What Is Supercritical CO2?

Carbon dioxide is in its supercritical fluid state when both the

temperature and pressure equal or exceed the critical point of 31°C

and 73 atm (see diagram). In its supercritical state, CO2 has both

gas-like and liquid-like qualities, and it is this dual characteristic of

supercritical fluids that provides the ideal conditions for extracting

compounds with a high degree of recovery in a short period of time.

CO2 Phase Diagram

By controlling or regulating pressure and temperature, the density,

or solvent strength, of supercritical fluids can be altered to simulate

organic solvents ranging from chloroform to methylene chloride to

hexane. This dissolving power can be applied to purify, extract,

fractionate, infuse, and recrystallize a wide array of materials.

Because CO2 is non-polar, a polar organic co-solvent (or modifier)

can be added to the supercritical fluid for processing polar

compounds. By controlling the level of

pressure/temperature/modifier, supercritical CO2 can dissolve a

broad range of compounds, both polar and non-polar.

Supercritical Fluid Extraction Systems

Supercritical Fluid (SCF) technology works! With today's

innovative, easy-to-use systems from Applied Separations, your

idea will be tomorrow's green process! No petroleum solvents and

no toxic residue.
We have built thousands of SCF systems. Get the benefit of our

experience. You have the ideas, we have the SCF systems - from

conception to production. From laboratory systems to pilot plants to

large scale production facilities.

Applications and process support? We have been involved in

hundreds of uses for supercritical fluids. Discuss your ideas with

us. We’ll evaluate your sample for free.

A few examples include:

Extracting herbs, spices and fragrances

Extraction of pharmaceuticals / nutraceuticals

Extracting nicotine and caffeine

Extraction from foods

Dyeing textiles

Cleaning medical implants

Making nanoparticles

Drying aerogels

Cleaning wafers

Developing photoresists

Extraction from polymers

Impregnation of biopolymers
We're partners.

Our support doesn't stop with the delivery of a system, we can help

you bring your development ideas to full scale production.

Pressurized Solvent Extraction

New applications for a time-tested, proven technology

Pressurized solvent extraction (pse), also known as accelerated

solvent extraction (ase), pressurized fluid extraction (pfe), and

solvolytic extraction, uses solvents at high temperatures and

pressures to accelerate the extraction process. The higher

temperature increases the extraction kinetics, while the elevated

pressure keeps the solvent from boiling.

Why Choose PSE Over Traditional Extraction Methods?

Save time

PSE replaces slow traditional extraction methods, saving time. In

fact, extractions taking 8 hours by Soxhlet can be done in as little

as 15 minutes by PSE.
 Reduce solvent cost

PSE uses as little as 15mL of solvent per 10 gram sample.

Reduce solvent waste

Traditional methods like Soxhlet and sonication can use up to

500mL of solvent per sample.

Reduce operating cost

PSE is faster and more efficient than traditional methods.

Applied Separations’ PSE process utilizes most of the solvents you

already use in traditional methods. We also offer many application

notes, further shortening the methods development process.

Polymers and Supercritical Fluid Applications

Interest in supercritical fluid processing of polymers has grown over

the last 15 years, and many purification, fractionation, and

polymerization applications have emerged. A significant motivation

for applying this technology to polymers is increased performance

demands required of polymer products coupled with the technical

limitations of more traditional purification and fractionation

methods. With increasing scrutiny of industrial solvents,

supercritical fluid technology, especially using carbon dioxide, is

receiving widespread attention as an environmentally conscious

method for replacing various organic solvents used in industrial

operations.

Phasex has been instrumental in developing many of the

supercritical fluid processes currently in production or advanced

development: purification of brain shunts, fractionation of medical

polymers, devolitilization of space grade and high vacuum

adhesives, and production of narrow molecular weight range high

density disk lubricants.

A few examples are presented here to demonstrate the breadth of

polymer applications using supercritical fluids.

Polymer Extraction and Fractionation

It is possible to tailor the performance of polymers by modifying

certain properties such as molecular weight, polydispersity, or

crystallinity via supercritical fluid extraction or fractionation. For

example, the undesirably high viscosity of a polymer can be

reduced by separating the very high molecular weight species from

the polymer via supercritical fluid fractionation. Similarly, undesired

low molecular weight or cyclic species in a silicone polymer, which

can migrate in some high temperature application, can be removed

by SCF extraction. Because their dissolving power can be fine-

tuned, often to high degree of selectivity, supercritical fluids can

separate polymers by molecular weight, which, as suggested

earlier, can enhance their performance.

Fractionation of a Perfluoroether

An example is presented to demonstrate the effectiveness of SCF

fractionation in preparing narrow polydispersity polymer fractions

which are useful in characterizing structure-property relations,

elucidating reaction kinetics, and even as calibration standards.

For the exact determination of molecular weight by SEC, narrow

standards of the polymer being analyzed must be used, but they

are not generally available, especially for polymers like the

perfluoropolyethers (Krytox®, Fomblin®), high molecular weight

silicones, and polyethylene and its copolymers.

The polydispersity of the parent polymer shown is

1.87. It has been reduced to an average of 1.08 for

the nine fractions. Molecular distillation cannot carry

out the fractionation of this polymer because its vapor pressure is

too low, but supercritical fluids have been effective in producing

narrow standards of the high molecular weight (>8,800)

perfluoropolyether.

Fractionation of Polyolefins

The properties of supercritical fluids can also be manipulated so as

to fractionate polymers by, for example, crystallinity. Fractionation

of polyethylene by molecular weight and side chain branching is

another example presented here of the advantages offered by

supercritical fluid processing.

Narrow fractions of polyethylene and its copolymers are desired for

many reasons e.g., for GPC calibration standards, properties

evaluation, kinetics studies or catalyst performance analysis.

Generally, the fractions are not commercially available. For the

specific case of GPC standards, hydrogenated polybutadiene is

sometimes used, but it is not a good model for commercial

polyethylene, such as LDPE, HDPE, LLDPE and certainly not for

experimental copolymers; there is, for example, no short and long

chain branching on hydrogenated polybutadiene, and although

molecular weight ranges of HDPE or LLDPE can be matched, the

hydrodynamic volume cannot be.

Quantities of very small (mg) size can be obtained by GPC

fractionation or by anti-solvent methods, and a laboratory process

called TREF (Temperature Rising Elution Fractionation) can

produce small quantities of polyethylene separated by crystallinity;

however, producing preparative amounts requires many liters of

solvent to process even a 5g charge.

At a preparative bench scale, fractionation with

supercritical fluids produces large quantities of narrow

MW fractions. Additionally, CITREF, Phasex Corporation's

supercritical variant of TREF, can separate ethylene polymers and

copolymers by side chain branching and chemical composition,

again producing large fractions. The HDPE described here was

fractionated by the process Phasex terms increasing pressure

profiling.

Mn, Mw, and polydispersity fraction table

Supercritical fluids can also fractionate polyethylene and its

copolymers (e.g., acrylate, methacrylate, acrylic acid, vinyl acetate)

by crystallinity/side chain branching/chemical composition. The

process Phasex terms CITREF (Critical Isobaric Temperature

Rising Elution Fractionation) can, like pressure profiling, produce

large fractions for fundamental studies, polymer properties

determination, or catalyst performance evaluation. A commercial

LLDPE was fractionated by amount of side branching. CITREF has

separated the LLDPE, not by narrow MW, but by crystallinity

(melting point).

Mn and Mw for all fractions

DSC thermograms of the thirteen LLDPE fractions

separated by side chain branching are shown in the

figure on the right and are compared with the DSC of

the parent polymer. The narrow transition range and the increasing

transition temperature of each fraction obtained by CITREF are

readily seen. The CITREF fractions of polyethylene are useful for

the overall evaluation of the polymerization process, the narrow

fractions providing quantitative information on kinetic profiles, and

catalyst life and performance (mols monomer/mol of active

catalyst).

Other polyolefins and copolymers produced by virtually any catalyst

technology can be readily processed with supercritical fluids by

pressure profiling, for molecular weight distribution, and by

CITREF, for crystal unity and chemical composition distribution.

Polyolefins and copolymers fractionated by molecular weight, side

chain branching, and chemical composition-at the kilogram scale-

can facilitate your determination of polymer structure/property

relationships and polymerization catalyst performance. Let Phasex

fractionate your polymers for kinetic studies, catalyst

life/performance evaluation, properties determination, and new

product development.

Extraction of Medical Polymers and Devices

Many medical devices that are in contact with the body or body

fluids or that are surgically implanted in the body are composed of

silicone polymers because of their biocompatibility. The silicone

parts are lightly cross linked to retain structure, but the cyclic

byproducts present in the silicone polymer are not incorporated into

the matrix; thus, they can migrate. Since the volatility of the cyclics

is so low, high temperature vacuum or nitrogen stripping is

ineffective. Organic liquid extraction can be effective in removing

the interfering species, but the issue of residual solvents in the

devices then becomes a concern. Supercritical fluid extraction of

residual cyclics from medical devices is attractive especially

because the purification process cannot be reasonably carried out

by any other technique. Cyclics and low molecular weight

oligomers content can be as high as 4 wt%, and extraction with

supercritical CO2 can reduce the level of these species to less than

10ppm. Several examples of medical products that have been

extracted using SCFs include aorta and other arterial grafts, neuro-

shunt lines, and catheters.

Supercritical fluids have also been used to extract other medical

and ocular materials, for example, to purify methacrylate

functionality silicone macromonomers that are used in the

manufacture of soft contact lenses. Because these

macromonomers are very heat labile and have very low volatility

(and thus require high temperature to purify them even under high

vacuum), they are virtually impossible to purify by any traditional

process.

Purification of Reactive Monomers

Reactive monomers are inherently difficult to process by traditional

methods. SCFs offer a useful alternative for extracting, for

example, odors from an acrylate monomer. The HPLC traces

shown demonstrate that even minute quantities of impurities can

be readily extracted from a temperature sensitive methacrylic

monomer.

Impregnation of Porous and Polymeric Matrices

Extraction and fractionation are the most common operations using

supercritical fluids, but the process can be reversed to deposit

materials, for example, into a porous or polymeric substrate. In this

application a supercritical fluid is used to convey an organic

compound into micropores of a substrate, the

pressure/temperature then reduced to bring about precipitation in

the micropores. With polymeric substrates, the SCF first swells the

polymer then conveys and deposits a compound in the matrix.

Monomers and polymers can also be impregnated into a porous

substrate, but the procedure is a bit more complex, viz., the

pressure/temperature must be selected so as to dissolve the entire

polymer (not just the low molecular species). Because the

dissolving power of SCFs can be adjusted over wide ranges, the

conditions can be manipulated so as to dissolve and deposit the

entire polymer homogeneously.

Photoresists

With the rapid evolution of products in the microelectronics industry

there is an increasing need for higher purity materials and safer,

more efficient solvents, and supercritical fluids are proving effective

in satisfying these needs in diverse photoresist applications ranging

from polymer purification and fractionation to image developing.

SCFs have been applied to improving the performance of

photoresist polymers by purification and/or fractionation. Specialty

polysiloxane and polysilane polymers that are being developed as

photoresists have broad molecular weight distribution resulting in a

variable sensitivity to radiation at 248-254 nm wavelength.

Sensitivity can be controlled by using near-monodisperse fractions

of these polymers in resist applications, but there is no traditional

synthesis method that can produce monodisperse polysilanes or

polysiloxanes; SCF fractionation overcomes this problem.

Supercritical fluids have also been applied as developers for

photoresist imaging; they eliminate problems associated with

organic liquid developers such as swelling and image distortion and

they minimize solvent waste. Furthermore, utilization of SCFs for

photoresist imaging is applicable to a number of new polymer

systems under development as next-generation resists. SCF

imaging has been demonstrated with several polymer systems

including silanes and siloxanes, fluorinated methacrylates, and

siloxane-modified methacrylates for creating positive or negative

tone images.

Toll Processing Plant

MINIMIZE PROCESS OPTIMIZATION COSTS

MAXIMIZE SPEED TO MARKET OR TEST MARKET
ELIMINATE EARLY STAGE HIGH RISK CAPITAL
INVESTMENT

Versatile Plant For Toll Processing

Initially installed to serve as a process optimization pilot plant, the

tolling plant (Plant A) came to its current capability by a series of

vessel, separator, and recycle compressor retrofits. The plant's

current processing capabilities are 100,000 kgs/yr, and it has been

designed for maximum flexibility and efficiency. And while it is still

available as a pilot plant for collecting scale-up and long term

processing operating data and for establishing integrated

extraction/separation gas recycle parameters, its primary function

is as a materials processing facility for the medical polymers and

nutraceuticals markets.
 The solids extraction section of
Plant A with its 80L and 150L
vessels

The plant can also process liquid feedstocks at large volume, in a

4in diameter, 17ft counter-current column. A 2in diameter, 12ft

high column serves as a process optimization unit or it can process

small (< 50 kg/day) amounts of material. Volatiles stripping,

purification, and fractionation campaigns are processed at

throughputs of 20 to 600 kg/day depending upon the specific

selectivity and distribution coefficients (which are determined

during feasibility and optimization testing). Surface area enhancing

internals result in contact efficiencies of 20 to 30 equilibrium stages

in the columns, providing a high degree of purification and

fractionation of lubricants, liquid polymers, and surfactants.

 Both counter-current columns

Integrating its broad technical base with a facility designed for rapid

scale up, process optimization, and large scale production, Phasex

Corporation reduces time to market, minimizes development costs,

and delivers superior quality products and processes.

Largest Specialty Materials Tolling Plant in the U.S.

Phasex is installing a larger toll processing facility (Plant B) with 2 x

320L vessels and a 800kg/hr gas recycle capacity. The installation

is literally in progress at the time of this posting, and we thought

we'd carry you through a bit of the construction history. We've had

some of our staff visit some of our suppliers (Vitco-Gray/ABB) to

capture on camera the various steps of vessel manufacture, heat

treating, forging, machining, etc., and these steps are depicted in

the photographs below; they show, in sequence, a hot (1000º C)

billet of stainless steel progressing to a completed vessel.

Billet Removed from Furnace, Forging, Machining,

Closure Attachment

The vessels were completed (welded & pressure tested) in early

2001, and they are now installed at Phasex. The photographs

below show the progression as the vessels are being installed on

their platform. Plant B will have processing capacity of 350,000

kg/yr of solid feedstocks and 300,000 kg/yr of liquid feedstocks.

Both plants have been provided with dedicated power, heating, and
refrigeration so that both can operate simultaneously, and the

combined capacity of Plants A and B are in excess of 500,000

kg/yr.

New Vessel Installation in Plant B

We work closely with our customers, both in the early research

phase and during long term production, and we work just as closely

with our vendors and suppliers during equipment design and

manufacturing stages. We obtained our vessels from Grayloc

Products (Division of ABB Vetco Gray, Inc.), and we thought we'd

give them a plug: The photo below shows their name on the

shipping crate protecting the Grayloc closure on the vessel just as

it was taken off the freight elevator. Our rigger and equipment
installer, Toupin Brothers of Dracut, MA, has been doing this for us

since 1989 when they installed our first vessel to expand the pilot

plant; one of their trucks is shown in the photo below.

Consider the production capabilities that we have now and that

we are installing when you evaluate your current product

extraction/concentration requirements or your planned new product

development.

PLANT OPERATING
SPECIFICATIONS

Operation Plant A Plant B

Parameters
Temperature 0- 0-
 135oC 140oC Pilot Plant Controls
Pressure 30-340 30-340
atm atm
Heating Duty 220,000 500,000
Btu/hr Btu/hr
Refrigeration 7 tons 16 tons
Power 100 kw 210 kw
Recycle 300 700
Compressor kg/hr kg/hr
Capacity

Additional Plant Data

Both recycle compressors are constructed with triple diaphragms,

designed expressly to eliminate lubricants contamination in the

recycle stream (and as long as we're passing out kudos, our

compressors are manufactured by Pressure Products Industries, a

supplier of "Rolls Royce" diaphragm compressors); we have four of

them. Plant A, initially a small process optimization plant, was

retrofitted with a 300 kg/hr unit and it adheres to Class 1, Division 2

electrical code so that we can process with the light hydrocarbons

propane and butane, incidentally GRAS solvents. Plant B is

designed from conception for Class 1, Division 2.

Although Supercritical CO2 is quite versatile in its extraction

capabilities, it is not universal in its dissolving characteristics.

Cosolvents, such as anhydrous ethanol, are occasionally employed

for extracting some of the more polar compounds; and the light

hydrocarbons, as previously noted, are effective for extraction of

reaction byproducts from medical polymers, and are safely

employed because of adherence to the Class 1, Division 2

electrical code.

About Supercritical Fluids

This article appeared in the May 1998 issue of European

Pharmaceutical Contractor (EPC) and is reproduced here with their

permission. We hope it will serve as an easy-to-read introduction

for those who are unfamiliar with the solvent properties of

supercritical fluids. Although the examples given in the article are

directed primarily to the pharmaceuticals and medical products

industries, we think all readers will find the applications described

of interest. If you desire more technical information, please contact

us.

Supercritical Fluids: Their Proliferation in the Pharma Industry

by Val Krukonis

Supercritical fluids are finding increasing application in the pharma

industry for the solution of difficult processing problems.

Supercritical fluids exhibit a pressure-tunable dissolving power,

they possess a liquid like density (and thus a high solvent

strength), and their gas like transport properties allow facile

extraction from dense botanical materials to be achieved. This

unique combination of properties is ideally suited for developing

processes for extracting, purifying, and recrystallizing fine

chemicals and pharmaceuticals and producing new product forms

that cannot be obtained by industry's more traditional processing

technologies.

BACKGROUND AND HISTORICAL PERSPECTIVE

The term 'supercritical fluid' describes a gas or liquid at conditions

above its critical temperature and pressure - i.e., above the critical
point. Drawing from physical chemistry texts, the critical point is

located at the 'end' of the vapor pressure curve, and Figure 1

shows a generalized vapor pressure curve and its 'end'. The

accented region in the figure denotes supercritical fluid space

where many gases exhibit the propensity to dissolve materials.

At a meeting of the Royal Society (London) in 1879, two

researchers, Hannay and Hogarth, reported that supercritical fluids

have a pressure-dependent dissolving power-the higher the

pressure, the higher their dissolving power (1). They described

their work and summarized their findings as follows: We have the

phenomenon of a solid dissolving in a gas, and when the solid is

precipitated by reducing the pressure, it is brought down as a

'snow' in the gas. The researchers referred to supercritical fluids as

gases, which, in fact, they are. In the interest of brevity, the term

'gas', or the abbreviation 'SCF' for supercritical fluids, will be used

liberally throughout this paper.

The solubility behavior found by Hannay and Hogarth was not

exploited until many, many years later, but it is of historical interest

to relate some of the events surrounding their findings. There arose

serious (but, as were the times, polite) controversy at the October

1879 society meeting: Some of the members who were present

said, "Gases cannot dissolve solid compounds. The researchers

must have erred and instead found solubility in superheated

liquids." In other carefully planned and executed experiments the

researchers did, however, substantiate their previous findings.

Gases, in other words, supercritical fluids, could indeed dissolve

many compounds.

A few years later, Eduard Buchner (of biochemistry and 1907

Nobel Prize fame) became the first in a long line of researchers to

measure the solubility of a model compound, naphthalene, in

supercritical carbon dioxide (2). The Proceedings of the Royal

Society (and other journals) describe much of the work during the

early years of supercritical fluids activity, and naphthalene is still

studied today for the information its solubility behavior presents to

new researchers in the SCF field.

 SOLUBILITY IN SUPERCRITICAL FLUIDS

The solubility of naphthalene in supercritical carbon

dioxide is shown in Figure 2. As one would expect, at

low pressure its solubility is essentially nil. As the pressure of the

gas is increased to above the critical pressure of carbon dioxide

(which is 73 atm), the solubility rises, and for many compounds

including naphthalene, the rise is often quite dramatic, as is seen in

the Figure. For example, at 200 atm and 45°C, the solubility is 7%.

The solubility behavior shown in Figure 2 is the basis of almost all

the supercritical fluid extraction/separation processes in operation

throughout the world: Soluble components are extracted from a

substrate by a high pressure gas, and the extracted components

that have been dissolved in the gas are precipitated from the gas

when the pressure is reduced, for example, across a pressure

reduction valve.

Starting in the 1960s, many research groups, primarily in Europe,

and then later in the U.S., examined SCFs for developing

'advanced' extraction processes. European researchers

emphasized extraction from botanical substrates, for example,

spices, herbs, coffee, tea, and so on, using predominantly

supercritical carbon dioxide, and by the 1980s there were several

large SCF extraction processes in operation in Germany, the UK

and the US, for decaffeinating coffee and tea and extracting flavors

and essential oils from hops, spices, and herbs. As an example of

size, a coffee decaffeination plant in Bremen processes more than

60,000,000 kg/year.

The major motivation for developing these SCF processes was the

elimination of residual solvents in the products, especially

methylene chloride, which had previously been used to

decaffeinate coffee. Solvent residues in pharma and food products

were becoming the focus of regulatory attention in the 1970s, and

increasing regulatory attention is today being directed to solvent

residues. Besides the elimination of solvent residues, there are

also other advantages that accrue from employing supercritical

fluids in coffee, spices, and herbs, i.e.: enhanced flavor and aroma
characteristics that cannot be obtained by the traditional organic

solvent extraction processes.

A schematic diagram of a generic supercritical fluid

extraction process is shown in Figure 3 and, for

concreteness, operation is described for the case of extracting

hops, the extracted flavors being used in the brewing of beer.

Compressed and pelleted hop flowers (called lupelones) are

charged to the extraction vessel, which is subsequently secured for

pressure operation. Carbon dioxide (from a reservoir not shown in

the diagram) is pumped into the vessel, and after the temperature

and pressure are adjusted to supercritical conditions of about 60°C

and 300 atm, respectively, continuous flow of carbon dioxide is

initiated. Hop flavors and lipids are extracted as the carbon dioxide

flows through the charge of hops, and the solution (of carbon

dioxide and flavors) is decreased in pressure to about 60 atm

across the pressure reduction valve shown in Figure 3. Because

the dissolving power of the carbon dioxide has been dramatically

lowered, the flavors and lipids precipitate from the gas phase and
collect in the separator; the carbon dioxide is recompressed and

recycled to the extractor, and the process CO2 flow continues until

all the flavors are extracted. The extraction vessel is then vented,

the spent hops are removed, fresh pellets are charged to the

vessel, and the process started again.

Besides the enhanced flavor characteristics and frequently higher

yields associated with supercritical fluid extraction, some other

technical and economic advantages reside in the use of carbon

dioxide for the extraction of hop flavors. Organic solvents such as

methylene chloride or hexane had previously been the solvents

used for the extraction of hops. To obtain the concentrated flavors,

it was necessary to distill off the organic solvents, and some of the

top note aromas are lost during this step. Carbon dioxide produces

a superior product because the top notes are not distilled off, and,

as mentioned above, the issue of solvent residues, which is a

constant spectre, is eliminated by the use of carbon dioxide.

In the 1980s other industrial applications of SCFs were being

explored, for example, extraction of undesired byproducts from

pharmaceuticals, purification of medical polymers, and separation

of complex synthesis mixtures. 'Non-extractive' processes, were

also being developed, the formation of ultra fine particles foremost

among them. Currently the recrystallization of materials via SCF

processing is under intense study at many pharma companies in

Europe and the US. To be sure, there is continuing development

on 'simple' extraction processes of residuals from medical

polymers, of impurities from surfactants, and of active components

or nutraceutical mixtures from botanical and biological substrates,

and some of these supercritical CO2 processes are now in

production, not at the huge production volume of coffee, tea, and

hops, but at levels of 1,000 to 100,000 kgs per year or so, as is

more characteristic of the medical products, fine chemicals, and

pharmaceuticals industries.

WHERE ARE SUPERCRITICAL FLUIDS BEST APPLIED?

The author has widely communicated his view on using

supercritical fluids for developing new products or processes - 'if it

ain't broke, don't fix it' (3), in other words, don't force fit supercritical

fluids into an application that is adequately handled by traditional

industrial operations, such as solvent extraction, distillation, wiped

film evaporation and the like. On the other hand, if research is

fundamental in nature, for example, dealing with physico-chemical

phenomena, thermodynamics, kinetic principles, and so on, it need

not have industrial application, especially in the university system

with its goals to teach, to instill curiosity, and to create knowledge.

Applied industrial research should be sufficiently and justifiably

motivated, especially in today's economic climate.

Where then, on both technical and economic grounds is the unique

combination of properties and attributes of supercritical fluids most

advantageously applied in developing improved processes and

products?

Where environmental compliance pressures will soon require

a change in the process
Where regulatory pressures will soon require a change in
product purity
Where increased product performance will soon be required
Where an improved product can create a new market position
 and where none of these can be achieved by industry's more
traditional industrial processes.

It has been lamented by some that processing with supercritical

fluids is not economical, and, unfortunately, the general impression

does exist that supercritical fluids are associated with high

processing costs; however, supercritical fluid decaffeinated coffee

available at competitive market prices (with organic solvent

decaffeinated coffee) certainly would contradict this impression.

The misassociation of high cost with supercritical fluid processes

has undoubtedly derived from the fate of several widely publicized

(but ill-advised) studies in the late 1970s, whose lack of industrial

viability was attributed solely to a high processing cost when, in

actuality, there were technical limitations (that were not described).

As with the 'if it ain't broke' discussion above, the author suggests

that a case-by-case evaluation of economic viability be made early

in any new application development. Supercritical fluids are

frequently excellent solvents technically, with far ranging

applications to many purification problems, but they may not be

economically viable in each case.

Three examples of successful applications of supercritical fluids in

the pharma, fine chemicals, and medical products industries are

described below.

RECRYSTALLIZATION OF PHARMACEUTICALS

Some pharma compounds are difficult to micronize by conventional

grinding or jet milling. For example, materials that have a low (less

that 60°C) melting point, or that are waxy, cannot be ground or

milled to fine size (less than 1 or 2 microns), because they will

smear or form amorphous and size unstable particles. Two

supercritical fluid processes have been developed in response to

these difficulties. In one, a supercritical fluid is employed as a

solvent to dissolve a pharma compound, then, by pressure

decrease, cause precipitation; in the other, the gas acts as an anti

solvent, causing recrystallization from a liquid solution because of a

solubility decrease when the gas and liquid solvent contract.

Recall Hannay and Hogarth's statement on the formation of 'snow'.

Assuredly, the snow was of a size different from that of the parent

material, and their observations of 100 years ago are the basis of
the particle formation process termed RESS (rapid expansion of

supercritical solutions). RESS is employed with SCF soluble

compounds. If a pharma compound is not soluble in a gas (and

many very polar compounds are not), the gas can be used an anti

solvent, causing recrystallization when the gas and an organic

solvent solution are admixed. The process, termed GAS (gas anti

solvent) recrystallization, exploits the miscibility of carbon dioxide

with virtually all laboratory and industrial solvents. With a gas anti

solvent, the rapidity and intimacy of mixing far exceeds what liquid

anti solvents can achieve, and thus GAS recrystallization can

achieve narrow particle size distribution in the 100s of nanometer

range.

The advantages of both processes reside in the

literally millisecond timescale for pressure reduction

or admixing of solution and gas, which creates a high

supersaturation ratio, thus resulting in the formation

of ultrafine particles of narrow size range. As related earlier, market

driven motivations for applying supercritical fluids to

recrystallization opportunities will enhance the probability of an

economic success; for example, creation of a new pharma product

that be delivered via inhalation, instead of parenterally, would

certainly justify the application of supercritical fluids, especially if

traditional jet milling can not achieve the desired product

characteristics.

Figure 4 shows comparative photomicrographs of one compound,

ßzlig-pregnanolone, recrystallized from supercritical carbon

dioxide. The parent material ranges in size from about 2 to 15

microns, and the supercritical fluid processed (by RESS) material

ranges from 1 to 2 microns. The photomicrographs exemplify the

capabilities of supercritical recrystallization, and as related earlier,

many pharma companies in the US and Europe are evaluating

supercritical fluids for forming nano-sized pharma compounds in

the development of advanced delivery formulations.

PURIFICATION OF SURFACTANTS

Liquid and solid surfactants are used in the formulation of many

pharma products. These surfactants are usually the same ones

that have been produced for less demanding, but very high volume

applications, ranging from food products to cleaning solutions and

floor wax. Many surfactants suffer from color, odor, byproducts or

other limitations and, usually, these surfactants have, for pharma

applications, been processed to the best purity levels achievable

with industry's traditional technologies. Increasingly, supercritical

fluid extraction is demonstrating the ability to purify several types of

surfactants of importance for pharma

formulations.

As an example of the separation of

color species, Figure 5 shows samples

of two surfactants and the

corresponding SCF purified materials.

The color of the parent materials is a result of polymerizing

reactions that occur during synthesis. Because the vapor pressure

of the materials is very low, they cannot be distilled to improve their

color. Supercritical carbon dioxide separates materials on the basis

of solubility, not vapor pressure, and thus it can purify heat

sensitive materials that cannot be processed by distillation or very

low vapor pressure.

EXTRACTION OF BYPRODUCTS FROM POLYMER

COMPONENTS

Over the past five years, there has been increased scrutiny of

potentially migratable species that are present in polymeric devices

that are inserted or surgically implanted in the body, for example,

urinary catheters, brain shunts, aorta grafts and the like. The

polymers, especially if they are silicone or polyester based,

normally contain several percent residual byproducts and raw

materials. Sometimes the objectionable components can be

removed from the polymer before it is manufactured into the

device, and sometimes they cannot, especially if the polymer is

silicone based. Silicone raw materials, for example, normally react

further during the manufacture of the device, the reaction producing

the byproducts directly in the finished part.

Organic solvents, such as hexane and methylene

chloride, can usually dissolve and extract objectionable

components, but vestiges of these solvents are themselves often

difficult to remove without degrading or altering the characteristics

of the polymer or device. The attributes of supercritical fluids,

especially CO2, are again extremely attractive in the polymer

extraction application. Carbon dioxide swells polymers sufficiently

to allow the interior volumes to be reached in order to dissolve and

carry away the undesired materials and, when the pressure on the

part is reduced, all the carbon dioxide is removed. Figure 6 shows

selected medical components that are currently being processed

with supercritical fluids to remove undesired species.

CONCLUDING REMARKS

When Professor Andrews of Queens College (4) determined the

critical point of carbon dioxide, he probably did not know of its

solvent properties, and Hannay and Hogarth (and Buchner, and

scores of others in the early 1900s) could not have envisaged that

a huge plant would be built in 1978 (in Bremen), decaffeinating

coffee with supercritical carbon dioxide in a process that eliminates

regulatory concerns about solvent residues, environmental

concerns about ozone depletion and hydrocarbon emissions, and

worker safety concerns (because carbon dioxide in non-toxic and

non-flammable), while simultaneously producing a product with

superior taste and at a cost competitive with the standard organic

solvent-based processes.

The pharma industry (as well as others) is starting to recognize the

technical, regulatory, and market attributes of supercritical fluids,

and is increasingly applying them to the solution of difficult

problems. It is opined that the 21st Century will see many

processes that have been developed to exploit the properties of

supercritical fluids. The caution, 'if it ain't broke, don't fix it', should

guide each evaluation. But if it is 'broke', maybe supercritical fluids

can fix it.

 References

(1) Hannay, J.B. and Hogarth, J., On the Solubility of Solids in

Gases, Proc. Roy. Soc., (London). 29:324. 1879

(2) Buchner, E.G., Die beschrankte Mischbarkeit von Flussigkeiten

das System Diphenyamin und Kohlensaure, Z. Phys. Chem.,
56:257. 1906

(3) Krukonis, V., Brunner, G., and Perrut, M., Industrial Operations
with Supercritical Fluids: Current Processes and Perspectives on
the Future, Proceedings 3rd International Symposium on
Supercritical Fluids, Tome 1. p1. Strasbourg, 17th October 1994

(4) Andrews, T., The Bakerian Lecture - On the Gaseous State of

Matter., Proc. Roy. Soc., (London). 24:455. 1875