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
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 finetuned, 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 scalecan 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, neuroshunt 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.
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 Temperature 00Plant A Plant B
135oC Pressure atm Btu/hr
140oC atm Btu/hr
Pilot Plant Controls
Heating Duty 220,000 500,000 Refrigeration 7 tons 16 tons Power Recycle Compressor Capacity 100 kw 210 kw 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.
(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