CA1249110A - Charge modified microporous hollow tubes - Google Patents

Abstract

CHARGE MODIFIED MICROPOROUS
HOLLOW TUBES
ABSTRACT
Charge modified microporous hollow tube filter membranes are provided. The tubes are comprised of an organic polymeric microporous filter membrane having a microstructure throughout the membrane and an amount of charge modifying agent bound to substantially all of the membrane microstructure without substantial pore size reduction or pore blockage.
The charge modified microporous hollow tubes may be used for the filtration of fluids, particularly parenteral or biological liquids contaminated with charged particulate, and for plasmapheresis and other cross-flow filtration applications. The tubes have low extractables and are sanitizable or sterilizable.

Description

LS. 16189(~1T~

CHARG~ P~ODIFIED MICRE)POl~OUS

HOLLOW TUBE'8 DA~ llO U~lD ~ v~ IOU
1. ~IELD I~IVEMTION
This invention relates to microporoui filter membranes, and more particularly to charge modified microporous membranes in the form of hollow tubes suitable for the filtration of aqueous fluids, such as biological liquids, and for plasmapheresis and other cross-flow filtration applications.

2. Prior Art Microporous membraneæ in both flat sheet and in hollow tube form are well known in the art. For example, U.S. Patent No.

3,876,738 to Marinaccio et al (lg75) describes a process for preparing a microporous membrane, for example, by quenching a solution of a film forming polymer in a non~olvent system for the polymer.
U.S.~ Patent No.~ 4,340~,4~79 ~ ~ and U.~. Patent No.

4,340,479 both to Pall describe a similar process.
(:~ther processes for producing microporous membranes are described, for example, in the following U.S. Patents:
3,642,668 to Bailey et al (1972);
4,203,847 to &randine,~ (1980);
4,203,848 to Grandine,ll (19gV); and 4,247,498 to Castr~ (1981~.

: .

, ,~ ,~.i ~, '~
' '' ' ~

LS. 16189~T~
Commercially available microporous membranesl for example, made of nylon9 are available from Pall Corporation, Glen Cove, New York under the trademark lJLTrpolR N66. Another commercially significant membrane made of polyvlnylidene fluoride is available frorn Millîpore Corp., Bedford, Massachusetts under the trademark DURl~POR~3. This membrane is probably produced by the aforementioned Grandme9D[ patents. Such membranes are advertised as useful for the sterile filtration of pharmaceuticals? e.g. removal of microorganisms.
Various studies in recent years, in particular Wallhallsser, Journal of Parenteral Drug Association, June 1979, Vol. 33 #3, pp.
156-170, and lHoward et al, Journal of the Parenteral Drug Association, March-April, 1980, Volume 34, ~2 pp. ~4-102, have reported the pherlomena of bacterial break-through in filtration media, in spite of the fact t~at the media had a low micrometer rating. For example, commercially available membrane filters for bacterial removal are typically rated as having an effective micrometer rating for the microreticulate membranes structure of ~.2 micrometers or less, yet such membranes typically have only a 0.357 effective micrometer rating for spherical contaminant particles, even when rated as absolute for Ps. diminuta~ the conventional test for bacterial retention. Thus p~ssage of few microorganisms through the membrane may be expected ~der certain conditions and within certain limits.
This problem has been rendered more severe as the medical uses of filter membranes increases. Brown et al highlights this problem in LS. 16189(EIT~l CRC Critical Reviews in ~nvironment Control, March 19807 page 279 wherein increased patient mortality and morbidity derived from contamination of sterile solutions for topical, oral, and intravenous therapy are reported.
One method of resolving this problem and its inevitable consequences, is to prepare a tighter filter, i.e. one with a sufficiently small effective pore dimension to enable the capture of the fine particulate, e~g., microorganisms, by mechanical sieving. Such filter structures, in the form of microporous membranes of 0.1 micrometer ratin~ or less, rnay be readily prepared. The flow Pate~ however, exhibited by such structures at conventional pressure drops is low.
Thus such modification of the internal geometry, i.e. pore size, of the microporous membrane is not an economical solution to the problem of bacterial breakthrough.
Attempts to increase the short life of filter media due to pore blockage and enhance flow rates through filter media having smaU pores have been made by charge modifyin~ the media by various means to enhance capture potential of the filter. For example, U.SO
Patent 4,007,113 and 4,0Q79114 to Ostreicher, describes the use of a melamine formaldehyde cationic colloid to charge modify fibrous and particulate filter elements; U.S. Patent No. 4,305,782, to Ostreicher et al describes the use OI an inorganic cationic colloidal silica to ch~rge modify such elemene~; alld U.S. Patent No. 4,309,247 describes the use of a polyamido-polyamine epiehlorhydrin cationic resin to charge modify such filter elements. Similar attempts at cationic charging of fi:lter elements were made in U.S. Patent No. 3,242,073 (l966) and 3,352,424 (]967) to Guebert et al; and U.S. Patent No. 4,178,438 to Hasse et al (1979).
Cationical]y charged membranes which are used for the fil-tration of anionic particulate contaminants are also known in the ar-t. For example, it is known to treat an isotropic cellulose mixed ester membrane with a cationic colloidal melamine formaldehyde resin to provide charge functionality. The membrane achieves only marginal charge modification. Additionally, the membrane was discolored and embrittled by the treatment, extractables exceeded desirable limits for certain critical applications, and the membrane was not thermally sanitizable or sterilizable. Treatmemt of the nylon membranes prepared by the methods described in U.S. Patent No. 2,783,894 to Lovell (195~) and U.S.
Patent No. 3,408,315 to Paine (1968) is suggested.
Nylon membranes so treated also demonstrate marginal charge modification, high extractable and/or are not thermally sanitizable or sterilizable.
Assignee ln order to solve the aforementioned problems has developed unique cationi.c charge modified .microporous membranes for use in the fil.tra-tion of fluids. These cationic membranes, their preparation and use are described and claimed in U.S. Patent Appli-ca-tion 268,543, filed on May 29, 1981 in -the name of "~
, LS. 16189(HT~
Barnes et al, now U.S.Patent ~o. 4~473,475 and li.PC Pub. Nos. 0066 814, and U.S. Patent Application Serial No. 314,3()7, filed on October 23, 1981 in the name of Ostrei~her et al, now U.S. Patent No.
4,473,474 and ~PC Pub. Nos. 0050 864.
Cationic charge modified nylon membranes covered by these inventions are now being sold by AMF CUNO Division under the trademark Z~TAPORo Pall Corp., Glen Cove, New York is also selling a cationic ch~ge modified nylon membrane under trademark N6B
PO~IDYN~.
To Applicant's knowledge, prior to this invention, no one has produced useful charge modified microporous filter membrane in the form of hollow tubes for the removal of fine charged particulates from liquids or for cross-flow filtration. The hollow tube form of charge modified membrane has unique applications in the separations art.
Th0re are numerous references which deseribe the treatment of reverse osmosis, ultrafiltration9 semipermeable type membranes for various objects. See for example, U.S~ Patent Nos.
3,556,305 to ~horr (1971), 3,556,992 to Massuco (1971), 3,944~485 ~1976) and 4,045,352 (19773 to Rembaum et al, 4,005,0:12 to Wrasidlo (1977), 4,125,462 to Latty ~Ig78), 4,214,020 to Ward et al (1980), and 4,239,714 to Sp~rks et 31~1980). Hollow tube membranes have also been treated to produce anionic ultrafiltration, reverse osmosis, semipermeable type membranes. For example, see the following U.S.
Patents:

" ~
. ":, J

L~. 1618~HT~
4,214,020 to Ward et al (19~O) is directed to eoating the exteriors OI hollow fiber semipermeable membranes. The coatings provide the desired selective separation and/or desirable flux. The process described in Ward et al involves immersing a bundle of hollow fibers in a coating liquid containing materials suitable for forrning the coating and providing a sufficient pressure drop from the exterior of the hollow fiber. Material suitable for forming the coating should have a sufficiently lQrge molecular size or particle size so that the material does not readily pass through the pores in the walls of the hollow fibers when subjected to the pressure drop used in the process.
The pores in the hollow fibers are said to have an average cross-sectional diameter less ~han about 205000 angstroms, and preferably less than about 1000 to 5000 angstroms. Nylon is a material of ehoice for the hollow fibers. The depositable material may be a poly (a~cyl acrylates) and poly (aL'cyl methacrylates) wherein the alkyl groups have, say 1 to about 8 carbons.
4,250,029 to Kiser et al (1981) is directed to coated membranes having two or more coatings of polyelectrolytes with oppositely charged adjacent pairs separated by a layer of material which substantially prevents charge neutrali~ation. The membranes coated are ultrafiltration, reverse osmosis and electrodialysis filtration membranes. Preferred membranes are said to be aliphatic and aromatic nylona The anionics useful are said to be polymeric anionic polyelectrolytes o~ relal~ ely high molecular weight, i.e. above 50,000 preferably above 500,000. Kiser et al states that since the LS. 16189(~T) anionics are preferably applied as a final eoating, after the cationic and on the same side of the membrane as the coatings, there is no essential requirement that the anionic be substantive to the membrane, i.e., the opposi~e charge of the previously applied cationic coating is sufficient to bind the anionic polyelectrolyte. However7 when both the cationic and anionic polyelectrolyte coatings are to be applied to the same side of a membrane they may be separated by a nonionic or neutral leyer whieh may be deposited in the same manner as the polyelectrolytes. This neutral layer separates the oppositely charged polyelectrolyte coating preventing neutralization of the charges. Among specific polyeleetrolytes having an anionic charge is poly (acrylic) acid. It is stated, however, that when a coating of cationic material is followed by an anionic layer with little or no neutral layer between the charged layers, the permeation properties of a hollow fiber membrane seems to decrease, as compared to a single layer coating.

.

I.S. 161~9~1~IT) OlBJECTS AND SUMMARY O~ TH~ 1VENTION
___ It is an object of this invention to provide a novel char~e modified microporous filter membrane in the form of hollow tubes or fibers, particularly suitable for the filtration of biological or parenteral liquids.
It ;s another object of this invention to provide charge modified microporous filter membranes in the form of hollow tubes of fibers whieh ~re useful for cross-flow filtration, e.g. plasmaphe~esis.
It ~s another obiect of this invention to provide an isotropic charge modified microporous filter membranes in the form of hollow tubes or fibers which have low extractables suitable for the filtration of biological or p~renteral liquids or for plasmapheresis.
It is yet another object of this invention to prepare a sanitizable or sterilizable eharge modified microporous membranes in the form of hollow tubes or fibers for the efficient removal of charged particulate contaminants from contamin~ted liquids, particularly without the adsorption of desirable constituents contained therein.
It is still a further object of this invention to provide microporous membranes in the form of hollow tubes or fibers capable of c~pturing charged particulate contaminant of a size smaller than the effective pore size of the membrane.
These and other objects of this invention are attained by a novel charge modified microporous hollow tube filter membrane. The tubes are comprised of a hydrophilic organie polymerie microporous membrane having a microstructure throughout the membr~ne and a '''' LS. lffl8~(~T~
charge modifying amount of a ~harge modifying agent bonded to slJbs~antially all of the membrane microstructure without substantial pore size reduction or pore blockage. The preferred microporous filter membrane is nyLon.
The charge modified microporous hollow tube membrane of thi~ invention may be used for the filtration of :eluids, particularly parenteral or biological liquids and for cross-flow filtration, e.g.

plasmapheresis~
According to the above objects, from a broad aspect, the present invention provides a charge modified hydro-philic organic polymeric microporous hollow fiber filter membrane for the removal of suspended solids and particu-late from aqueous liquids. The fiber has a microporous membrane wall. The wall. comprises a substantially skin-less, isotropic hydrophilic organic polymeric microporous filter membrane having an internal microstructure through-ou-t the membrane and a pore size of at l.east .05 microns.
The pore size permits substantially all dissolved solids to pass therethrough. A charge modifying amount of an anionic or cationioc charge modifying agent is bonded to substantially all of the membrane microstruc-ture without substantial pore size reduction or pore blockage providing the membrane wall with an improved capture potential for oppositely charged suspended solids and particulate and a decreased adsorptive capacity for like charged suspended solids and particulate.

, ~ , , , LS. 16189(HT~

Figure 1 is a schematic of the system employed in ~xample IV herein.
Figure 2 is a summary plot of the five membranes evaluated in Example IV.
~ igure 3 is a schematic of the system employed in ~xample V herein.
Figure 4-7 are summary plots for Example V herein.

f~

I.S. 16189SHT) D~TAIL~D D~GRIPIION OF TH~ I~V~NTION
The anionic charge modified microporous hollow tube membranes of this invention are produced from organic polymerie microporous membrane. Such membranes are weLI known in the art.
By the use of the term "microporous filter membrane" as used herein9 it is meant an asymmetric or symmetric, microporous membrane having a pore si~e of at least .05 microns or larger, or an initial bubble point (IBX~, as ~hat term is used herein, in water of less than 120 psi. A maximum pore size useful for this imrention is about 1.2 micron or an IBP of greater than about 10 psi. Additionally, the membrane has a fine microstructure throughou~ the membrane. By "symmetrical" it is meant that the pore structure is substanti~lly the same on both sides and throughout the membrane. By the use of the term "asymrnetrie" it is meant that the pore size differs from one surface to the other. A number of commercia}ly available membranes not encompassed by the term "microporous filter membrane" are those having one side formed with a thin skin whieh is supported by a much more porous open structure which are typic 17y used for reverse osmosis, ultraîiltration and dialysis. Thus by the use of the term '7microporous filter membrane" it is meant membranes suitable for the removal of suspended solids and particulates from fluids which permit dissolved so3ids to pass therethrough. These membranes, however, may have other uses both known and unknown.
By the use of the term "hydrophilic" in describing the preformed and the charge modified microporous membrane of this ., .;
"' '' ' LS. 161891EIT) ins~enti3n, it is meant a membrane which adsorbs or absorbs water.
Generally, such hydrophilicity is produced by a sufficient amount of hydroxyl (OH-), carboxyl (-COOH), amino (-N~I2) and/or similar functional groups on the surface of the membrane. Such groups assist in the adsorption and/or absorption of water onto the membrane. Such hydrophilicity of the membrane and internal microstructure (which may be obtained or enhanced by treatment of the preformed membrane) is a necessary element for ~he preformed membrane which is treated in order to provide the adequate inclusion of the charge modifying agent to the microporous membrane internal microstructure. Sueh hydrophilicity of the membrane of this invention is necessary in order to render the membrane more useful for the fUtration of aqueous fluidso A preferred microporous filter membrane is one produced from nylon. The term "nylon" is intended to embrace film ~orming polyamide resins including copolymers &nd terpolymers which include the recurring amido grouping. While, generally, the various nylon or polyamide resins are all copolymers of a diamine and a dicarboxylic acid, or homopolymers of a lactam or an amino acid, they vary widely in crystallinîty or solid structure, melting point, and other physical properties. Preferred nylons for use in this in~rention are copolymer~
of hexamethylene diamine and adlpic acid and homopolymers of poly-o-caprolMctam.
Alternatively~ these preferred polyamide resins have a ratio of methylene (CH2~ to amide ~NHCO~ groups within the range , . ., , : , `: , "~'' '; , LS. 16189(HT3 about 51 to about 8:1, most preferably about 5:1 to about 7~1. The pre~erred nylon 6 and nylon 66 each have a ratio of 8:1, whereas nylon 610 h~s a ratio of 8:1.
The nylon polymers are available in a wicle variety of grades, which vary appreciably with respect to molecular w~ight, within the range from about 15,000 to about 42,000 ~nd in other characteristics.
The highly preferred species of the units comprising the polymer ehain is polyhexarnethylene adipamide, i.e. nylon 66, and molecular weights in the range above about 309000 are preferred.
Polymers free of additives are generally preferred, but the addition of antioxidants or similar additiveis may have benefit under some conditions.
The preferred membrane subs~rates are produced by the method disclosed in U.S. Patent No. 3,876,738 to Marinaccio et al.
Another sirnilar method of producing such membranes is deseribed in ~uropean Patent Application No. 0 005 536 and U.S. Patent ~o.
4,340,479 to PalL

, . ~ .,.,: :
The preferred ~arina~cio et al process for producing membrane develops a unigue fine microstruicture throughout the membrane through the quench technique described therein, offering a superior substrate for filtration. Broadly, I!~sEinaccio et al produces microporous films by casting or extruding a solution of a film-forming polymer in a solvent system into a quenching bath comprised of A non-~, .

~ .
..
:. :
,. ~ .
.. .

LS. 1B189(HT)solven~ system for the polymer. Althou~h the non-solvent system may comprise only a non-solvent, the solvent system may consist OI any combination of materials provided the resultant non-solvent system is capable of setting a film and is not deleterious to the formed film.
For example, the non solven~ system may consist of materials such as water/salt, alcohol/salt or other solvent-chemical mixtures. The Mari;2accio et al process is especially effective for producing nylon microporous hollow tubes. More speoific~lly, the general steps of the process involve first forming a solution of the film-forming polymer, casting the solution to form a hollow tube and quenching the tube in a bath which includes a non-solvent for the polymer.
The nylon solutions which can be used in the MaP~nac~io et al process include solutions of certain nylons in l~arious solvents, such as lower alkanols, e.g., methanol, ethanol and butanol, including mixtures thereof. It is known that other nylons will dissolve in solutions of acids in which it behaves as a polyelectrolyte and such solutions are useful. Representative acids include, Ior example,formic acid, citric acid, acetie acid, maleic acid and similar acids which react with nylons through protonation of nitrogen in the amide group characteristic of nylon.
The nylon solutions are diluted with non~lvent for nylon, the non-solvent employed being miscibl~ with the nylon solution.
Dilution with non-solvent may, according to MlariDac~io et al, be effected up to the point of incipien$ preoipitation of the nylon. The non-solvents are selected on the basis of the nylon solvent utilized.

'~

, ~ :
:, ' `
,:

L~. 16189(~T) For example, when water-miscible nylon solvents are employed, water can be employed. Generally, the non-solvents can be methyl formate, aqueous lower alcohols, such as me~hanol and ethanol, polyols such as glycerol, ~y¢ols, polyglycols, and ethers and esters thereof, water and mixtures of such compounds. Moreover, salts can also be used to control solution properties.
The quenching bath may or may not be comprised of the same non-solvent selected for preparation OI the nylon solution and may also contain small amounts of the solvent employed in the nylon solution. However, the ratio of solvent to non-solvent is lower in the quenching bath than in the polymer solution in order that the desired result be obtained. The quenching bath may also inelud~ other non-solvents, e.g., water.
The formation of the polymer hollow tubes can be accomplished by any of the recognized methods familiar to the art.
Typically, hollow tubes are formed by extrusion over a fluid core and quenching in an appropriate bath using appropriately designed and shaped nozzles. In general, the wall thickness will be cast at thickness in the range of from about 1 mil. to about 20 mils., preferably from about 1 to about 10 mils. Preferably~ the polymer solution is cast and simultaneously quenched~ although it may be desirable to pass the cast tube through a short air evaporation zone prior to the quench bath.
This latter technique is, however, not preterred. After the polyrrler solution is cast and quenched, the tube is removed ~rom the quench bath and preferably washed ~ree of solvent and or non-solvent.

., , .

'~
..

LS. 18189(~T3 Subsequently ~he tube can be at least partially dried and then charged modified~
Pall's aforementioned ~uropean Patent Application No. O
005 536 and U.S. Pa~ent No. ~,340~479 des¢ribe a similar method for the conversion of polymer into microporous membrane. This process may be appropriately modified to produce hollow tubes. Broadly, Pall provides a process for preparing skinless hydrophilic alcohol-insoluble polyamide membranes by preparing a solution of an ~leohol insoluble polyamide resin in a polyamide solvent. Nucleation of the solution is induced by the controlled addition to the solution of a non-solvent for the polyamide resin, under controlled conditions of concentration, temperature, addition rate, and degree of agitation to obtain a visible prec.ipitate of polyamide resin partieles (which may or may not partially or completely redissolve) thereby forming a casting solution~
The easting~ solution is cast and then contacted and diluted with e mixture of solvent and non-solvent liquids containing a substantial proportion of the solvent liquid, but less than the proportion in the casting solution, thereby precipitating polyamide resin from the casting s~lution in the form of ~ thin skinless hydrophilic membraneO The resulting membrane is then washed and dried.
In Pall's preferred embodimerlt o~ the process, the solvent ~or the polyamide resin solution is formic aeid and the non-solvent is water. The polyamide resin soluffon film is contacted with the non-solvent by immersing the film, carried on the substrate, in a bath o:~

LS. 16189(1ITj non-solvent comprising ~f water containing a substantial proportion of formic acid.
These preïerred nylon membranes9 i.e. deseribed in Marinaccio et al and Pall, are characteri~ed by a hydrophilic, isotropie structure, having a high effective surface area and a fine internal microstructure of controlled pore dimensions with nsrrow pore si~e distribution and aclequate pore volume throughout the membrane structure. For example, a representative 0.22 miclometer ra$ed nylon 66 membrans (polyhexamethylene adipamide) exhibits an initial bubble point (IBP) of about 45 to 50 psid., a foam all over point (FAOP) of about 50 to 55 psid.,provides a flor~ of from 70 to 80 ml/min of water at 5 psid (47 mm. diameter discs), has a surface area (Bf~T, nitrogen adsorption) of about 13 m2/g and a thickness of about 4O5 to 4.75 mils.
The charge modifying agent, i.e. anionic or eationic charge modifying agent, is bound to substantially all of the internal microstru~ture of the microporou~ membrane. By the u5e of the term "bound1' it is me~nt that the charge modifying ~gent is sufficiently attached to or incorporated into the membrane so that it will not significantly extract under the intended conditions of use. By the use of the term "substantially all of the internal microstrueture'7 as used herein it is meant substantially all of the external surface and internal pore surfaces. TypicalIy this is meant the surfaces which are wetted by a fluid~ e~g., water, passing through the membrane or in which the membrane is immersed. By the use of the term "charge modifying agent", it is rneant a compound or composition that when bound to the LS~ 16189t}~T) microporous filter membrane alters the "zeta potential" of the membrane (see Knight et al, "Measuring the Electrokinetic Properties of Charged Filter Media," ~iltration and Separation, pp30-34, Jan./Feb. 1981). The charge modifying agent can be part of the solvent-non-solvent casting system and/or quench b~lth or a subsequent treatment to the formed membrane.
The anionic or cationic charge modifying agent is a compourld or composition which is capable of bonding to the membrane microstruc~ure without substantial pore size reduction or pore blockage and provides an anionic or cationic charge or negative or positive zeta potential to the membrane microstructure. Preferably, such anionic or cationic charge modifier is a water soluble compound having substituents capable of binding to the membrane and substituents which are capable of producing a more negative or more positive "zeta potential" in the use environment (e.g. aqueous) or anionic functionQl groupsO
Preferred anionic functional groups may be carboxyl, phosphonous, phosphonic and sulfonic. Preferably, the anionic charge modifying agent, may be- a water soluble organic polymer having a molecular weight greater than about 2,000 and less than about 5D0,000 and capable of of becoming a non-extraetabls constituent of the membrane.
The anionic charge modifying agent can also be cros~-linked to the membrane thrcugh a cross-linking agent9 for example, an aliphatic polyepoxide having a molecular weight of less than about 500 . .~ .

- 20 - LS~ 16189(HT3 and preferably methylated urea formaldehyde resin and mehmine formaldehycle.
The anionic charge modifying agents which may b~a used in thi~ invention are polymeric anionic polyelectrolytes. Generally, these polyelectrolytes have relatively low molecular weight, e.g. less than 500,000, and are water or other solvent soluble at the desired levels of applicationO If the anionic agents are applied direetly to the membrane it is necessary that they be capable of binding thereto. I~
they are applied to a cationically charge modified membrane ~discussed below), they need only bond to the cationic eharge on the membrane.
The anionic charge modifying agent may have either a high or low charge density, or anything between these extremes, however, high charge density is preferred. Specific preferred anionic charge mcdifying agents useful herein are poly (styrene sulfonic) acid, poly (toluene sulfonic) acid, poly (vinyl sulfonic) acid and poly (acrylic) acid. Other anionic charge modifying agents are poly ~methacrylic acid), poly (itaconic acid), hydrolyæed poly (styrene/maleic anhydride) and poly (vinyl phosphonie acid). Additionally, the aUcali and alkaline earth meW salts of all of the foregoing may be utilized.
Highly preferred anionic charge modifying agents are poly (styrene sulfonic) acidso --21 ~
L~. 16189~HT) ~H - CH~n HS~3-having a molecular weight between 2000 and 300,000, and poly (acrylic~ acid:

~ClI~ ~ CH3 n C =

having a molcular weight between 2000 and 300,000.
The anionic oharge modifyin~ agent may also be cross-linked to the microporous membrane structure through an aliphatic polyepoxide cross-linking agent having a molecular weight of less than about 500. Preferably, the polyepoxide is a di- or tri-epoxide baving a molecular welght of from about 146 to about 30û. ~uch polyepoxides have viscosities (undiluted) of less than about 200 centipoise at 25C.
Highly preferred polyepoxides hAYe the eormula:

R (~CH2 -C\-C~ 2)n O

wherein R is an alkly of 1 to 6 carbon atoms and n is from 2 to 3~ The limitation that the number of carbon atoms in the non-epoxide portion ~R~--be les. than 6 Is 90 that the polyepoYide will be soluble in :

,.
, '~ .~ , ' ,, ~z~

LS. 1618~EIT~
water or ethanol-water mixtures, e.g. up to 20% ethanol. While higher carboll content materials are functionally suitable, their application would involve the use of polar organic solvents with resulting problems in toxicity, ~lammability and vapor emissions.
Certain diglycidyl ethers of aliphatic diols may be used as the polyepoxide cross-linking agents. These compounds mfly be represented as follows:
CEI2-C -C~2-O-R-O-CH2-C~-C/ 2 For example:
When R is (C~z)2, HO-R~H is 1, 2 -ethanediol When R is (CH2)3, HO-R-OEI is 1, 3 -propanediol When R is (CH2~4, HO-R-OH is 1, 4 -butanediol The preferred diglycidyl ether of 1, 4-butanediol, is commerci~lly available from Ciba-Geigy, Ine. as RD-2 a~d from Celanese Corp. as Epi-Rez 5022 and Polyscience.
Other higher carbon diglycidyl ethers may be used as the polyepoxide cross-linking agent, for example when R is (CH2)s the 17

5-pentarlediol diglycidyl ether is producedO As stated previously, however, the appropriate polar organic solvents must be used for dilu$ing such polyepoxides.
Triglycidyl ethers, i.e. tri-epoxides may also be utilized as the polyepoxide cross-linking agent. For example, the triglycidyl ether of glyeerol may be utilized. These tri-epoxides have the following formula * ~ s~d ~k :

- ~L2~

I.S 16189(~IT~

CH2 CH-CH2-O-CH2- ~H-CH2~-CH2-C~-C~Ia O O O
~H2 CH
/o The triglycidyl ether of glycerol is available from Shell, Inc. as ~pon*
812 and Celanese Corp. as ~pi-Rez 5048*
Another preferred cross-linking agent is methylated urea formaldehyde resin, commercially available h~om AmericQn Cyanamid;
for example, Beetle 65*and melamine formaldehyde, e.g., Cymel 303*
from American Cyanamide.
Optionally, the anionic charge modifying agent may be applisd to a membrane which has been previou~ly treated to produce a hydrephilic cationic charge modified membrane Preferred membranes and methcds of producing such f~ationic charge modified membranes are described in Assignees aforementioned ~-IJ . S . patents : 4,473,4~75 to:Rarnes et ~al and~4,473,;474.to 0str~lcher~et al.

Treating~ a cationically charge modified membrane in accordance with this invention enhances the bonding of the anionic chArge modifier to the membrane and/or reduces the requirements for a cross-linking agellt.

* Registered Trademark ` "' ~:'; ' ~": ~`:, , ':

LS. 16189(HT~
The process for anionically charge modi~ing ~ hydrophilic organic poiymeric microporous membrane7 e.g. nylon, comprises applying and binding to substantially all of the membrane microstructure, without substantial pore size reduetion or pore blockage, a chsrge modifying amount of the anionic charge modifying agent. Preferably, the process comprises la) contacting th~
membrane,i.e. hollow tubes with an aqueous solution OI the anionic charge modifying agent; and (optionally~ (b) contacting the membrane with an aqueous solution of the cross-linking agent. The contacting steps may be peri~rmed in any order, i.e. step (a) followed by step ~b)~
vice versa or simul~neously. It is preferred, to perforrn steps (a) and (b) simultaneously to minimize e~tractables and f4r ease of manufacture.
In order to provide the charge modi Eying amount o~
anionic charge modifying agent to the membrane9 it is preferred that the aqueous solu$ion of anionic charge modifying agent that the membrane is contacted with contain at least about .5% by weight charge modifying agent in the aqueous solution. The upper range is limited by economic and solubility limitations. ~or e2~ample, an excess of charge modifying agent which is not bonded to the microporous membrane will not be ecorlomically utilized and will constitute an undesirable extractive from the membrane. It has been found that the amount OI charge modifying agent in the aqueous solution should not exceed about 10% by weight of the solution.

~ ':

LS. 16189(~1'r) The amount of cross-linking agent used in the aqueous solutiorl is highly dependent on the specific cross-linking agen$ and the amount and type anionie charge modifying agent used, and the cross-linking mechanism between these compounds to provide the bonding of such charge modifying agent to the microporous membrane. For general guidance however, it has been found that a weight ratio of anionic charge modifying agent to cross-linking agent of from about 1:1 to about 500:1, preferably from about 1:1 to about 20:1 in the aqueous solutions contacted with the membrane, is generally sufficient to provide the binding of the anionic charge modifying agent to the membrane. It has been found that if the aqueous solution containing the cross-linking agent contains at least about .1% cross-linking agent by weight of the solution, up to a maximum of about 5% weight of the solution when used in conjunction with the aforementioned aqueous solution of anionic charge modifying agent, that adequate bonding of the charge modifying agent to the microporous membrane is obtained.
Both the anionic charge modifying agent ~nd the cross-linking agen$ may be contacted with the membranes hollow tube by dipping the tubes in the aqueous solutions of these compounds for a period of time sufficient to effect the desired degree of pick-up.
Alternatively, the agents may be applied by spraying or contacting a wick or roll along the surface of the microporous membrane which almost immedial:ely adsorbs and/or absorbs the aqueous solution due to the membrane's hydrophilicity.

,~ ` , -:

I.S. 16189~T) The preferred eationic charges membranes used in this invention are deseribed in the aforementioned Barnes et al and Ost~ei<~her et ~1 u. S . patents .
The preferred char~e modifying agent described in Oskeicher et al is a water-soluble organic polymer having a molecular weight greater than about 1,0~0, wherein the monomer has at least one epo:~ide substituent capable of bonding to the surface of the membrane and at least one tertisry amine or quaternary ammonium group capable of providing a cationic charge site. Prefer~Jably, this charge modifier is a polyamido-polyamine epichlorohydrin cationic resin, in pRrticular, thosP described in the following UOS. patents:
2,926,116 to Keim 2,926,154 to Keim 39229L,986 to Butler et al.
3,311,594 to ~¢le, Jr.
3,332,901 to Eeim 3,382,096 to Bo~dm~
3,761,350 to ~unjat et al.

The preferred polyamido-polyamine epichlorohydrin cationic resins are available commercially as Polycup 172* 1884, 2002 or S 2064 (Hercules); Cascamide Resin pR-420 (Borden); or Nopcobond 35 ~Nopco). Most preferably, the polyamid~polyamine epichlorohydrin resin is Hercules R 4308, wherein the charged nitrogen atom forms * Registered Trademark ,: .

.

L~ 189~IT) part of a heterocyclic grouping, ~nd ls bonded through a methylene moiety to a depending, reactive epo~ide group.
Most preferably, when the charge modifying agent is a water-soluble organic polymer having a molecular weight greater than about 1,000, a secondary charge modifying agent can be used to enhance the cationi~ modifying agent and/or enhance the bonding of the primary charge modifying agent to the microporous surace and/or itself.
The secondary charge modifying agent used in this invention is selected from the group consisting of:
(i) aliphatic polyamines having at least one primary amine or at least two secondary amine moieties; and (ii) aliphatic amines having at least one secondary amine and a carboxyl or hydroxyl substituent.
Preferably, the secondary charge modifying agent is a polyamine having the formul~:

H

H2N-(R~ )x-R2-N~2 wherein R1 and R2 are aLI<yl of 1 to 4 carbon atoms and x is an integer from O to 4. Preferably Rl ~nd R2 are both ethyl.
Preferred polyamines are:
~thylene diamine H~N~CH2)2-N~2 I)iethylenetriamine H2N ~cH2)2-NH~cH2)2-NH2 Triethylenetetramine H2N~CH2-CH2-NH)2-CH2-CH2-NH2 Tetraethylenepentamine H2N~CH2-CH2-NH)3-CH2-CH2-NH2 :

'~' ' . ' LS. 16189(EIT~
The highly preferred polyamine is tetraethylene pentamine.
Alternatively, aliphatic amines used in this invention may have at least one secondary amin~ moiety and a carboxyl or hydroxyl substituent. Exemplary of such aliphatic amines are gamma amino-butyric acid (H2NcH2cH2cH2cooH) and 2-aminoethanol (H2NCH2CH~OH).
Th~ secondary charge modifying agent is bonded to the microporous membrane by bonding to a portiDn of the epoxide substituents of the polymeric primary charge modi~ying agentO
The amount of primary and secondary cationic charge modifying agent utilized is an amount sufficient to enhance the electropositive capture potential of the microporous membrane. Such an amount is highly dependent on the specific charge modifying agents utili~ed.
Broadly, the foregoing primary and secondary cationically charge modifying agents are bonded to a hydrophilic organic polymeric mieroporous membrane~ e.g., nylon, by applying to the membrane a charge modifying amount of the primary catiollic charge modifying agent bonded to the membrane structure through the epoxide substituent. Preferably, the process comprises (a) contacting the membrane i.e., hollow tube, with an aqueous solution of the primary cationic charge modifying agent and (b) contacting the membrane with an aqueous solution of the secondary charge modifying agent. The contacting steps may be performed in any order, i.e., step (a) prior to step (b) or vice-versa. It is preferred, however, ïor optimum ~2~
~9 I.5. 1618~(~IT) (minimum) extractables to first contact the membrane with an aqueous solution of the primary cationic charge modi~ing and then subsequently contact the so treated membrane with the aqueous solution of the secondary charge modifying agent.
In another method of cationically charging the hollow tubes the foregoing secondary charge modifying agent can be used as the charge modiIying agent provided it is bonded to the microporous membrane structure through the aforedescribed aLiphatic poly-epoxide crosslinking agents used to produce the aforedescribed anionically modified membrane.
The aliphatic polyamirle ch~ge modifying agent can be bonded to the microporous membrane by (a) contacting the membrane with an aqueou3 solution of the cationic charge modifying agent and (b) contacting the membrane with an aqueous solution of the polyepoxide crosslinking agent. The contacting steps may be performed in any order, i.e., step (a) prior to step (b) or vice-versa.
Such contacting steps also include contacting the membrane with an agu~ous solution of a mixture of the charge modifying agent and the polyepo2~ide crosslinking agent. It is preferred~ however, for optimum (minimum) flushout times to first contact the membrane with an aqueous solutioTI of the cal ior~iç charge modifying agent and then subsequently contact the so treated membrane with the aqueous solution of the polyepoxide crosslinking agent. For maximizing charge modification, however, it is preferred to contact the membr~ne with an aqueous solution of a mixture of the charge modifying agent and the polyepoxide crosslinking agent.
. .

:, :

LS. lB18g~1EIT~
33etween each contactirlg step of the process for producing the membrane, the membrane is drained for a period o~ time suffieient to r emovs most of the water and ehemical compound(s) not absorbed or adsorbed onto the surface of the membrane. The membrane may be transferred directly Erom the first contacting step to a subsequent contacting step, although this is less preferred.
After the microporous membrane has been contacted with the aqueous solution(s), it may then be washed9 dried and cured.
The final drying and curing temperature for the filtration membrane should be sufficient to dry and eure the membranes.
Preferably this temperature is from about 120C to 1~0C for minimization of drying time without embrittlement or other detrimental effects to the membranes. The total thickness of the filtration membrane is preferably from about 3 mils to about 30 mils and most preferably about 3 to 15 mils thick ~dry thickness).
The filtration membrane, i.e. hollow tubes may then be rolled and stored under ambient conditions for further processing into the usual commercial formsJfor example, cartridges by methods well known to the art.
The present invention provides an charge modified microporous hollow tubes llaving integral, coherent hydrophilic microporous membrane wall of retained internal pore geometry. The charge modified membrane has an improved effective filtration rating relative to the untreated micr~reticulate polymer oppositely charged structure for cationic submicronic particlllate contaminants and has a LS. 16189~T) decreased adsorptive capacity for like charged submicronic particulate9 such particulates often being desirably retained in the liquid to be filtered, as for example, in cross-flow filtration d contaminant particulate that can cause pore blockage of the membrane. These properties are brought about by charge sites or regions attached to, bonded to or populating thle microstructure or pore surfaces throughout the membralle. These charge sites are effective oYer a broad range of pH's in enhancing filtration performance through eletrokinetic effects. The choice OI charge modifying agent, cross-linking agent ~d process conditions assures that the foregoing is accomplished without substantial pore size reduetion or pore blockage.
The resulting charge modified membrane o~fers improved micrometer rating, for oppositely charged submicronic particulate, at equivalent flow and capacity with retention of membrane structure, yet without evidence of significant resin extractables~ and improved cross-elow filtration effectiveness, partieularly in plasmapheresis. In effect, the effective micrometer rating for oppositely charged contaminant particles is less than the effective micrometer rating of the microreticulate membrane structure, but not for similarly charged particulate. Adsorption of critical or required anionic particulate or consistituents is minimi~ed or eliminated. By the use of the term "effective micrometer rating ~or contaminant particles" it is meant the actual size of the particles that the membrane will quantitatively remove from the fluid being filtered. By the use of the term LS. 16189(ElT) "effective micrometer rating of the microretic~ate membrane structure" it is mPant the size of the particulate that would pass through the membrane if all adsorptive effects OI the membrane were eliminated.
For so-called sterile filtrations or plasnnapheresis involving biological li~uids, the filter is sanitized or sterilized by autoclaving or hot water flushing. Preparation for use in sterile filtration, requires that the membrane be sterilized as by treatment in an autoclave at 121C under 15 psig. for 1 hour. Accordingly, the charge modified membrane must be resistant to this type treatment, and must retain its integrity in use. Any modification to the filter structllre, especially brought about by chemical agents which may be unstable under conditions of treatment and use, must be scrutinized with care to minimize the prospect of extractables contaminating the filtrate, interfering with analysed and potentially introducing harmful toxins to a patient. Specifically, any such filter must meet the test stand~rds in the industry~ e.g. ASTM D 3861-79, ~ ~
and generally have less than 5 mg. of extractables in 250 ml solvent (water at 80C.; 35% ethanol at room temperature) for a 293 mm diameter disc. The membrane and process of this invention insures low extraction levels.
The resulting charge modified membrane is characterized by retention of internal microstructure, thus offering essentially the same flow characteristics as the untreated membrane.

~b :, :

"

Lg~ 16189(EIT) The charge modified microporous hollow tube membranes additionally are to handle and readily formed into cartridges. By reason of its rehined flow characteristics, it may be employed directly into existing installations without pumping modifications.
These favorable properties are secured without sacrifice to other eharacteristics. The membrane may also be constructed to meet or exceed extractable requirements.
Biological liquids, as that term is employed in the specification and claims, is a liquid system which is derived from or amenable to use with living organisms. Such liquids are ordin~ily handled and proeessed under sanitary or sterile conditions and therefore require sanitized or sterilized media for filtration. Included within such term are isotonic solutions for intermuscular (im) or intravenous (iv) administration, solutions ~esigned for administration per os, as weLI as solutions for topical use, biological wastes or other biological fluids which may contain cationic impurities, e.g., asbestos, aL'cali metal hydroxides or other cationic contaminants which are desirably isolated or separated for examination or disposal by immobilization or fixation upon or entrapment within a filter media.
This can be accomplished with a minimum OI removal or adsorption of desirable anionic particulates.
Hollow tube filter membranes in accordance with this invention may be employed alone or in combination with other filter media to treat pharmaceuticals such as antibodies, saline solutions, dextrose solutions, v~ccines, blood plasma, serums, sterile water or ,..

LS. 16189(HT~
eye washes, beverages, such as cordials9 gin? vodka, beer, seotch, whisky, sweet and dry wines, champagne or brandy; cosmetics sueh as mouthwash, perfume, shampoo, hair tonic, face cream or shaving lotion; food products such as vinegar, vegetable oils; chemicals such as antiseptics, insecticides, photographic solutions, electroplating solutions, cleaning compounds, solvent purification and lubrication oils, and the like. The hollow microporous tubes are also suitable for plasmapheresis, amd more broadly for cross-flow filtration.
By the use of the term "cross-flow filtration1' it is meant the separation of undissolved particulate and suspended solids from a fluid, e.g., liquid, blood, mixture by passing or circulating, parallel or tangential to the surface of the membrane the fluid mixture producing ~: Q circulating ef~luent of concentrated particles or solids continuing to flow tangential to the membrane. Such techniques are well known in the art, particularly for plasmapheresis. It is believed tha1; the charge on the membrane prevents the similarly charged particulate or suspended solids in the fluid from clogging of blucking the pores by preventing excessive adsorption thereof, thus enhancing the efficiency and effectiveness of filtration.
Having now generally described this invention, the same will become better understood by reference to certain specific examples, which ~re included herein for the purposes of illustration only ~md Pre not intended to be bmitin of th~ invenhon.

::~
:
' ~

'' ' ', "~'' `'' , .

~2~

I.S. 1ff189~HT~
~3XAP~PLES
The ~'ollowing are the measurement and test procedures utilized in some of the Examples for flat membranes.
Thickness The ~ry membrane thickness was measured with a 1 inch (1~27 cm) diameter platen dial thickness gauge~ Gauge accuracy was ~0.00005 inches (~.05 mils).

, r."~ (mr~ 7~ Over Point (FAOP) Tests A 47 mm diameter disc of the membrane sample is placed in a special test holder whieh seals the edge of the disc. Above the membrane and directly in contact with its upper face, is a perforated stainless steel support sereen which prevents the membrane from deforming or rupturing when air pressure is applied to its bottom face.
Above the membrane and support screen, the holder provides an inch deep capacity into which distilled water is introduced. A regulated air pressure is increased until a first stream of air bubbles is emltted by the water wetted membrane into the quiescent pool o~ water. The air pressure at which this first stream of air bubbles is emitted is called the Initial Bubble Point ~IBP) o~ the laegest pore in that membrane sample - see ASTM F-316-70.

Onee the Initial Bubble Point pressure has been determined and recorded, the air pressure is further increased until the air flow through the wetted membrane sample, as measured by a flow meter in I.S. 16189(~1T3 the line between the regulator and the sample holder, Peaches 100û
c~/min. The air pressure at this flow rate, is called the Foam-All-Ove~Poin~ ~FAOP), and is direc~ly proportional to the mean pore diameter of the sample membrane. In this series of tests, these two parameters (IE~P and FAOP) are used to determine iI any change has occurred in the maximum or mean pore size of the membrane sample as a result of the charge modifyirlg process utilized.
Flow Rate Test A 47 rnm diameter disc of the membrane sample is placed in a test housing which allows pressurized water to flow through the membrane. Prefiltered water is passed through the membrane sample at a pressure differential of 5 psid. A graduated cylinder is used to measure the volume of water passed by the membrane sarnple in a one minute period. In this series of tests this parameter is used in conjunetion with the IBP and FAOP to determine: if any reduction in pore size or pore bloclcage has occurred AS ~ result 9f the anionic charge modifying process utilized.
METHYL~NIE BLIJ~ DY~ TESTS FOR ANIONIC M~3MB~3 A 47 mm diameter disc of the membrane sample is placed in a test housing which allows pressurized water to flow thru the membrane. The challenge solution consists of distilled water at a pH
of 7.D, and methylene blue dye. The dye inlet concentration is adjusted to produce a 34 percent transmittance at a wavelength of 660 nm, as measured on a Bausch dc Lomb Spectronic 710 Spec~rophotometer. By means of a peristaltic pump the challenge L~. 16189(~T) solution is flowed thru the membrane sample at a flovv rate of 28 ml/min. The transmittance of the effluent is measured by passing i~
thru a c~nst~nt flow cell in the aforementioned spectrophotometer.
The effluent transmittance and pressure drop across the membrane is rneasured and recorded as a funetion of time. The test is terminated when the effluent transmittance increases to 45 percent of the inlet transmittance. In this series of tests, ~he length of time that it takes to reach the 45 pereent transmittance in the eYfluent is called the "brealcthru" time. Since methylene blue i~ a low molecular weight cationic dye incapable of being mechanically removed ~filtered) by the membrane, this b~eakthl~u time is proportional to the anionic adsorptive capacity of the msmbrane sample. This test is therefore used to determine the effectiveness of the charge modiIication technique.
C~ Y-M ~
~ xtractables are determined by A$1'M D-3861-79. The quantity of water~oluble extractables present in membrane filters is determined by immersing a preweighed membrane in boiling reagent grade water ~or an extended time and then drying and rewei~hing the membraneO A control membrane is employed to eliminate weighing errors c~used by balanee changes or changing moisture content of the membrane in the weighing procedures. Weight changes of the control membrane are applied as a corre~tion factor to the weight change o~
the test membrane filters.

.. . .

. ^ ~

, . ..

~ , ~
. . . .

LS. 16189(~1T3 ~AMPL~ LA

Pl~EPA:EIATION OF l~ICROPOROUS ME~ ANE F~P~
A representative nylon 66 membrane of 0.22 micrometer nominal rating, having a nominal surface area of about 13 m2/g, an Initial Bubble Roint of about 47 psi~ a Foam-All-Ove~Point of about 52 psi was prepared by the method of Marina~io et al, U.S. Patent 3,876,7389 utilizing a dope composition of 16 percent by wei~ht nylon 66 (Monsanto Vydyne 66B~, 7.1~ methanQl and ~.9~6 formic acid, a quench bath composition of 25% methanol, 75% water by vol~me (regenerated as required by the method of Kni~ht et_al, U.S. Patent 3,928,517) a casting speed of 24 inches/minute (61 cm/min.), and a quench bath temperature of 20C. The membrane was cast just under the surface of the quench bath by application to a casting drum rotating in the bath (9 to 10 mils as cast wet, to obtain 4.5 to 5.5 mils dry) and allowed to separate frorn the drum about 90 of arc from the point of applic~tion. A portion of the uniform opaque film was dried (in restrained condition to resi~st shrinkage) in a forced air oven at 80-90C for 30 minutes.

* Registered Trade~ark ' ,.:.
- ~

Lq'3~

LS. 16189(~IT3 ~MPL~ lB

PR~PI~.RATION O~ A~ICROPOROUS MEMBRAN~ HOLLOW TUBES
The following basic steps were used for making microporous membrane hollow tubes:
I. ~!!~!~
The casting solution was twenty~ix percent solids and had a viscosity of about 90,000 cp. The eastin~ solution was made by combining 40 gm methanol (99.5% Dupont Technical ~rade) with 2180 gm formic acid (98% Union Carbide, glacial) in a one gallon glass jar which was allowed to stand at least two hours at room temperature.
AIter standing the requisite time, 780 gm o~ nylon 66 pellets (Monsanto, Vydyne 66B) was added to the jar, which was then placed on a mech~nical roller operating in a 30C environment. Rolling was continued until all the pellets were dissolved, usually requiring about 12 to 18 hours Typicall ~lat sheet membrane properties using this casting solution were:

IBP 31 psi FAOP 43 psi Flow 0.38 ml/min-psi-cm2 Thickness 3.7 mils.

. .
. .
. . .
; . . .

.~

LS. 16189(HT) II ~
The standard quench system consist~d of 25 percent methanol in 75 percent D.I. water, by volume. The same quench fluid was used inside as well as outside the hollow fiber. The queneh fluid wes recirculated at about two gallons per minute by a 316 s~ainless steel cenkifugal pump and was filtered through a five micron polypropylene Microwynd cartridge (AMP Cuno).
III F ber Casffn~
The casting opera~ion was done at four to six feet per minute with the extrusion die oriented vertic~lly downward. DweLI
time in the quench bath was At least 2û to 30 seconds.
The die plate was 316 stainless steel with an orifiee of ~L0 mils and a land length of about 0.125 inch. Quench fluid was delivered at a rate of about 0.2 ml/min to the center of the hollow fiber by means of a number 26 hypodermic needle ~18 mils OD x 10 mils ID) positioned so that the end of the needle was flush with the outer face of the die plate~
I)ellvery of dope ~o the extrusion die was accomplished frQm a stainless steel reservoir of 500 ml capacity, pressurized to about 80 psi. Another reservoir was used for the center quench fluid and was pressurized to 20 to 60 psi. Control of the dope flow was achieved by changing reservoir pressure, while the center quench flow was controlled by a rotameter eguipped with a vernier valve.

* Registered Trademark .
; ~

LS. 1618!1~ T~
The center quench fluid was filltered ~hrough a five microrl polypropylene MICROWYND cartridge. The casting solution was not filtered.
N Fi~e -The porous hollow fiber was wound on a 3.5 ineh OD PVC
core four inches long. A level wind apparatus distributed the fiber uniformly over the core surface and left a relat;vely open winding pattern which enhanced wash fluid cireulation in a subsequent step.
T'he windup was capable OI handling fiber production of up to 25 feet per minute. A constant speed nip roll positioned just before the windup further improved the windup system.

V ~
Washing was accompIished by putting the fiber wound on tak~up spools into a laboratory pipette washer connected to a source of room temperature D.I. water. A typie~l wash cyele entailed a total of 20 fi~U and empty cycles over a period of about 60 minutes and used a total of about 80 gallons of wash vvatsr.
Drying was done by exposing the spools of washed fiber t ambient laboratory conditions. This mode of drying did not result in sticking together of the fibers whers they touch on the spool, presumably because such contact was minimized by the winding pnttern~ Thus far no advantage has been noted when the fibers were streteh dried on a dryirlg frame.

~L2 --I.S. 1618g(~31T) VI Hollow Piber Test n~
~ iber IBP and FAOP were measured by potting one end of a dry fiber about four inches lon~ into a 3/8 inch OD polyolefin tubing, using one of several available polyurethane potting compounds. After the urethane was cured, the potted section was sliced througlh with a knife blade and the fiber OD and ID were measured under a 40 power mi~roscope fitted with an eyepiece s~ale. The other end of the fiber was closed off with a blob of hot melt adhesiYe and the potted tubing end was fitted to a source of pressurized air ancl a pressure gauge.
The porous fiber was immersed in wa~er and the IE~P and FAOP was noted as the air pressure applied to the potted tube end was slowly increased.
A similar test module was used for measuring flow through the fiber walls, only in this ease ten or twenty fibers each about six inches long were bundled together. A Masterflex pump was used to pump D.I. water through the fiber walls, with pressure and flow measured by a mercury manometer and rotameter, respectively. The characteristic, K, of the fibers was then calcula$ed from the relationship:

* Registered Trademark : . :

~2~

LS. 16189(~T) Flow (ml/min) K
psi x (total internal fiber ~rea (cm~) VII 3~e~

E ollow Fiber Elnt Sheet OD x ID (mils) 24 x 8 (3.7 thiek) IBP (psi) 34 31 ~AOP (psi~ 60 43 Flow (ml/min-psi-cm2) 0.012 0.43 Flow (acid quench) 0.1 .

.. ..
: ' ~
,.

L~ 189~1T) EXAMPLE IC
CONSTl~UCTION AND SPEClEIC~TIONS OF MICROPOROUS
HOLLOW TIJBE CA~TRID~E
Two microporous hollow tube cartridge!s were constructed.
The first car~ridge had 500 fibers with an I.D~ of 19.6 mils, O.D. of 30 mils and length of 7.68 in-~hess Approximate pore size was 0.6 microns. The measured flow rate of the cartriclge was 637 ml/min with 0.5 psi outside pressure. This is equal to a flow of 1.7 gpm for a 5 f~2 unit (about 1500 fibers3.
The second cartridge had about 10S2 fibers of 17.5 mil I.D., 31 mil O.D., 7.68 inches in length. Approximate pore si3e of 0.2u with flow rate of 730 ml/min at 0.6 psi external pressure. This is equivalent to a flow of 1.8 gpm for a 5 ft2 cartridge at 3.6 psi applied pressure.

"

, '' L~3. 16189(1HT) MIS::ROPOROU5 ~
ART:E~lDG~ (8105-50 ~ UntPeated A~ F'iber Cheracterists 1. Number of fibers 1047 ~. Fiber I.D. x O~Do (mils) 1~.5 2C 31.0 3. Fiber length (inches~ 7.68 4O Internal fiber area (ft2) 3.1 5. Fiber material Nylon 66

6. Approx. pore size (microns) 0.2 B. ~5~
1. Body material polycarbonate 2. ~nd cap material polycarbonate 3. Potting medium polyurethane 4~ 13nd gaskets rubber 5. Threaded rod me.terial nylon 6. Access port thread size 1/4 inch FNPT
C.
1. Initial bubble point by 48.4 (air pressure diffusion test (psi) outside fibers) 2. Air diffusion rate at 2.9 for this 3.1 ft2 40 psi (ml/min unit. This is equivalent to 4.7 ml/min for a 5 ft2 unit. Pall Company specifies a maximum rate of 8 mVmin for 5 ft2 n.2 um cartridge.
3. Water flow rate 73û ml/min measured with 0.6 psi applied to outside of fibers, This is equivalent to 1.8 gpm for a 5 ft2 unit operated at 3.6 psi applied pressure.

:

:. i ;

,~
., . ':

' ~z~
--~6 --LS. 16189(HT~
~AMPLE II

PRf~PARATION OF REPR~SENTATIY~ CATIC)NIC CHARG~ ~[ODIFIED MEMBR~N~
Two layers of wet rnicroporolls membrane, made as in Example I, were laminated together and dried to 20-25~6 moisture~
The double layer of membrane was introduced into a 1.25%
by weight solution sf Hercules R4308. The pH of ~he bath was 10.S
This b~th was produced by diluting 331bso (17~17 Kg.) of Hercules R4308 resin from its initial 20% by weight concentration to 5%. Five normal ~5N) sodium hydroxide solution was then added to raise the pH to 10.5. The solution was then diluted with D.I. water having greater than 150,000 ohm~m resistivity in a ratio (volume) 2.5:1. The total volume of bath solution was S0 gallons.
Upon exiting this bath, the membrane was wiped on the bottom surface to remove excess water. A 3 minute air soak with cool air movement w~s used before the membrane entered the secondary charge modifying agent bath.
This bath was produced by adding û.0~3% tetraethylene pentamine by weight or .113 lbs. (.û513 kg) to 60 gaLlons (227. liters) of D.l. water (at least 150,000 ohm -cm resistivity). The pH was about 9.
The immersion conditions are identical to the first bath o~ primary : charge modifying agent. The membrane was then wrapped around a take up roll.
Pursuant to U.S.~Patent 4,473,474 to~Ost~elcher et al.

, . , .
. :

L?~

~ 4~ ~
L5a 1618g(~1T) The take up roll of wet membrane w~s stored for at least 3 hours. The roll was then dried at 250F (121C) for 3 minutes to complete the reaction of the charge modifying agents.
The membrane was then washed in a subsequent operation and checked for extraction levels.

.

LS~ 1618~(~IT~
e2ZAMPL13 111 In all of the following ~3xamples nylon membrane, including hollow tubes, was treated with a water solution of charge modiPying agent and, where indicated, a cross-linking agent. Since solubility of some cross-linking agents in water is limited, the agent was first diluted in alcohol and then mixed with the aqueous solution of anionic charge modifying agent. The membrane was drained, washed and dried in an oven at from lOOoC to 125C for 15-20 minutes. The membrane was then washed. The treatments and test res1l1ts are tabullated on the attached Table 1.

.~

¢

.~ ,~3 3 ~o .~ o .
~ 5~ o '~ 'o ~ o ~
6~ ~ r ~ 4~ ~ '~ ' 'Q~

~: ~ ~ d ~ 8 o ~ ., o ~ ~ ~ ~ $
~ 8 ,3 o .~ ,o ~ ~ ~ U 4 ~o ~ o ,~, , a' ~3 ~ 3 C ~3 ~
'`"~ .. S ¢ CC ~ ~i, ¢ ¢ :4 ¢ ¢ r~ r~ r~O ¢ ,~
¢ ~, F~ rn ~ ~ r, ae U~ ¢,,, ¢ ~ ~ ~
*
C~ ~ *O ~
~ O Z; Z; .
E¦ ,, ~,, ," ~ ~ 3 D

C ~ ~: . X
,~ , C
,, ~ ~ r ,~
.~ o '~ g 'o ~ ~ ~ g o v '~ ,C s ~;~ ~3 0 ~ d E
'~ S o ~ r~

I '~3 ';1 ~ _~ v ~6 .

:. ' o~
o ,a _ O _ e ~
8 .~ o ~ O
~ '~ ¢ ~ ¢ ~ O
O ~ ~ $
~1 ' ' ~ ~E ,,~ ~' ", ", o ~
~ ~ ~ 3 aQ 3 ~
~ ~ ~ ~ ~ V
* * *
* ~ ~ ~ ¢
V C) C) ~ ¢ ~
o o o ¢ CJ~ * o ~ o ~ ~ ~o ~ ~o ~
V ~ ~ ~ V
a ¢ ~ ~ o~ ¢ 00 ¢ ;~ ¢ ¢
- ~o c ,~ E

!~ C ~ ~ o o o o o o c ~ bD h O O O e., O e~ ~o, ~ E~

~9 ~ o ~ o o ~ c~ e: o o c~ ,o ,U~
t~ Z~

~ iql ~ ~ r~ ~ ~ ~1 ~ ~ C~ W ~ ~ **

~ V ~ t~ V V O V V t.) O V
.~i . ~'' '' ;' O o .;~ C o o E E E e ~ E

, V r~ _ _ d 1 ~ e æ ~e E E E

¦ E E E E E E

~ ¢ ~ , ¢ C) ~ ~
Q, ~ 'C ¢ ~ ~ ~,, O ¢
a~ X ~

c~ o o o ~ c~
b v v ~, v ~, v ¢ ¢ ¢ ¢ ~ ¢ ¢ ¢ ~ ~ ¢
¢ ¢ ¢ ¢ ~ ¢ ¢ ¢ ~ ~ ~ ,~

c c ,~"~" 3 C o E

~ ,~ ~ O O O O O O O O
~a~
U~ ~ ~ O O O O O C~ O C~ O ~ C;

cl ' o V O ~ ~ C) V V O O ~ O

.
... .
.
.
' ~ o o c,~

ol o o, o o o ol u~ O O O ~ O ~;

~ u~ o o o o o ~ l . ~
v r-~1 o CDCD C~O o ~ O U~ O ~ ~

Ln ~ ~ ¢ ¦ r-- o o o o ~ ~ ~ ~ ~ ~ ~

P.l C,, , ~
c E ~q ~¦ ~ ~ d d d ~ ~ ~ ~ ~ a, E ~ ~j ,~ o ~

O c a ~ E ~

J E3 ~ E E ~ E ~ E - ~ ~ ~ 3 S
~I Cl o * ~ * ~ o o o o o o E3 ~ ~ *

o o o o o o o 3 ~ T~ T~T , T , T T
~o~ a:~ ¢ ~ ~ ¢ r~ m c~ m ~:~ cp ~" ~ e g ~ O O O O O

T , ~ T ~ ~ T
C) O O C) O C) C) C) . , CD ~ O, ~ 1 N O
al ~ ~ , , , , , I , , o I ~ o O . O. o. O
h~ I '~

~, ~ ol O O O O u~ O c~ O
e~ /XI di C~
~1 ~ d ' I ~ C`l I C`~
¢
o ~a o ~ o ~ o o ~ c; o ~3 3~ 1 o o o o o ~ 1 ~ ~ r1 .~ ~ ~ ~ d~ ~
~ C~

E~~I c~
¢ E

3 3 ~ ~~ ~
$ ~ - ¢ ~ ~ ¢ ~ ¢ ~ ~ ¢

~ ,~ o ~ ~ ¢ V ~
c ~ ~ c O ~ ~ ~ m E.~ ."
;, o ~ ,~ o j~
r ~ C
e Y 3 e E Y E E E c E ~ E ~ a ~
~ ~ c; O' O c; c~ O O c: o c:, c;

s~ r c~c~
~ T T T T '~ T T ' ,~ C~
o o o ~ ~ o o E c~ c~ c~
"; $ ~2 ~) ~,) (,) O O ~O ' O C) .

''3~
o. o. o. o o. o. o o ~1 ~

ol o O ,~ o o.
U~ ~ ~ O Cr~ CD O cn C~
e ~1 O ~ O O O O O O O

U~ ~ ~ ~

~ ol O O O O O O O ~ ~

~ ~ 9 ~9 C- C-I ~ c~le;l e6 o o o Q,.
e I ~o ~ O O ~ O r4 C~ e ~
V ~ V V C) V ~ ~
¢ <!C ¢ '~ ¢ ~t ¢ ¢ ¢ ;~¢ 'Dq ~ Q
C ~ ~

~ c ~ c c ~
c- s : s ~ o ô c, o O ,, a) E ~ '.
~ ~ ~ e E C, ~ Ei e ~ E~
E3 rt~ Ir~ 1~1 0 ~ O C~
1 o o o o o c~ o c:! o o o )c O O O O O V
~ T T T T
c" ~ O Cl~ } o o T ~ o o '~ ' : .

J~

LS. 16189(HT) TABL~ I (Cont'd) FOOTNOT~S:

1- P~A is polystyrene sulfonic acid (POLYSCI~NC~):

~H - CH~n 2~ ~GDGI~ is ethylene glycol diglycidyl ether (POLYSCIENCE~.

3~ PAA is polyacrylic acid (GOOD-RIT~ K702~ 722, ~32, 752, GOODRICH):
-~CHJ r~
COOH
4~ Pll~ronia is a polyol (BASF WYANDOlY h~.
5~ 1884 is polyamide polyamine epichlorohydrin resin (POLYCUP, H~RCUL~S).
6- PI~A is polymaleie anhydride (GANTR~Z AN9 GAF):

l CH3 CH2-CH-7H CH n ~I=c~,~=o O ~ .

7- 4308 is polyamido - polyamine epiehlorohydrin resin ~POLYCUP, H ~RCULI3S).
~- T)3PA is tetraethylene pentamine (UNION CARBID~3):
H2N(cH2)2NH(cH2)2NH(cH2)2NH(cH2)2N~I2 9~ C~3û3 is hexa methoxy-methyl melamine resin (CYMEL 303, AMERICAN CYANAMID).

* Kegistered ':rrademark i .
7~i ,`.
':

~ 56 ~
LSo 16189~1T~
10. C-35201 is water borne epoxy resin (CMD 35201, CELANES~).
11- B 65 is methylated urea fo~maldehyde resin (BE~TL~ 657 AM~RICAN CYANAMID3.
12- Dowfs~ is sodium mono and didodecyl disulfollated diphenylo~ide (DOW).

* Registered Trademark i, ' , ' . '.

.

LS. 16189~1T) E~AMPL~ IV
__ E~ALUATION OF ME~B~ANES FC)lR PI.~S~llAP~[~Rf3SlS
_ Four nylon membranes û.45 micron untreated (~xample 1~, 0.45 micron anionic (Sample 24) or 0.45 mieron cationic (Example II) and 0.2 mieron untreated (~3xample I), were evaluated for the separation of plasma and cellular components of blood.
The test criteria is the rate of hemoglobin appearance into the plasma phase vs. the filtration rate. The test procedure and results are described below~ The 0.2 micron untreated membrane gave the best results, however9 the charged modified 0.45 micron membranes performed better than the untreated 0.45 micro membrane. lFour merDbranes (0.45 mieron untreated, 0.45 micron anionic, 0~45 micron cationic, and 0.2 micron untreated) were presented for comparison with the membrane emplo~ed most ~requently in prior studies with this system, SARTORIIJS 0.45 micron cellulose nitrate.
MET~IODS A~I) APPA~ATUS
The sys~em employed in these studies is shown in ~igure L
A modified SARTORlUS membrane cell is assembled with three 16 a:
1& cm membrane sheets and connected as shown. Plasma (250 ml) is circulated over the membranes as a pretreatment. Approximately 300 ml OI whole human blood ~drawn no more than 3 hours prior to the run) is added to a beaker containing 500 IU of heparin. The blood pump is started and set to read "10'~ on the speed meter ~about 38 ml/min).
AEter about 4 minutes for stabilizal:ion and sufficient washout of the * Registered Trademark 1 ' .,. . -,..

:, --58 ~
LS. 16189~HT) filtrate side of the cell by fresh filtrate, the filtration rate is measured by diverting the f1ltrate into a ~acluated cylinder and samples 9f îiltrate and blood are taken for analysis. The blood pump speed meter reading is incrernental by 5 and the procedllre is repeated until two obviously pink/red samples have been obtained.
Filtrate samples are analy~ed for hemoglobin (Hgb~ by spectrophotometric techniqu2s. Blood samples are analyzed for hematocrit, and plasma and total Hgb by a Coulter counter. One sample ea~h of blood and filtrQte is selected for protein electrophoresis.

RESULTS AND DlSCUSSION
O~served and computed results of the membrane te~ts are presented in Tables II through VI. Each table lists; the input blood flow rate, QI, the filtration rate, QE; the concentration of H~b in the plasma phase of the inflowing blood, CI. (mgJdl~; the Hgb concentration in the filtrate, CF; and the rate of IIgb appearance into the plasma phase, D, for the indicated membr~ne; where D is approximated as: D ~ QI (CF - C~ 00 all values are for a three membrane system.
The optimally functioning primary separation ~it of a plasmapheresis system must be capable of producing the greatest flow of plasma svith the least damage to the cellular blood components. In the terms employed above, QF must be maximized while holding D to some arbitrarily ac~eptable value. The evaluation of the five membranes tested can most readily be peformed in this manner from a - s9 -LS. 16189~1T3 plot of the E~gb appearance rate, D, as a function OI the filtrate rate, Q, shown in ~igure 2. The curve furthest to the lower right will specify the membrane of choice9 based on the above stated criteria.
Clearly, the 0.2u untreated membrane gave the b~est results. At the Hgb appearance rate 1.5 mg/min, this test produced 9.3 mllmin of filtrate. The seeond best performer, th0 0.45u negative gave 74 percent (6.9 ml/min) OI this value for the same criteriorl. The control membrane (Satorius 0.45u cellulose nitrate) produced only 4.6 mVmin or 4~ percent as much filtrate as did the 0.2u.
Interestingly~ the 0.45u untreated membrane gave the poorest performance of aU while the cationic and anionic modifications of this membrane produced filtration rates about midway between those of the neutral 0.2 and û.45u. This may be due to a greater mlmber of cells being convected into the 0.45u membrane with subseguent plugging of the membrane pore structures. Subjective visual examination of the membranes after each run found that "staining" of the mermbranes (probably due to the cells impacted into pores) appeared to correlate inversely with the maximum filtration rate, lending some credence to this hypothesis. This observation suggests that the process involved in modifying the membranes may make them less susceptible ~o plugging by such a mechallism, thus raising the maximum filtration rate. The anionic modification gave slightly better results than the cationic.
All protein electrophoresis results for the filtrate samples had the appearance of normal plasma results.

L~. lB189(~1T~
ABLE D[

~ ~ 0.45u Membrm~ Test QI QF CI CF D
(mVm~m)(ml/min) 3.0 24.6 24.6 *
10~ ~.7 28.6 30.1 1.50 132 5.3 35.1 36.9 2.3 16~ 7.0 ' `''"';';: .

'' '': .

9~

LS. lG189(HT~
TABLE III
.
-_t~ cl tl. ~ /nl~ ~emC/~IlerreE;t m~
37.8 1.1 18.d~ 18.5 0.04 68.6 1.3 18.7 18.8 0.07 99.4 2.1 19.2 19.3 0.10 13Q 3.5 ~.1 25.2 1.43 161 4.4 40.~ 43.6 4.83 1~2 5.4 68.2 72.4 8.06 .. .

: :' s~

La 1618g(HT) TABLE IV

R~ul~ of the 0.2u Untreated Membrane T~st QI QF Cl CF D
~ml/min?(mVmin) 37.~ 4.7 15.7 19.2 1.3 68~6 6.4 2~.0 22.3 1.6 99.~ 7.a 23.1 24.3 1.2 13~ 9.2 26.8 27.~ 1.4 161 9.6 31~8 32.9 1.8 192 9.9 38.7 40.1 2.7 223 10.1 80.8 87.9 15.
253 10.3 139. 148. 22.8 ,~

LS. 16189~:EIT) TAiBI.J3 V

Results o~ ~he O.d~5u Positive i aembr~ e Test (ml/min) ~m~Fmin) ~E~ ~ (mEL~

37~8 2n9 26~1 27~9 0~7 68.B 4.8 2~.7 31.6 1.3 99.4 6.1 34.2 35.9 1.7 130. 73 47.8 51.7 5.1 161. 8.3 137. 1580 33.g ,~

,~

' LS. 16189~[T) TA~3Lf~ VI

(ml/mjn~ ~ ~ D

37.84.0 26.9 27~8 0.28 68.65.6 ~9.1 30.1 0.6~
99.47.0 34.~ 36.5 1.69 130.8.9 48.1 51.2 4.03 161.7~2 64.9 6~.1 5.15 192.7.3 114. 122. 15.36 ,, I.S. 1618~(~IT~
~MPL~ V
~ALIJATION OF lHOLLOW ~ R MODUL~ES FOR Bl OOD COMPONENT SEPARATION

The present evalua~ion involves six hol]Low fiber modules:
two each of the unmodi~ied fiber, anionic (negative) surface Illodified, and cationic (positive) sur~ce modified.
The anionic ibers were prepared pursuant to Sample 29 (C-

8 30-2~. The cationic fibers were treated in a manner similar to Example 1~ (C-8-31-1~

The system employed in these studies is shown in ~gure 3.
It consists of a Travenol Laboratories roller-type blood pump (used on the Travenol RSP hemodialyzer), clot filter, 0~7~0 mm Hg pressure ~auge, Swagelok fittings for colmection to the hollow ~iber modulet Manostat Calcuflow flow meter, and fluid reservoir svith stirrer.
The apparatus is assem~led with the desired test module oriented vertically (with flow from top to bottom) and 250 ml of human plasma is added to the reservoir beaker. The plasma is circulated through the system for 15 minutes at approximately 1~0 ml/min. This allows for leak checks and for deposition of plasma proteins Oll rough or otherwise biologically reactive surfaces.
Pretreatment of the system in this manner has been shown to decrease the degree o hemolysis that occurs on the initial conta¢t of the blood with the membrane. At the end of the pretreatment, the pump is stopped and the pump inl0t line is transferred to a second reservoir * Registered Trademark .

~'', -- 6~ --LS~ 16189(ElT) beaker containing 250-300 ml of fresh human b]ood and 500 IU of heparin. An initial blood sample is taken from the beaker. The pump is restarted and the module and filtrate ou~let lines are moved to th0 blood beaker when the first evidenee of blood leaYing the module is noted. Timing of the run begins at this point.
The remainder of the test is divided into intervals of ten minutes each. At the midpoint of each interval, the inlet pressure and filtration rate are recorded~ At the end of each interval, a filtrate sample is taken for analysis. Each sample is immediately centrifuged and the plasma is separated from any cells or fragments that are present. This will lessen the likelihood of falsely high plasma hemoglobin values. The pump is incremented and the next interval begins. At the end of the test, a blood sample is taken from the beaker to provide a check on the mass balance.
ilL IS Alll ~ ~ ualO 11 Table VII lists the characteristics OI the hollow fiber modules tested. Observed ~nd computed results of the tests are presented in Tables VIII - XIII. ~ach table lists each input blood flow rate tested, QI (ml/min); the coreesponding filtration rate, QF
(mVmin); concentration of Hgb in the plasma phase of the inflowing Mood at the end of the measurement interval, CI(mgldl); EIgb concentration in the filtrate at the end of the interval, CF (mg/dV;
and rate of Hgb release in the plasma, D (mg/rnin), where D is approximated QS: D = QI (CF - CI)/100- The values for the Hgb appearance rate D have been corrected for the hemolysis effeets of the blood pump and other hardware and represent only the effects produced by the test module.

I ~. 16189~T) It should be noted that blood leaks into the filtrate were a significant problem with three of the surface modified fiber modules:
8207-2 (anionic), 8207-5 (cationic) and 8207-6 (cationic). In the test of module 8207-2 (anionic) the leak was so severe that it was diIficult to distinguish betvveen the fluid in the ~iltrate and blood outlet lines until the sample~ had been centrifuged. Normally, the filtrate has the appearance of plasma with slight brown or pink coloration. The extent to which this leakage affected the results is Imknown.
Figure 4 presents the filtration rate for each module as a function of the blood inflow rate. With the exception of the anionie unit 8207-~ (which developed the leak early in the test), the surface modified fibers produced greater filtration rates for a given blood flow rate than did the unmodified fibers. At an inflow rate of 300 ml/min, the modified fiber modules averaged about 29 percent more filtrate than the untreated fiber modules.
Figure 5-7 present the rate of hemoglobin appe~rance, D, as a function of the filtration rate QF, for the various modules.
Figure 5 shows the performance of the unmodified fibers. Both modules exhibited relstively high initial hemolysis rates which declined sharply as the filtration rate increased. After reaching a minimum rate of hemolysis, corresponding to filtration rates of 40-45 ml/mina hemolysi3 increased with further increases in filtration rate.
The minimum hemolysis rates for both modules were below the arbitrary standard of 1.5 mg/min. (By this standard, A patient with a plasma volume of 3 liters could be treated for 6 hours and have the plasma ~Igb increase b~ 15 mg/dl. The normal plasma Hgb is about ml/dl.) --6~ --LS. 1618~ IT~
F~gure 6 presents the results for the modllles Wit]l the cationic modified fibers. Module 8207-5 performed similarly to the unmodified units, although the minimum hemolysis rate was not as low. The other module, 8207-B, exhibited extremely high initial hemolysis. The rate for this module did drop significantly and might have reached an acceptably low value if the blood leak had not occurred~
The results of the anionic surface modified fibers are presented in Figure 7. Both modules performed similarly at low filtra~ion rates with results much like the unmodified fibers.
Interestingly, module 8207-7, which did not leak, did not exhibit the minimum in the hemolysis raSe seen in other tests, but instead seemed to have an asymptote for the rate. This module's performance was far superior to all others. Module 8207-2 developed the blood leak before sufficient data could be collected to confirm this result. It should thus be possible to obtain high flow rates of low EIgb plasma with anionic surface modified fiber.
A problem common to all of the tests was significent initial hemolysis rates. There are a number of factors which may be responsible including roughness of the fiber walls, particularly at the entrance of the fiber. Microscopic examination of an unused module may be helpful in this determination and revision of the fiber potting procedure to produce smoother fiber ends may be advantageous for those modules to be used in blood separation.

.

,: . .

- t39 -LS~ 16189~E~TJ
Finally, a number of paired filtrate and outlet blood samples were tested to determine if sieving of albumin by the fibers cvuld be detected. No significant difference wa~ found in the results.
If sieving occurs, it is probably quite smalL

1.~;. 16189~IT) TABL~ V~
__ ~Is>llow Piber ~llodule Chara~teristi~
Module Codes 8148-48/49 8207-2/7 8207-5/6 Surface Modification None Anionic Cationic (negative) (E)Sitive) Trea~ment Mode - Sample 29 ~xample II
Number of fibsrs 130 120 120 Fiber ID (cm) 0.0376 .0378 0.0358 Fiber OD (cm) 0.0627 000638 0.0630 Fiber leng~h (cm~ 16 16 16 InternalArea (sq cm) 246 228 216 D3P (psi) 31.0 33.8 32.1 FAOP (psi~ 34.2 37.0 36.0 FLOW (ml/min-psi-cm2) 0.37 0.38 0.35 Module Test Pressure (psi) 10 10 7/10 .
, - , ,:
., .
, . . .
.
: .... ...
..
...... ,. ,~,.. ..

LS. 16189 (HT) TABL~ vm ~!~ll~l~a QI QF Pin1et CI C~ D
(ml/min)(mVmin) ~ ~ ~/dl) (mg/min) 116 21.8 * 55.2 6'j.6 12.1 174 29.0 * ~3.9 76.7 4.9 ~9 33.3 ~ 82.6 83.5 2.2 322 39.1 * 90.0 gO.6 1.9 396 45.0 * 119.212~.9 6.7 * Pressure monitor failed . .
: .
:.; ~ ... . . .

LS. 16189 (:~T3 ~BLE ~
~¦~a QI Q~, Pinlet CI CF ` D
(ml/min)(mVmin) ~ ~ ~Jdl) 116 23.5 225-238 47.1 5~.97.9 174 30.0 3S3-373 65.0 67.54.g 249 36.0 472-~03 81.9 8~.54.0 322 42.5 607-647 92.6 93.32u3 39~ 55.2 ~49-790 126,0 127.87.1 :, .. :
. ., "
,, .

LS. 16189 (HT) Te~BLE ~

QI QF Pinlet CI CF D
(mVmin~(mVmin~ ~ ~ ~/dl) 116 20.5 26~-273 35.0 40.7 6.6 174 27.0 389-407, 48~2 50.2 3.5 249 36.5 531-553 61.7 S3.1 3.5 322 45.0 672-703 77.1 78.2 3.5 ':
.~, , ., '' , :.. : , LSo 1618~ (flT~
~rAsL~ Xl QI QF Pi~et CI CF D
(ml/min) ~(m~;/dl~ ~/dl~

116 24.5 320-333102.8 122.4 22.7 174 32.0 ~76-500161.1 169.~ 14.4 249 3~.0 647-~93198.2 201.7 8.7 322 56.û 750223.8 225.6 5.8 .

~ , ~- ' LS. 16189 (HT) TABL~ ~

QI QF Pin1et CI CF D
(ml/min) (ml/min) ~ ~ (m~l)(m~/min) 116 17.5 258-272 ~9.6 5~.,9 3.6 174 24.2 423-445 75.9 80c1 7.3 249 31.0 580-615 9~.5 92.1 ~.0 322 38.5 750 11~.~ 123.214.2 ,`~' '` ' ;, ~ ' ' ' ~2~!~3 LS. :16189 ~HT~
TABL~ ~m 7 (~On1e~ Data QI QF Pi~et CI CF D
1/min) (mmHg~ ~ ~ dl3 116 23.0 272-2~333.1 37. ~ 5.6 174 3~.0 ~08-~2648.8 51.1 4.0 249 38.0 572-60560.2 61.3 2.7 322 49.0 735-78~76.7 77.9 3.9 396 70.4 ~80 g9.5 90.2 2.8 ~;" ~

16189~HT~
~MPLE VI
(81099 8026, LS. 16250) Polysulfone was solubilized in 1, 2~ichloroethane ~DC~) and reacted with chlorosulfonic acid, washed throughly in DCE and redissolved in dirr.ethylformamide (DFM). (lt is imlportant to note that the sl~lfonated polysulfone is not soluble in DC~ as was the base polymer). At this point the sulfonated polymer is relatively free of ~hlorosul~onic acid and therefore could easily be handled in ~queous media.
Nylon microporous membranes have been eharge modified with dilute solutions of the sulfonated polysulfone polymer (SPS). Such treatment should produce a membrane that is compatible with blood since red blood cells are negatively charged.
IJntreated nylon microporous membrane ~21~-E13-0102) made pursuant to ~xample I, was charge modified using the sulfonated polysulfone polymer solution produced above. The polymer solution was further diluted to 1:2, 1:5, and 1:8 in dimethyl formamide (DMF~.
Microporous nylon membranes were equi~ibrated in the diluted polymer solutions, air dried and then challenged with a dilute solution (0.02 ppm~ of methylene blue. Methylene blue is a cationic dye9 i.e., a dye with an immobilized positive charge.

:3~.Z~

16189(~IT) The treated membranes exhibited a negative charge when challenged with the methylene blue dye solution, as shown in Table ~IV below.

TABLS Z~IV

Flow *Conc. IBP FAOP Rate Init Final Ret Tisne SPS ~ psi ml/min ~ Mm ___ 0 46 52 117 3.~ - 2 1:2 ~4 51 51 5.7 23.8 40 1:5 43 5~ 120 S.8 11.0 25 1:8 9~3 52 10~ a~.4 9.1 20 *RelatiYe concentrations of sulfonated polysulfone from bateh sulfonated polymer solution.
In effect, the nylon membrane has been coated with a polymer containing an immobilized negative charge, i.e., SO3-- The methy~ne blue, as mentioned beore9 possesses a positive charge, i.e., CH3~. The methylene blue is adsorbed to the ~PS coated nylon membrane through the SO3- group on the sulfonated polysul~one.

Claims (31)

The embodiments of the invention in which an exclusive property or privilege is claimed are defined as follows:

1. A charge modified hydrophilic organic polymeric microporous hollow fiber filter membrane for the removal of suspended solids and particulate from aqueous liquids, said fiber having a microporous membrane wall, said wall compris-ing:
a substantially skinless isotropic hydrophilic organic polymeric microporous filter membrane having an internal microstructure throughout said membrane and a pore size of at least .05 microns, said pore size permitting substantially all dissolved solids to pass therethrough; and a charge modifying amount of an anionic or cationic charge modifying agent bonded to substantially all of the membrane microstructure without substantial pore size reduc-tion or pore blockage providing the membrane wall with an improved capture potential for oppositely charged suspended solids and particulate and a decreased adsorptive capacity for like charged suspended solids and particulate.

2. The hollow fiber of claim 1 wherein the organic polymeric microporous membrane is a hydrophilic poly-vinylidene fluoride.

3. The hollow fiber of claim 1 wherein the organic polymeric microporous membrane is a hydrophilic ester of cellulose.

4. The hollow fiber of claim 1 wherein the organic polymeric microporous membrane is a hydrophilic nylon.

5. The hollow fiber of claim 1 wherein the organic polymeric microporous membrane is a hydrophilic polyhexa-methylene adipamide.

6. The hollow fiber of claim 1 wherein the charge modifying agent is a water soluble polymer having substi-tuents thereon capable of bonding to the membrane and substituents thereon which are anionic or cationic.

7. The hollow fiber of claim 1 wherein the charge modifying agent is anionic and a water soluble polymer having substituents thereon capable of bonding to the membrane and anionic functional groups.

8. The hollow fiber of claim 7 wherein the anionic functional groups are selected from the group consisting of carboxyl, phosphonous, phosphonic and sulfonic groups or mixtures thereof.

9. The hollow fiber of claim 7 wherein the anionic functional groups are carboxyl.

10. The hollow fiber of claim 7 wherein the anionic functional groups are sulfonic.

11. The hollow fiber of claim 7 wherein the anionic charge modifying agent is a water soluble organic polymer having a molecular weight of about 2,000 to 500,000.

12. The hollow fiber of claim 7 wherein the anionic charge modifying agent is bonded to the membrane through a cross-linking agent.

13. The hollow fiber of claim 12 wherein the cross-linking agent is an aliphatic polyepoxide having a molecular weight of less than about 500.

14. The hollow fiber of claim 7 wherein the anionic charge modifying agent is poly (styrene sulfonic) acid having a molecular weight between 2,000 and 300,000.

15. The hollow fiber of claim 7 wherein the anionic charge modifying agent is poly (acrylic) acid having a molecular weight between 2,000 and 300,000.

16. The hollow fiber of claim 14 wherein the poly-epoxide is a di- or tri-epoxide.

17. The hollow fiber of claim 14 wherein the poly-epoxide has a molecular weight of from about 146 to about 300.

18. The hollow fiber of claim 1 wherein the charge modifying agent is a primary charge modifying agent which is a water-soluble organic polymer having a molecular weight greater than about 1,000, and wherein each monomer thereof has at least one epoxide group capable of bonding to the surface of the membrane and at least one tertiary amine or quaternary ammonium group.

19. The hollow fiber of claim 18 wherein a portion of the epoxy groups on the charge modifying agent are bonded to a secondary charge modifying agent selected from the group consisting of:
(i) aliphatic amines which are polyamines having at least one primary amine or at least two secondary amines;
and (ii) aliphatic amines having at least one secondary amine and a carboxyl or hydroxyl substituent.

20. The hollow fiber of claim 18 or 19 wherein the primary charge modifying agent is a polyamido-polyamine epichlorohydrin resin.

21. The hollow fiber of claim 19 wherein the secondary charge modifying agent is an amine of the formula:
wherein R1 and R2 are alkyl of 1 and 4 carbon atoms and x is an integer from 0 to 4.

22. The hollow fiber of claim 21 wherein the primary charge modifying agent is a polyamido-polyamine epichloro-hydrin resin.

23. The hollow fiber of claim 21 or 22 wherein the amine is tetraethylene pentamine of the formula:

24. The hollow fiber of claim 19 wherein the charge modifying agent is a cationic charge modifying agent bonded to the membrane microstructure through an aliphatic poly-epoxide cross-linking agent having a molecular weight of less than about 500, wherein the charge modifying agent is selected from the group consisting of:
(i) aliphatic amines which are polyamines having at least one primary amine or at least two secondary amines;
and (ii) aliphatic amines having at least one secondary amine and a carboxyl or hydroxyl substituent.

25. The hollow fiber of claim 24 wherein the charge modifying agent is an amine of the formula:

wherein R1 and R2 are alkyl of 1 and 4 carbon atoms and x is an integer from 0 to 4.

26. The hollow fiber of claim 25 wherein R1 and R2 are ethyl.

27. The hollow fiber of claim 25 wherein the amine is tetraethylene pentamine of the formula:

28. The hollow fiber of claim 24 wherein the poly-epoxide is a di-or tri-epoxide.

29. The hollow fiber of claim 28 wherein the poly-epoxide has a molecular weight of from about 146 to about 300.

30. The hollow fiber of claim 25 wherein the poly-epoxide has a formula:

wherein the R is an alkyl of 1 to 6 carbon atoms and n is an integer from 2 to 5.

31. The hollow fiber of claim 26 wherein the poly-epoxide is 1,4-butanediol diglycidyl ether of the formula: