In the 1960's, researchers discovered that there could be an alternative method for supporting injured lungs. They found that mice whose lungs were filled with an oxygenated saline solution could survive for several hours. Further uses with oxygenated silicone oils had some success, but were later found to be toxic.
Liquid ventilation is accomplished through a liquid called perfluorocarbon (PFC). Leland C. Clark, Jr. and Frank Gollan published an article in 1966 about their experiment with fluorocarbon. They discovered that oxygen and carbon dioxide are very soluble in certain silicone oils and fluorocarbon liquids. Experimenting with mice and cats, it was found that these liquids would support the animals' respirations. What was strange was that the mice and cats that breathed the silicone oil died shortly after returning to breathing normal air, while those that remained in the fluorocarbon survive for weeks. The cats proved to have excellent arterial oxygenation, but there was a problem with carbon dioxide elimination. The most significant discovery that resulted from this period of time was the potential for the use of these perfluorochemical liquids.
Studies of total (tidal) liquid ventilation were first performed in treatments of several premature babies in 1989. These studies showed improvement in patients' lung compliance and gas exchange, but could not be pursued further due to the lack of technology to provide an applicable liquid ventilator system. Also at that time there was not a pharmaceutical-grade PFC available.
Perfluorocarbon
Partial liquid ventilation would not be possible without this remarkable chemical known as perfluorocarbon (PFC). These liquids are clear, colorless, odorless, nonconducting, and nonflammable. They are approximately twice as dense as water, and are capable of dissolving large amounts of physiologically important gases (mainly oxygen and carbon dioxide). PFCs are generally very chemically stable compounds that are not metabolized in body tissues. PFCs require a high FIO2 to maintain high oxygen concentrations within the fluid. It is only the carrier of oxygen and carbon dioxide. PFCs do not produce the gases.
Chemistry of PFC
Perfluorcarbons (PFCs), fluorocarbons, or perfluorochemicals (terms which can be used interchangeably) are formally derived from hydrocarbons by replacing all the hydrogen atoms with fluorine atoms.
First synthesized in the 1920s, PFCs were developed for industry in the 1940s as part of the Manhattan project. Liquid PFCs are uniquely characterized by very high intramolecular bonding and very low intermolecular forces. The C-F bond is the strongest single bond encountered in organic chemistry, and its strength is further increased when several fluorine atoms are present on the same carbon atom. The presence of fluorine even reinforces the C-C bonds. PFCs are taken from fluorinating organic compounds. This altered chemical is fairly stable with some varying physical properties. Those physical properties include vapor pressure, density, and viscosity. PFCs may stay in the body for some time but not affect any functions. After a few years they are completely excreted from the body. PFCs are lipid soluble, but they are totally insoluble in water. This may be the reason that they remain in the body for longer periods of time.
PFCs are used in a variety of industries. They are used in paints to make them spread easier and in textile manufacturing as a fabric protectant. PFCs are also being used as blood substitutes and radiological imaging agents.
One PFC that is being used in the FDA clinical trials of liquid ventilation therapy is Perflubron or "LiquiVent®" by Alliance Pharmaceutical Corporation.
Effects
Perflubron has several unique characteristics that make it very efficient in ventilation and oxygenation.
Perflubron is an excellent medium to carry respiratory gases. PFC at one atmosphere of pressure can carry 20 times as much oxygen than saline.
It can be used as a surfactant product in premature infants, or in patients with ARDS or lung injury. In an ARDS patient, surface tension in the lung is noted to be 67 to 75 dynes/cm. In a lung with perflubron, the surface tension is only 18 dynes/cm which helps prevent alveolar collapse and reduces alveolar opening pressures.
It will spread uniformly and quickly throughout the lungs when being used for treatment of ARDS or as a surfactant. It does this because of its chemical make up.
PFCs are almost twice as dense as water. It will tend to circulate in dependant areas and those areas where gas exchange is most diminished. This characteristic is useful in the removal of foreign bodies or pulmonary edema.
The components of PFCs are not taken up by the body but evaporated by the lungs. Continuous administration may be necessary to maintain an adequate dosage. This is allowable because it does not break down into toxic metabolites like high concentrations of gaseous oxygen.
From these unique characteristics of LiquiVent®, there are many potential benefits that can be gained from its administration. It can,
Improve gas exchange
Wash out debris
Open atelectatic areas by recruitment, increasing total lung capacity
Act as a surfactant
Reduce injury to the lung caused by excessive ventilator pressures
Decrease chance of oxygen toxicity
Decrease inflammation in the lung
Decrease pulmonary blood flow to injured lung areas creating better oxygenation.
Radiology
Radiology images have shown dramatic changes with the administration of perflubron. Before the initiation of PFCs, the CXR will take the appearance of the initial problem. (e.g. Respiratory Distress Syndrome (RDS) in infants will have the ground glass appearance, air bronchograms, low volumes, and bell shaped chest). During PLV the CXR becomes completely radiopaque. The amount of opacification increases with the amount of lung tissue being ventilated. The Anterior-posterior CXR can then be scored from 0-5 on the amount of lung opacification.
5 represents complete opacification of the lungs with no air alveolograms or air bronchograms distal to the main bronchi
4 represents 67%-99% opacification
3 represents 33%-66% opacification
2 represents 10%-32% opacification
1 represents minimal or less than 10 % opacification of the lung with perflubron
0 is defined as no detecable perflubron
This scoring occurs until the PFCs are discontinued and they evaporate from the lung. Then the CXR will take the appearance of a normal lung or show the underlying disease.
A similar scoring system is in place for lateral CXR. The AP dimension is divided into three compartments of equal width: anterior, middle, and posterior. Again the 0-5 scale is applied to each compartment. Perflubron located outside of the lungs would be noted, and the symmetry of right and left perflubron distribution would also be noted.
Sunday, 27 December 2009
Perfluorocarbon compounds and drug delivery
Acute respiratory distress syndrome (ARDS) is a life threatening form of lung injury that results from an impairment of gas exchange due to fluid buildup in the lung. Several experimental treatment modalities are under investigation to reduce the mortality in ARDS patients, including “liquid ventilation” with a biocompatible perfluorocarbon compound (PFC). During liquid ventilation, the diseased lung is partially or totally filled with a PFC. Both animal and clinical studies suggest that liquid ventilation can recruit alveolar volume and facilitate gas exchange in the diseased lung. There is also evidence that PFCs can decrease the inflammatory response characteristic for ARDS and less severe forms of acute lung injury.
PFCs used during liquid ventilation are perfluorinated aliphatic compounds (i.e., all hydrogen atoms in the molecule are replaced by fluorine) that have a high solubility for oxygen and carbon dioxide. They are evenly distributed in the lung due to unique properties, such as low surface tension, low viscosity, high spreading coefficients and high density. Their systemic uptake is minimal because of their low solubility in water, biological fats and lipids. The main route of elimination of PFCs is exhalation because of the combined hydrophobic and lipophobic character.
Because of their properties, PFCs have been suggested as vehicles for the administration of pharmacological agents directly to the diseased lung. This approach has several advantages compared to conventional drug delivery approaches, such as intravenous administration. For example, intrapulmonary drug administration is expected to achieve higher drug concentrations in the lung while at the same time reducing systemic uptake of the drug. At the same time, the even distribution of the PFC in the lung would result in a homogenous distribution of the drug. Furthermore, PFCs can deliver drugs to diseased parts of the lung by displacing fluid present in the diseased lung because of their higher density and immiscibility with water.
Unfortunately, PFCs are extremely poor solvents for typical drug molecules. This represents a challenge for using PFCs as vehicles for the pulmonary administration of drugs. A number of approaches have been investigated to overcome this solubility problem and move PFC-based administration of drugs towards clinical application. These approaches include dispersions of aqueous drug solutions or solid drug particles, PFC-soluble prodrugs and reverse (water-in-PFC) emulsions.
Several animal studies have investigated the administration of PFC-based dispersions of solid drugs or aqueous drug solutions to the diseased lung. Early studies relied on “bulk flow turbulent mixing” in the lung to achieve a homogeneous distribution of the drug in the lung. More recently, porous nanoparticles of drugs have been developed to obtain stable dispersions of the drug in the PFC. These novel dispersions allow a more controlled administration of the drug to the lung. The intrapulmonary administration of dispersions of drugs in a PFC typically had a greater effect on the pulmonary response relative to systemic responses. Drugs administered dispersed in a PFC were evenly distributed within the lung, with higher levels of the drug in the lung compared to intravenous administration.
Some pharmacological agents, such as fluorinated anesthetics, are soluble in PFCs. For example, the anesthetic halothane was successfully delivered to hamsters undergoing liquid ventilation. In addition, the solubility of drug molecules in PFCs can be enhanced by covalently attaching a perfluoroalkyl moiety to the parent drug molecule. This can be accomplished by synthesizing a perfluoroalkyl ester of the drug of interest. Subsequently, a PFC-soluble prodrug can be administered to the diseased lung where it is expected to partition into lung tissue and release the parent drug by chemical or biological degradation. Although this approach has not been investigated in vivo, prodrugs of nicotinic acid have been shown to be soluble in PFCs. Furthermore, they can release the parent drug, nicotinic acid, in vitro and increase cellular levels of NAD.
In addition to dispersions and PFC-soluble prodrugs, reverse water-in-PFC (micro-)emulsions have been investigated for their potential to administer typical drug molecules to the diseased lung. The goal of this approach is to dissolve the drug in the aqueous phase of the (micro-)emulsion while retaining desired properties such as high fluidity and high solubility for oxygen and carbon dioxide. Although this approach is straightforward and versatile, only fluorinated dimorpholinophosphates have been reported to form biocompatible reverse water-in-PFC (micro-)emulsions. The emulsions can dissolve clinically relevant concentrations of a broad range of drugs and are stable for extended periods of time.
Although the results from these studies are encouraging, administration of drugs dispersed in PFCs is still far from a clinical application.
Acute respiratory distress syndrome (ARDS) is a life threatening form of lung injury that results from an impairment of gas exchange due to fluid buildup in the lung. Several experimental treatment modalities are under investigation to reduce the mortality in ARDS patients, including “liquid ventilation” with a biocompatible perfluorocarbon compound (PFC). During liquid ventilation, the diseased lung is partially or totally filled with a PFC. Both animal and clinical studies suggest that liquid ventilation can recruit alveolar volume and facilitate gas exchange in the diseased lung. There is also evidence that PFCs can decrease the inflammatory response characteristic for ARDS and less severe forms of acute lung injury.
PFCs used during liquid ventilation are perfluorinated aliphatic compounds (i.e., all hydrogen atoms in the molecule are replaced by fluorine) that have a high solubility for oxygen and carbon dioxide. They are evenly distributed in the lung due to unique properties, such as low surface tension, low viscosity, high spreading coefficients and high density. Their systemic uptake is minimal because of their low solubility in water, biological fats and lipids. The main route of elimination of PFCs is exhalation because of the combined hydrophobic and lipophobic character.
Because of their properties, PFCs have been suggested as vehicles for the administration of pharmacological agents directly to the diseased lung. This approach has several advantages compared to conventional drug delivery approaches, such as intravenous administration. For example, intrapulmonary drug administration is expected to achieve higher drug concentrations in the lung while at the same time reducing systemic uptake of the drug. At the same time, the even distribution of the PFC in the lung would result in a homogenous distribution of the drug. Furthermore, PFCs can deliver drugs to diseased parts of the lung by displacing fluid present in the diseased lung because of their higher density and immiscibility with water.
Unfortunately, PFCs are extremely poor solvents for typical drug molecules. This represents a challenge for using PFCs as vehicles for the pulmonary administration of drugs. A number of approaches have been investigated to overcome this solubility problem and move PFC-based administration of drugs towards clinical application. These approaches include dispersions of aqueous drug solutions or solid drug particles, PFC-soluble prodrugs and reverse (water-in-PFC) emulsions.
Several animal studies have investigated the administration of PFC-based dispersions of solid drugs or aqueous drug solutions to the diseased lung. Early studies relied on “bulk flow turbulent mixing” in the lung to achieve a homogeneous distribution of the drug in the lung. More recently, porous nanoparticles of drugs have been developed to obtain stable dispersions of the drug in the PFC. These novel dispersions allow a more controlled administration of the drug to the lung. The intrapulmonary administration of dispersions of drugs in a PFC typically had a greater effect on the pulmonary response relative to systemic responses. Drugs administered dispersed in a PFC were evenly distributed within the lung, with higher levels of the drug in the lung compared to intravenous administration.
Some pharmacological agents, such as fluorinated anesthetics, are soluble in PFCs. For example, the anesthetic halothane was successfully delivered to hamsters undergoing liquid ventilation. In addition, the solubility of drug molecules in PFCs can be enhanced by covalently attaching a perfluoroalkyl moiety to the parent drug molecule. This can be accomplished by synthesizing a perfluoroalkyl ester of the drug of interest. Subsequently, a PFC-soluble prodrug can be administered to the diseased lung where it is expected to partition into lung tissue and release the parent drug by chemical or biological degradation. Although this approach has not been investigated in vivo, prodrugs of nicotinic acid have been shown to be soluble in PFCs. Furthermore, they can release the parent drug, nicotinic acid, in vitro and increase cellular levels of NAD.
In addition to dispersions and PFC-soluble prodrugs, reverse water-in-PFC (micro-)emulsions have been investigated for their potential to administer typical drug molecules to the diseased lung. The goal of this approach is to dissolve the drug in the aqueous phase of the (micro-)emulsion while retaining desired properties such as high fluidity and high solubility for oxygen and carbon dioxide. Although this approach is straightforward and versatile, only fluorinated dimorpholinophosphates have been reported to form biocompatible reverse water-in-PFC (micro-)emulsions. The emulsions can dissolve clinically relevant concentrations of a broad range of drugs and are stable for extended periods of time.
Although the results from these studies are encouraging, administration of drugs dispersed in PFCs is still far from a clinical application.
more »
PFCs used during liquid ventilation are perfluorinated aliphatic compounds (i.e., all hydrogen atoms in the molecule are replaced by fluorine) that have a high solubility for oxygen and carbon dioxide. They are evenly distributed in the lung due to unique properties, such as low surface tension, low viscosity, high spreading coefficients and high density. Their systemic uptake is minimal because of their low solubility in water, biological fats and lipids. The main route of elimination of PFCs is exhalation because of the combined hydrophobic and lipophobic character.
Because of their properties, PFCs have been suggested as vehicles for the administration of pharmacological agents directly to the diseased lung. This approach has several advantages compared to conventional drug delivery approaches, such as intravenous administration. For example, intrapulmonary drug administration is expected to achieve higher drug concentrations in the lung while at the same time reducing systemic uptake of the drug. At the same time, the even distribution of the PFC in the lung would result in a homogenous distribution of the drug. Furthermore, PFCs can deliver drugs to diseased parts of the lung by displacing fluid present in the diseased lung because of their higher density and immiscibility with water.
Unfortunately, PFCs are extremely poor solvents for typical drug molecules. This represents a challenge for using PFCs as vehicles for the pulmonary administration of drugs. A number of approaches have been investigated to overcome this solubility problem and move PFC-based administration of drugs towards clinical application. These approaches include dispersions of aqueous drug solutions or solid drug particles, PFC-soluble prodrugs and reverse (water-in-PFC) emulsions.
Several animal studies have investigated the administration of PFC-based dispersions of solid drugs or aqueous drug solutions to the diseased lung. Early studies relied on “bulk flow turbulent mixing” in the lung to achieve a homogeneous distribution of the drug in the lung. More recently, porous nanoparticles of drugs have been developed to obtain stable dispersions of the drug in the PFC. These novel dispersions allow a more controlled administration of the drug to the lung. The intrapulmonary administration of dispersions of drugs in a PFC typically had a greater effect on the pulmonary response relative to systemic responses. Drugs administered dispersed in a PFC were evenly distributed within the lung, with higher levels of the drug in the lung compared to intravenous administration.
Some pharmacological agents, such as fluorinated anesthetics, are soluble in PFCs. For example, the anesthetic halothane was successfully delivered to hamsters undergoing liquid ventilation. In addition, the solubility of drug molecules in PFCs can be enhanced by covalently attaching a perfluoroalkyl moiety to the parent drug molecule. This can be accomplished by synthesizing a perfluoroalkyl ester of the drug of interest. Subsequently, a PFC-soluble prodrug can be administered to the diseased lung where it is expected to partition into lung tissue and release the parent drug by chemical or biological degradation. Although this approach has not been investigated in vivo, prodrugs of nicotinic acid have been shown to be soluble in PFCs. Furthermore, they can release the parent drug, nicotinic acid, in vitro and increase cellular levels of NAD.
In addition to dispersions and PFC-soluble prodrugs, reverse water-in-PFC (micro-)emulsions have been investigated for their potential to administer typical drug molecules to the diseased lung. The goal of this approach is to dissolve the drug in the aqueous phase of the (micro-)emulsion while retaining desired properties such as high fluidity and high solubility for oxygen and carbon dioxide. Although this approach is straightforward and versatile, only fluorinated dimorpholinophosphates have been reported to form biocompatible reverse water-in-PFC (micro-)emulsions. The emulsions can dissolve clinically relevant concentrations of a broad range of drugs and are stable for extended periods of time.
Although the results from these studies are encouraging, administration of drugs dispersed in PFCs is still far from a clinical application.
Acute respiratory distress syndrome (ARDS) is a life threatening form of lung injury that results from an impairment of gas exchange due to fluid buildup in the lung. Several experimental treatment modalities are under investigation to reduce the mortality in ARDS patients, including “liquid ventilation” with a biocompatible perfluorocarbon compound (PFC). During liquid ventilation, the diseased lung is partially or totally filled with a PFC. Both animal and clinical studies suggest that liquid ventilation can recruit alveolar volume and facilitate gas exchange in the diseased lung. There is also evidence that PFCs can decrease the inflammatory response characteristic for ARDS and less severe forms of acute lung injury.
PFCs used during liquid ventilation are perfluorinated aliphatic compounds (i.e., all hydrogen atoms in the molecule are replaced by fluorine) that have a high solubility for oxygen and carbon dioxide. They are evenly distributed in the lung due to unique properties, such as low surface tension, low viscosity, high spreading coefficients and high density. Their systemic uptake is minimal because of their low solubility in water, biological fats and lipids. The main route of elimination of PFCs is exhalation because of the combined hydrophobic and lipophobic character.
Because of their properties, PFCs have been suggested as vehicles for the administration of pharmacological agents directly to the diseased lung. This approach has several advantages compared to conventional drug delivery approaches, such as intravenous administration. For example, intrapulmonary drug administration is expected to achieve higher drug concentrations in the lung while at the same time reducing systemic uptake of the drug. At the same time, the even distribution of the PFC in the lung would result in a homogenous distribution of the drug. Furthermore, PFCs can deliver drugs to diseased parts of the lung by displacing fluid present in the diseased lung because of their higher density and immiscibility with water.
Unfortunately, PFCs are extremely poor solvents for typical drug molecules. This represents a challenge for using PFCs as vehicles for the pulmonary administration of drugs. A number of approaches have been investigated to overcome this solubility problem and move PFC-based administration of drugs towards clinical application. These approaches include dispersions of aqueous drug solutions or solid drug particles, PFC-soluble prodrugs and reverse (water-in-PFC) emulsions.
Several animal studies have investigated the administration of PFC-based dispersions of solid drugs or aqueous drug solutions to the diseased lung. Early studies relied on “bulk flow turbulent mixing” in the lung to achieve a homogeneous distribution of the drug in the lung. More recently, porous nanoparticles of drugs have been developed to obtain stable dispersions of the drug in the PFC. These novel dispersions allow a more controlled administration of the drug to the lung. The intrapulmonary administration of dispersions of drugs in a PFC typically had a greater effect on the pulmonary response relative to systemic responses. Drugs administered dispersed in a PFC were evenly distributed within the lung, with higher levels of the drug in the lung compared to intravenous administration.
Some pharmacological agents, such as fluorinated anesthetics, are soluble in PFCs. For example, the anesthetic halothane was successfully delivered to hamsters undergoing liquid ventilation. In addition, the solubility of drug molecules in PFCs can be enhanced by covalently attaching a perfluoroalkyl moiety to the parent drug molecule. This can be accomplished by synthesizing a perfluoroalkyl ester of the drug of interest. Subsequently, a PFC-soluble prodrug can be administered to the diseased lung where it is expected to partition into lung tissue and release the parent drug by chemical or biological degradation. Although this approach has not been investigated in vivo, prodrugs of nicotinic acid have been shown to be soluble in PFCs. Furthermore, they can release the parent drug, nicotinic acid, in vitro and increase cellular levels of NAD.
In addition to dispersions and PFC-soluble prodrugs, reverse water-in-PFC (micro-)emulsions have been investigated for their potential to administer typical drug molecules to the diseased lung. The goal of this approach is to dissolve the drug in the aqueous phase of the (micro-)emulsion while retaining desired properties such as high fluidity and high solubility for oxygen and carbon dioxide. Although this approach is straightforward and versatile, only fluorinated dimorpholinophosphates have been reported to form biocompatible reverse water-in-PFC (micro-)emulsions. The emulsions can dissolve clinically relevant concentrations of a broad range of drugs and are stable for extended periods of time.
Although the results from these studies are encouraging, administration of drugs dispersed in PFCs is still far from a clinical application.
more »
Perfluorocarbons
Perfluorocarbons (PFCs) are fluorocarbons, compounds derived from hydrocarbons by replacement of hydrogen atoms by fluorine atoms. PFCs are made up of carbon and fluorine atoms only, such as octafluoropropane, perfluorohexane and perfluorodecalin. A perflourocarbon can be arranged in a linear, cyclic, or polycyclic shape.
Perfluorocarbon derivatives are perfluorocarbons with some functional group attached, for example perfluorooctanesulfonic acid. Perfluorocarbon derivatives can be very different from perfluorocarbons in their properties, applications and toxicity.
The term Perfluorinated compounds or perflourochemical (also abbreviated to PFC) may indicate perfluorcarbons, but is often used to include perfluorocarbon derivatives.
Properties
Perfluorocarbons have chemical inertness and thermal stability. This is attributed to the strength of the carbon-fluorine bond and the shielding effect of the fluorine atoms. The electronegativity of fluorine reduces the polarizability of the electron clouds. This results in reduced van der Waals forces between fluorocarbons, as these species tend to be volatile and have low cohesive energies in liquids.
There are six perfluorocarbon gases; tetrafluoromethane (carbon tetrafluoride) (bp −128 °C), hexafluoroethane (bp −78.2 °C), octafluoropropane (perfluoropropane) (bp −36.5 °C), perfluorocyclobutane (bp −6 °C), perfluoro-n-butane (bp −2.2 °C) and perfluoro-iso-butane (bp −1 °C). Virtually all the other commercially available perfluorocarbons are liquids (the exception being perfluorocyclohexane, which sublimes at 51 °C.
Perfluorocarbon liquids are colorless. They have high density, up to over twice that of water, due to their high molecular weight. Very low intermolecular forces gives the liquids low viscosities (compared to liquids of similar boiling points), low surface tension and low heats of vaporization. They have particularly low refractive indices too.
They are not miscible with most organic solvents (eg, ethanol, acetone, ethyl acetate and chloroform), but are miscible with some hydrocarbons (eg, hexane in some cases). They have very low solubility in water, and water has a very low solubility in them (on the order of 10 ppm). However, they are relatively good solvents for gases, again because of the very low intermolecular forces.
The number of carbon atoms in the perfluorocarbon molecule largely defines most physical properties. The greater the number of carbon atoms, the higher the boiling point, density, viscosity, surface tension, critical properties, vapour pressure and refractive index. Gas solubility decreases as carbon atoms increase, while melting point is determined by other factors as well, so is not readily predicted.
Manufacture
Prior to World War II, the only known route to perfluorocarbons was by direct reaction of fluorine with the hydrocarbon. This highly exothermic process was capable only of synthesising tetrafluoromethane, hexafluoroethane and octafluoropropane; larger hydrocarbons decomposed in the extreme conditions. The Manhattan project saw the need for some very robust chemicals, including a wider range of perfluorocarbons, requiring new manufacturing methods. The so-called "catalytic" method involved reacting fluorine and hydrocarbon on a bed of gold-plated copper turnings, the metal removing the heat of the reaction (so not really acting as a catalyst at all), allowing larger hydrocarbons to survive the process. However, it was the Fowler process that allowed the large scale manufacture of perfluorocarbons required for the Manhattan project.] The Fowler Process
The Fowler process uses cobalt fluoride to moderate the reaction. In the laboratory, this is typically done in two stages, the first stage being fluorination of cobalt difluoride to cobalt trifluoride.
2 CoF2 + F2 → 2 CoF3
During the second stage, in this instance to make perfluorohexane, the hydrocarbon feed is introduced and is fluorinated by the cobalt trifluoride, which is converted back to cobalt difluoride. Both stages are performed at high temperature.
C6H14 + 28 CoF3 → C6F14 + 14 HF + 28 CoF2
Industrially, both steps are combined, for example in the manufacture of the Flutec range of perfluorocarbons, using a vertical stirred bed reactor, with hydrocarbon introduced at the bottom, and fluorine introduced half way up the reactor. The perfluorocarbon vapor is recovered from the top.
Electrochemical fluorination
An alternative technique, electrochemical fluorination (ECF) (also known as the Simons' process) involves electrolysis of a substrate dissolved in hydrogen fluoride. As fluorine is itself manufactured by the electrolysis of hydrogen fluoride, this is a rather more direct route to perfluorocarbons. The process is run at low voltage (5 - 6 V) so that free fluorine is not liberated. The choice of substrate is restricted as ideally it should be soluble in hydrogen fluoride. Ethers and tertiary amines are typically employed. To make perfluorohexane, trihexylamine is used, for example:
2 N(C6H13)3 + 90 HF → 6 C6F14 + 2 NF3 + 45 H2
The perfluorocarbon amine will also be produced:
N(C6H13)3 + 42 HF → 2 N(C6F13)3 + 21H2
Both of these products, and others, are manufactured by 3M as part of the Fluorinert range.
Medical applications
Medical applications require high purity perfluorocarbons. Impurities with nitrogen bonds can have high toxicity; hydrogen-containing compounds (which can release hydrogen fluoride) and unsaturated compounds must also be excluded. Infrared spectroscopy, nuclear magnetic resonance and cell cultures can be used to test the perfluorocarbon.
Eye surgery
Perfluorocarbons are commonly used in eye surgery as temporary replacements of the vitreous humor in retinal detachment surgery.[citation needed] Retinal tears following a penetrating trauma or retinal detachments associated with proliferative vitreoretinopathy can be corrected with surgery in which the dense perfluorocarbon liquid, typically perfluoro-n-octane, is injected into the eye, to push out vitreous liquid trapped behind the retina, and to aid removal of membranes (essentially scar tissue) Perfluoro-1,3-dimethylcyclohexane has been used in the removal of a lens nucleus dislocated into the vitreous cavity, the lens floating on the heavy perfluorocarbon for easy removal .
Octafluoropropane can be used almost in a reverse sense. It is injected into the eye diluted in air (typically 12% to 16%). The patient must then lie face down for about an hour. The gas bubble pushes onto the retina to perform the same task as before . The octafluorpropane may remain in the eye for up to three months after surgery before it is completely expelled. Air travel or other environments involving changes in pressure should be avoided. Use of nitrous oxide as an anaesthetic can be disastrous to the possible future optical abilities of the patient ; dissolved nitrous oxide from the blood accumulates in the bubble, increasing intraocular pressure to the point that blood flow to the retina is cut off and the retina dies.
Imaging
Perfluorocarbons are also used in contrast-enhanced ultrasound to improve ultrasound signal backscatter. The perfluorocarbons used in the microbubbles are gases at body temperature (though they may be liquids at room temperature). The gas-filled microbubbles oscillate and vibrate when a sonic energy field is applied and characteristically reflect ultrasound waves. This distinguishes the microbubbles from surrounding tissues. Their stability, inertness, low diffusion rate and solubility increase the duration of contrast enhancement as compared to microbubbles containing air.
Perfluorocarbons can also be used in magnetic resonance imaging (MRI), though this is not as common. Usually MRI is set up to detect hydrogen nuclei, but it is also possible to use MRI for 19-fluorine nuclei. As there is no fluorine in the human body naturally, it is very easy to determine exactly where the sample has gone. Perfluorocarbons can be introduced into the blood in an emulsion, or neat in the lungs.
In radiographic imaging, the perfluorocarbon derivative perfluorooctyl bromide (PFOB) is employed, as this is more opaque to X-rays.
Liquid breathing
Main article: Liquid breathing
Perfluorocarbons dissolve relatively high concentrations of gases, for example, 100 ml of perfluorodecalin at 25°C will dissolve 49 ml of oxygen at STP. This led Leland C. Clark in 1966 to experiment with liquid breathing, resulting in the submersion of a mouse for several hours in an oxygenated perfluorocarbon. The mice he used later died due to trauma to their lungs; however, this may have been due to impurities in the perfluorocarbon. In recent years there has been new interest in liquid breathing for various procedures from lung lavage to treatment of congenital diaphragmatic hernia. Perfluorocarbon liquids (and liquids in general) are much denser and more viscous than air; rates of breathing, and therefore of gas exchange, are limited, and there are challenges still to be overcome such as efficient removal of carbon dioxide.
Artificial blood
Main article: Blood substitutes
Clark's experiments also triggered interest in using perfluorocarbons in artificial blood (perhaps more accurately described as artificial erythrocytes, as they only serve as gas carriers). The Green Cross Corporation attempted to commercialize this technology in the 1980s under the Fluosol tradename, without success. Recently, however, there has been renewed interest in this field.
In this application, the perfluorocarbon is used as a part of an emulsion, typically using Pluronic F-68 or egg yolk phospholipids (lethicin) as surfactants, in water. For example, Fluosol-DC:
Ingredient w/v%
Perfluorodecalin 25.0
Yolk phospholids 3.6
Fatty acid (emulsion stabilizer) trace
D-Sorbitol (emulsion stabilizer) 3.5
NaCl 0.204
KCl 0.010
MgCl2 0.007
Sodium lactate 0.105
Due to perfluorocarbons size of 0.1 -0.2μm this enables the molecule to be present in the plasma gaps between erythrocytes in the microcirculation structures. These molecules are able to carry 40 to 50 times more oxygen than hemoglobin which is an advantage when oxygen supply to tissue by red blood cells is low due to acute anemia or hemodilution. Perfluorocarbons are most effective in small capillaries or blood vessels, where under normal circumstances blood cells would not be able to flow. PFC's can augment local oxygen delivery and increase the oxygen content in the arterial blood. All oxygen carried by perfluorocarbons is in a dissolved state which results in higher oxygen partial pressures, which in turn augments the driving pressure for the diffusion of dissolved oxygen into the tissue.
Side effects
Some common side effects were recorded while performing clinical studies such as delayed febrile reaction and flu-like symptoms. The magnitude of the side effects is directly related to the size of the emulsion droplets, if the particles are smaller than 0.2μm it seems to be undetectable for the reticuloendothelial system. These side effects occur when the body is excreting/eliminating the perfluorocarbon. The excretion depends on vapour pressure and lipid solubility of the perfluorocarbons. It usually takes on average three to four days for the compound perfluoroocytl bromide and eight days for perfluorodichlorooactane. This process is relatively slow since perfluorocarbons are inert to biochemical degradation. The perfluorocarbon will then diffuse back into the blood where they dissolve into plasma lipids. The plasma lipids will then transport the perfluorocarbon molecules to the lungs where they are excreted through exhalation along with other gases.
Treatment of decompression sickness
Perfluorocarbons accelerate nitrogen washout after venous gas emboli. Success in the treatment of decompression sickness has been shown in rat, swine, hamster models. This treatment shows great potential as a future adjunctive therapy for decompression sickness in humans.
Non-medical applications
Electrical and electronic applications
Perfluorocarbons have high dielectric strengths and high insulating properties, and so can be used in direct contact with high voltage components, either as dielectric fluids or as coolants.
Perfluorcarbon tracers
Perfluorocarbons can be detected at extremely low levels using electron capture detectors or negative ion mass spectroscopy. They can be released at a certain point and the concentration measured in the surrounding area. Perfluorocarbon tracers (PFTs) have been used to map oil fields, study building ventilation, track pollution, detect cable oil leaks and even recover ransom money.
Cosmetics
Inspired by the medical applications, several companies incorporate perfluorocarbons in their cosmetic formulations, claiming the oxygen dissolved in the perfluorocarbon has an anti-aging effect on the skin.
Other applications
PFCs are being used in refrigerating units as replacements for CFCs (haloalkanes), often in conjunction with other gases, and as "clean" fire extinguishers. They are used in plasma cleaning of silicon wafers. Perfluorocarbons are also used in high end racing ski waxes due to their hydrophobic nature, which is responsible for reduced friction in wet snow conditions.
In fluorous biphase catalysis a perfluorocarbon is used to dissolve a catalyst with a perfluoroalkyl group, while the substrate is dissolved in an organic solvent. At elevated temperature, the perfluorocarbon and organic solvent become miscible, and so the mixture becomes homogeneous, facilitating the reaction. Upon cooling, the two phases separate, allowing the catalyst to be recovered from the perfluorocarbon, and the product from the organic solvent.
Environmental effects
PFCs are extremely potent greenhouse gases, and they are a long-term problem with a lifetime up to 50,000 years. In a 2003 study, the most abundant atmospheric PFC was tetrafluoromethane.The greenhouse warming potential (GWP) of tetrafluoromethane is 6,500 times that of carbon dioxide, and the GWP of hexafluoroethane is 9,200 times that of carbon dioxide. Several governments concerned about the properties of PFCs have already tried to implement international agreements to limit their usage before it becomes a global warming issue. PFCs are one of the classes of compounds regulated in the Kyoto Protocol.
The primary source of tetrafluoromethane in the environment is from the production of aluminium by electrolysis of alumina. Aluminium producers are taking effective steps in reducing emissions by better controlling the electrolysis process.
Two PFC derivatives, perfluorooctanesulfonic acid and perfluorooctanoic acid, have been found to be persistent in the environment and are detected in blood samples all over the world.
Perfluorocarbon derivatives are perfluorocarbons with some functional group attached, for example perfluorooctanesulfonic acid. Perfluorocarbon derivatives can be very different from perfluorocarbons in their properties, applications and toxicity.
The term Perfluorinated compounds or perflourochemical (also abbreviated to PFC) may indicate perfluorcarbons, but is often used to include perfluorocarbon derivatives.
Properties
Perfluorocarbons have chemical inertness and thermal stability. This is attributed to the strength of the carbon-fluorine bond and the shielding effect of the fluorine atoms. The electronegativity of fluorine reduces the polarizability of the electron clouds. This results in reduced van der Waals forces between fluorocarbons, as these species tend to be volatile and have low cohesive energies in liquids.
There are six perfluorocarbon gases; tetrafluoromethane (carbon tetrafluoride) (bp −128 °C), hexafluoroethane (bp −78.2 °C), octafluoropropane (perfluoropropane) (bp −36.5 °C), perfluorocyclobutane (bp −6 °C), perfluoro-n-butane (bp −2.2 °C) and perfluoro-iso-butane (bp −1 °C). Virtually all the other commercially available perfluorocarbons are liquids (the exception being perfluorocyclohexane, which sublimes at 51 °C.
Perfluorocarbon liquids are colorless. They have high density, up to over twice that of water, due to their high molecular weight. Very low intermolecular forces gives the liquids low viscosities (compared to liquids of similar boiling points), low surface tension and low heats of vaporization. They have particularly low refractive indices too.
They are not miscible with most organic solvents (eg, ethanol, acetone, ethyl acetate and chloroform), but are miscible with some hydrocarbons (eg, hexane in some cases). They have very low solubility in water, and water has a very low solubility in them (on the order of 10 ppm). However, they are relatively good solvents for gases, again because of the very low intermolecular forces.
The number of carbon atoms in the perfluorocarbon molecule largely defines most physical properties. The greater the number of carbon atoms, the higher the boiling point, density, viscosity, surface tension, critical properties, vapour pressure and refractive index. Gas solubility decreases as carbon atoms increase, while melting point is determined by other factors as well, so is not readily predicted.
Manufacture
Prior to World War II, the only known route to perfluorocarbons was by direct reaction of fluorine with the hydrocarbon. This highly exothermic process was capable only of synthesising tetrafluoromethane, hexafluoroethane and octafluoropropane; larger hydrocarbons decomposed in the extreme conditions. The Manhattan project saw the need for some very robust chemicals, including a wider range of perfluorocarbons, requiring new manufacturing methods. The so-called "catalytic" method involved reacting fluorine and hydrocarbon on a bed of gold-plated copper turnings, the metal removing the heat of the reaction (so not really acting as a catalyst at all), allowing larger hydrocarbons to survive the process. However, it was the Fowler process that allowed the large scale manufacture of perfluorocarbons required for the Manhattan project.] The Fowler Process
The Fowler process uses cobalt fluoride to moderate the reaction. In the laboratory, this is typically done in two stages, the first stage being fluorination of cobalt difluoride to cobalt trifluoride.
2 CoF2 + F2 → 2 CoF3
During the second stage, in this instance to make perfluorohexane, the hydrocarbon feed is introduced and is fluorinated by the cobalt trifluoride, which is converted back to cobalt difluoride. Both stages are performed at high temperature.
C6H14 + 28 CoF3 → C6F14 + 14 HF + 28 CoF2
Industrially, both steps are combined, for example in the manufacture of the Flutec range of perfluorocarbons, using a vertical stirred bed reactor, with hydrocarbon introduced at the bottom, and fluorine introduced half way up the reactor. The perfluorocarbon vapor is recovered from the top.
Electrochemical fluorination
An alternative technique, electrochemical fluorination (ECF) (also known as the Simons' process) involves electrolysis of a substrate dissolved in hydrogen fluoride. As fluorine is itself manufactured by the electrolysis of hydrogen fluoride, this is a rather more direct route to perfluorocarbons. The process is run at low voltage (5 - 6 V) so that free fluorine is not liberated. The choice of substrate is restricted as ideally it should be soluble in hydrogen fluoride. Ethers and tertiary amines are typically employed. To make perfluorohexane, trihexylamine is used, for example:
2 N(C6H13)3 + 90 HF → 6 C6F14 + 2 NF3 + 45 H2
The perfluorocarbon amine will also be produced:
N(C6H13)3 + 42 HF → 2 N(C6F13)3 + 21H2
Both of these products, and others, are manufactured by 3M as part of the Fluorinert range.
Medical applications
Medical applications require high purity perfluorocarbons. Impurities with nitrogen bonds can have high toxicity; hydrogen-containing compounds (which can release hydrogen fluoride) and unsaturated compounds must also be excluded. Infrared spectroscopy, nuclear magnetic resonance and cell cultures can be used to test the perfluorocarbon.
Eye surgery
Perfluorocarbons are commonly used in eye surgery as temporary replacements of the vitreous humor in retinal detachment surgery.[citation needed] Retinal tears following a penetrating trauma or retinal detachments associated with proliferative vitreoretinopathy can be corrected with surgery in which the dense perfluorocarbon liquid, typically perfluoro-n-octane, is injected into the eye, to push out vitreous liquid trapped behind the retina, and to aid removal of membranes (essentially scar tissue) Perfluoro-1,3-dimethylcyclohexane has been used in the removal of a lens nucleus dislocated into the vitreous cavity, the lens floating on the heavy perfluorocarbon for easy removal .
Octafluoropropane can be used almost in a reverse sense. It is injected into the eye diluted in air (typically 12% to 16%). The patient must then lie face down for about an hour. The gas bubble pushes onto the retina to perform the same task as before . The octafluorpropane may remain in the eye for up to three months after surgery before it is completely expelled. Air travel or other environments involving changes in pressure should be avoided. Use of nitrous oxide as an anaesthetic can be disastrous to the possible future optical abilities of the patient ; dissolved nitrous oxide from the blood accumulates in the bubble, increasing intraocular pressure to the point that blood flow to the retina is cut off and the retina dies.
Imaging
Perfluorocarbons are also used in contrast-enhanced ultrasound to improve ultrasound signal backscatter. The perfluorocarbons used in the microbubbles are gases at body temperature (though they may be liquids at room temperature). The gas-filled microbubbles oscillate and vibrate when a sonic energy field is applied and characteristically reflect ultrasound waves. This distinguishes the microbubbles from surrounding tissues. Their stability, inertness, low diffusion rate and solubility increase the duration of contrast enhancement as compared to microbubbles containing air.
Perfluorocarbons can also be used in magnetic resonance imaging (MRI), though this is not as common. Usually MRI is set up to detect hydrogen nuclei, but it is also possible to use MRI for 19-fluorine nuclei. As there is no fluorine in the human body naturally, it is very easy to determine exactly where the sample has gone. Perfluorocarbons can be introduced into the blood in an emulsion, or neat in the lungs.
In radiographic imaging, the perfluorocarbon derivative perfluorooctyl bromide (PFOB) is employed, as this is more opaque to X-rays.
Liquid breathing
Main article: Liquid breathing
Perfluorocarbons dissolve relatively high concentrations of gases, for example, 100 ml of perfluorodecalin at 25°C will dissolve 49 ml of oxygen at STP. This led Leland C. Clark in 1966 to experiment with liquid breathing, resulting in the submersion of a mouse for several hours in an oxygenated perfluorocarbon. The mice he used later died due to trauma to their lungs; however, this may have been due to impurities in the perfluorocarbon. In recent years there has been new interest in liquid breathing for various procedures from lung lavage to treatment of congenital diaphragmatic hernia. Perfluorocarbon liquids (and liquids in general) are much denser and more viscous than air; rates of breathing, and therefore of gas exchange, are limited, and there are challenges still to be overcome such as efficient removal of carbon dioxide.
Artificial blood
Main article: Blood substitutes
Clark's experiments also triggered interest in using perfluorocarbons in artificial blood (perhaps more accurately described as artificial erythrocytes, as they only serve as gas carriers). The Green Cross Corporation attempted to commercialize this technology in the 1980s under the Fluosol tradename, without success. Recently, however, there has been renewed interest in this field.
In this application, the perfluorocarbon is used as a part of an emulsion, typically using Pluronic F-68 or egg yolk phospholipids (lethicin) as surfactants, in water. For example, Fluosol-DC:
Ingredient w/v%
Perfluorodecalin 25.0
Yolk phospholids 3.6
Fatty acid (emulsion stabilizer) trace
D-Sorbitol (emulsion stabilizer) 3.5
NaCl 0.204
KCl 0.010
MgCl2 0.007
Sodium lactate 0.105
Due to perfluorocarbons size of 0.1 -0.2μm this enables the molecule to be present in the plasma gaps between erythrocytes in the microcirculation structures. These molecules are able to carry 40 to 50 times more oxygen than hemoglobin which is an advantage when oxygen supply to tissue by red blood cells is low due to acute anemia or hemodilution. Perfluorocarbons are most effective in small capillaries or blood vessels, where under normal circumstances blood cells would not be able to flow. PFC's can augment local oxygen delivery and increase the oxygen content in the arterial blood. All oxygen carried by perfluorocarbons is in a dissolved state which results in higher oxygen partial pressures, which in turn augments the driving pressure for the diffusion of dissolved oxygen into the tissue.
Side effects
Some common side effects were recorded while performing clinical studies such as delayed febrile reaction and flu-like symptoms. The magnitude of the side effects is directly related to the size of the emulsion droplets, if the particles are smaller than 0.2μm it seems to be undetectable for the reticuloendothelial system. These side effects occur when the body is excreting/eliminating the perfluorocarbon. The excretion depends on vapour pressure and lipid solubility of the perfluorocarbons. It usually takes on average three to four days for the compound perfluoroocytl bromide and eight days for perfluorodichlorooactane. This process is relatively slow since perfluorocarbons are inert to biochemical degradation. The perfluorocarbon will then diffuse back into the blood where they dissolve into plasma lipids. The plasma lipids will then transport the perfluorocarbon molecules to the lungs where they are excreted through exhalation along with other gases.
Treatment of decompression sickness
Perfluorocarbons accelerate nitrogen washout after venous gas emboli. Success in the treatment of decompression sickness has been shown in rat, swine, hamster models. This treatment shows great potential as a future adjunctive therapy for decompression sickness in humans.
Non-medical applications
Electrical and electronic applications
Perfluorocarbons have high dielectric strengths and high insulating properties, and so can be used in direct contact with high voltage components, either as dielectric fluids or as coolants.
Perfluorcarbon tracers
Perfluorocarbons can be detected at extremely low levels using electron capture detectors or negative ion mass spectroscopy. They can be released at a certain point and the concentration measured in the surrounding area. Perfluorocarbon tracers (PFTs) have been used to map oil fields, study building ventilation, track pollution, detect cable oil leaks and even recover ransom money.
Cosmetics
Inspired by the medical applications, several companies incorporate perfluorocarbons in their cosmetic formulations, claiming the oxygen dissolved in the perfluorocarbon has an anti-aging effect on the skin.
Other applications
PFCs are being used in refrigerating units as replacements for CFCs (haloalkanes), often in conjunction with other gases, and as "clean" fire extinguishers. They are used in plasma cleaning of silicon wafers. Perfluorocarbons are also used in high end racing ski waxes due to their hydrophobic nature, which is responsible for reduced friction in wet snow conditions.
In fluorous biphase catalysis a perfluorocarbon is used to dissolve a catalyst with a perfluoroalkyl group, while the substrate is dissolved in an organic solvent. At elevated temperature, the perfluorocarbon and organic solvent become miscible, and so the mixture becomes homogeneous, facilitating the reaction. Upon cooling, the two phases separate, allowing the catalyst to be recovered from the perfluorocarbon, and the product from the organic solvent.
Environmental effects
PFCs are extremely potent greenhouse gases, and they are a long-term problem with a lifetime up to 50,000 years. In a 2003 study, the most abundant atmospheric PFC was tetrafluoromethane.The greenhouse warming potential (GWP) of tetrafluoromethane is 6,500 times that of carbon dioxide, and the GWP of hexafluoroethane is 9,200 times that of carbon dioxide. Several governments concerned about the properties of PFCs have already tried to implement international agreements to limit their usage before it becomes a global warming issue. PFCs are one of the classes of compounds regulated in the Kyoto Protocol.
The primary source of tetrafluoromethane in the environment is from the production of aluminium by electrolysis of alumina. Aluminium producers are taking effective steps in reducing emissions by better controlling the electrolysis process.
Two PFC derivatives, perfluorooctanesulfonic acid and perfluorooctanoic acid, have been found to be persistent in the environment and are detected in blood samples all over the world.
Wednesday, 23 December 2009
Tuesday, 22 December 2009
Hamburg
On 4 and 5th Dec 2008, I was in a conference in Hamburg to deliver my speech regarding to artificial blood and blood substitues.
My honours project
Flow cytometric determination of platelet factor 3 activities on the surface of activated and quiescent platelets by Annexin V binding.
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