what is super critical co2
DESCRIPTION
Fluido supercritico,supercritical fluid and CO2.Comportamento do CO2 numa fase Supercritica.TRANSCRIPT
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
Parameters
Plant A Plant B
Temperature 0- 0-
135oC 140oC Pilot Plant Controls
Pressure 30-340
atm
30-340
atm
Heating Duty 220,000
Btu/hr
500,000
Btu/hr
Refrigeration 7 tons 16 tons
Power 100 kw 210 kw
Recycle
Compressor
Capacity
300
kg/hr
700
kg/hr
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