CA1327023C - Rotary filtration device with hyperphilic membrane - Google Patents
Rotary filtration device with hyperphilic membraneInfo
- Publication number
- CA1327023C CA1327023C CA000606727A CA606727A CA1327023C CA 1327023 C CA1327023 C CA 1327023C CA 000606727 A CA000606727 A CA 000606727A CA 606727 A CA606727 A CA 606727A CA 1327023 C CA1327023 C CA 1327023C
- Authority
- CA
- Canada
- Prior art keywords
- groups
- polymer
- substituted amide
- filter
- hydrophilic
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired - Fee Related
Links
Classifications
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01D—SEPARATION
- B01D67/00—Processes specially adapted for manufacturing semi-permeable membranes for separation processes or apparatus
- B01D67/0081—After-treatment of organic or inorganic membranes
- B01D67/0093—Chemical modification
- B01D67/00931—Chemical modification by introduction of specific groups after membrane formation, e.g. by grafting
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01D—SEPARATION
- B01D67/00—Processes specially adapted for manufacturing semi-permeable membranes for separation processes or apparatus
- B01D67/0081—After-treatment of organic or inorganic membranes
- B01D67/0093—Chemical modification
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01D—SEPARATION
- B01D63/00—Apparatus in general for separation processes using semi-permeable membranes
- B01D63/16—Rotary, reciprocated or vibrated modules
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01D—SEPARATION
- B01D71/00—Semi-permeable membranes for separation processes or apparatus characterised by the material; Manufacturing processes specially adapted therefor
- B01D71/06—Organic material
- B01D71/40—Polymers of unsaturated acids or derivatives thereof, e.g. salts, amides, imides, nitriles, anhydrides, esters
- B01D71/42—Polymers of nitriles, e.g. polyacrylonitrile
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01D—SEPARATION
- B01D71/00—Semi-permeable membranes for separation processes or apparatus characterised by the material; Manufacturing processes specially adapted therefor
- B01D71/06—Organic material
- B01D71/40—Polymers of unsaturated acids or derivatives thereof, e.g. salts, amides, imides, nitriles, anhydrides, esters
- B01D71/42—Polymers of nitriles, e.g. polyacrylonitrile
- B01D71/421—Polyacrylonitrile
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01D—SEPARATION
- B01D2323/00—Details relating to membrane preparation
- B01D2323/38—Graft polymerization
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- Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Inorganic Chemistry (AREA)
- Engineering & Computer Science (AREA)
- Manufacturing & Machinery (AREA)
- Health & Medical Sciences (AREA)
- Transplantation (AREA)
- Separation Using Semi-Permeable Membranes (AREA)
Abstract
ABSTRACT OF THE DISCLOSURE
A rotary filtration device having at least two members, one at least partially within the other to define a fluid gap therebetween, is disclosed. One or more filters are located on one or more of the members facing the fluid gap.
Sufficient uncharged hydrophilic polar groups, preferably uncharged substituted amide groups, are located on the surface of the filter to render the surface hydrophilic.
A rotary filtration device having at least two members, one at least partially within the other to define a fluid gap therebetween, is disclosed. One or more filters are located on one or more of the members facing the fluid gap.
Sufficient uncharged hydrophilic polar groups, preferably uncharged substituted amide groups, are located on the surface of the filter to render the surface hydrophilic.
Description
~327~2~:
BA~KG~OU~ OF TH~ I~YENTU~ -Filtration devices are used to separate one or mor~
components of a 1uid from the other components.. Processes that may be carried out in such devices include filtration, reverse osmosis, ultrafiltration, and pervaporation. These separation processes make use of the greater permeability o~
some fluid components than o~hers through he filter. The fluid components that pa~s through the filter comprise the permeate and those that do no~.pass through (i.e., are rejected~ comprise the retentate. Depending on the proces~, the valuabl~ frac~ion may be the permeate or ~he retentate or in some ca~ ba~h may be valuable.
A comman problem in all filtra~ion devises is blinding or clogging of,the ~ilter. Th~ permeate passes through the filter from the flui~ layer adjacent the feed side o the fil~er, leaving a retentate layer adjacent that side of the ~ilter having a di~ferent composi~ion than ~he bulk eed fluid 06~4~
~327~2~
composition or the permeate composition. This material may bind to the filter, e.g., clog its pores (if it is a porous filter), or remain as a stagnant layer near the filter (e.g., a gel layer) and in either case reduce mass transport through the filter. Use of rotation (e.g., having the filter mounted on a rotating member) has been one attempt to break up and remove this stagnant layer and reduce clogginy of the ~ilter.
Regarding rotary filtration devices, see the commonly owned applications of Membrex, Inc.- PCT Published application W0 85/02783, published July 4, 1985; U.S. Patent No. 4,790,942; U.S. Patent No. 4,911,847; U.S. Patent No.
4,876,013; and U.S. Patent No. 4,867,878. Also see patents of Sulzer-Escher Wyss Ltd.: U.S. Patent Nos. 3,797,662, 4,066,554, 4,093,55~, and 4,427,552.
Rotary filtration devices have a rotating memb~r (e.g., a cylinder) and a s~cond member that may be stationary sr rotate in the same or a different direction as the first member. A rotating member may alternate direction of rotation, e~g., clockwise, then counterclockwise, then clockwise, and so on. Fluid to be filtered is placed in the gap between the two members and permeate flows through the one or two filters facing the gap. Filters (e.g., membrane~) may be mounted on one or both members. For example, with a device having an i32~023 inner cylindrical member and an out~r cylindrical member that together define a narrow cylindrical gap between them, the filter may be mounted only on the outside of the inner member, or only on the inside of the outer member, or a filter may be mounted on each, and either or both members may rotate in the same or different directions.
The gap between the inner and outer members may be of any size and shape. However, it has been found desirable in some rotary filtration devices to use a gap width sufficiently small and to operate the device in such a manner (e.g., high enough rotational speed) to establish Taylor vortices in the fluid in the gap. These vortices generally help improve mass transf~r through the one or more filters by reducing the relatively stagnant layer that tends to exist near a filter surface.
Various schemes have been used for cleaning the filters in filtration devices and for trying to prevent blinding of the filters. Sulzer-Escher Wyss literature (see, e.g., Sulzer Biotechnics nDynamic Pressure Filtration,"
8ulletin 23-43-00-40-V85-10, two-page bro~hure (1985)~ and the Membre~ applications noted above show the use of ~aylor vortices in rotary devices. In Huntington U.S. Patent No.
3,355,382 the reverse osmosis desalination membranes are periodically cleaned by suddenly raising the product.pressure above the feed pressure to create a water hammer. In Huntington U.S. Patent No. 3,396,10~ the shape of the ~iltering ~` .
~ -3-~,....
. ' ~
surface results in fluid flow paths that tend to break up the stagnant Sboundary) layer. In Manjikian U.S. Patent Nos.
3,821,108, 3,830,372, and 3,849,305 stirrers are used to keep the feed fluid mixed to prevent blinding. In U.~. Patent Nos.
1,603,746 and 1,603,747 two rotors operating at different speeds and centripetal force are used to reduce filter blinding. A filter that was strong and durable enough to withstand use in a rotary filtration device yet inherently had a reduced tendency to clog or become blinded would be most adYantageous.
A variety of materials have been used for filters.
Such materials must have sufficient chemical resistance, physical strength, etc. to be useful. For e~ample, filters for reverse osmosis, ultrafiltration, microfiltration, pervaporation, and dialysis often are subjected to pressure to ~fect the desired separation or concentration. Therefore, the filter material must maintain its physical integrity and desired properties under pressure. Rotary filtration units are particularly difficult working environments for filters, in part ~ecaus~ the filters m~y addltionally be subjec~ed to high centrifugal forces.
It is well known that polymers are useful raw materials for the production of filters. Typically, the polymers useful for the fabrication of rigid porous ar~icles tend not to bP dissolved by or swell in water and are commonly referred to as being hydropho~ic, e.g., acrylonitrile polymers . ~.
` ~327023 or copolymers. Unfortunately, the polymeric qualities that give crystallinity and physical strength to filters of these materials cause adsorptive interactions during separation and concentration operations. As a consequence, the filters become fouled by materials in the feed. As e~plained above, fouling is a major problem because the formation of a fouling layer upon the filter's surface interferes with its operation, thereby necessitating cleaning.
Polymeric compositions that tend not to e~hibit adsorptive interactions during separation also tend to lack the necessary physical strength for pressure-driven separations.
Thos~ compositions are pressure-sensitive and can readily be compressed and distorted by applied pressure. Agarose and polyacrylamide are examples of such compositions. Because throughout their struetures they are hydrophilic and thus interact with water and swell, they form hydrated gels.
Attempts have b~en made to overcome the disadvantages of hydro~hobic-type polymeric compositions by chemically modifying the surface of porous articles formed from those compositions. Lin~er UOS. Patent Nos. 4,5~4,103 and 4,477,634 concern me~hods of increasing the pressure stability of a polyacrylonitrile-containing membrane by reacting it with hydro~ylamine followed by additional steps, including reaction with a polyfunctional oligomer and a compound containing at least one ionic group. A disadvantage o~ this method, however, is that the resulting modified membranes contain charged 'g5~"
~ . _ .
- 1327~3 groups, thereby making them unsuitable for some applications.
Additionally, the methods sufer from defects such as the n~ed for expensive reagents and poor control over the e~tent of modification.
Sano U.S. Patent No. 4,265,959 concerns a method for the preparation of semipermeable membranes, which comprises sulfonating porous membranes of acrylonitrile polymers. In that method, a porous membrane is e~posed to a gaseous sulfonating agent, e.g., sulfuric anhydride, under pressur~.
The resulting modified membrane is claimed to possess superivr chemical, mechani~al, and thermal properties due to crosslinking of its surface mole~ules and its increased hydrophilic character. However, the Sano method suffers from similar defects as described above ~i.e., the need for expensive reagents and poor control over the extent of modification). In fact, the patent notes that if the whola membrane i5 sulfonated it becomes brittle.
Sano U.S. Patent No. 4,147,745 concerns a surface-modifying method that comprises e~posing a membrane of acrylonitrile-~ype polymer~ to a plasma. The resulting membrane is claimed to have a surface whose polymer molecules are cross-linked, thereby increasing its ph~sical strength.
Nakanishi U.S. Patent No. 4,501,785 concerns a method of hydrophilizing a porous membrane made of a polyolefin'(e.g., polyethylene) by coating the suraces that define the pores with polyethylene glycol. These Sano and Nakanishi methods 7 ~ ~ ~
also involve expensive procedures. Furthermore, the Nakanishi method is limited to membranes whose pores can accommodate the polyethylene glycol molecule.
There is a continuing need for rotary filtration devices that are more effective and efficient ~for example, have a reduced tendency to become clogged). There is also a need for rota~y filtration devices having stxong and durable filters that inherently have a reduced tendency to become blinded or to clog.
SUMMARY OF THE INVENTION
Applicant~ have already disclosed a material having superior properties suitable for use as filter~ (among other things) in U.S. Patent No. 4,906,379. (See also Dean, Jr., and Nerem (editors), Bioproaess Enqineexina Collo~ium (American Society of Mechanical Engineers, New York), pages 93-96: Hildebrandt and Saxton, "The Use of Taylor Vortices in Protein Processing To Enhance Me~brans Filtration Per~ormance" (1987).) ~pplicants have discovexed that the use of such filter~ in a rotary filtration device is of particular valuer maklng the device more effect~ve and efficiant.
In one a~pect, the present invention provide~ a rotary filtration device comprising:
(a) an outer member having an inner surface~
~32~023 (b) an inner member having an outer surface and mounted at least partially within the outer member to define a fluid gap between the inner surface of the outer mem~er and the outer surface of the inner member;
(c) means for rotating the outer member or the inner member or both; and (d~ filt~r means for filtering fluid in the ~luid gap, the filter means beî~g located on the inner surface of the outer member or on the outer surface of the inner member or on both and comprising molecules of a suitable polymer that provides solely on the surface of the filter means suficient uncharged substituted amide groups to render the surface hydrophilic.
Preparation of those filters involves a ch~mical reaction between nitrile groups o a hydrophobic-type polymer an~ an aldehyde ~o produce hydrophilic amide groups only on the surface of the filter. The fundamental chemistry of this reaction is well-known (see, e.g., Magat, T Am r~ c., volume 73, pagss lQ28 1037 ~lgSl~; Mowry U.S. Patent No.
BA~KG~OU~ OF TH~ I~YENTU~ -Filtration devices are used to separate one or mor~
components of a 1uid from the other components.. Processes that may be carried out in such devices include filtration, reverse osmosis, ultrafiltration, and pervaporation. These separation processes make use of the greater permeability o~
some fluid components than o~hers through he filter. The fluid components that pa~s through the filter comprise the permeate and those that do no~.pass through (i.e., are rejected~ comprise the retentate. Depending on the proces~, the valuabl~ frac~ion may be the permeate or ~he retentate or in some ca~ ba~h may be valuable.
A comman problem in all filtra~ion devises is blinding or clogging of,the ~ilter. Th~ permeate passes through the filter from the flui~ layer adjacent the feed side o the fil~er, leaving a retentate layer adjacent that side of the ~ilter having a di~ferent composi~ion than ~he bulk eed fluid 06~4~
~327~2~
composition or the permeate composition. This material may bind to the filter, e.g., clog its pores (if it is a porous filter), or remain as a stagnant layer near the filter (e.g., a gel layer) and in either case reduce mass transport through the filter. Use of rotation (e.g., having the filter mounted on a rotating member) has been one attempt to break up and remove this stagnant layer and reduce clogginy of the ~ilter.
Regarding rotary filtration devices, see the commonly owned applications of Membrex, Inc.- PCT Published application W0 85/02783, published July 4, 1985; U.S. Patent No. 4,790,942; U.S. Patent No. 4,911,847; U.S. Patent No.
4,876,013; and U.S. Patent No. 4,867,878. Also see patents of Sulzer-Escher Wyss Ltd.: U.S. Patent Nos. 3,797,662, 4,066,554, 4,093,55~, and 4,427,552.
Rotary filtration devices have a rotating memb~r (e.g., a cylinder) and a s~cond member that may be stationary sr rotate in the same or a different direction as the first member. A rotating member may alternate direction of rotation, e~g., clockwise, then counterclockwise, then clockwise, and so on. Fluid to be filtered is placed in the gap between the two members and permeate flows through the one or two filters facing the gap. Filters (e.g., membrane~) may be mounted on one or both members. For example, with a device having an i32~023 inner cylindrical member and an out~r cylindrical member that together define a narrow cylindrical gap between them, the filter may be mounted only on the outside of the inner member, or only on the inside of the outer member, or a filter may be mounted on each, and either or both members may rotate in the same or different directions.
The gap between the inner and outer members may be of any size and shape. However, it has been found desirable in some rotary filtration devices to use a gap width sufficiently small and to operate the device in such a manner (e.g., high enough rotational speed) to establish Taylor vortices in the fluid in the gap. These vortices generally help improve mass transf~r through the one or more filters by reducing the relatively stagnant layer that tends to exist near a filter surface.
Various schemes have been used for cleaning the filters in filtration devices and for trying to prevent blinding of the filters. Sulzer-Escher Wyss literature (see, e.g., Sulzer Biotechnics nDynamic Pressure Filtration,"
8ulletin 23-43-00-40-V85-10, two-page bro~hure (1985)~ and the Membre~ applications noted above show the use of ~aylor vortices in rotary devices. In Huntington U.S. Patent No.
3,355,382 the reverse osmosis desalination membranes are periodically cleaned by suddenly raising the product.pressure above the feed pressure to create a water hammer. In Huntington U.S. Patent No. 3,396,10~ the shape of the ~iltering ~` .
~ -3-~,....
. ' ~
surface results in fluid flow paths that tend to break up the stagnant Sboundary) layer. In Manjikian U.S. Patent Nos.
3,821,108, 3,830,372, and 3,849,305 stirrers are used to keep the feed fluid mixed to prevent blinding. In U.~. Patent Nos.
1,603,746 and 1,603,747 two rotors operating at different speeds and centripetal force are used to reduce filter blinding. A filter that was strong and durable enough to withstand use in a rotary filtration device yet inherently had a reduced tendency to clog or become blinded would be most adYantageous.
A variety of materials have been used for filters.
Such materials must have sufficient chemical resistance, physical strength, etc. to be useful. For e~ample, filters for reverse osmosis, ultrafiltration, microfiltration, pervaporation, and dialysis often are subjected to pressure to ~fect the desired separation or concentration. Therefore, the filter material must maintain its physical integrity and desired properties under pressure. Rotary filtration units are particularly difficult working environments for filters, in part ~ecaus~ the filters m~y addltionally be subjec~ed to high centrifugal forces.
It is well known that polymers are useful raw materials for the production of filters. Typically, the polymers useful for the fabrication of rigid porous ar~icles tend not to bP dissolved by or swell in water and are commonly referred to as being hydropho~ic, e.g., acrylonitrile polymers . ~.
` ~327023 or copolymers. Unfortunately, the polymeric qualities that give crystallinity and physical strength to filters of these materials cause adsorptive interactions during separation and concentration operations. As a consequence, the filters become fouled by materials in the feed. As e~plained above, fouling is a major problem because the formation of a fouling layer upon the filter's surface interferes with its operation, thereby necessitating cleaning.
Polymeric compositions that tend not to e~hibit adsorptive interactions during separation also tend to lack the necessary physical strength for pressure-driven separations.
Thos~ compositions are pressure-sensitive and can readily be compressed and distorted by applied pressure. Agarose and polyacrylamide are examples of such compositions. Because throughout their struetures they are hydrophilic and thus interact with water and swell, they form hydrated gels.
Attempts have b~en made to overcome the disadvantages of hydro~hobic-type polymeric compositions by chemically modifying the surface of porous articles formed from those compositions. Lin~er UOS. Patent Nos. 4,5~4,103 and 4,477,634 concern me~hods of increasing the pressure stability of a polyacrylonitrile-containing membrane by reacting it with hydro~ylamine followed by additional steps, including reaction with a polyfunctional oligomer and a compound containing at least one ionic group. A disadvantage o~ this method, however, is that the resulting modified membranes contain charged 'g5~"
~ . _ .
- 1327~3 groups, thereby making them unsuitable for some applications.
Additionally, the methods sufer from defects such as the n~ed for expensive reagents and poor control over the e~tent of modification.
Sano U.S. Patent No. 4,265,959 concerns a method for the preparation of semipermeable membranes, which comprises sulfonating porous membranes of acrylonitrile polymers. In that method, a porous membrane is e~posed to a gaseous sulfonating agent, e.g., sulfuric anhydride, under pressur~.
The resulting modified membrane is claimed to possess superivr chemical, mechani~al, and thermal properties due to crosslinking of its surface mole~ules and its increased hydrophilic character. However, the Sano method suffers from similar defects as described above ~i.e., the need for expensive reagents and poor control over the extent of modification). In fact, the patent notes that if the whola membrane i5 sulfonated it becomes brittle.
Sano U.S. Patent No. 4,147,745 concerns a surface-modifying method that comprises e~posing a membrane of acrylonitrile-~ype polymer~ to a plasma. The resulting membrane is claimed to have a surface whose polymer molecules are cross-linked, thereby increasing its ph~sical strength.
Nakanishi U.S. Patent No. 4,501,785 concerns a method of hydrophilizing a porous membrane made of a polyolefin'(e.g., polyethylene) by coating the suraces that define the pores with polyethylene glycol. These Sano and Nakanishi methods 7 ~ ~ ~
also involve expensive procedures. Furthermore, the Nakanishi method is limited to membranes whose pores can accommodate the polyethylene glycol molecule.
There is a continuing need for rotary filtration devices that are more effective and efficient ~for example, have a reduced tendency to become clogged). There is also a need for rota~y filtration devices having stxong and durable filters that inherently have a reduced tendency to become blinded or to clog.
SUMMARY OF THE INVENTION
Applicant~ have already disclosed a material having superior properties suitable for use as filter~ (among other things) in U.S. Patent No. 4,906,379. (See also Dean, Jr., and Nerem (editors), Bioproaess Enqineexina Collo~ium (American Society of Mechanical Engineers, New York), pages 93-96: Hildebrandt and Saxton, "The Use of Taylor Vortices in Protein Processing To Enhance Me~brans Filtration Per~ormance" (1987).) ~pplicants have discovexed that the use of such filter~ in a rotary filtration device is of particular valuer maklng the device more effect~ve and efficiant.
In one a~pect, the present invention provide~ a rotary filtration device comprising:
(a) an outer member having an inner surface~
~32~023 (b) an inner member having an outer surface and mounted at least partially within the outer member to define a fluid gap between the inner surface of the outer mem~er and the outer surface of the inner member;
(c) means for rotating the outer member or the inner member or both; and (d~ filt~r means for filtering fluid in the ~luid gap, the filter means beî~g located on the inner surface of the outer member or on the outer surface of the inner member or on both and comprising molecules of a suitable polymer that provides solely on the surface of the filter means suficient uncharged substituted amide groups to render the surface hydrophilic.
Preparation of those filters involves a ch~mical reaction between nitrile groups o a hydrophobic-type polymer an~ an aldehyde ~o produce hydrophilic amide groups only on the surface of the filter. The fundamental chemistry of this reaction is well-known (see, e.g., Magat, T Am r~ c., volume 73, pagss lQ28 1037 ~lgSl~; Mowry U.S. Patent No.
2,534,204). Mowry British Patent No. 677,516 describes a method utilizing this chemical reaction for the synth~sis of nylon-type polymers. However, the Mowry method produces polymers having ~he resultin~ amide groups 3S part of the , ~327~23 polymar backbone and, therefore, articles formed from these polymers have the amide groups throughout their structures.
In contrast, the process of U.S. Patent No. 4,906,379, reacts the nitrile groups pendent to the polymer backhone in pre~ormed matrices. The reaction rate may be controlled so that only the surface of the filter contains amide groups, thereby providing fouling resistance to the surface while maintaining the physical strength of the fil~er.
In another e~bodiment the present invention provides a rotary filtration devic~ comprising:
(a) an outer member having an inner sur~ace;
(b) an inner member having an outer surfac~ and mounted at least partially within the outer member to define a fluid gap between the inner surface of the outer member and th~ outer surface of the inner member;
(c) means for rotating the outer member or the inner member or both; and (d) filter m2ans for filtering fluid in the fluid gap, the ~ilter mean~ being located on the inner sur~ace of the out~r me~ber or on the outer surface o~ the inner mem~er or on both and ~omprising molecules of a suitable poly~er that provid~s solely on the ~urface of the filter sufficient uncharged hydrophilic polar groups ~o render the surface hydrophilic, the polar groups having been obtained by derivatization of reactive pendent groups o~ the polymer.
_g_ In another embodiment the polymer is a nitrile-containing polymer and the substituted amide groups are derived from the nitrile groups. The polymer may be of acrylonitrile or methacrylonitrile and the substituted amide groups may be N-methylolamide groups. Ligands (for example, bio-selective affinity groups) may be attached either directly or through intermediate linking groups to the filter. The filter polymer may be crosslinked~
As used herein "filter means" includes one or more filters. The word "filterH includes any filter, m~mbrane, sieve, separation article, rod, ~iber bundles, sheet, and the like that can be utilized for "filtering" in a rotary filtration device. A "filter" may move ~e.g., rotate) or be stationary in the device. One, two, or more filters may be used. For e~ample, the rotary filtration device may have three concentric cylindrical m~mbers, with filters mounted on each, -and cne~ two, or three of ~he members may rotate. "Filtering"
and "fi~.ration~ each include the processes of filtration, ultrafiltration, microfiltration, reverse osmosis, dialysis, pervaporation, water-splitting, sieving, affinity chrom~tography, affinity purification, affinity separation, afinity adsorption, and ~he like. The design of the rotary filtration apparatus of this invention is not critlcal; the device need only have at least two members, at least one of whi~h rotates, means for effecting the rotation, and at least -~ 1327023 one filter on one of the members and having solely on its surface sufficient uncharged groups to render the surface sufficiently hydrophilic.
The devices of this invention have significant advantages over previous filtration devices. The combination of rotation and the hydrophilic membrane yields a device that is significantlY more effective and efficient in part because of the reduced tendency of the device to become blinded or clogged. Furthermore, it is believed that with the combination, the rejection of, for e~ample, proteins in a fluid being filtered can be adjusted to an extent not known before by, for example, controlling the speed of rotation. It is believed that other advantageous and une~pected phenomena flow from the combination.
BRIEF DESCRI~IQN OF THE DRAWI~GS
To facilitate further description of the rotary filtration device of this invention, the following drawings are provide~ in which:
Figure 1 is a schematic showing Taylor vortices in ~luid wi~hin a f luid gap between ~wo concentric cylindrical members of a rotary fil~ration device shown partially in section;
Figure 2 i5 an enlarged Yiew of a portion of F;gure l;
Figure 3 is a side elevational view of a ro~ary filtration device of this invention shown partially in section;
Figure 4 is an enlarged view showing drops of water on .
~ ~L3~7~
hydrophobic and hydrophilic s~rfaces and the angle theta between the solid surface and the liquid surface in each case;
and Figure 5 is an elevational sectional view of a preferred rotary filtration device of this invention.
These drawings are for illustrative purposes only and should not be construed to limit th~ scope of the invention, ~TAILED DESCRIP~IQ~ QE_T~E I~ENTIO~
The design of the rotary filtration device of this invention is not ~ritical and any design may be used so long as the device has at least two members (at least one of which rotates) to define a filtration gap~ means for effecting the rotation, and at least one filter facing the filtration gap and having solely on its surface sufficient uncharged groups to render the surface hydrophilic. The uncharged groups on the filter are uncharged hydrophilic polar groups, prefera~ly obtained by derivatization of reactive pendent groups o the polymer ~f the filter. Preferably the polar groups are substituted amide groups and the reactive pendent groups are nitrile groups If the filter is a ~heet, desirably at least one major planar surface of the filter has suficien~ uncharged groups and that planar surface faces the fluid in the gap.
Desirably Taylor vortice.~ are employed in tha fluid in the fluid gap to help reduce blinding of the filter 5urface and maintain filtration efficiency. The ins~abilities in fluid flow between concentric cylinders where only the inner cylinder :
~3270~3 is in motion were first investigated by Lord Rayleigh. Taylor found that when a certain Taylor's number was e~ceeded, a~ially circumferential vortices appear, which rotate in alternately opposite directions.
Figure l shows this phenomenon in simplified form.
Outer stationarY cylinder 10 is separated from inner rotating cylinder 12 of radius Ri by a gap of width d. The gap is filled with fluid 140 Under the proper conditions, set forth below, vortices rotating clockwise (16, 18, 20, 22~ and counter-clockwise (17, l9, 213 exist.
Taylor determined that the minimum condition for the establishment of such vortices, defined as the Taylor number (Ta)~ was ~ i d ~ d a ~ \ ~i > 41.3 ~here ~ is the kinematic viscosity of the fluid and ~ i is the peripheral velocity o inner cylinder 12. Taylor and others d~termined that ~he vortices would persist in some cases at Ta ~ 400 and in other cases up to Ta ~ 1700, but that turbulence would ensue i~ the Reynolds number (Ra) ros~ above about 1000. Ra ~ ~ , where ~ is asial velocity.
In ~igure 2, poin~s A and B denote positions on th~
respective inner and outer walls opposite the center of a vorte~, and points C and D denote positions between ~-~air of vortices. The shear stresses due to tangential velocity, vz, at one point A are in one direction and at the ne~t point A are ~,...._ . 1327~23 in the opposite direction. In a rotary filtration device, inner wall 12 or outer wall 10 or both may be a filter. When there is a net a~ial velocity due to the feeding of parent fluid (arrow 23) and removal of permeate and concentrate in a filtration device, the individual vortices assume what appears to be a helical shape (rather than planar circular) and mov~
from the inlet to the outl~t. Whether the vortices are helical or plana~ circular, the surface of the filter i~ continuously scoured by the solution itself, and particulates, gels, and colloids that would otherwise collect thereon are maintained in the solution.
One embodiment of the present invention is shown in Figure 3. Apparatus 30 is supported on rack 32 to which is also attached drive motor 34. The stationary portions of apparatus 30 comprise an outlet (lower3 housing 36 with outlet 33 centered in the bottom thereof, inlet (upper) housin~ 40, including gas line fitting 42, central opening 44 to accommoaate drive shaft 46, and gasket ~eal) 48. Housings 36 and 40 hold between them outer (stationary) cylinder 50, which may be made of any suitable material, e.g., p~astic. There m~y be several interchangeable cylinders 50, all having the same outside diameter bu~ each having a different inside diameter, whereby gap width d may also be varied. Cylinder 50 ma~ be provided with inlet 52 and outlet 54 (shown in phantom) so that filtrations involving feed recirculation can be performed.
~3270~3 The rotating portions of apparatus 30 comprises drive shaft 46, upper housing 56, lower housing 58, and porous (rotating) inner cylinder 60 supported between housings 56 and 58. Cylinder 60 includ~s vertical slot 61 for accommodating the ends of filter membrane 74 wrapped therearound. Slot 61 can be opened slightly for insertion of filter ends 76 but normally will be sealed tightly. Housings 56 and 58~are sized to make a tight friction seal a~ainst the filter to pre~ent any leakage. Upper housing 56 has drive shaft 4fi a~ially fitted into its top for rotation therewith. Lower housing 58 includes axial opening 62, which is the permeate outlet, and bushing 64 formed of a material selected for minimuim resistanc~ (e.g., Teflon plastic). ~asket (seal) 65 i5 provided between (rotatin~) lower housing 58 and (stationary) housing 36.
O-rings 66 and 68 are provided between outer cylinder 50 and housings 36 and 40, respectively, to prevent fluid leakage.
The outside diameter of upper housing 56 is less than the insi~e diameter of outer cylinder 50, ther~by providing a fluid communication path 78 between chamber 70 at the top of th~ apparatus and 1uid gap 72 between cylinders 50 and 60 for gas fed from gas line 42. Even if the fluid sample does not fill space 72, a larqe mem~rane area relative to the ~luid in fluid gap 72 is presented and gas pressure from line 42 can pressurize the sample and aid iltration.
The design of the rotary filtration unit used in this invention is not critical. Other possible designs are shown and described in Membre~'s PCT Application Publication No. (~f~
In contrast, the process of U.S. Patent No. 4,906,379, reacts the nitrile groups pendent to the polymer backhone in pre~ormed matrices. The reaction rate may be controlled so that only the surface of the filter contains amide groups, thereby providing fouling resistance to the surface while maintaining the physical strength of the fil~er.
In another e~bodiment the present invention provides a rotary filtration devic~ comprising:
(a) an outer member having an inner sur~ace;
(b) an inner member having an outer surfac~ and mounted at least partially within the outer member to define a fluid gap between the inner surface of the outer member and th~ outer surface of the inner member;
(c) means for rotating the outer member or the inner member or both; and (d) filter m2ans for filtering fluid in the fluid gap, the ~ilter mean~ being located on the inner sur~ace of the out~r me~ber or on the outer surface o~ the inner mem~er or on both and ~omprising molecules of a suitable poly~er that provid~s solely on the ~urface of the filter sufficient uncharged hydrophilic polar groups ~o render the surface hydrophilic, the polar groups having been obtained by derivatization of reactive pendent groups o~ the polymer.
_g_ In another embodiment the polymer is a nitrile-containing polymer and the substituted amide groups are derived from the nitrile groups. The polymer may be of acrylonitrile or methacrylonitrile and the substituted amide groups may be N-methylolamide groups. Ligands (for example, bio-selective affinity groups) may be attached either directly or through intermediate linking groups to the filter. The filter polymer may be crosslinked~
As used herein "filter means" includes one or more filters. The word "filterH includes any filter, m~mbrane, sieve, separation article, rod, ~iber bundles, sheet, and the like that can be utilized for "filtering" in a rotary filtration device. A "filter" may move ~e.g., rotate) or be stationary in the device. One, two, or more filters may be used. For e~ample, the rotary filtration device may have three concentric cylindrical m~mbers, with filters mounted on each, -and cne~ two, or three of ~he members may rotate. "Filtering"
and "fi~.ration~ each include the processes of filtration, ultrafiltration, microfiltration, reverse osmosis, dialysis, pervaporation, water-splitting, sieving, affinity chrom~tography, affinity purification, affinity separation, afinity adsorption, and ~he like. The design of the rotary filtration apparatus of this invention is not critlcal; the device need only have at least two members, at least one of whi~h rotates, means for effecting the rotation, and at least -~ 1327023 one filter on one of the members and having solely on its surface sufficient uncharged groups to render the surface sufficiently hydrophilic.
The devices of this invention have significant advantages over previous filtration devices. The combination of rotation and the hydrophilic membrane yields a device that is significantlY more effective and efficient in part because of the reduced tendency of the device to become blinded or clogged. Furthermore, it is believed that with the combination, the rejection of, for e~ample, proteins in a fluid being filtered can be adjusted to an extent not known before by, for example, controlling the speed of rotation. It is believed that other advantageous and une~pected phenomena flow from the combination.
BRIEF DESCRI~IQN OF THE DRAWI~GS
To facilitate further description of the rotary filtration device of this invention, the following drawings are provide~ in which:
Figure 1 is a schematic showing Taylor vortices in ~luid wi~hin a f luid gap between ~wo concentric cylindrical members of a rotary fil~ration device shown partially in section;
Figure 2 i5 an enlarged Yiew of a portion of F;gure l;
Figure 3 is a side elevational view of a ro~ary filtration device of this invention shown partially in section;
Figure 4 is an enlarged view showing drops of water on .
~ ~L3~7~
hydrophobic and hydrophilic s~rfaces and the angle theta between the solid surface and the liquid surface in each case;
and Figure 5 is an elevational sectional view of a preferred rotary filtration device of this invention.
These drawings are for illustrative purposes only and should not be construed to limit th~ scope of the invention, ~TAILED DESCRIP~IQ~ QE_T~E I~ENTIO~
The design of the rotary filtration device of this invention is not ~ritical and any design may be used so long as the device has at least two members (at least one of which rotates) to define a filtration gap~ means for effecting the rotation, and at least one filter facing the filtration gap and having solely on its surface sufficient uncharged groups to render the surface hydrophilic. The uncharged groups on the filter are uncharged hydrophilic polar groups, prefera~ly obtained by derivatization of reactive pendent groups o the polymer ~f the filter. Preferably the polar groups are substituted amide groups and the reactive pendent groups are nitrile groups If the filter is a ~heet, desirably at least one major planar surface of the filter has suficien~ uncharged groups and that planar surface faces the fluid in the gap.
Desirably Taylor vortice.~ are employed in tha fluid in the fluid gap to help reduce blinding of the filter 5urface and maintain filtration efficiency. The ins~abilities in fluid flow between concentric cylinders where only the inner cylinder :
~3270~3 is in motion were first investigated by Lord Rayleigh. Taylor found that when a certain Taylor's number was e~ceeded, a~ially circumferential vortices appear, which rotate in alternately opposite directions.
Figure l shows this phenomenon in simplified form.
Outer stationarY cylinder 10 is separated from inner rotating cylinder 12 of radius Ri by a gap of width d. The gap is filled with fluid 140 Under the proper conditions, set forth below, vortices rotating clockwise (16, 18, 20, 22~ and counter-clockwise (17, l9, 213 exist.
Taylor determined that the minimum condition for the establishment of such vortices, defined as the Taylor number (Ta)~ was ~ i d ~ d a ~ \ ~i > 41.3 ~here ~ is the kinematic viscosity of the fluid and ~ i is the peripheral velocity o inner cylinder 12. Taylor and others d~termined that ~he vortices would persist in some cases at Ta ~ 400 and in other cases up to Ta ~ 1700, but that turbulence would ensue i~ the Reynolds number (Ra) ros~ above about 1000. Ra ~ ~ , where ~ is asial velocity.
In ~igure 2, poin~s A and B denote positions on th~
respective inner and outer walls opposite the center of a vorte~, and points C and D denote positions between ~-~air of vortices. The shear stresses due to tangential velocity, vz, at one point A are in one direction and at the ne~t point A are ~,...._ . 1327~23 in the opposite direction. In a rotary filtration device, inner wall 12 or outer wall 10 or both may be a filter. When there is a net a~ial velocity due to the feeding of parent fluid (arrow 23) and removal of permeate and concentrate in a filtration device, the individual vortices assume what appears to be a helical shape (rather than planar circular) and mov~
from the inlet to the outl~t. Whether the vortices are helical or plana~ circular, the surface of the filter i~ continuously scoured by the solution itself, and particulates, gels, and colloids that would otherwise collect thereon are maintained in the solution.
One embodiment of the present invention is shown in Figure 3. Apparatus 30 is supported on rack 32 to which is also attached drive motor 34. The stationary portions of apparatus 30 comprise an outlet (lower3 housing 36 with outlet 33 centered in the bottom thereof, inlet (upper) housin~ 40, including gas line fitting 42, central opening 44 to accommoaate drive shaft 46, and gasket ~eal) 48. Housings 36 and 40 hold between them outer (stationary) cylinder 50, which may be made of any suitable material, e.g., p~astic. There m~y be several interchangeable cylinders 50, all having the same outside diameter bu~ each having a different inside diameter, whereby gap width d may also be varied. Cylinder 50 ma~ be provided with inlet 52 and outlet 54 (shown in phantom) so that filtrations involving feed recirculation can be performed.
~3270~3 The rotating portions of apparatus 30 comprises drive shaft 46, upper housing 56, lower housing 58, and porous (rotating) inner cylinder 60 supported between housings 56 and 58. Cylinder 60 includ~s vertical slot 61 for accommodating the ends of filter membrane 74 wrapped therearound. Slot 61 can be opened slightly for insertion of filter ends 76 but normally will be sealed tightly. Housings 56 and 58~are sized to make a tight friction seal a~ainst the filter to pre~ent any leakage. Upper housing 56 has drive shaft 4fi a~ially fitted into its top for rotation therewith. Lower housing 58 includes axial opening 62, which is the permeate outlet, and bushing 64 formed of a material selected for minimuim resistanc~ (e.g., Teflon plastic). ~asket (seal) 65 i5 provided between (rotatin~) lower housing 58 and (stationary) housing 36.
O-rings 66 and 68 are provided between outer cylinder 50 and housings 36 and 40, respectively, to prevent fluid leakage.
The outside diameter of upper housing 56 is less than the insi~e diameter of outer cylinder 50, ther~by providing a fluid communication path 78 between chamber 70 at the top of th~ apparatus and 1uid gap 72 between cylinders 50 and 60 for gas fed from gas line 42. Even if the fluid sample does not fill space 72, a larqe mem~rane area relative to the ~luid in fluid gap 72 is presented and gas pressure from line 42 can pressurize the sample and aid iltration.
The design of the rotary filtration unit used in this invention is not critical. Other possible designs are shown and described in Membre~'s PCT Application Publication No. (~f~
3, published July 4, 1985. Still other designs are ~S~9 known to those skilled in the art. A preferred design is shown in Figure 5 and is described below.
As will be understood from reading this application, the key features of the device are at least two members, one mounted at least partially within the other to define a ~luid gap therebetween, means for rotating either or both mem~ers, and filter means on a~ least one of the members and facing the fluid gap, the filter having sufficient uncharged polar groups (e.g., amide groups) to render the surface hydrophilic.
Two, three, or more members may be in the device and one, some, or all of them may have filters mounted thereon. If two or more filters are used, they may be of the same or different material. One, some, or all of the members may .ro~ate. The rotation may be accompanied by an up-and-down motion. Members that do not rota~e may move up and down (i.e., translate a~ially). Th~ one or more members that rotate need not be.the one or more members that carry the one or more filters. Rotation may be at a constant or varying speed and in a single direction or in alternating directions. I~ two or more.members rotate, they may rotate in the same or different directions and at the same or different speeds.
The filters may be mounted on their respective members usin~ the scheme of Figure 3, or with adhesive, or by clamps or straps. Any method of mounting may be used providsd it does .~ .
~327023 not unduly hinder operation of the device. Preferably the method of mounting does not significantly reduce the active area of the filter.
Fluid may be introduced into the 1uid ~ap continuously or in batches. Permeate may be removed continuously or in batches. Retentate may be removed continuously or in batches.
A series of channels may be present on the surface of a member carrying a filters. Permeate that passes through the filter will be collected in the channels and flow ~o a common collection point (e.g., the interior of a member) ~or collection and/or withdrawal.
Because three or more members may be used, there may be more than one fluid gap. Taylor vortices may be used in none, ons, or more of the fluid gaps.
The filter used herein may comprise molecules of a suitable polymer that provides solely on its surface, sufficie~t uncharged substituted amide groups to render the surface hydrophilic. Suitable polymers may have as pendent yroups substituted amide ~roups or groups that can be derivatized to substituted amide groups. The polymer may be a homopolymer or a copolymer. In copolymers only one moncmer need contain as pendent groups the substituted amides or groups which can be derivatized to substi~uted amide groups.' The other monomers may, but need not, contain these pendent groups.
1327~23 If the pendent groups before derivatization are nitrile groups, suitable monomers that may be present with the nitrile-containing monomer in a copolymer are monomers capable of polymerizing with the nitrile-containing monomer. E~amples of such monomers include styrene-type monomers, such as styrene, methylstyrene, ethylstyrene, nitrostyrene, chlorostyrene, bromostyrene, chloromethylstyrene; acrylis or . methacrylic acid ester-type monomers; conjugated dienes;
; halogenated olefins; vinylether monomers and like monomers.
The polymerization may be performed using standard techniques in the art, such as susp~nsion polymerization or emulsion polymerization in an aqueous system. The polymer may also be blended with other polymers that may or may not contain substituted amide groups or groups which san be derivatized to substituted.amide groups. The polymer can also be grafted to another polymer. The matrix may comprise molecules of essentially any polymer containing the appropriate pendent groups. .For e~ample, suitable polymers include polymers .:
containing acrylonitril~-typ~ monomers, cyanostyrene monomers, pentenenitrile monomers, butenenitrile monomçrs, and cyanoethylester acrylir acid monomers. The preferred polymers contain acrylonitrile-type monomers, such as acrylonitrile, ~ methacrylonitrile, chloroacrylonitrile, ~luoroacrylonitrile, i; and cinnamnitrile, particularly acrylonitrile or m~thacrylonit ri le .
,.
,`~ `,. ~5 ~ -18-.
.
`:
.
1~27023 Suitable substituted amide groups are groups which are hydrophilic, that is, show an af~inity to water. These amide groups may be obtained by derivatization of the pendent groups of the polymer or they may be "prefabricated~ and then deposited or gra~ted directly onto the polymer at the surface of the filter matrix. It is likewise possible to deposit nitrile or other pendent groups on the surface of the matri~
and then derivatize all or a portion of the groups to the substituted amide groups to render the sur~ace hydrophilic.
Likewise, monomers containing the appropriate pendent groups or amide groups may be deposited or grafted onto the surface o~
the matrix.
The acyl portion of the amide groups may comprise an alkyl group or an aryl group, depending on the structure of th~
groups prior to derivatization. The amino portion of the amide groups may be mono- or di-substituted; some o~ the amide groups may be unsubstituted. In the preferred filter, the amide groups a~e predominately mono- and di-sub~tituted groups. The substituted portion may comprise an alkyl group or an aryl group, of which alkyl groups are preferred, pati~ularly methylol ~roups. In the most preerred embodiment~, the substituted amide groups are N-methylolamides.
The sur~ace of a polymer matrix has voids ormed by imperfections in the outer part of the matri~ and micropores ~ormed by the molecular struc~ure of the matrix. The term ~L
~327023 "surfaceN i5 intended to include the polymers or portions thereof that define these voids and micropores.
Small amounts of substituted amide groups may be present in areas of the matrix other than the surface.
However, only the surface of the ilter will have 5ufficient substituted amide groups to render the surface hydrophilic.
The other areas of the matri~ will not contain sufficient amide groups to render those areas hydrophilic.
The substituted amide groups are uncharged at neutral or near-neutral pH's. It is po~sible to induce a charge on the substituted amide groups by changing their environment.
The polymer matrix may also comprise a plurality of ligands attached to a portion of the hydrophilic substi~uted amide groups or derivatives thereo~E. Suitable ligands include any ligand capable of attaching to the substituted amide groups of the matrix or to a derivative o~ the substituted amide groups. Preferred ligands comprise bio-selective af~inity groups ~hat selectively bind to biologically active substances and are typically used for the purification of biologically ac~ive sub~tances. The inven~ory of useful affinity ligands is large and rapidly increasing. Most often, such ligands are derived from nature (i.e., biological-originating substances~, while others are wholly or partially synthetic ~i.e., bio-mimic substances). Many ligands can be referred to by traditional biochemical class names, for example, nucleotides, polynucleotidas, nucleic acids ~including DNA and RNA), :,~
.
1~2~023 carboh~drates, saccharides, polysaccharides, lipids, amino acids, peptides, and proteins. Others can be described as combinations of these substances, for example, lipopolysaccharides, lipo-proteins, and nusleo-proteins.
Sub-class terms are often useful (e.g., enzymes and antibodies as sub-classes of proteins). Many other useful affinity ligands are better described by bio-function, such as steroids, hormones, vitamins, enzyme or metabolic co-factors, enzyme inhibitors, enzyme reactors, drugs, drug re eptors, antibiotics, neurotransmittors, and antagonists. Still other ligands may be referred to as chromophores, dyes, ion-exchangers, amphiphiles, and the like.
The ligand a-ttached to the filter may but need not be attached through a coupling molecule disposed between the substituted amide group or derivative thereof and the ligand.
Numerous coupling molecules are well known and may be utilized in the present invention or attaching afinity ligands.
Reagents for thi~ purpose include cyanog~n hali~es, triazinyl halides (e.g., trihalo-s-triazine and substituted halo-s-triazines), sulfonyl halides (e.g., alkyl and~or aryl sulfonyl-halides, including bis-sulfonyl halides), acyl halides ~e.g., bis-acyl-halides), vinylsulfones, epogides (e.g., bis-oxiranes~, and the like.
Displacement reagents may also be used for ~upling ligands. The reagents are reacted with ~he matri~ surface groups and subsequently undergo displacement reac~ion with the ~ . _ .
iL327023 affinity ligand. Such reagents include sulfonyl halides such as aryl-sulfonyl halides (e.g., tosyl-halides), alkyl sulfonyl halides (e.g., methane sulfonyl halide), halo-alkyl-sulfonyl halides (e.g., trifluoroethane sulfonyl halides~, halopyrimidines (e.g., 2-fluoro-1-methylpyridinium toluene-4-sulfonate), and the like. Other preferred ligands and methods for attaching the ligands to the matri~ of this invention will become apparent to those skilled in the art of affinity sorption and enzyme immobilization from the present application.
In some of the filters used herein, a portion of the molecules of the polymer matri~ are crosslinked to other such molecules. Crosslinking imparts properties to the filter that in most applications are desirable, e.~., increased structural ri~idity and increased resistance to organic solvents.
Preferably the crosslsnking is between substituted amide groups. In filters where the substituted amide groups are ~-methylolamide groups, th~ crosslinking is thought to be by means of methylene-bis-amide. The most preferred fllter is a porous article comprising a matrix wherein the polymer comprises acrylonitrile or methacrylonitrile, the hydrophilic substituted amide groups are N-methylolamide g~oups, and the molecules of the polymer are crosslinked to other suc~ polymer molecules in the matrix.
Th~ ~ilter may be formed from a matrix comprising molecules of a suitable polymer having reactive pendent group~
-22~
,~,..,.,~
- ~327~
that prov;de essentially only on the surface of the filter sufficient uncharged hydrophilic polar groups to render the surface hydrophilic. The polar groups are obtained by derivatization of the pendent groups. Preferably, the reactive pendent groups are nitrile groups and the polar groups are substituted amide groups.
Hydrophilicity o a solid surface relates to the surface's affinity toward aqueous solutions. Hydrophilicity is an indication of a il~er's biocompatability, i.e., its ability to be used effectively with proteins and similar substances without encountering significant fouling problemsO Although hydrophilicity is not quan~itatively defined in tha industry, it can be qualitatively measured by the degree to which water spreads over the solid surface or by the angle theta of contact between the liquid surface and the ~olid surface when a drop of water rests on the solid surface (see Figure 4). The more hydrophilic a surface is, the lower angle theta will be.
The hydrophilicity o the filter used herein can be preselected during its manufac~ure by control of reac~ion rates, reagent concentratiQn, catalys~ concentration, etc. Th~
hydrophilicity can range from nearly that o the untreated nitrile-containing polymer to "hyperhydrophilic" Ot "hyperphilic~ (i.e., contact angles theta below about lS
degrees). Preferably, the hydrophilic sur~ace of the ilter has a contact angle less than about 30 de~rees when measured in a pH between 2 and 12 and more preerably less ~han about 15 .
. .
~ 327~2~
degrees. The most preferred filters used herein are hyperhydrophilic. Filters that are relatively more hydrophilic than the original untreated matri~es may be used in the devices of this invention, regardless of whether the filters would be considered hydrophilic or hydrophobic by one skilled in the art.
Suitable polymers for the filter include polymers that contain pendent groups which can be dsrivatized to substituted amide groups, e.g., nitrile-containing polymers. For making some filters used herein, derivatizing comprises contacting the molecules of the nitrile-containing polymer with an aldehyde or an aldehyde-generating compound. Generally, any aldehyde may be used; however,~ the size o the aldehyde molecule may limit the usefulness of the aldehyde in embodiments where the ~ilter is porous. In such cases, the size of the pores will determine the suitahility of the aldehyde by imposing an upper limit on the aldehyde's molecular size. The most pref~rred aldehyde i5 formaldehyde and the most preferred aldehyde-generat;ng compound~is a formaldehyde-generating compound, particularly dimetho~ymethane, trio~ane, and paraformaldeh~de.
The contact time for contactiny the nitrile-containing polymer with the aldehyde or ~he aldebyde-generating compound should be long enough to p~rmit ~he formation of sufficient substituted amide ~roups to make the filter's surface hydrophilic but not long enough to hydrophilize the ~ntire filter structure. This operation may be carried out i~ the presence of a catalyst, which may comprise one or more acids, ... .
i~27~23 preferably a combination of a strong acid and a weak acid.
Many strong acids are known to those skilled in the art and can be used. Common mineral acids (e.g., hydrochloric, phosphoric, and sulfuric) ar~ preferred. Other preferred strong acids include alkylsulfuric, alkylsulfonic, halosulfuric, and the like, for example, trifluoromethane sulfonic acid and fluorosulfuric acid. Preferred weak aci~s include acetic acid. The acid may be generated by an acid-ge~erating substance, e.g., boron trifluoride and aluminum chloride.
Other suitable acids will be apparent to those skilled in the art.
The reaction rate may be varied by controlling catalyst strength. If the catalyst is an acid, catalys~
strength means both the concentration and the inherent strength of the acid. The degree of hydrophilicity of the filter ~urface may be controlled by adjusting the relative concentrations of the strong acid, the weak acid, and of the aldehyde;or aldehyde-90nerating compound.
Contact with the aldehyde or aldehyde-generating compound is preferably carried out by soaking ~he ma~rix in a reagen~ ba~h containing the aldehyde or the aldehyde-genera~ing compound. The time of soaking, ~he temperature of the reagent bath, and the concentration of the reagents will depend on the type o~ aldehyde or aldehyde-generating compound used, the type o~ nitrile-containing polymer present, the quantity and strength of the catalyst (if present~, and the filter properties desired.
To prevent polymerization of the aldehyde or re-polymerization of the polymer, the water content of the reaction bath should be kept low. The precise level required will vary with the particular acid used, but the level in all cases should be such as to avoid competing reactions. In the embodiments where the nitrile-containing polymer comprises an acrylonitrile-type monomer, preferably ~he hydrophili~
substituted amide groups are N m~thylolamide groups, the contacting is effected with a formaldehyde-generating compound in the presence of an acid, the soaking bath reaction lasts between 1 m;nute and about 48 hours, and the temperature of the r~agent bath is from about 1C to about 90C. For preferred filters, in which portion of the molecules of the pol~ner on the surface of the matri~ are crosslinked to other such molecules, the duration of ~h~ soaking bath reaction is from several ~inutes to about 24 hour~ and the temperature of the reagent bath is from about 10C to about 60C.
Manufacture of filters useful herein and use of such filters in a rotary filtration device are described in the examples which follow. These examples are intended to aid in understanding the invention but are not intended to, and should not be construed to, limit in any way the invention ~ set forth in the claims which follow.
-2fi-13~70~3 EgAMPL~_l A porous thin flat sheet membrane composed of polyacrylonitrile polymers of greater than 90% acrylonitrile was treated for 4 hours in a bath containing 34.2 parts of concentrated sulfuric acid, 13.1 ~arts of concentrated acetic acid, 37.8 parts of formic acid, and 14.9 parts of trio~ane as the formaldehy~e source. The freshly composed reagent bath was allowed to equilibrate at 30C for l hour be~ore use.
Following the bath treatment, the membrane was soaked in a water bath at 2C for 30 minutes. The membrane was then soaked for 60 minutes at ambient temperatures in an aqueous bath consisting of 3.8 parts sodium borate, pH , 9.
Drops of water applied to the surface of the treated membrane readily spread. In similar drop tests with an untreated mèmbrane, the water beaded and did not spread. The treated membrane was mounted in a conventional stirred cell apparatus and tested ~or 1uid flu~, protein rejection, and, after e~osure to protein, for recovery of fluid flux. The test results show that in contrast with the untreated membrane, the treated membrane resisted fouling by protein and i~
recovered fluid ~lu~ aft~r a simple flushing operation (see Table 13. This membrane was suitable for use in a rotary filtration device.
~O~.t`
~ 327~23 TABhE_l ~uffer Flux~
(liters/hour-square meter) Prot~in Untreated Memb~a~8 Treated Mem~rane none 149 +/- 7 178 +/- 9 myoglobin 6S 134 ovalbumin 52 184 bovine serum albumin 53 179 bovine gamma-globulins 24 175 ~ 10 psi transmembrane pressure dif~erence EXAMPLE_2 A membrane was treated for 3 hours in a reagent bath at 30C. The article was composed of greater than 90~
acrylonitrile monomers. The reagent bath contained 15.0 parts of trioxane-~ 13.2 parts of acetic acid, 37.4 par~s of formic acid,. and ~4.4 parts of concentrated sulfuric acid. After treatment, the membrane was rinsed with water and soaked at ambient eemperature or 60 minutes in an aqueous bath consisting of 3.8 parts sodium borate, pH ~ 9.
After rin3ing with water and blotting dry, the membrane could be wetted hy wa~er, which readily spread upon the hydrophilic surfac~. Hydrophilicity of the membrane was also indicated by the solid-liquid contact angle theta made by application of a drop o~ an aqueous solution applied ~o the membrane surface according to the method of Whitesides et al.
m~i~, volume 1, pages 725-740 ~1985). The contact angle . . -2~-.
1327~23 measured 30 seconds after drop application was 4 degrees for the treated membrane and 46 degrees for the untreated membrane. For comparison, the contact angl~s were also measured for conventional commercially available membranes made of other materials. It became obvious from these results that the membrane is markedly more hydrophilic (~'hyperphilicn) than well-known so-called hydrophilic membranes. Comparative results are shown in Table 2.
Contact Angle Membra~e (dear~s)*
hyperphilic filter ~treated) . 4 untreated filter 46 conventional polyethersulfone 65 "hydrophilized" polyethersulfone 49 "hydrophilic" cellulosic 24 x contact angle measured at 30 seconds after drop application to surface The hydrophilicity of the treated membrane wa~ also examined by measurements of fluid flu~ in a conventional stirred cell apparatus before and af~er e~posure to protein.
It became eviden~ from ~he ~est results that the treated membrane resisted fouling by pro~ein and recovered fluid ~lux after a simple flushing op~ra~ion ~Table 3). The tre~ted membrane was suitable or us~e as ~ filter in a rotar~
filtration device.
-2~-13~7~23 TABLE_~
Buffer Flu~ After Sample Filtration*
SamPle (li~ers/hour-squ~re meter~.
buffer 596 bovine serum albumin 630 bovine gamma-globulins 589 * 10 p~i transmembrane pressure difference E~A~PLE ~
~ membrane composed of polyacrylonitrile-containing polymers was treated for 60 minutes at 23~ in a bath containing 25 parts dimethoxymethane and 75 parts sulfuric acid. The bath was equilibrated at 23C for 1 hour ~efore use. Following this bath, the membrane was soaked in a water bath at 2C for 30 minutes and then in an aqueous bath containing 3.8 parts of sodium borate, pH ~ 9, at ambient temperature for 60 minutes.
As in the preceding e~amples, drops o water applied to the s~rface of the treated membrane spread readily~
Similarly, when the membrane was examined in a stirred cell for recovery of 1uid flus after esposure to protein, it became evident that the ~reated membrane resisted fouling by protein and recovered fluid flux after a simple 1ushing opera~ion.
For e~ample, the ~reated membrane e~hibited an initial buffer flu~ of 44.7 liters per hour-square meter at 20 psi -~transmembrane pressure before exposur~ to protein. ~ter ultrafiltration of individual protein solueions o~ myoglobin, i32~23 chymotrypsin, ovalbumin, and bovine serum albumin, the initial buffer flu~ was recovered for each protein.
A membrane composed of polyacrylonitrile-containing polymers was treated for 1 hour at 23C in a reaction bat~
containing 21.9 parts dimetho~ymethane, 65.3 parts of concentrated sulfuric acid, and 12.8 parts of acetic acid. The treated membrane was then soaked in a cold water bath and a borate bath as described in Example 3.
Drops of wa~er spread readily when applied to the surface of the treated membrane. When the membrane was e~amined in a stirred cell for recovery of fluid flus after exposure to protein, it was observed that the treated membrane resisted fouling by protein and recovered fluid flu~ after a simple flushing operation. This membrane filter was suitable or use in a rotary filtration device.
In other studies, the treated membrane was found to resist d~sruption and dissolu~io~ by organic solv~nts that rapidly and completely dissolved untreated membranes. For e~ample, a~ter a tr~ated membrane and an untreated membrane had been soak~d in a solvent bath of gamma-~utyrolactone at ambient temperature for one h~ur, the untrea~ed membrane had dissolved while the treated membrane was still intact. A treated membrana e~pos~d for 4 days to ~amma-butyrolactone i~'a solvent bath at ambient temperature showed no significant di~ference ~, .
' from treated membrane that had not ~een e~posed to solvent (see Table 4).
TABL~ 4 Buffer Flu3 After Sample Filtration*
~liters/hour-square meter) Samole ~efore SoLvent Atç~_5Qlvent~
buffer ~1 ~4 myoglobin 44 46 ovalbumin 44 46 bovine serum albumin ~4 g6 bovine gamma-globulin 41 41 ~ 10 psi transmembrane pressure difference *~ solvent bath 100% gamma-butyrolactone at ambient temperature~
membrane solvent exposure time 4 days EXAMPLE_5 A membrane composed of polya~rylonitrile-containing polymers was treated for 6 hours at 23C in a formaldehyde reaction bath containing 5.8 parts of paraformaldehyde~ 44.2 parts of çoncentrated sulfuric acid, and 50 part~ of concentrated acetic a~id. The treated membrane was soak~d in a water bath at 2C for 30 minutes and then for 60 minutes at 23OC in an aqueous bath containing 3.8 parts of sodium borate, pH ~ 9. The treated article had hydrophilic character, as shown by the degree ~o which water spread. In studies similar to those described above, the treated m~mbrane recovered i~s initial buffer elu2 after ultrafiltration of protein solutions. The ~r~ated membran~ filter was suitable for use in a rotary filtration device.
~_ .
.
~327023 A membrane was treated as in E~ample 2 and then e~posed to an aqueous solu~ion consisting of approximately O.OlM sodium carbonate, 0.3M sodium chloride, and 2 milligrams per ml of "reactive dye." The reactive dye was Procion Red Reactive Dye MX-2~ (PolySciences~, which is a red colored, chromophore-substituted, triazinyl-halide that reacts like an acyl-halide with suitable nucleophiles, among which are N-methylolamides. The.r~action between the reactive dye and the treated membrane was conducted overnight ~16 hours~ at ambient temperatures. Th~ reacted membrane was washed -extensively with water and saline solution to remove unreacted dye.
The resulting membrane was found to be permanently derivatized to show a red color that could not be removed by ~urther washin~s. In this e~ample, the red chromophore is considered as a potential af~inity-sorptive ligand and the reactiv~triazinyl moie~y represen~s a well-es~ablished reagent for linking affinity ligands in general to suitable matri~
materials (e.g., Hodgins, L.T., and Levy, ~., "Affinity Adsorbent Preparation: Chemical Feat~lres o~ Agarose Derivatization with Trichloro-s-triazine," J~ChromatQaraPhY, volume 202, page 381 (1980)~.
~L~ '' A comm~rcially available polyacrylonitrile homopolymer .~
~; (presumably about 99~ ~crylonitrile) was dissolved and cast on ~L3~7~23 a standard polypropylene non-woven fabric using conventional casting techniques to make a porous membrane having a 100,000-molecular weight cut-off. That membrane was treated using the procedure and materials of Example 2 to produce a filter that was mounted in a rotary filtration device essentially the same as that shown in Figure 5. (The Figure 5 device is described in detail in Membrex U.S. Patent No.
As will be understood from reading this application, the key features of the device are at least two members, one mounted at least partially within the other to define a ~luid gap therebetween, means for rotating either or both mem~ers, and filter means on a~ least one of the members and facing the fluid gap, the filter having sufficient uncharged polar groups (e.g., amide groups) to render the surface hydrophilic.
Two, three, or more members may be in the device and one, some, or all of them may have filters mounted thereon. If two or more filters are used, they may be of the same or different material. One, some, or all of the members may .ro~ate. The rotation may be accompanied by an up-and-down motion. Members that do not rota~e may move up and down (i.e., translate a~ially). Th~ one or more members that rotate need not be.the one or more members that carry the one or more filters. Rotation may be at a constant or varying speed and in a single direction or in alternating directions. I~ two or more.members rotate, they may rotate in the same or different directions and at the same or different speeds.
The filters may be mounted on their respective members usin~ the scheme of Figure 3, or with adhesive, or by clamps or straps. Any method of mounting may be used providsd it does .~ .
~327023 not unduly hinder operation of the device. Preferably the method of mounting does not significantly reduce the active area of the filter.
Fluid may be introduced into the 1uid ~ap continuously or in batches. Permeate may be removed continuously or in batches. Retentate may be removed continuously or in batches.
A series of channels may be present on the surface of a member carrying a filters. Permeate that passes through the filter will be collected in the channels and flow ~o a common collection point (e.g., the interior of a member) ~or collection and/or withdrawal.
Because three or more members may be used, there may be more than one fluid gap. Taylor vortices may be used in none, ons, or more of the fluid gaps.
The filter used herein may comprise molecules of a suitable polymer that provides solely on its surface, sufficie~t uncharged substituted amide groups to render the surface hydrophilic. Suitable polymers may have as pendent yroups substituted amide ~roups or groups that can be derivatized to substituted amide groups. The polymer may be a homopolymer or a copolymer. In copolymers only one moncmer need contain as pendent groups the substituted amides or groups which can be derivatized to substi~uted amide groups.' The other monomers may, but need not, contain these pendent groups.
1327~23 If the pendent groups before derivatization are nitrile groups, suitable monomers that may be present with the nitrile-containing monomer in a copolymer are monomers capable of polymerizing with the nitrile-containing monomer. E~amples of such monomers include styrene-type monomers, such as styrene, methylstyrene, ethylstyrene, nitrostyrene, chlorostyrene, bromostyrene, chloromethylstyrene; acrylis or . methacrylic acid ester-type monomers; conjugated dienes;
; halogenated olefins; vinylether monomers and like monomers.
The polymerization may be performed using standard techniques in the art, such as susp~nsion polymerization or emulsion polymerization in an aqueous system. The polymer may also be blended with other polymers that may or may not contain substituted amide groups or groups which san be derivatized to substituted.amide groups. The polymer can also be grafted to another polymer. The matrix may comprise molecules of essentially any polymer containing the appropriate pendent groups. .For e~ample, suitable polymers include polymers .:
containing acrylonitril~-typ~ monomers, cyanostyrene monomers, pentenenitrile monomers, butenenitrile monomçrs, and cyanoethylester acrylir acid monomers. The preferred polymers contain acrylonitrile-type monomers, such as acrylonitrile, ~ methacrylonitrile, chloroacrylonitrile, ~luoroacrylonitrile, i; and cinnamnitrile, particularly acrylonitrile or m~thacrylonit ri le .
,.
,`~ `,. ~5 ~ -18-.
.
`:
.
1~27023 Suitable substituted amide groups are groups which are hydrophilic, that is, show an af~inity to water. These amide groups may be obtained by derivatization of the pendent groups of the polymer or they may be "prefabricated~ and then deposited or gra~ted directly onto the polymer at the surface of the filter matrix. It is likewise possible to deposit nitrile or other pendent groups on the surface of the matri~
and then derivatize all or a portion of the groups to the substituted amide groups to render the sur~ace hydrophilic.
Likewise, monomers containing the appropriate pendent groups or amide groups may be deposited or grafted onto the surface o~
the matrix.
The acyl portion of the amide groups may comprise an alkyl group or an aryl group, depending on the structure of th~
groups prior to derivatization. The amino portion of the amide groups may be mono- or di-substituted; some o~ the amide groups may be unsubstituted. In the preferred filter, the amide groups a~e predominately mono- and di-sub~tituted groups. The substituted portion may comprise an alkyl group or an aryl group, of which alkyl groups are preferred, pati~ularly methylol ~roups. In the most preerred embodiment~, the substituted amide groups are N-methylolamides.
The sur~ace of a polymer matrix has voids ormed by imperfections in the outer part of the matri~ and micropores ~ormed by the molecular struc~ure of the matrix. The term ~L
~327023 "surfaceN i5 intended to include the polymers or portions thereof that define these voids and micropores.
Small amounts of substituted amide groups may be present in areas of the matrix other than the surface.
However, only the surface of the ilter will have 5ufficient substituted amide groups to render the surface hydrophilic.
The other areas of the matri~ will not contain sufficient amide groups to render those areas hydrophilic.
The substituted amide groups are uncharged at neutral or near-neutral pH's. It is po~sible to induce a charge on the substituted amide groups by changing their environment.
The polymer matrix may also comprise a plurality of ligands attached to a portion of the hydrophilic substi~uted amide groups or derivatives thereo~E. Suitable ligands include any ligand capable of attaching to the substituted amide groups of the matrix or to a derivative o~ the substituted amide groups. Preferred ligands comprise bio-selective af~inity groups ~hat selectively bind to biologically active substances and are typically used for the purification of biologically ac~ive sub~tances. The inven~ory of useful affinity ligands is large and rapidly increasing. Most often, such ligands are derived from nature (i.e., biological-originating substances~, while others are wholly or partially synthetic ~i.e., bio-mimic substances). Many ligands can be referred to by traditional biochemical class names, for example, nucleotides, polynucleotidas, nucleic acids ~including DNA and RNA), :,~
.
1~2~023 carboh~drates, saccharides, polysaccharides, lipids, amino acids, peptides, and proteins. Others can be described as combinations of these substances, for example, lipopolysaccharides, lipo-proteins, and nusleo-proteins.
Sub-class terms are often useful (e.g., enzymes and antibodies as sub-classes of proteins). Many other useful affinity ligands are better described by bio-function, such as steroids, hormones, vitamins, enzyme or metabolic co-factors, enzyme inhibitors, enzyme reactors, drugs, drug re eptors, antibiotics, neurotransmittors, and antagonists. Still other ligands may be referred to as chromophores, dyes, ion-exchangers, amphiphiles, and the like.
The ligand a-ttached to the filter may but need not be attached through a coupling molecule disposed between the substituted amide group or derivative thereof and the ligand.
Numerous coupling molecules are well known and may be utilized in the present invention or attaching afinity ligands.
Reagents for thi~ purpose include cyanog~n hali~es, triazinyl halides (e.g., trihalo-s-triazine and substituted halo-s-triazines), sulfonyl halides (e.g., alkyl and~or aryl sulfonyl-halides, including bis-sulfonyl halides), acyl halides ~e.g., bis-acyl-halides), vinylsulfones, epogides (e.g., bis-oxiranes~, and the like.
Displacement reagents may also be used for ~upling ligands. The reagents are reacted with ~he matri~ surface groups and subsequently undergo displacement reac~ion with the ~ . _ .
iL327023 affinity ligand. Such reagents include sulfonyl halides such as aryl-sulfonyl halides (e.g., tosyl-halides), alkyl sulfonyl halides (e.g., methane sulfonyl halide), halo-alkyl-sulfonyl halides (e.g., trifluoroethane sulfonyl halides~, halopyrimidines (e.g., 2-fluoro-1-methylpyridinium toluene-4-sulfonate), and the like. Other preferred ligands and methods for attaching the ligands to the matri~ of this invention will become apparent to those skilled in the art of affinity sorption and enzyme immobilization from the present application.
In some of the filters used herein, a portion of the molecules of the polymer matri~ are crosslinked to other such molecules. Crosslinking imparts properties to the filter that in most applications are desirable, e.~., increased structural ri~idity and increased resistance to organic solvents.
Preferably the crosslsnking is between substituted amide groups. In filters where the substituted amide groups are ~-methylolamide groups, th~ crosslinking is thought to be by means of methylene-bis-amide. The most preferred fllter is a porous article comprising a matrix wherein the polymer comprises acrylonitrile or methacrylonitrile, the hydrophilic substituted amide groups are N-methylolamide g~oups, and the molecules of the polymer are crosslinked to other suc~ polymer molecules in the matrix.
Th~ ~ilter may be formed from a matrix comprising molecules of a suitable polymer having reactive pendent group~
-22~
,~,..,.,~
- ~327~
that prov;de essentially only on the surface of the filter sufficient uncharged hydrophilic polar groups to render the surface hydrophilic. The polar groups are obtained by derivatization of the pendent groups. Preferably, the reactive pendent groups are nitrile groups and the polar groups are substituted amide groups.
Hydrophilicity o a solid surface relates to the surface's affinity toward aqueous solutions. Hydrophilicity is an indication of a il~er's biocompatability, i.e., its ability to be used effectively with proteins and similar substances without encountering significant fouling problemsO Although hydrophilicity is not quan~itatively defined in tha industry, it can be qualitatively measured by the degree to which water spreads over the solid surface or by the angle theta of contact between the liquid surface and the ~olid surface when a drop of water rests on the solid surface (see Figure 4). The more hydrophilic a surface is, the lower angle theta will be.
The hydrophilicity o the filter used herein can be preselected during its manufac~ure by control of reac~ion rates, reagent concentratiQn, catalys~ concentration, etc. Th~
hydrophilicity can range from nearly that o the untreated nitrile-containing polymer to "hyperhydrophilic" Ot "hyperphilic~ (i.e., contact angles theta below about lS
degrees). Preferably, the hydrophilic sur~ace of the ilter has a contact angle less than about 30 de~rees when measured in a pH between 2 and 12 and more preerably less ~han about 15 .
. .
~ 327~2~
degrees. The most preferred filters used herein are hyperhydrophilic. Filters that are relatively more hydrophilic than the original untreated matri~es may be used in the devices of this invention, regardless of whether the filters would be considered hydrophilic or hydrophobic by one skilled in the art.
Suitable polymers for the filter include polymers that contain pendent groups which can be dsrivatized to substituted amide groups, e.g., nitrile-containing polymers. For making some filters used herein, derivatizing comprises contacting the molecules of the nitrile-containing polymer with an aldehyde or an aldehyde-generating compound. Generally, any aldehyde may be used; however,~ the size o the aldehyde molecule may limit the usefulness of the aldehyde in embodiments where the ~ilter is porous. In such cases, the size of the pores will determine the suitahility of the aldehyde by imposing an upper limit on the aldehyde's molecular size. The most pref~rred aldehyde i5 formaldehyde and the most preferred aldehyde-generat;ng compound~is a formaldehyde-generating compound, particularly dimetho~ymethane, trio~ane, and paraformaldeh~de.
The contact time for contactiny the nitrile-containing polymer with the aldehyde or ~he aldebyde-generating compound should be long enough to p~rmit ~he formation of sufficient substituted amide ~roups to make the filter's surface hydrophilic but not long enough to hydrophilize the ~ntire filter structure. This operation may be carried out i~ the presence of a catalyst, which may comprise one or more acids, ... .
i~27~23 preferably a combination of a strong acid and a weak acid.
Many strong acids are known to those skilled in the art and can be used. Common mineral acids (e.g., hydrochloric, phosphoric, and sulfuric) ar~ preferred. Other preferred strong acids include alkylsulfuric, alkylsulfonic, halosulfuric, and the like, for example, trifluoromethane sulfonic acid and fluorosulfuric acid. Preferred weak aci~s include acetic acid. The acid may be generated by an acid-ge~erating substance, e.g., boron trifluoride and aluminum chloride.
Other suitable acids will be apparent to those skilled in the art.
The reaction rate may be varied by controlling catalyst strength. If the catalyst is an acid, catalys~
strength means both the concentration and the inherent strength of the acid. The degree of hydrophilicity of the filter ~urface may be controlled by adjusting the relative concentrations of the strong acid, the weak acid, and of the aldehyde;or aldehyde-90nerating compound.
Contact with the aldehyde or aldehyde-generating compound is preferably carried out by soaking ~he ma~rix in a reagen~ ba~h containing the aldehyde or the aldehyde-genera~ing compound. The time of soaking, ~he temperature of the reagent bath, and the concentration of the reagents will depend on the type o~ aldehyde or aldehyde-generating compound used, the type o~ nitrile-containing polymer present, the quantity and strength of the catalyst (if present~, and the filter properties desired.
To prevent polymerization of the aldehyde or re-polymerization of the polymer, the water content of the reaction bath should be kept low. The precise level required will vary with the particular acid used, but the level in all cases should be such as to avoid competing reactions. In the embodiments where the nitrile-containing polymer comprises an acrylonitrile-type monomer, preferably ~he hydrophili~
substituted amide groups are N m~thylolamide groups, the contacting is effected with a formaldehyde-generating compound in the presence of an acid, the soaking bath reaction lasts between 1 m;nute and about 48 hours, and the temperature of the r~agent bath is from about 1C to about 90C. For preferred filters, in which portion of the molecules of the pol~ner on the surface of the matri~ are crosslinked to other such molecules, the duration of ~h~ soaking bath reaction is from several ~inutes to about 24 hour~ and the temperature of the reagent bath is from about 10C to about 60C.
Manufacture of filters useful herein and use of such filters in a rotary filtration device are described in the examples which follow. These examples are intended to aid in understanding the invention but are not intended to, and should not be construed to, limit in any way the invention ~ set forth in the claims which follow.
-2fi-13~70~3 EgAMPL~_l A porous thin flat sheet membrane composed of polyacrylonitrile polymers of greater than 90% acrylonitrile was treated for 4 hours in a bath containing 34.2 parts of concentrated sulfuric acid, 13.1 ~arts of concentrated acetic acid, 37.8 parts of formic acid, and 14.9 parts of trio~ane as the formaldehy~e source. The freshly composed reagent bath was allowed to equilibrate at 30C for l hour be~ore use.
Following the bath treatment, the membrane was soaked in a water bath at 2C for 30 minutes. The membrane was then soaked for 60 minutes at ambient temperatures in an aqueous bath consisting of 3.8 parts sodium borate, pH , 9.
Drops of water applied to the surface of the treated membrane readily spread. In similar drop tests with an untreated mèmbrane, the water beaded and did not spread. The treated membrane was mounted in a conventional stirred cell apparatus and tested ~or 1uid flu~, protein rejection, and, after e~osure to protein, for recovery of fluid flux. The test results show that in contrast with the untreated membrane, the treated membrane resisted fouling by protein and i~
recovered fluid ~lu~ aft~r a simple flushing operation (see Table 13. This membrane was suitable for use in a rotary filtration device.
~O~.t`
~ 327~23 TABhE_l ~uffer Flux~
(liters/hour-square meter) Prot~in Untreated Memb~a~8 Treated Mem~rane none 149 +/- 7 178 +/- 9 myoglobin 6S 134 ovalbumin 52 184 bovine serum albumin 53 179 bovine gamma-globulins 24 175 ~ 10 psi transmembrane pressure dif~erence EXAMPLE_2 A membrane was treated for 3 hours in a reagent bath at 30C. The article was composed of greater than 90~
acrylonitrile monomers. The reagent bath contained 15.0 parts of trioxane-~ 13.2 parts of acetic acid, 37.4 par~s of formic acid,. and ~4.4 parts of concentrated sulfuric acid. After treatment, the membrane was rinsed with water and soaked at ambient eemperature or 60 minutes in an aqueous bath consisting of 3.8 parts sodium borate, pH ~ 9.
After rin3ing with water and blotting dry, the membrane could be wetted hy wa~er, which readily spread upon the hydrophilic surfac~. Hydrophilicity of the membrane was also indicated by the solid-liquid contact angle theta made by application of a drop o~ an aqueous solution applied ~o the membrane surface according to the method of Whitesides et al.
m~i~, volume 1, pages 725-740 ~1985). The contact angle . . -2~-.
1327~23 measured 30 seconds after drop application was 4 degrees for the treated membrane and 46 degrees for the untreated membrane. For comparison, the contact angl~s were also measured for conventional commercially available membranes made of other materials. It became obvious from these results that the membrane is markedly more hydrophilic (~'hyperphilicn) than well-known so-called hydrophilic membranes. Comparative results are shown in Table 2.
Contact Angle Membra~e (dear~s)*
hyperphilic filter ~treated) . 4 untreated filter 46 conventional polyethersulfone 65 "hydrophilized" polyethersulfone 49 "hydrophilic" cellulosic 24 x contact angle measured at 30 seconds after drop application to surface The hydrophilicity of the treated membrane wa~ also examined by measurements of fluid flu~ in a conventional stirred cell apparatus before and af~er e~posure to protein.
It became eviden~ from ~he ~est results that the treated membrane resisted fouling by pro~ein and recovered fluid ~lux after a simple flushing op~ra~ion ~Table 3). The tre~ted membrane was suitable or us~e as ~ filter in a rotar~
filtration device.
-2~-13~7~23 TABLE_~
Buffer Flu~ After Sample Filtration*
SamPle (li~ers/hour-squ~re meter~.
buffer 596 bovine serum albumin 630 bovine gamma-globulins 589 * 10 p~i transmembrane pressure difference E~A~PLE ~
~ membrane composed of polyacrylonitrile-containing polymers was treated for 60 minutes at 23~ in a bath containing 25 parts dimethoxymethane and 75 parts sulfuric acid. The bath was equilibrated at 23C for 1 hour ~efore use. Following this bath, the membrane was soaked in a water bath at 2C for 30 minutes and then in an aqueous bath containing 3.8 parts of sodium borate, pH ~ 9, at ambient temperature for 60 minutes.
As in the preceding e~amples, drops o water applied to the s~rface of the treated membrane spread readily~
Similarly, when the membrane was examined in a stirred cell for recovery of 1uid flus after esposure to protein, it became evident that the ~reated membrane resisted fouling by protein and recovered fluid flux after a simple 1ushing opera~ion.
For e~ample, the ~reated membrane e~hibited an initial buffer flu~ of 44.7 liters per hour-square meter at 20 psi -~transmembrane pressure before exposur~ to protein. ~ter ultrafiltration of individual protein solueions o~ myoglobin, i32~23 chymotrypsin, ovalbumin, and bovine serum albumin, the initial buffer flu~ was recovered for each protein.
A membrane composed of polyacrylonitrile-containing polymers was treated for 1 hour at 23C in a reaction bat~
containing 21.9 parts dimetho~ymethane, 65.3 parts of concentrated sulfuric acid, and 12.8 parts of acetic acid. The treated membrane was then soaked in a cold water bath and a borate bath as described in Example 3.
Drops of wa~er spread readily when applied to the surface of the treated membrane. When the membrane was e~amined in a stirred cell for recovery of fluid flus after exposure to protein, it was observed that the treated membrane resisted fouling by protein and recovered fluid flu~ after a simple flushing operation. This membrane filter was suitable or use in a rotary filtration device.
In other studies, the treated membrane was found to resist d~sruption and dissolu~io~ by organic solv~nts that rapidly and completely dissolved untreated membranes. For e~ample, a~ter a tr~ated membrane and an untreated membrane had been soak~d in a solvent bath of gamma-~utyrolactone at ambient temperature for one h~ur, the untrea~ed membrane had dissolved while the treated membrane was still intact. A treated membrana e~pos~d for 4 days to ~amma-butyrolactone i~'a solvent bath at ambient temperature showed no significant di~ference ~, .
' from treated membrane that had not ~een e~posed to solvent (see Table 4).
TABL~ 4 Buffer Flu3 After Sample Filtration*
~liters/hour-square meter) Samole ~efore SoLvent Atç~_5Qlvent~
buffer ~1 ~4 myoglobin 44 46 ovalbumin 44 46 bovine serum albumin ~4 g6 bovine gamma-globulin 41 41 ~ 10 psi transmembrane pressure difference *~ solvent bath 100% gamma-butyrolactone at ambient temperature~
membrane solvent exposure time 4 days EXAMPLE_5 A membrane composed of polya~rylonitrile-containing polymers was treated for 6 hours at 23C in a formaldehyde reaction bath containing 5.8 parts of paraformaldehyde~ 44.2 parts of çoncentrated sulfuric acid, and 50 part~ of concentrated acetic a~id. The treated membrane was soak~d in a water bath at 2C for 30 minutes and then for 60 minutes at 23OC in an aqueous bath containing 3.8 parts of sodium borate, pH ~ 9. The treated article had hydrophilic character, as shown by the degree ~o which water spread. In studies similar to those described above, the treated m~mbrane recovered i~s initial buffer elu2 after ultrafiltration of protein solutions. The ~r~ated membran~ filter was suitable for use in a rotary filtration device.
~_ .
.
~327023 A membrane was treated as in E~ample 2 and then e~posed to an aqueous solu~ion consisting of approximately O.OlM sodium carbonate, 0.3M sodium chloride, and 2 milligrams per ml of "reactive dye." The reactive dye was Procion Red Reactive Dye MX-2~ (PolySciences~, which is a red colored, chromophore-substituted, triazinyl-halide that reacts like an acyl-halide with suitable nucleophiles, among which are N-methylolamides. The.r~action between the reactive dye and the treated membrane was conducted overnight ~16 hours~ at ambient temperatures. Th~ reacted membrane was washed -extensively with water and saline solution to remove unreacted dye.
The resulting membrane was found to be permanently derivatized to show a red color that could not be removed by ~urther washin~s. In this e~ample, the red chromophore is considered as a potential af~inity-sorptive ligand and the reactiv~triazinyl moie~y represen~s a well-es~ablished reagent for linking affinity ligands in general to suitable matri~
materials (e.g., Hodgins, L.T., and Levy, ~., "Affinity Adsorbent Preparation: Chemical Feat~lres o~ Agarose Derivatization with Trichloro-s-triazine," J~ChromatQaraPhY, volume 202, page 381 (1980)~.
~L~ '' A comm~rcially available polyacrylonitrile homopolymer .~
~; (presumably about 99~ ~crylonitrile) was dissolved and cast on ~L3~7~23 a standard polypropylene non-woven fabric using conventional casting techniques to make a porous membrane having a 100,000-molecular weight cut-off. That membrane was treated using the procedure and materials of Example 2 to produce a filter that was mounted in a rotary filtration device essentially the same as that shown in Figure 5. (The Figure 5 device is described in detail in Membrex U.S. Patent No.
4,867,~78.) In Fig. 5 device 120 comprises cartridge 124 rotating inside housing 122 having longitudinal axis 184.
The direction of rotation is indicated by arrow 136 and rotational velocity is indicated by omega~ Feed liquid enters the device through fluid inlet 130 and flows into the space between th~ cartridge and the housing, which space includes fluid gap 126~ Some of the fluid in the gap flows through filtration membrane 128, through ~ollection grooves (not shown) on the outer surface of cartridge side wall 176, through ports 140 in side wall 176 into plenum 142, and through longitudinal passageway 154 in drive shaft 132 out of the device. Ret~ntate leaves the void space between the housing and the rotating cartridge through outlet nozzle 134 as shown by arrow 178. Internal cavity 138 is closed and does not contain fluid.
Cartridge 124 has top plug 144 and housing 122 has bottom plug 146, the top part of which is convexity 162.
That convexity has a frusto-conical shape with sid~ surface 164 and .. .
~702~
top surfac~ 166. 8ecause Fig. 5 is a longitudinal cross-section of the device with longitudinal housing axis 184 lying in the plane of the cross-section, frusto-conical convexity 162 appears as a trapezoid. The opposing slanted ~angled) sides 164a and 164b of that trapezoid form an angle alpha of about 30 degrees.
Cartridge 124 has matching frusto-conical concavity 168, which has top side 172 and side wall 170. In th~
cross-section of Fig. 5, the three-dimensional curved side wall 170 has straight side walls 170a and 170b.
The cartridge is rotated by drive means (not shown) located above section line 158 in top 156 of the housin~.
Rotational force is transmitted by means of drive shaft 132, which passes through bearing/seal 160, and drive shaft e~tension 148. Drive shaft e~tension 1~8 is friction-fit inside matching concarity 180 in top plug 144 of the car~ridge. O-ring 152, which fits within circular groove 155 in exten~ion 148, provid~s a fluid-~ight seal between filtrate in plenum 14~ and retentate in the void space. As result of rotation and of the bearing surfac~ 170 in the bottom of the cartridge being slanted, a vertical upwards force against sur~ace 170 also develops and pushes the cartridge up, thereby insuring a fluid-tight ~eal. Cartridge 124 has outer diameter 194 and cartridge concavity 168 has outer diameter 192.
The outer member of the rotary filtration device employed had an inner diameter o~ 3.6 cm, the outer diameter of ~ ~
.
~ -35-~3~7~2~
the inner member was 3.2 cm, and the gap width was 0.2 cm.
The ef~ective membrane filtration area was 63.6 cm2~ The membrana was mounted on the inner member, which was of polypropylene, by heat-sealing the polypropylene backing thereto.
.~n aqueous buffered ~pH 7) 0.05 weight percent solution o~ ferritin (a protein of 440,000 Daltons molecular weight3 was filtered with this device in the following manner. Fresh solution was combined with recycled retentate and the total stream fed to the liquid inlet/ and permeate and retentate (for recycle) were continuously withdrawn. The transmembrane pressure was 10 psi, the inner member was rotated at 2000 rpm, and the outer housing member was stationary.
Filtration continued until the ferritin concentration in the retentate reached about 0.10 weight percent. The overall protein rejection was 99.3% and the average permeate flux was 226 liters/m2-hour, which remained essentially constant.
.~ ,
The direction of rotation is indicated by arrow 136 and rotational velocity is indicated by omega~ Feed liquid enters the device through fluid inlet 130 and flows into the space between th~ cartridge and the housing, which space includes fluid gap 126~ Some of the fluid in the gap flows through filtration membrane 128, through ~ollection grooves (not shown) on the outer surface of cartridge side wall 176, through ports 140 in side wall 176 into plenum 142, and through longitudinal passageway 154 in drive shaft 132 out of the device. Ret~ntate leaves the void space between the housing and the rotating cartridge through outlet nozzle 134 as shown by arrow 178. Internal cavity 138 is closed and does not contain fluid.
Cartridge 124 has top plug 144 and housing 122 has bottom plug 146, the top part of which is convexity 162.
That convexity has a frusto-conical shape with sid~ surface 164 and .. .
~702~
top surfac~ 166. 8ecause Fig. 5 is a longitudinal cross-section of the device with longitudinal housing axis 184 lying in the plane of the cross-section, frusto-conical convexity 162 appears as a trapezoid. The opposing slanted ~angled) sides 164a and 164b of that trapezoid form an angle alpha of about 30 degrees.
Cartridge 124 has matching frusto-conical concavity 168, which has top side 172 and side wall 170. In th~
cross-section of Fig. 5, the three-dimensional curved side wall 170 has straight side walls 170a and 170b.
The cartridge is rotated by drive means (not shown) located above section line 158 in top 156 of the housin~.
Rotational force is transmitted by means of drive shaft 132, which passes through bearing/seal 160, and drive shaft e~tension 148. Drive shaft e~tension 1~8 is friction-fit inside matching concarity 180 in top plug 144 of the car~ridge. O-ring 152, which fits within circular groove 155 in exten~ion 148, provid~s a fluid-~ight seal between filtrate in plenum 14~ and retentate in the void space. As result of rotation and of the bearing surfac~ 170 in the bottom of the cartridge being slanted, a vertical upwards force against sur~ace 170 also develops and pushes the cartridge up, thereby insuring a fluid-tight ~eal. Cartridge 124 has outer diameter 194 and cartridge concavity 168 has outer diameter 192.
The outer member of the rotary filtration device employed had an inner diameter o~ 3.6 cm, the outer diameter of ~ ~
.
~ -35-~3~7~2~
the inner member was 3.2 cm, and the gap width was 0.2 cm.
The ef~ective membrane filtration area was 63.6 cm2~ The membrana was mounted on the inner member, which was of polypropylene, by heat-sealing the polypropylene backing thereto.
.~n aqueous buffered ~pH 7) 0.05 weight percent solution o~ ferritin (a protein of 440,000 Daltons molecular weight3 was filtered with this device in the following manner. Fresh solution was combined with recycled retentate and the total stream fed to the liquid inlet/ and permeate and retentate (for recycle) were continuously withdrawn. The transmembrane pressure was 10 psi, the inner member was rotated at 2000 rpm, and the outer housing member was stationary.
Filtration continued until the ferritin concentration in the retentate reached about 0.10 weight percent. The overall protein rejection was 99.3% and the average permeate flux was 226 liters/m2-hour, which remained essentially constant.
.~ ,
Claims (29)
1. A rotary filtration device comprising:
(a) an outer member having an inner surface;
(b) an inner member having an outer surface and mounted at least partially within the outer member to define a fluid gap between the inner surface of the outer member and the outer surface of the inner member;
(c) means for rotating the outer member or the inner member or both; and (d) filter means for filtering fluid in the fluid gap, the filter means being located on the inner surface of the outer member or on the outer surface of the inner member or on both and comprising molecules of a suitable polymer that provides solely on the surface of the filter sufficient uncharged substituted amide groups to render the surface hydrophilic.
(a) an outer member having an inner surface;
(b) an inner member having an outer surface and mounted at least partially within the outer member to define a fluid gap between the inner surface of the outer member and the outer surface of the inner member;
(c) means for rotating the outer member or the inner member or both; and (d) filter means for filtering fluid in the fluid gap, the filter means being located on the inner surface of the outer member or on the outer surface of the inner member or on both and comprising molecules of a suitable polymer that provides solely on the surface of the filter sufficient uncharged substituted amide groups to render the surface hydrophilic.
2. The device of claim 1 wherein the polymer is a homopolymer.
3. The device of claim 1 wherein the polymer is a copolymer.
4. The device of claim 3 wherein the uncharged substituted amide groups are attached to less than all the monomeric units of the copolymer.
5. The device of claim 1 wherein the polymer is blended with other polymers.
6. The device of claim 1 wherein the polymer is grafted to another polymer.
7. The device of claim 1 wherein the hydrophilic surface has a contact angle of less than about 30 degrees when measured at a pH between 2 and 12.
8. The device of claim 7 wherein the hydrophilic surface has a contact angle less than about 15 degrees.
9. The device of claim 1 wherein the polymer is a nitrile-containing polymer.
10. The device of claim 9 wherein the substituted amide groups are derived from nitrile groups of the nitrile-containing polymer.
11. The device of claim 1 wherein the substituted amide groups are grafted to the polymer or attached to monomers that are grafted to the polymer.
12. The device of claim 9 wherein the polymer comprises an acrylonitrile-type monomer.
13. The device of claim 12 wherein the acrylonitrile-type monomer is acrylonitrile or methacrylonitrile.
14. The device of claim 13 wherein the substituted amide groups comprise N-methylolamide groups.
15. The device of claim 14 wherein the N-methylolamide groups are derived from nitrile groups of the nitrile-containing polymer.
16. The device of claim 14 wherein the N-methylolamide groups are grafted to the polymer or attached to monomers that are grafted to the polymer.
17. The device of claim 1 further comprising a plurality of ligands attached to at least some of the substituted amide groups.
18. The device of claim 17 wherein at least some of the ligands comprise bio-selective affinity groups.
19. The device of claim 18 wherein the bio-selective affinity group comprises a nucleic acid, polynucleotide, monosaccharide, polysaccharide, lipid, amino acid, peptide, protein, hormone, vitamin, metabolic co-factor, drug, antibiotic, or a combination thereof.
20. The device of claim 18 wherein the ligands have coupling molecules disposed between the substituted amide groups and the bio-selective affinity groups.
21. The device of claim 1 wherein molecules of the polymer are crosslinked to other such molecules.
22. The device of claim 21 wherein the substituted amide groups are N-methylolamide groups and the crosslinking is by means of a methylene-bis-amide.
23. A rotary filtration device comprising:
(a) an outer member having an inner surface;
(b) an inner member having an outer surface and mounted at least partially within the outer member to define a fluid gap between the inner surface of the outer member and the outer surface of the inner member;
(c) means for rotating the outer member or the inner member or both; and (d) filter means for filtering fluid in the fluid gap, the filter means being located on the inner surface of the outer member or on the outer surface of the inner member or on both and comprising molecules of a suitable polymer that provides solely on the surface of the filter sufficient uncharged hydrophilic polar groups to render the surface hydrophilic, the polar groups having been obtained by derivatization of reactive pendent groups of the polymer.
(a) an outer member having an inner surface;
(b) an inner member having an outer surface and mounted at least partially within the outer member to define a fluid gap between the inner surface of the outer member and the outer surface of the inner member;
(c) means for rotating the outer member or the inner member or both; and (d) filter means for filtering fluid in the fluid gap, the filter means being located on the inner surface of the outer member or on the outer surface of the inner member or on both and comprising molecules of a suitable polymer that provides solely on the surface of the filter sufficient uncharged hydrophilic polar groups to render the surface hydrophilic, the polar groups having been obtained by derivatization of reactive pendent groups of the polymer.
24. The device of claim 23 wherein the reactive pendent groups are nitrile groups.
25. The device of claim 24 wherein the polar groups are substituted amide groups.
26. The device of claim 25 wherein the polymer comprises an acrylonitrile-type monomer and the substituted amide groups comprise N-methylolamide groups.
27. The device of claim 26 further comprising a plurality of ligands attached to at least some of the N-methylolamide groups.
28. The device of claim 27 wherein at least some of the ligands comprise bio-selective affinity groups.
29. The device of claim 26 wherein the molecules of the polymer are crosslinked to other such molecules by means of methylene-bis-amide.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US22500088A | 1988-07-27 | 1988-07-27 | |
| US225,000 | 1988-07-27 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1327023C true CA1327023C (en) | 1994-02-15 |
Family
ID=22843126
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA000606727A Expired - Fee Related CA1327023C (en) | 1988-07-27 | 1989-07-26 | Rotary filtration device with hyperphilic membrane |
Country Status (2)
| Country | Link |
|---|---|
| CA (1) | CA1327023C (en) |
| WO (1) | WO1990000922A1 (en) |
Families Citing this family (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1999025463A1 (en) * | 1997-11-14 | 1999-05-27 | Massachusetts Institute Of Technology | Apparatus and method for treating whole blood |
| US9309132B2 (en) | 2010-08-16 | 2016-04-12 | Board Of Trustees Of Michigan State University | Water and oil separation system |
| FR2966144B1 (en) | 2010-10-14 | 2013-04-12 | Total Sa | TREATMENT OF WATER IN AT LEAST ONE MEMBRANE FILTRATION UNIT FOR ASSISTED HYDROCARBON RECOVERY |
| FR2966145B1 (en) | 2010-10-14 | 2016-12-30 | Total Sa | TREATMENT OF WATER IN AT LEAST ONE MEMBRANE FILTRATION UNIT FOR ASSISTED HYDROCARBON RECOVERY |
| US9423234B2 (en) | 2012-11-05 | 2016-08-23 | The Regents Of The University Of California | Mechanical phenotyping of single cells: high throughput quantitative detection and sorting |
Family Cites Families (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US2534204A (en) * | 1947-12-30 | 1950-12-12 | Monsanto Chemicals | Method of preparing amides |
| ZA814216B (en) * | 1980-06-27 | 1982-07-28 | Akzo Nv | Porous inorganic support material coated with an organic stationary phase for use in chromatography and process for its preparation |
| US4614714A (en) * | 1982-08-21 | 1986-09-30 | Yamasa Shoyu Kabushiki Kaisha | Use of novel L-glutamic acid oxidase |
| US4790942A (en) * | 1983-12-20 | 1988-12-13 | Membrex Incorporated | Filtration method and apparatus |
-
1989
- 1989-07-26 CA CA000606727A patent/CA1327023C/en not_active Expired - Fee Related
- 1989-07-27 WO PCT/US1989/003244 patent/WO1990000922A1/en unknown
Also Published As
| Publication number | Publication date |
|---|---|
| WO1990000922A1 (en) | 1990-02-08 |
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