsin a batch crystallizer we normally aim at a constantgrowth rate G.
Since Gis the product of the mass transfer coefficient,kD, and the degree of product supersaturation, (c- c*)and since the coefficient kDdoes not change much withtemperature we have to control the crystal growth ratevia the temperature dependence of c*.
We have seen from the solubility variation that c*decreases with decreasing temperature. Thus for aconstant crystal growth rate we want to cool, since cisdecreasing over time, so that (c- c*) is staying constant !
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The Cooling Curve
We can calculate now the necessary temperature variationwith time in order to keep Gconstant (the cooling curve)
initial temperature
final temperature
seed mass
maximum possible crystal mass minus seed mass
dimensionless time
final crystal radius
seed radius
final time
An Example: Penicillin Purification This classic process is the model
for a huge group of antibiotics,including cephalosporins, which
are based on -lactams. Thesemolecules can be made either
chemically or microbiologically.
In the microbiological route,mutants of Penicillium
chrysogenumare grown in 100 m3
aerated fermenters that are
charged primarily with lactose,corn steep liquor, and calciumcarbonate.
After about 7 days, the broth
contains perhaps 80 mg/L ofpenicillin.
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Penicillin Purification
How to isolate and purify the penicillin from the broth?
Key to this purification is the recognition that penicillin is acarboxylic acid. When the pH is above about 5.5, theCOOH group ionizes to COO- and the penicillin becomeswater soluble. When the pH is below 5, the COOH groupremains protonated, and the penicillin is more soluble inorganic extraction solvents
The first step is to separate the penicillin containing brothfrom the large biomass of micro-organisms. Because
normal filters tend to plug, this separation involvesadsorption of the microbes on diamataceous earth (Filter-Aid) and then filtration
The clarified broth is acidified and then extracted with amyl acetate.
Because the acid form of the penicillin is less stable, this extraction shouldbe as fast as possible. (The first amyl acetate extract is decolorized byadsorption on activated carbon)
Then the amyl acetate is extracted with water at pH 7.5, so the productmoves back into the water.
This entire process is repeated until the penicillin is concentrated perhaps100 times.
The last aqueous extract may be dried as a crude product before it isredissolved
Finally, butanol is added to the aqueous penicillin solution under a defined
temperature profile to precipitate crystals of sodium or potassium penicillin