Chemical Product Design PartI Speciality Chemicals

8/6/2019 Chemical Product Design PartI Speciality Chemicals

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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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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


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

Chemical Product Design PartI Speciality Chemicals

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