DE4445973B4 - Polyvinylidene fluoride membrane - Google Patents

Abstract

Isotropic, skinless, porous polyvinylidene fluoride membrane, characterized in that the pore size distribution of the membrane is predetermined so that the membrane
a) a K _UF coefficient of at least about 103 kPa in the test using liquid pairs with an interfacial tension of about 4 mN / m and / or
b) a titer reduction of at least about 10 ⁸ against T ₁ bacteriophage
having.

Description

The Invention relates to a porous Polyvinylidene fluoride-containing membrane and a process for the preparation and a use of such a membrane. The invention relates in particular an isotropic, skinless, porous polyvinylidene fluoride membrane.

The inventive membrane has proven to be especially useful in the filtration of pharmacological and other solutions, especially when removing viruses from such solutions.

at the production of solutions, intended for administration to animals or human host organisms are such as pharmacological and life support solutions, it is important that such Solutions like that free as possible of substances which are unfavorable Can trigger reactions in the host organism. One of these impurities, which is of particular importance are viruses. Viruses are the ones Cause for many of the dreaded Diseases of the world, such as Polio, hepatitis and aids.

Several different physical and non-physical processes currently used to either remove or inactivate the viruses. Non-physical method used to inactivate viruses include, e.g. the pasteurization by heating and chemical Treatment. However, these methods do not affect all viruses in same size. About that in addition, in the event that biotherapeutic Funds are present, these funds are also inactivated. additionally can Chemicals used in a chemical treatment a harmful one Influence on exercise the host organism.

A alternative solution involves a physical separation process. Such processes use filtration membranes, e.g. symmetric or asymmetric microporous or ultrafiltration membranes, for Removal of viruses from a solution. Such membranes remove viruses either by adsorption, a Sieving effect or a combination of adsorption and sieving. The Screening is generally preferred over adsorption, because over the screening process one better control possible and because the screening is less likely one Virus accidentally allowed passage through the filtration membrane.

If Viruses are filtered, you have to the size of the target viruses to select the appropriate filtration medium. There Not all viruses are the same size, viruses are typically characterized as "large" viruses or "small" viruses. The big ones Close viruses Viruses of approx. 0.08 μm effective diameter and larger, e.g. Adenoviruses, rheoviruses and herpes viruses. The small viruses close viruses one having an effective diameter of about 0.025 to 0.028 μm, e.g. Hepatitis viruses, polioviruses and parvoviruses.

The Efficient screening of viruses is currently available through the available filtration membranes limited. Although both microporous as well as ultrafiltration membranes have been proposed to viruses seven, each of these membranes is unsuitable in several respects.

Microporous membranes are characterized as isotropic and skinless. In other words: they have a uniform pore structure and their property of removing particles, for example is measured as the titer reduction depends on the pore size and the Thickness of the membrane from. The smallest mean pore size that However, currently available for this type of membranes is only 0.04 μm, e.g. Ultipor N66-NDP (Pall Corporation, Glen Cove, New York). Even though Such membranes are capable of producing relatively large viruses remove when using membranes of sufficient thickness, can they generally do not remove viruses that fall into the category fall small size. The efforts to make a microporous membrane with smaller pores were so far without success.

Ultrafiltration membranes are characterized as asymmetric, i. they own one uneven pore size, over their Fat seen. In particular, such membranes typically exist from a one-piece double layer, one layer being a thin skin is what is called slit-like Fissures or columns, while the other layer has a represents thick substructure, which is a high concentration finger-like Indentations or macro cavities contains. The thin one Skin has a relatively small pore size, while the thick substructure a relatively large one Has pore size. It is the skin that is closely linked to the balance of the membrane and which determines the membrane with its filtration properties. Ultrafiltration membranes are generally in a pore diameter range of 0.001 to 0.02 μm available.

Ideally cover the one-piece Skin completely the macro cavities the thick carrier. In practice, however, contains the skin above the macrocavities almost always considerable Defects, e.g. Cracks, pinholes and other defects and defects that either break the skin layer or lead to a failure in use. That is why there is a shortage of Undamaged membrane and its removal performance no certainty.

Even though Untrafiltration membranes are used in practice these membranes on a statistical basis with respect to the defects the integrity used. That means there's only a small part the liquid to be filtered will pass through one of the defects and there only one part the entire liquid to be filtered undesirable Material to be removed contains that given the probability is that only a small amount of such material passes through the membrane. Although this for certain Areas of application may be acceptable, this is for many other applications unacceptable, especially in such Situations where the filtered liquid is intended to to be administered to a human or an animal, and where each Virus or the like passing through the membrane could trigger a serious health problem for the recipient.

Moreover, it is difficult to fabricate acceptable ultrafiltration membranes in view of their structure and defects which unavoidably accompany this structure. To date, no ultrafiltration membrane has been made that is indeed free of defects. Further, because of the extremely thin skin (on the order of a few microns thick), which is responsible for all the filtration characteristics of an ultrafiltration membrane, it is quite difficult to uniformly reproduce ultrafiltration membranes having the same level of defects, pore size and pore size distribution. In addition, the integrity and other properties of such membranes can not even be easily checked after manufacture and before actual use, since typical testing procedures, such as the bubble point and K _L tests, require that excessively high test pressures be used around the membranes tearing or otherwise damaging it.

In order to there is a serious need for a filtration membrane that provides an effective and predictable removal small particles, e.g. Viruses, from a liquid can cause. Such a membrane should preferably be minimal Have adsorption properties to contaminants and others undesirable To avoid filtration effects. Furthermore, the filtration membrane should be easily reproducible and an integrity test before actual use accessible be. A commercially applicable method for the production of such Membrane is also desirable.

• a) einem Koeffizienten K_UF von mindestens ca. 103 kPa (15 psi), gemessen bei der Prüfung unter Verwendung von Flüssigkeitspaaren mit einer Grenzflächenspannung von ca. 4 mN/m (4 dynes/cm) und/oder
• b) einer Titerverminderung von mindestens ca. 10⁸ gegenüber T₁-Bakteriophage.

According to the invention, such a membrane is provided with an isotropic, skinless, porous polyvinylidene fluoride membrane

• a) a coefficient K _UF of at least about 103 kPa (15 psi) as measured by testing using liquid pairs having an interfacial tension of about 4 mN / m (4 dynes / cm) and / or
• b) a titer reduction of at least about 10 ⁸ against T ₁ bacteriophage.

More particularly, the invention relates to an isotropic, skinless, porous polyvinylidene fluoride membrane having a coefficient K _UF of preferably below about 345 kPa (50 psi). The titer reduction of the membrane according to the invention is at least 10 ⁸ against T ₁ bacteriophage, more preferably also against PR772 coliphage and even more preferably also against PP7 bacteriophage. The membrane of the invention may have a thickness of about 500 μm or less and be as thin as about 125 μm or less.

The The invention also provides a method for producing a Such membrane by providing a casting solution, which Polyvinylidene fluoride and a solvent therefor contains the casting solution on a uniform temperature from about 57 ° C up to 60 ° C heated is, the casting solution on a substrate is distributed to form a film, the film quenched in a quench bath to form a porous membrane, which is washed and dried.

These and further advantageous embodiments of the invention and their Use are explained in more detail below with reference to the drawing. It show in detail:

1A and 1B Scanning electron micrographs of a polyvinylidene fluoride membrane according to the invention at 500 × magnification ( 1A ) and a 5000x magnification ( 1B );

2A and 2 B Electron scanning microscope images of the top ( 2A ) and bottom ( 2 B ) of a polyvinylidene fluoride membrane according to the invention at a magnification of 10100 times.

3 a graph with a curve showing the relationship between the casting solution temperature in degrees C and the resulting factor K _{UF of} the membrane;

4 a graph containing a curve representing the relationship between the pressure drop across the membrane (ΔP) divided by the thickness of the membrane (cm Hg / μm, logarithmic scale) and the coefficient of the membrane K _UF (in kPa).

The present invention provides a new, isotropic, skinless, porous membrane having pore dimensions smaller than those previously obtained with such membranes. The pore size properties of the membrane of the present invention can be expressed by the coefficient K _UF as well as the titer reduction. More particularly, the present invention provides an isotropic, skinless, porous polyvinylidene fluoride membrane having a coefficient K _UF of at least about 103 kPa, preferably at least about 117 kPa, and more preferably at least about 138 kPa, as measured using liquid pairs with one Interfacial tension of about 4 mN / m. The membrane of the present invention typically has a coefficient K _UF below 345 kPa, eg, about 103 kPa to about 345 kPa, and will generally have a coefficient K _UF below about 276 kPa, eg, about 117 kPa to about 276 kPa , measured using liquid pairs having an interfacial tension of about 4 mN / m. More preferably, the membrane according to the invention will have a coefficient K _UF below about 207 kPa, eg about 124 kPa to about 207 kPa, measured using liquid pairs having a surface tension of about 4 mN / m.

The membrane of the invention can also be defined by its titre reduction against various phages. The membrane of the invention preferably has a titer reduction of at least about 10 ⁸ against T ₁ bacteriophage, more preferably also against the smaller PR772 coliphage, and most preferably against the even smaller PP7 bacteriophage. The titer reduction of a particular membrane according to the invention can be predicted essentially on the basis of the coefficient K _UF and the thickness of the membrane. In addition, titer reduction can be tailored within narrow limits, demonstrating a narrow pore size distribution. For example, the membrane of the invention may have a titer reduction of at least about 10 ⁸ against T ₁ bacteriophage, or even against PR772 coliphage, while there is a titer decrease of about 10 ² or less against PP7. In general, the membrane of the invention will have a thickness of about 500 μm or less, preferably about 250 μm or less, and most preferably about 125 μm or less. For most applications, the membrane of the invention may have a thickness of about 75 microns to about 125 microns. The membrane according to the invention can have these different thicknesses and nevertheless be characterized by the aforementioned coefficients K _UF and / or the titre reduction values. Therefore, although the membrane of the present invention can be made very thin, eg, about 25 to 125 μm thick, or even as thin as 25 to 75 μm, the membrane of the present invention still has excellent titer reduction values against viruses.

Since the membrane of the invention is isotropic, it has a substantially uniform and symmetric pore structure. Representative membranes of the invention show the scanning electron micrographs of 1A (500x) and 1B (5000 times), which show a fine and uniform pore structure of the membrane, as well as the electron micrographs of the 2A and 2 B (both 10100x) showing the top and bottom views of the same membrane. In addition, the isotropic nature of the membrane of the invention is represented by a straight line graph in FIG 4 shown. In this figure, the pressure drop across the membrane (ΔP), irrespective of the membrane thickness (cm / Hg / mil), is recorded on a logarithmic scale against the membrane's coefficient K _UF (kPa). The resulting line indicates an isotropic membrane.

K _UF determination

Test methods known, for example, as "Bubble Point" (ASTM F316-86) and the K _L Test Method (US Patent 4,340,479) have been used in the past to determine the pore size characteristics of microporous membranes. Although these test methods, particularly the K _L test method, can be used to study the membranes of the present invention, these tests require high pressures in conjunction with very small pore membranes, which can lead to reliability issues. Therefore, the membrane of the present invention is preferably characterized using the K _UF coefficient test method developed by Pall Corporation to obtain a Possibility of more reliable determination of pore size and membrane integrity of membranes with very small pore dimensions.

The K _UF test method is described in U.S. Patent Application Serial No. 07 / 882,473 (filed May 13, 1992). In accordance with the K _UF test method, the membrane to be tested is first wetted thoroughly with a wetting liquid capable of completely wetting the membrane. A displacement fluid which is immiscible with the wetting liquid used to wet the membrane but has a small, stable interfacial tension is brought into contact with the upstream side of the wetted membrane. Pressure is then gradually applied to the displacement fluid and the flow of the displacing fluid through the membrane is measured as a function of applied pressure. The displacing liquid should be stable but not miscible with the wetting liquid, and the interfacial tension between the two liquids should be about 10 mN / m (10 dynes / cm) or less. Specification of the interfacial tension to less than 10 mN / m allows fluid displacement at substantially lower pressures than similar test methods normally performed with a water / air interface (eg, in the K _L or bubble point test method). In addition, it is important that the interfacial tension between the two fluids remain constant during the test procedure. An application of the flow rate of the displacing liquid per unit area of the membrane through the membrane as a function of the applied pressure can be made and a straight line can be drawn through the steep part of the resulting curve using the regression analysis, the straight line being the horizontal axis at a given pressure value cuts. This point of intersection is assumed to be the K _UF value and is directly linked to the pore diameter of the membrane. Since there is no diffusion flow through a membrane which is free of defects, the flow rate of the displacing liquid through the membrane before the K _UF value is zero, ie a horizontal line in a typical graph of flow rate versus pressure.

The K _UF values, which are mentioned here, are determined by means of a liquid pair with an interfacial tension of about 4 mN / m. Specifically, the K _UF values mentioned herein are determined using n-pentanol saturated with water as the wetting liquid and water saturated with n-pentanol as the displacing liquid. The immiscible phases are mutually saturated to ensure that the interfacial tension between the liquids, which is about 4.4 mN / m at ambient temperature, does not change by dissolving one phase in the other. Other factors, such as temperature, should also remain relatively constant during the test procedure so as to avoid significant changes in interfacial tension between the immiscible fluids during testing. Although other pairs of liquids can be used to determine the K _UF value, such as n-butanol and water, n-pentanol and water are used here because the K _UF values thus obtained are in a convenient range and because of the high mutual solubility of n-pentanol and water ensures that if selective adsorption of any of the components occurs through the membrane, such adsorption will have little or no effect on the K _UF values obtained. Other alcohol / water systems include, for example, n-octanol / water and n-hexanol / water, and other non-alcohol based fluid pairs could, of course, be similarly used to determine K _UF values.

The Interfacial tensions for different organic liquids, which form a phase boundary with water, as published in the book "Interfacial Phenomena", 2nd edition by J.T. Davies and E.K. Rideal (1963), are below stated together with the solubilities of the various compounds in water, as in the Chemical Rubber Handbook (CRC), edition of 1970, is reported.

Although only organic liquids and water have been listed in the table above, the K _UF test method, as previously mentioned, can also be performed with any other pair of immiscible liquids.

According to the K _UF test method, the wetting liquid may be a single liquid compound, such as n-octanol, and the displacing liquid may also be a single compound, such as water, which is substantially insoluble in the n-octanol. Alternatively, the wetting liquid may be an equilibrium mixture comprising a first liquid compound such as n-pentanol which is saturated with a second liquid compound such as water. The second liquid compound saturated with the first is then used as the displacement liquid. With respect to other embodiments, it is important that the interfacial tension between the two liquids remain relatively constant during the performance of the test. It is therefore recommended that the phases in the composition should be stable, ie, when the phases are in contact with each other, there should be no net flow of any of the fluids across the interface. Thus, there is no significant change in the solubility of the displacing liquid in the wetting liquid, which, if present, could affect the results.

In practice, the K _UF test is usually carried out with each of the immiscible phases saturated with the fluid with which it is in close contact. For example, the solubility of n-pentanol in water is 2.7 g / 100 g of water at 22 ° C. Since some n-pentanol will dissolve in water, it is preferred to saturate the aqueous phase with n-pentanol. Likewise, it is preferred in the n-pentanol phase to saturate them with water. Mutually saturated phases can be readily obtained by shaking a mixture containing sufficient quantities of each of the liquids, together in a container or a separatory funnel. In the tests and examples described here, the organic phase was used in each case to wet the membrane. It is an obvious extension of the process to exchange the fluids, ie to wet the membrane with the aqueous phase and the upstream side of the membrane under pressure with the organic phase to feed.

The absolute K _UF values will, of course, vary depending on the particular alcohol / water system, although the values obtained when using other alcohol / water systems are generally related to the n-pentanol / water system -K _UF values can be correlated using the ratio of their respective interfacial tensions. For example, corresponding to a K _UF of about 310 kPa in n-pentanol / water system a K _UF of about 124 kPa in the n-butanol / water system (ie 310 kPa × 1.8 / 4, 4).

titer reduction

The titre reduction refers to an ability of a particular membrane to remove predetermined particles from a fluid. As such, titer reduction is a standard measure of the ability of the membrane to remove biological organisms such as bacteria and viruses. Although any suitable particle can be used to determine titer reduction, the titer reduction of the membrane of the invention was tested by testing the membrane for T ₁ and PP7 bacteriophages (generally a 50:50 mixture of the two bacteriophages at a level of 10 ⁹ to 10 ¹⁰ bacteriophages per milliliter) in a gel-phosphate buffer. For the purposes of the investigations reported here, E. coli ATCC # 11303 was used as the source of the T ₁ phages and P. aeruginosa ATCC # 15612 as the source of the PP7 phages. In addition to the T ₁ and PP7 bacteriophages, the membrane of the invention was also tested against the PR772 coliphage. The source of the PR772 phage for the purposes of the investigation reported here was Prof. HW Ackerman, Department of Microbiology, Faculty of Medicine, Laval University, Quebec, Canada.

The titer attenuation of a membrane is defined as the ratio of the phages contained in the influent, based on the content in the effluent. Since the size of the T ₁ phage is approximately 0.078 μm, the size of the PR772 phage is approximately 0.053 μm and the size of the PP7 phages is approximately 0.027 μm, these phages provide excellent models for determining the efficiency of the separation for a membrane with respect to larger, intervening and smaller viruses. A membrane is generally considered to have an absolute releasability with respect to a particular particle, eg the T ₁ phages as representatives of larger viruses, if it has a titer reduction against this particle of at least 10 ⁸ and preferably at least 10 ¹⁰ . Of course, an absolute ability to segregate a membrane with respect to the PR772 or PP7 phage assures an absolute ability to segregate this membrane for larger viruses.

Since these biological organisms are able to multiply rapidly, they allow easy detection of even the smallest amounts in the filtrate of a test solution. Therefore, the inability to detect any amount of a particular such model biological organism in the filtrate of a test solution is an excellent confirmation of the fact that the particular membrane in fact prevents all biological organisms in the test fluid from passing through the membrane. In addition, the ability of the membrane of the invention to exhibit a titre reduction of 10 ⁸ or higher provides almost absolute certainty for the separation of all viruses from a wide range of liquids, especially those treated in commercial processes, eg, in pharmaceutical production because the amount of virus found as contaminants in most commercial processes hardly ever exceeds 10 ⁴ per milliliter. Titer reduction is a function of the K _UF value of a membrane and the thickness of the membrane. Since the pressure drop across a membrane is exponentially influenced by the K _UF value of a membrane, while on the other hand the pressure drop across a membrane is only linearly affected by the thickness of the membrane, small improvements in titer degradation of a particular membrane can generally be achieved in a more economical manner by increasing the thickness of the membrane, for example by creating multiple layers of the same membrane.

pressure drop

Of the Pressure drop over a membrane is in the use of such membranes for filtering purposes of particular importance. The membrane according to the invention advantageously offers the desired Titre reduction against a particular particle together with one satisfactory pressure drop (ΔP) over the Membrane. The pressure drop referred to here will using conventional Techniques such as these e.g. in U.S. Patent 4,340,479 and all pressure drop values reported here (cm Hg), at a constant air flow rate of 61 cm / min (2 ft / min).

production method

The membranes of the present invention are made from polyvinylidene fluoride (PVDF) using the wet-casting process as described in U.S. Patent 4,340,479, in conjunction with the particular temperature conditions discussed herein. It can be used any suitable polyvinylidene fluoride, such as Kynar ^® -761 and 761 PVDF resins. The polyvinylidene fluoride will typically have a molecular weight of at least about 5000 daltons, preferably a molecular weight of at least 10,000 daltons.

The process of the present invention for producing the membranes as described herein comprises providing a casting solution comprising polyvinylidene fluoride and a solvent therefor, heating the casting solution to a uniform temperature of from about 57 ° C to about 60 ° C Dispersing the casting solution on a substrate to form a film, quenching the film in a quench bath to form a porous membrane, and washing and drying the porous membrane. The temperature of the casting solution is directly related to the K _UF value of the resulting membrane, as shown in the graph of FIG 3 which contains a recorded curve of the casting solution temperature in degrees C versus the resulting membrane K _UF values (in kPa). For example, a casting solution temperature of approximately 58 ° C. will result in the formation of a membrane having a K _UF value of approximately 214 kPa, while a casting solution temperature of approximately 60 ° C. will result in the formation of a membrane having a K _UF value of approx 117 kPa.

Surprisingly, it has been found that the temperature at which the polyvinylidene fluoride casting solution is maintained is very critical for the preparation of the membranes of the invention. Great care must be taken to ensure that the casting solution temperature is uniform, ie at a certain temperature +/- 0.01 ° C, to ensure a true uniformity of the pore structure within the membrane. Moreover, it appears that the casting solution has at least a short memory effect, so that it is difficult to prepare the membrane of the present invention with a desired K _UF value if the temperature of the casting solution is about 60 ° C at any time during the treatment of the casting solution even if the temperature has subsequently been lowered below about 60 ° C, it being understood that the invention is not intended to be bound by any particular theory.

A possible statement For this ocular Effect is that though a single temperature for the Casting solution specified In fact, the specified temperature may be an average a range or a distribution of temperatures within represents the casting solution, so that one noticeable part of the casting solution actually clear can be above the specified temperature. This may be the special one Success in making suitable membranes by use explain the preferred techniques of the method according to the invention, the includes, the desired Temperature of the casting solution with heaters of rising higher precision to approach (Which not only efficiently a uniform temperature for the Create casting solution, but about it still considerable the possibility lessen that individual Parts of the casting solution the Temperature of about 60 ° C exceed considerably and more preferred that the desired final Temperature of the casting solution at any step of the heating process is exceeded).

Even though the inventive method can be performed in a variety of suitable ways is at a preferred embodiment the method according to the invention with the formation of a solution, which is polyvinylidene fluoride in powder form, a solvent for the Resin, advantageously dimethylacetamide, and a non-solvent, preferably isopropanol, started. The solution comprises about 10 to about 20% by weight, preferably about 15 to about 17% by weight of polyvinylidene fluoride. The remainder of the solution comprises the solvent and the non-solvent in a weight ratio, which is in the range of 90:10 to 70:30, preferably about 80:20.

The Temperature of the polymer solution will then be on the desired casting solution raised. Small amounts of the polymer can be efficient at uniform temperatures in a one-step process, e.g. few 100 g polymer in one liter of solution can evenly in one jacketed boiler to be heated while using a speed mixer high speed of rotation. For larger quantities, in particular At commercial production levels, it is not practical to have one single-stage heating process too use as well as the jacketed boiler, due to the noticeable Temperature deviations in the casting solution, which are avoided have to, to satisfactorily produce the membranes of the invention.

For larger quantities, therefore, the temperature of the casting solution is preferably raised in stages in order to be able to carefully control the temperature uniformity while minimizing the time required to increase the temperature. At each successive stage, the temperature is raised and brought closer to the casting temperature necessary to produce a membrane having the desired K _UF value, but in a manner which ensures greater uniformity (ie, a narrower temperature distribution) it is ensured that the casting solution does not exceed the desired casting temperature.

Especially can be a larger amount to polyvinylidene fluoride in a thermostatically controlled tank and in a suitable mixture of solvent and non-solvent be dispersed. While mixing the casting solution the temperature of the tank is kept at a temperature that allows it that the Content a temperature of about 47 ° C up to 51 ° C gets which is well below the desired casting solution temperature is. This average temperature is selected to ensure that no noticeable parts of the solution the desired casting solution between about 57 ° C and exceed about 60 ° C. The Components should remain in the tank until the polyvinylidene fluoride dissolved has, and the resulting solution gets even with this equipment heated, e.g. For about 16 hours or something like that.

The Casting solution then preferably through a heat exchanger transported to raise its temperature to about 52 ° C, and then through passing an in-line mixer (or other suitable high-precision heater), which raises the temperature of the casting solution the desired uniform casting solution temperature between 57 ° C and raises 60 ° C ± 0.01 ° C. The uniformity the temperature is very important for uniformity the pore structure within the resulting membrane.

After this the casting solution in the inline mixer was heated and before the casting solution on When a substrate is distributed (i.e., poured), the viscosity of the casting solution becomes typically lifted by passing the casting solution through a viscosity leveler, e.g. another heat exchanger, the temperature of the casting solution on about 30 ° C or the like diminished. The casting solution is then placed on a suitable Substrate, e.g. Mylar, by the action of a suitable Quench bath, e.g. an aqueous solution of Dimethylacidamide and isopropanol, quenched or hardened and, e.g. with deionized water, using conventional techniques for formation the membrane of the invention washed.

After the washing is finished, the wet membrane is picked up and dried. Although drying may be accomplished by any suitable means, for example, by heating in an oven, it has been discovered that drying through the direct application of heat, such as in an oven, results in an undesirable increase in the pore size of the resulting membrane. However, this problem has been overcome by the application of microwave energy to the membrane to dry the membrane. Microwaves at a frequency of about 24 MHz are preferably used, although other frequencies may be used as long as the pore size or K _UF values of the membrane are not unduly compromised.

heat treatment

The obtained Polyvinylidenfluoridmembran can be heat treated or annealed if desired is to improve the properties. In particular, the membrane according to the invention Conditions are heated, the strength and subsequent Improve hydrophilization of the membrane.

Preferably is the membrane of the invention heated to a temperature of at least 80 ° C for a period of time, which is sufficient to achieve such a state that when it is subsequently hydrophilized, the resulting hydrophilized Membrane substantially uniform having hydrophilic properties. Of course, the membrane of the invention should are not heated to such a high temperature that the membrane becomes soft and deforms, either under its own weight or due to tensile forces, which are exercised by mechanical means by which the Membrane during held the heating process or worn. Typically, the upper temperature limit about 160 ° C be. The duration of the heating becomes with the heating temperature vary and the nature of the membrane that is heated. For example can small membrane pieces in a flat leaf shape, which is in direct contact with a surface with high temperature, only a short duration of treatment, e.g. less than a minute, for need the heating, while a rolled up membrane of several hundred linear feet many Hours of low temperature heating for the membrane may need to to achieve a suitable equilibrium temperature. Most the membrane according to the invention is preferred to a temperature of about 120 ° C while Approximately 24 to 72 hours heated, especially for about 48 hours.

The heat treatment the membrane of the invention can be effected without fixing or clamping the membrane; however, the membrane preferably becomes in dimensions during the heat treatment fixed so as expansion changes to minimize or avoid the membrane, e.g. a shrinking. Any suitable means can be used to seal the membrane in to fix their dimensions. For example, Can the membrane in a frame brought or wound up on a core or a roll be, preferably with an intermediate material, such as e.g. a fibrous non-woven material to layer one Avoid positional contact of the membrane. Most preferred is the inventive membrane heat-rolled in rolled-up form, with a nonwoven polyester fiber material interposed becomes.

The heat treatment Polyvinylidene fluoride membranes are described in greater detail in US patents 5,196,508 and 5,198,505. These patents also describe the improvements in surface modifications, in the heat treatment of polyvinylidene fluoride membranes can be obtained.

surface modification

The obtained Polyvinylidenfluoridmembran is hydrophobic and shows a remarkable tendency to adsorb proteins and the like, which in the liquid to be filtered currently could be. These properties are undesirable as she becomes a higher one Pressure drop over contribute to the membrane and ultimately in premature pollution the membrane and / or in certain cases to form a second Sieving layer on the surface lead the membrane can. As a result, the membrane of the present invention is preferably attached the surface modified to make them hydrophilic (i.e., a critical wetting surface tension (CWST) of at least about 72 mN / m) as determined by the CWST test which is described in US Patent 4,880,548, and less vulnerable for protein adsorption and pollution.

Such surface modifications the membrane of the invention can in any suitable manner, and preferably by graft polymerization of a suitable monomer onto the surface of the Membrane performed. Preferred examples of such monomers include acrylic or methacrylic monomers which have alcoholic functional groups, e.g. Hydroxyethyl acrylate, hydroxyethyl methacrylate, hydroxypropyl acrylate, Hydroxypropylmethacrylat and Kombinatio nen thereof, in particular Hydroxypropyl acrylate and / or hydroxyethyl methacrylate. These monomers can be combined with small amounts of acrylic monomers, which have no alcoholic functional groups, e.g. methyl methacrylate, as described in U.S. Patent 5,019,260.

each suitable agents may be used to prepare the appropriate monomers to polymerize on the membranes of the present invention. Radiation grafting is the preferred technique to do so Result. The source of radiation can be from radioactive Isotopes such as cobalt 60, strontium 90 and cesium 137 come from or on devices such as e.g. X-ray machines, electron accelerators and UV devices. Preferably, however, the radiation is in the form of electron radiation used. It has been found that by using this Form of radiation is a very uniform distribution of radiation can be provided. This in turn results in a final product, which grafted more uniformly is compared to such membranes, using different Radiation sources, e.g. Cobalt 60, grafted.

The grafting is typically carried out either by irradiating the membrane and then exposing a suitable solution of the monomer or irradiating the membrane while exposing a suitable solution to monomer. Regardless of which method is used, grafting should be carried out in the absence of oxygen, eg, under a nitrogen atmosphere, since oxygen reacts with the reactive sites generated by the radiation, reducing the number of sites that are desired Polymer bond are available, is lowered. If the membrane is irradiated prior to immersion in the monomer solution, the membrane should be contacted with the monomer solution as soon as possible to avoid undesirable reactions resulting in loss of reactive sites for attachment of the polymer to the surface of the membrane , The monomer solution may contain any suitable concentration of the monomer to be grafted, typically 1 to 10% by volume of monomer in a solvent system, generally water as such, or with a suitable alcohol such as tertiary butyl alcohol. The preferred monomer solution in the context of the invention includes 4% by volume of hydroxypropyl acrylate, 25% by volume of tertiary butyl alcohol and 71% by volume of deionized water. The details and parameters of polymer grafting of membranes are very good in the art known.

Even though the graft polymerization in the absence of crosslinking agents it is preferred that crosslinking agent be used Especially when the aforementioned acrylate monomers on the surface the membrane are graft polymerized. Any suitable crosslinking agent may be used in conjunction with the present invention. Suitable crosslinkers include di- or polyacrylates and methacrylates of diols and polyols, in particular linear or branched aliphatic Diols, e.g. Ethylene glycol, 1,2-propylene glycol, diethylene glycol, dipropylene glycol, Dipentylene glycol, polyethylene glycol, polypropylene glycol, polytetramethylene oxide glycol and poly (ethylene oxide-copropylene oxide) glycol as well as triol acrylates, such as. Trimethylolpropane. Examples of other crosslinking monomers, which can be used in the present invention include Allyl, maleimide, unsaturated dicarboxylic acids, aromatic vinyl compounds, polybutadienes and trimellitic acid esters. Other suitable crosslinking agents are disclosed in U.S. Patents 4,440,896, 4,753,988, 4,788,055 and 4,801,766.

Polyethylenglycoldimethacrylate, whose molecular weight of the polyethylene glycol is about 200 to about 600 are preferred crosslinking agents in the context of the present invention Invention. Polyethylene glycol 600 dimethacrylate, in particular in Related to the radiation grafting of hydroxypropyl acrylate on the surface the membrane is the most preferred crosslinking agent.

The Crosslinking agent may be used in any suitable amount. Typically, the crosslinking agent of the grafting solution in in an amount of about 0.025% by volume to about 5% by volume, further typically in an amount of about 0.05% by volume to about 2% by volume. For example, a monomer solution, which 4% by volume of hydroxypropyl acrylate in water and tertiary butyl alcohol contains preferably about 0.5 vol.% Polyethylene glycol-600-dimethyl acrylate as Contain crosslinking agent.

exemplary applications

The inventive membrane can be used in any suitable application, including many Applications where ultrafiltration membranes are currently used become. In view of the excellent titre reduction of Membrane against viruses and similar size Particles have the membrane according to the invention Practical use in the filtration of pharmacological fluids and the like, although the inventive membrane for filtering each suitable liquid can be used.

Accordingly, the present invention provides a method of filtering a fluid comprising passing a fluid through a membrane of the invention comprising, in particular, an isotropic, skinless, porous polyvinylidene fluoride membrane having a K _UF of at least about 103 kPa as tested with a fluid pair an interfacial tension of about 4 mN / m, and / or with a titer reduction of at least about 10 ⁸ against T ₁ bacteriophage. The fluid which is passed through the membrane of the invention may contain viruses, eg more than 10 ² per ml or even 10 ⁴ per ml, before it passes through the membrane, which removes viruses from the fluid, so that the fluid is less than 10 ² per ml or even no viruses after passing through the membrane. Thus, the membrane of the present invention can be used to treat fluids to reduce or eliminate the number of viruses therein as well as to recover and concentrate viruses from fluids for virus identification, testing, or the like.

The ability the membrane according to the invention, tested in their integrity in a relatively simple manner to be able to and to be equally producible on a commercial basis, that the inventive membrane a predictable rate of removal of given substances having. About that In addition, the excellent separation properties of the membrane according to the invention at. reasonable Pressure drops over the Membrane obtained. Thus, to the extent that the membrane of the invention can be used in applications where ultrafiltration membranes are currently used be, the membrane of the invention desirable and exceed ultrafiltration membranes in the same fields of application.

The membrane of the invention may be used alone or joined to a suitable support structure. Similarly, the membrane of the invention may be used in suitable filters, filter cartridges and the like. Of course, given the high performance of the pore structure within the membrane of the invention as well as the low susceptibility to protein adsorption in the grafted embodiments of the membrane membrane of the invention also be used in the so-called dead-end filtration applications as well as in tangential or cross-flow filtration applications. The membrane of the present invention is expected to be particularly useful in filter elements, such as filter cartridges, as generally described in U.S. Patent 4,340,479. Preferred filter elements using the membrane of the present invention include the sheet-like membrane of the present invention in which the sides of the membrane are overlapped and sealed with each other to obtain a tubular structure having an outer surface, an inner space, and two ends and ends covers are sealed to the ends of the tube, wherein at least one of the end caps has a central opening which provides access to the interior of the tube, and wherein all seals are fluid-tight. The membrane of the invention will preferably be corrugated in such a filter element to provide a larger membrane surface area for the volume of the filter element. At least one of the sides of the membrane is typically stitched to a porous support layer, and in such a situation, the membrane and the porous support layer will generally be both corrugated. The filter element may comprise a single membrane according to the invention, or more preferably a plurality of such membranes which are stitched together. If there are several membranes in a filter element, the membranes are preferably separated by a porous support layer to which each membrane is attached. Other aspects of the filter element may be of any suitable construction and made of any suitable material. For example, the end caps may be made of a suitable polymeric material such as polyester, especially polybutylene glycol terephthalate or polyethylene glycol terephthalate. The filter element may be fabricated using techniques that are well known in the art.

The The following examples serve to further describe the invention and of course not as their limitation thought.

example 1

This example describes the preparation of multiple filtration membranes in accordance with the present invention. The various filtration membranes are prepared using various casting solution temperatures to illustrate the effect of the casting solution temperature on the K _UF values of the resulting filtration membrane.

A Casting solution was from 17.0% by weight of polyvinylidene fluoride resin, 66.4% by weight of dimethylacetamide (solvent) and 16.6% by weight of isopropanol (non-solvent). The Casting solution was stirred in a closed container to the polyvinylidene fluoride resin in the 80:20 parts by weight per part by weight mixture of solvents and non-solvents dissolve, and the temperature of the casting solution became increased to 50.9 ° C and at maintained this temperature.

Four casting solution samples were then passed through an in-line mixer and each of the casting solution samples was raised to a different temperature. Each of the solutions was then cooled to increase the viscosity when a film was cast on a substrate and subjected to a quench bath containing 42% by weight of water, 51% by weight of dimethylacetamide and 7% by weight of isopropanol. The quench bath was maintained at 30 ° C. The cast film was generally held in contact with the quench bath for less than 1 minute. The resulting membrane was then washed with water to remove the solvent, and the membrane was microwaved in the clamped state to avoid shrinkage. The membranes were prepared from each of the four casting solution samples. The temperatures of each of the casting solution samples and the K _UF values of each of the obtained membranes are shown below.

The data obtained are in the form of a casting solution temperature (in ° C) against the K _UF values (in kPa) as a curve in 3 recorded. As can be seen from the data, an increase in the casting solution temperature within the range of about 57 ° C to about 60 ° C causes a corresponding decrease in the K _UF value of the filtration membrane made from this casting solution.

Example 2

This Example describes the preparation of polyvinylidene fluoride membranes according to the present invention, which is graft-polymerized Coating are provided to make the membranes hydrophilic and less vulnerable against protein binding. The properties of such membranes, and indeed before and after grafting are determined to demonstrate that the Grafting process the Porous properties of the membrane are not adversely affected and only to a slight increase in pressure loss across the filtration membrane leads.

Several membranes with different K _UF values were prepared in accordance with the procedure described in Example 1. A portion of each membrane was grafted using the electron beam grafting method. In particular, the membranes were passed under an electron beam generator (with 175 kV and 3 mAmp settings) at a rate of 20 feet / min to achieve a total radiation dose of 2.4 Mrad. The membranes were then passed into a grafting solution of 4% by volume of hydroxypropyl acrylate, 25% by volume of tertiary butyl alcohol and 71% by volume of deionized water, rolled up under a nitrogen atmosphere (ie protected from oxygen) and stored for several hours prior to washing off ungrafted monomer. The grafted membranes were then dried in frame at 100 ° C for 10 minutes.

The K _UF values, thickness and pressure drop (ΔP) across each membrane in ungrafted and grafted form were determined and the results are shown below.

As can be seen from the data obtained, the grafting of the membranes according to the invention gives rise to membranes which are preferably hydrophilic, ie water-wettable, while negative effects on the K _UF values and the pressure drop properties of the membrane occur only slightly.

Example 3

This Example describes the excellent titer reductions against various viruses which are characteristic of the membranes according to the invention are.

Various membranes (142 mm disks having a thickness of about 38 to 50 μm) were prepared in accordance with the method as described in example 1 and were prepared in accordance with the method as described in example 2, grafted. The grafted membranes are probed with a 50:50 mixture of T ₁ and PP7 bacteriophages (at a level of about 10 ¹⁰ bacteriophages per milliliter) in a gel phosphate buffer. As previously discussed, the size of the T ₁ phages is about 0.078 μm while the size of the PP7 phages is about 0.027 μm. Thus, these bacteriophages are fairly representative of larger or smaller viruses. The titer reduction of each membrane, single or multiple layered, was determined as the ratio of the particular phage as contained in the feed to those contained in the effluent. The K _UF values of the ungrafted membrane, the number of Memb ranges tested and titer reduction (T _R ) for each phage are listed below.

The data obtained show that the filtration membrane of the present invention can show a very high titre reduction and is able to perform an absolute removal of viruses, as becomes particularly clear in Example 3A. In addition, this high titer reduction property can be achieved with remarkably thin membranes as exemplified in Sample 3C. In addition, the obtained data show that the filtration membrane of the present invention has a very uniform pore structure. For example, sample 3H is able to remove all of the T ₁ bacteriophages while allowing substantially all of the PP7 bacteriophages to pass through. Therefore, the membrane of Sample 3H has a pore size between about 0.07 μm and about 0.027 μm, which represents a very narrow pore size distribution.

Example 4

This Example also illustrates the excellent virus titre reduction, which for the membrane of the invention is characteristic.

The grafted filtration membrane of Example 3, designated Sample 3F, was treated with a mixture of PR772 coliphage (at a content of 5.2 x 10 ⁸ phage / ml) and PP7 bacteriophage (at a content of 1.7 x 10 ⁹ phages / ml) in a gel phosphate buffer. As previously described, the size of the PR772 phage is about 0.053 μm, while the size of the PP7 phage is about 0.027 μm. Thus, these phages are quite representative of medium-sized and smaller viruses. The titer reductions of each membrane, single or multiple layered, were determined as the ratio of the individual phages contained in the influent to their presence in the effluent. The K _UF values of the ungrafted membrane, the number of membrane layers tested, and the titer reduction (T _R ) for each individual phage are listed below.

The confirm the results obtained the excellent titre reduction of the membrane according to the invention across from medium-sized Viruses. About that It also shows that the Pore size of this special membrane sample is quite small, i. below about 0.053 μm in terms of on the moderate effectiveness with respect to the removal of this particular membrane sample the much smaller PP7 phage while the pore size distribution Again, the sample shows to be very narrow, i. about below approx. 0.027 μm below about 0.053 μm.

Example 5

This Example shows the approximated lower operating limit based on the pore size of the membrane of the invention in view of a satisfactory titre reduction against larger viruses.

A 46 μm thick membrane was prepared in accordance with the procedure described in Example 1, and with respect to K _UF values, pressure drop (ΔP) and titer reduction (T _R ) versus T ₁ - and PP7 bacteriophages as described in Example 3, tested. The data obtained are listed below.

The data obtained show that the membrane of the invention with a K _UF value of about 117 kPa and a thickness of at least about 92 microns will have a titre reduction of more than 10 ⁸ against larger viruses. The fact that the inventive membrane of this example exhibits an absolute removal property with respect to the larger T ₁ phages, while having substantially no separation effect with respect to the smaller PP7 phages, shows that the membrane of the present invention is not just one Pore size of between about 0.078 microns and about 0.027 microns, but also that the pore size distribution is fairly narrow, ie below about 0.078 microns to above about 0.027 microns.

Example 6

This Example shows the adsorption characteristic for low proteins for a grafted one Filtration membrane according to the present invention.

A loading and binding test was performed by immersion with samples of grafted filtration membranes made in accordance with the method of Example 2 (samples 6A-6D) as well as with ungrafted control membranes (samples 6E and 6F). Each membrane was immersed in an IgG solution containing ¹²⁵ I goat IgG and 20 μm / ml unlabeled goat IgG for 60 minutes. Each membrane was washed with phosphate buffered saline (PBS) and assayed for adsorbed IgG. The membranes were then washed with an aqueous solution of 1% SDS in 2 molar urea solution and rechecked for adsorbed IgG. The results of these tests are listed below.

The obtained data show that the filtration membrane of the present invention, which has been suitably graft-polymerized, shows a low protein adsorption. The membranes of the invention grafted with hydroxyethyl methacrylate (HEMA) show a significantly reduced level of protein adsorption compared to the ungrafted control. In addition, the inventive adsorbs The membrane grafted with hydroxypropyl acrylate (HPA) only about half the protein of the HEMA grafted membranes of the present invention.

Example 7

This Example shows that the Microwave drying on the membrane of the invention no appreciable negative effect the filtration properties of the membrane has.

Two membrane samples were prepared according to the procedure described in Example 1. One of the membranes was dried with a microwave dryer (designated 7A) while the other of the membranes was dried with a steam drum dryer (designated 7B). The K _UF values of the two membranes are determined both before and after drying, and the results are listed below.

The Results show that the Microwave drying of the membranes in contrast to conventional Drying essentially no negative effect on the pore size of the membrane of the invention Has.

Example 8

This Example shows the isotropic nature, i. the symmetric pore structure the membrane of the invention.

Several membranes with different K _UF values were prepared in accordance with the procedure described in Example 1. The K _UF value and the pressure drop (ΔP) divided by the thickness (in cm Hg / μm) were determined for each membrane and the results are listed below.

The resulting data are expressed as the pressure drop values across the membrane (ΔP) divided by the thickness of the membrane (in cm Hg / μm) on a logarithmic scale versus the membrane K _UF values (kPa) in the graph of 4 entered. The solid curve is the result of least squares matching and has a correlation factor of 0.87. As can be seen from the data, an increase in K _UF values results in a logarithmic reduction in pressure drop values as a function of the thickness of the filtration membrane. This relationship is characteristic of an isotropic filtration membrane and confirms that the filtration medium of the present invention is inherently isotropic.

Alles the above referenced quotations are here in their Whole than added consider.

Even though the invention has been described with emphasis on preferred embodiments, is it for the Specialist clear that deviations can be used by the preferred products and methods and that intends is that the Invention also be carried out in a manner other than specifically described herein can. Accordingly includes the invention all modifications within the basic idea and the scope of the invention as defined by the following claims is.

Claims (26)

Isotropic, skinless, porous polyvinylidene fluoride membrane, characterized in that the pores The membrane size distribution is predetermined such that the membrane a) has a K _UF coefficient of at least about 103 kPa when tested using liquid pairs with an interfacial tension of about 4 mN / m and / or b) a titer reduction of at least about 10 ⁸ against T ₁ bacteriophage has. Membrane according to claim 1, characterized in that the membrane has a K _UF coefficient of about 103 kPa to about 345 kPa. Membrane according to claim 1 or 2, characterized in that the membrane has a titer reduction of at least about 10 ⁸ against T ₁ bacteriophage. A membrane according to claim 3, characterized in that the membrane has a titer reduction of at least about 10 ⁸ against PR772 coliphage and / or PP7 bacteriophage. Membrane according to one of claims 1 to 4, characterized in that the membrane has a titer reduction of about 10 ² or less against PP7 bacteriophage. Membrane according to one of Claims 1 to 5, characterized that the Membrane has a thickness of about 500 microns or less. Membrane according to one of Claims 1 to 6, characterized that the Membrane a surface coating a polymer which makes the membrane hydrophilic and less susceptible for the Adsorption of proteins makes. Membrane according to claim 7, characterized in that that this Polymer one or more acrylic or methacrylic monomers with functional Hydroxyl groups. Membrane according to claim 7 or 8, characterized that this Polymer was grafted onto the membrane. Membrane according to claim 9, characterized that the Radiation is electron beam radiation. Process for producing a porous membrane, characterized in that a wet cast membrane is dried by means of microwave radiation under conditions that are sufficient to remove the liquid from the membrane cause. Method according to claim 11, characterized in that that the Membrane comprises polyvinylidene fluoride. A process for producing a membrane, comprising: Produce a casting solution, which Polyvinylidene fluoride and a solvent therefor comprises Heat the casting solution a uniform temperature from about 57 ° C up to approx. 60 ° C, Distribute the casting solution a substrate to form a film, quenching the film in a quenching bath to form a porous membrane and washing as well Dry the porous Membrane. Method according to claim 13, characterized in that that the Membrane at least partially by the action of microwave radiation dried. Method according to claim 13 or 14, characterized that the Membrane is treated to the membrane with a surface coating of a polymer which makes the membrane hydrophilic and less susceptible for the Adsorption of proteins makes. Method according to claim 15, characterized in that that the Treatment of the binding of a polymer to the surface of the Membrane comprises, wherein the polymer is one or more acrylate or methacrylate monomers comprising hydroxyl functional groups. Method according to claim 15 or 16, characterized that this Polymer is radiation grafted onto the membrane. A method according to claim 17, characterized in that the radiation is electron beam radiation is. Membrane made by a method according to one the claims 11 to 18. Method for filtering a fluid containing the Passing a fluid through a membrane according to one of claims 1 to 10 or 19. Method according to claim 20, characterized in that that this Contains fluid viruses, before it passes through the membrane and contains fewer viruses after it was passed through the membrane. Filter element comprising a membrane after a the claims 1 to 10 or 19 with overlapping and to form a tubular structure sealed sides, which have an outer surface, a Inner and two ends and end covers, the latter on the ends of the tube are sealed, wherein at least one of the end caps has a central opening, which provides access to the interior of the tube, and all Seals are fluid-tight. Filter element according to claim 22, characterized that the Membrane is corrugated. Filter element according to claim 22 or 23, characterized characterized in that at least one of the sides of the membrane is connected to a porous carrier layer. Filter element according to claim 24, characterized that this Filter element comprises multiple, interconnected membranes. Filter element according to claim 25, characterized that the Membranes over each other a porous one backing are separated, to which each membrane is bound.