U.S. patent application number 14/364755 was filed with the patent office on 2014-11-06 for doped membranes.
The applicant listed for this patent is GAMBRO LUNDIA AB. Invention is credited to Ralf Flieg, Markus Hornung, Karl Heinz Klotz, Bernd Krause, Markus Storr.
Application Number | 20140326669 14/364755 |
Document ID | / |
Family ID | 47324160 |
Filed Date | 2014-11-06 |
United States Patent
Application |
20140326669 |
Kind Code |
A1 |
Flieg; Ralf ; et
al. |
November 6, 2014 |
DOPED MEMBRANES
Abstract
Synthetic membranes for the removal, isolation or purification
of substances from a liquid. The membranes include at least one
hydrophobic polymer and at least one hydrophilic polymer. 5-40
wt.-% of particles having an average particles size of between 0.1
and 15 .mu.m are entrapped. The membrane has a wall thickness of
below 150 .mu.m. Methods for preparing the membranes in various
geometries, and use of the membranes for the adsorption, isolation
and/or purification of substances from a liquid are explored.
Inventors: |
Flieg; Ralf; (Rangendingen,
DE) ; Storr; Markus; (Filderstadt, DE) ;
Krause; Bernd; (Rangendingen, DE) ; Hornung;
Markus; (Nehren, DE) ; Klotz; Karl Heinz;
(Jungingen, DE) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
GAMBRO LUNDIA AB |
Lund |
|
SE |
|
|
Family ID: |
47324160 |
Appl. No.: |
14/364755 |
Filed: |
December 10, 2012 |
PCT Filed: |
December 10, 2012 |
PCT NO: |
PCT/EP2012/074899 |
371 Date: |
June 12, 2014 |
Current U.S.
Class: |
210/651 ;
210/500.23; 210/500.27; 210/500.35; 210/500.38; 210/500.41;
210/500.42; 210/500.43; 210/650 |
Current CPC
Class: |
B01D 69/141 20130101;
B01D 2325/42 20130101; B01D 69/06 20130101; B01D 2325/38 20130101;
B01D 69/08 20130101; B01D 69/147 20130101; B01D 69/088 20130101;
B01D 69/087 20130101; B01D 69/148 20130101; B01D 67/0011 20130101;
B01D 2325/36 20130101 |
Class at
Publication: |
210/651 ;
210/500.23; 210/650; 210/500.27; 210/500.38; 210/500.41;
210/500.35; 210/500.43; 210/500.42 |
International
Class: |
B01D 69/14 20060101
B01D069/14; B01D 69/08 20060101 B01D069/08 |
Foreign Application Data
Date |
Code |
Application Number |
Dec 15, 2011 |
EP |
11193795.9 |
Claims
1. A membrane for the removal of substances from a liquid, the
membrane comprising at least one hydrophobic polymer selected from
the group consisting of polysulfones, polyethersulfones,
polyarylethersulfones, polyamides and polyacrylonitriles and at
least one hydrophilic polymer, the membrane comprising 1-40 wt.-%
of at least one of hydrophilic particles and hydrophobic particles,
the particles having an average diameter of between 0.1 .mu.m and
15 .mu.m.
2. The membrane according to claim 1, wherein the particles have an
average diameter of between 0.1 .mu.m and 10 .mu.m.
3. The membrane according to claim 1 wherein the hydrophobic
particles are chosen from the group consisting of activated carbon,
carbon nanotubes, hydrophobic silica, styrenic polymers,
polydivinylbenzene polymers and styrene-divinylbenzene
copolymers.
4. The membrane according to claim 1, wherein the hydrophilic
particles are anion or cation exchange particles.
5. The membrane according to claim 4 wherein the anion exchange
particles are based on polyquaternary ammonium functionalized
styrene divinylbenzene copolymers.
6. The membrane according to claim 5 wherein the anion exchange
particles are based on polyquaternary ammonium functionalized
vinylimidazolium methochloride vinylpyrrolidone copolymers.
7. The membrane according to claim 5 wherein the polyquaternary
ammonium copolymer is a copolymer of styrene and divinylbenzene
with dimethyl(2-hydroxyethyl) ammonium and/or trimethylbenzyl
ammonium functional groups.
8. The membrane according to claim 1 wherein the membrane is one of
a hollow fiber membrane and a flat sheet membrane.
9. The membrane according to claim 1 wherein the wall thickness of
the hollow fiber is below 150 .mu.m.
10. The membrane according to claim 1 wherein the particles are
present in an amount of from 20 wt.-% to 35 wt.-% relative to the
weight of the membrane.
11. The membrane according to claim 1 wherein the membrane is at
least one of a microporous membrane, a protein separation membrane
and an ultrafiltration membrane.
12. A method for preparing a hollow fiber membrane comprising at
least one hydrophobic polymer selected from the group consisting of
polysulfones, polyethersulfones, polyarylethersulfones, polyamides
and polyacrylonitriles and at least one hydrophilic polymer, the
membrane comprising 1-40 wt.-% of at least one of hydrophilic
particles and hydrophobic particles, the particles having an
average diameter of between 0.1 .mu.m and 15 .mu.m, the method
comprising (a) grinding the particles to an average diameter of at
least 15 .mu.m in an aqueous solution; (b) combining the at least
one hydrophilic and the at least one hydrophobic polymer with the
suspension of (a); (c) stirring the polymer particle suspension to
obtain a homogeneous polymer solution wherein the particles are
suspended; (d) degassing the polymer particle suspension; (e)
extruding the polymer particle suspension through an outer ring
slit of a nozzle, wherein a center fluid is extruded through an
inner opening of the nozzle; (f) immersing the precipitating fiber
in a bath of non-solvent; (g) washing the membrane.
13. A method for preparing a flat sheet membrane comprising at
least one hydrophobic polymer selected from the group consisting of
polysulfones, polyethersulfones, polyarylethersulfones, polyamides
and polyacrylonitriles and at least one hydrophilic polymer, the
membrane comprising 1-40 wt.-% of at least one of hydrophilic
particles and hydrophobic particles, the particles having an
average diameter of between 0.1 .mu.m and 15 .mu.m, the method
comprising (a) grinding the particles to an average diameter of at
least 15 .mu.m in an aqueous solution; (b) combining the at least
one hydrophilic and the at least one hydrophobic polymer with the
suspension of (a); (c) stirring the polymer particle suspension to
obtain a homogeneous polymer solution wherein the particles are
suspended; (d) degassing the polymer particle suspension; (e)
casting the polymer particle suspension as a uniform film onto a
smooth surface; (f) washing the membrane.
14. The method according to claim 12, wherein the water of (a) is
the total amount of water which is needed for forming the final
polymer solution.
15. (canceled)
16. A method for at least one of the adsorption of compounds, the
isolation of compounds and the purification of a liquid, the method
comprising preparing a hollow fiber membrane comprising at least
one hydrophobic polymer selected from the group consisting of
polysulfones, polyethersulfones, polyarylethersulfones, polyamides
and polyacrylonitriles and at least one hydrophilic polymer, the
membrane comprising 1-40 wt.-% of at least one of hydrophilic
particles and hydrophobic particles, the particles having an
average diameter of between 0.1 .mu.m and 15 .mu.m, and exposing
the at least one of the compounds and the liquid to the
membrane.
17. The method of claim 16, wherein the compounds are selected from
the group consisting of nucleic acids, unconjugated bilirubin,
chenodeoxycholic acid, diazepam, cytokines and endotoxins.
18. A device for at least one of the adsorption of compounds and
purification of a liquid, the device comprising at least one of
hollow fiber membranes and flat sheet membranes, the at least one
of hollow fiber membranes and flat sheet membranes comprising at
least one hydrophobic polymer selected from the group consisting of
polysulfones, polyethersulfones, polyarylethersulfones, polyamides
and polyacrylonitriles and at least one hydrophilic polymer, the at
least one of hollow fiber membranes and flat sheet membranes
comprising 1-40 wt.-% of at least one of hydrophilic particles and
hydrophobic particles, the particles having an average diameter of
between 0.1 .mu.m and 15 .mu.m.
19. The membrane according to claim 2 wherein the hydrophobic
particles are chosen from the group consisting of activated carbon,
carbon nanotubes, hydrophobic silica, styrenic polymers,
polydivinylbenzene polymers and styrene-divinylbenzene
copolymers.
20. The membrane according to claim 2 wherein the hydrophilic
particles are anion or cation exchange particles.
21. The membrane according to claim 19 wherein the hydrophilic
particles are anion or cation exchange particles.
Description
TECHNICAL FIELD
[0001] The present disclosure relates to synthetic membranes for
the removal, isolation or purification of substances from a liquid,
comprising at least one hydrophobic and at least one hydrophilic
polymer, wherein 5-40 wt.-% of particles having an average
particles size of between 0.1 and 15 .mu.m are entrapped in the
membrane and wherein the membrane has a wall thickness of below 150
.mu.m. Further disclosed are methods for preparing such membranes
in various geometries and their use for the adsorption, isolation
and/or purification of substances from a liquid.
DESCRIPTION OF THE RELATED ART
[0002] Synthetic membranes with entrapped particles or ionic
charges have been described before in the prior art.
[0003] WO 2004/003268 A1 describes the basic approach for the
preparation of porous polymeric fibers comprising a broad variety
of functionalized or active particles, wherein a solution of one or
more polymers is mixed with particulate material and wherein the
mixture is extruded into a fiber by a two-step inversion process.
WO 2004/003268 A1 also describes that porous polystyrene or
styrene-divinylbenzene type particles, either unmodified or
modified with sulphonic acids or quaternary amines may possibly be
used as particulate material. However, WO 2004/003268 A1 does not
teach how stable porous or non-porous membranes can be prepared
which contain ion exchange particles in amount of about 5-40 wt.-%,
wherein the particles have a very small average diameter. Whereas
the reference teaches that it may be beneficial to have small
particles, below 15 .mu.m, entrapped in the membrane, it is taught
that particle load should be higher. In the examples, all membranes
have a particle load of 50 wt.-% or higher. Such high load of
particles of above 50% wt.-% is said to be preferred for improving
the accessibility of the particles and for obtaining a stable
membrane structure under avoidance of the formation of macrovoids
(Example 6 and FIGS. 7 and 8).
[0004] It is a problem, when preparing membranes with entrapped
particles, to obtain stable membranes, especially hollow fiber
membranes. In the processes as described in the prior art, hollow
fiber membranes tend to get unstable due to the formation of
macrovoids and varying wall thicknesses. The spinning is generally
difficult and the process is often interrupted because the fibers
get torn at the spinning nozzle during spinning. Therefore, fibers
as can be seen in the prior art are generally solid fibers or
hollow fibers with higher wall thickness of about 250 .mu.m.
[0005] The applicants have found that it is possible to prepare
membranes, especially also hollow fiber membranes with a wall
thickness of below 150 .mu.m with a considerably lower particle
load of below 40 wt.-%, wherein both the physical stability and
efficiency of the membrane is improved in comparison to membranes
with higher particle load and/or particles with an average diameter
of above about 20 .mu.m. This is achieved by an improved process
for preparing a membrane with entrapped particles, comprising an
improved generation and maintenance of particles with an average
size of about 0.1 to 15 .mu.m and an improved process for
generating a spinning solution comprising said particles, resulting
in a stable spinning process and stable membranes.
[0006] WO 2006/019293 A1 relates to hollow or solid fiber membranes
having multiple porous layers which are concentrically arranged,
and wherein at least one of the layers comprises functionalized or
active particles as described in WO 2004/003268 A1 above. The layer
containing high loads of particles can be either the outer or the
inner layer, wherein the function of the other layer, without
particles, is to provide mechanical stability to the fiber. As
described before, WO 2006/019293 A1 does not disclose ways to
obtain stable membranes with low particle load which can be
prepared as hollow fiber membranes without adjacent stabilizing
layers.
[0007] EP 1 038 570 A1 describes the preparation of positively
charged membranes including a sulfone polymer and PVP and a
cationic imidazolinium compound. However, the cationic material is
not present in the membrane in form of particulate material.
[0008] The applicants have found methods to produce and provide
mechanically stable membranes which can be produced as solid,
hollow fiber or flat sheet membranes and which have specifically
and stably entrapped therein particles such as ion exchange
particles in an amount of preferably 5-40 wt.-%, wherein the
average particle size is below 15 .mu.m and generally in the range
of between 0.1 and 10 .mu.m, especially in the range of from 0.1 to
1.0 .mu.m. The applicants further found that based on the process
for preparing the new membranes and the resulting nature of such
membranes of the invention, the comparatively low particle load of
the membrane is highly effective for adsorbing, isolating and/or
removing certain compounds from liquids, such as, for example,
nucleic acids, toxins, such as endotoxins, unconjugated bilirubin,
diazepam, and also problematic endogenous substances such as
cytokines or the like.
SUMMARY
[0009] It is an object of the present invention to provide more
efficient and mechanically more stable synthetic membranes which
can be used for the adsorption, purification or isolation of
compounds from a liquid. One object of the present invention was to
provide membranes in a hollow fiber geometry with a wall thickness
which is smaller compared to the prior art, thus providing better
accessibility and higher efficiency of the membrane when used.
[0010] It was found, surprisingly, that very efficient and
mechanically stable doped membranes may be prepared wherein the
membrane has entrapped therein particles which are very small. The
membrane is further characterized by a low particle load. At the
same time the wall thickness of the membranes is considerably lower
than in the art. It was found that such membranes should have
entrapped therein particles with an average size (diameter) of
between 0.1 and 1.0 .mu.m, and not essentially more than 15 .mu.m,
even though relatively good membranes can be obtained with 20 .mu.m
particles as well. Further, a particle load of up to 50%, generally
of between 5 and 40 wt.-%, may be achieved.
[0011] Accordingly, it was a further aspect of the present
invention to devise a process for preparing such membranes. It was
one object of the invention to provide a process which allows the
preparation of particles with an average size of well below 15
.mu.m, wherein the new process should also prevent the
agglomeration of the particles once they are added to the spinning
solution and during the spinning process.
[0012] It was also an object of the present invention to provide a
doped membrane such as a hollow fiber membrane with increased
effectiveness of the membrane when used in methods for removing a
specific target substance from a liquid.
[0013] The membranes with such small size particles and low
particle load show an improved activity or efficiency with regard
to the removal or adsorption of the respective target substances
from a liquid compared to membranes having a higher particle load
and/or larger particles and higher wall thickness.
BRIEF DESCRIPTION OF THE DRAWINGS
[0014] FIG. 1 shows a SEM of a microporous hollow fiber membrane
according to Examples 2.1 and 3 which is based on polyethersulfone
and PVP and wherein the particles were grinded in the presence of
NMP and water. FIG. 1A shows the complete cross-section
(200.times.) of the membrane, whereas FIG. 1B shows the
magnification (1000.times.) of the cross-section of FIG. 1A. The
entrapped basic anion exchange particles (cholestyraminee
(DOWEX.TM. 1.times.2-Cl)) in which quaternary ammonium groups are
attached to a styrene/divinylbenzene copolymer chain are not
visible in the membrane at a magnifications of 200. It is possible,
at a magnification of 1000 (see also FIG. 2A), to discern tiny
particles which are completely entrapped in the membrane. It can be
seen that the particles' average size is well below about 5 .mu.m
(see also FIG. 2).
[0015] FIG. 2 shows a SEM of the inner and outer surface of the
microporous hollow fiber membrane. The SEM have been taken from the
same membrane as the SEM of FIG. 1. FIG. 2A shows the inner or
lumen side of the membrane at a magnification of 2.500. FIG. 2B
shows the outer surface of the hollow fiber membrane at the same
magnification.
[0016] FIG. 3 shows a SEM of the cross-section of a hollow fiber
membrane with a magnification of 200 (FIG. 3A). FIG. 3B shows the
wall of the membrane at a magnification of 1000. The membrane was
prepared according to Comparative Examples 2, 2.2 and 3 (Batch C),
wherein the anion exchange particles (DOWEX.TM. 1.times.2-Cl) were
grinded in NMP in the absence of water to about the same initial
size as in Example 2.1 (see also FIGS. 1 and 2). As can be seen,
the particles as present in the final membrane are larger as in
FIG. 1, even though it should be noted that the SEM shows a dry
membrane wherein the particles have undergone some shrinking. They
are present in distinct cavities within the membrane and eventually
break through the surface of the membrane, thus increasing the risk
of particles being washed out into the adjacent liquid. Without
wanting to be limited to the theory, it is assumed that the
cavities are formed by the water which is taken up by the particles
and serves as a precipitating agent around said particles. During
use of the membrane, the membrane will usually be contacted again
with water or an aqueous solution, which will lead to the renewed
swelling of the particles. The actual average diameter of the
particles during use is thus larger than the average diameter
displayed in the SEM.
[0017] FIG. 4 shows the average size (diameter in .mu.m) of two
exemplary batches of cholestyramine particles after grinding in
aqueous solution in the presence of an organic solvent in a LabStar
LS 1 LMZ machine with ZrO.sub.2 as agitator grinding medium and a
temperature of 50.degree. C. (see Ex. 1). The data are shown as
provided by the Horiba LA950 for Windows Version 3.40 software. The
particles of FIG. 4A were obtained after 60 minutes of grinding;
the particles of FIG. 4B were obtained after 120 minutes of
grinding.
[0018] FIG. 5 shows the average size (diameter in .mu.m) of another
exemplary batch of cholestyramine particles after 300 minutes of
grinding in the presence of an organic solvent (NMP) in a LabStar
LS 1 LMZ machine with ZrO.sub.2 as agitator grinding medium and a
temperature of 50.degree. C. The data are shown as provided by the
Horiba LA950 for Windows Version 3.40 software. The average
diameter was about 8.0 .mu.m.
[0019] FIG. 6 shows Lp and DNA retention capability of different
membranes of hollow fiber and flat sheet geometry. For comparative
reasons, a standard ultrafiltration membrane without any added
material was tested (see also Example 6). Also shown is a hollow
fiber membrane with entrapped Amberlite.RTM. IRA-410 particles and
a hollow fiber membrane with modified PPE ion-exchanger additive
(Example 7). A flat sheet membrane was also tested. It contained
Luviquat.RTM. FC 370 (Example 5). DNA retention is improved in the
presence of ion exchange material in membranes which have been
prepared according to the invention.
[0020] FIG. 7 shows a SEM of a comparative flat sheet membrane
containing Amberlite.RTM. IRA-410 particles. The membrane was
prepared according to Example 6 and is shown at a magnification of
2020. Larger particles are clearly visible in the membrane
structure, as are ruptures on the surface of the pores of the
membrane.
[0021] FIG. 8 shows the results of DNA retention (adsorption) tests
done with mini-modules prepared from Amberlite.RTM. IRA-410
containing membranes produced according to Example 4. The Figure
shows the feed DNA solution and the DNA concentration in the
filtrate for a standard membrane without Amberlite.RTM.IRA-410
(Table Vb, Samples 10-13) and with different concentrations of
Amberlite.RTM. IRA-410 (Table Vb, Samples 3-5 and 6-8,
respectively). The presence of Amberlite.RTM. IRA-410 leads to a
significant adsorption of the DNA, with a higher rate for membranes
with a higher content of Amberlite.RTM. IRA-410.
DETAILED DESCRIPTION
[0022] The present invention is directed to more efficient and
mechanically stable synthetic membranes which can be used for the
adsorption, purification or isolation of compounds from a liquid,
wherein the membranes have entrapped therein particles which can be
chosen according to the needs of the adsorption, purification or
isolation task.
[0023] The expression "doped membrane" as used herein refers to the
inclusion of particles (which might also be referred to as
"impurities") into a membrane during its formation for the purpose
of modulating its properties.
[0024] The expression "particles" as used herein, refers to solid
or gel-like fragments of certain solid or gel-type materials, such
as hydrophobic materials or ion exchange materials. The expression
"gel" or "gel-type" as used herein, refers to materials or resins
with no permanent pore structures. Said pores are generally
considered to be small and, in general, not greater than 30 .ANG.,
and are referred to as gelular pores or molecular pores. The pore
structures are determined by the distance between the polymer
chains and cross-links which vary with the crosslink level of the
polymer, the polarity of the solvent and the operating conditions.
The gel type resins are generally translucent. The fragments or
particles may have different shapes, such as approximately
spherical shapes or irregular, edged shapes which may be stretched
or cubical. The particles as discussed in the context of the
present invention have an average size (diameter) of from 0.1 to
about 100 .mu.m.
[0025] The expression "ion exchange material" as used herein,
refers an insoluble polymeric matrix containing labile ions capable
of exchanging with ions in the surrounding medium. Generally, ion
exchange resins are supplied water wet in the form of approximately
spherical beads having a particle diameter between 0.30 and 1.2 mm.
A given resin has a characteristic water content associated with
the functional groups and adhering to the outer surface of the
resin particles. Notably, water wet ion exchange resins shrink or
swell when they change from one ionic form to another and they
shrink when they are dried and/or are in contact with non-polar
solvents.
[0026] It is one aspect of the present invention that the membranes
according to the invention can be provided in various geometries,
covering flat sheet and solid fibers as well as hollow fibers. It
is a specific aspect of the present invention that hollow fiber
membranes can be prepared which have a wall thickness which is
smaller compared to the prior art, thus providing better
accessibility and higher efficiency of the membrane when used.
[0027] It is a problem, when preparing membranes with entrapped
particles according to the prior art to obtain stable membranes,
especially hollow fiber membranes. In the processes as described in
the prior art, hollow fiber membranes tend to get unstable due to
the formation of macrovoids and varying wall thicknesses. The
spinning is generally difficult and the process is often
interrupted because the fibers get torn at the spinning nozzle
during spinning. Therefore, fibers as can be seen in the prior art
are generally solid fibers or hollow fibers with higher wall
thickness of about 250 .mu.m. Accordingly, in one aspect of the
present invention, the membranes, either hollow fiber or flat sheet
membranes, have a wall thickness of below 150 .mu.m. According to a
specific aspect of the present invention, the wall thickness is
between 100 and 150 .mu.m.
[0028] According to another aspect of the present invention, it is
crucial for obtaining such membranes wherein both the physical
stability of the membrane is improved in comparison to membranes of
the prior art and the wall thickness is reduced, to prepare
membranes with a lower particle load of below 40 wt.-%. According
to a specific aspect of the present invention, the particle load
should be in the range of between 5 wt.-% and 40 wt.-% relative to
the total weight of the membrane. In yet another aspect of the
present invention, the particle load should be in a range of from
20 wt.-% and 35 wt.-% of the total weight of the membrane.
[0029] At the same time, it is important to closely control the
average size of the particles and their behaviour in the spinning
solution. Particle size data, as used herein, refer to the
particles in a wet state both as such and when incorporated in a
membrane. It was found that particles with an average diameter of
more than 15 or 20 .mu.m are problematic for obtaining useful
membranes. The same is true for smaller particles of below said 15
to 20 .mu.m, which may be as small as between 1 .mu.m and 0.1 .mu.m
in diameter at the time of grinding, if the process of grinding and
preparing a spinning solution as well as the spinning itself are
not controlled in a way that the particles stay apart from each
other and will not agglomerate immediately upon grinding and
especially during formation of the spinning solution and the
spinning itself. Accordingly, it is one aspect of the present
invention to provide a membrane wherein the entrapped particles
have an average diameter of below 20 .mu.m, preferably below 15
.mu.m. According to one aspect of the present invention, the
entrapped particles should have an average diameter of below 10
.mu.m. According to one aspect of the present invention, the
average diameter of the entrapped particles should be below 15
.mu.m. According to another aspect of the present invention, the
average diameter of the entrapped particles should be in a range of
from 0.1 .mu.m to 10 .mu.m.
[0030] The particles which can be entrapped in a membrane according
to the invention and the processes disclosed herein may be of
various nature, such as also disclosed in the prior art (WO
2004/003268 A1, incorporated herein by reference). According to one
aspect of the present invention, the particles are ion exchange
particles which are prepared from ion exchange material widely
known in the art which is also commercially available. According to
one specific aspect of the present invention, cation or anion
exchange material can be used for preparing the doped membranes of
the invention. According to another aspect of the present
invention, the particles are hydrophobic particles chosen from the
group consisting of activated carbon, carbon nanotubes, hydrophobic
silica, styrenic polymers, polydivinylbenzene polymers and
styrene-divinylbenzene copolymers.
[0031] According to one aspect of the invention, basic anion
exchange material is used for preparing the doped membranes, which
may be based on polystyrene or styrene-divinylbenzene and which may
be modified with sulphonic acids, polyamines or quaternary or
tertiary amines. According to one aspect of the invention, the
particles are based on a copolymer of styrene and divinylbenzene
carrying active groups such as quaternary ammonium groups,
dimethylethanolamine groups, dimethylethanolbenzyl ammonium groups,
benzyltrialkyl ammonium groups, benzyldimethyl(2-hydroxyethyl)
ammonium and/or trimethylbenzyl ammonium functional groups.
According to a specific aspect of the present invention, the
particles used are based on a copolymer of styrene and
divinylbenzene carrying quaternary ammonium groups. According to
one aspect of the invention, the copolymer of styrene and
divinylbenzene carries trimethylbenzyl ammonium functional groups,
which is also referred to as cholestyramine, Cuemid, MK-135,
Cholbar, Cholbar, Questran, Quantalan, Colestyramine or Dowex.RTM.
1.times.2-Cl and as cholestyramine from Purolite.RTM.. According to
another aspect of the present invention the anion exchange material
is used in the chloride form.
[0032] Anion exchange media which can also be used are known, for
example, under the trade name Amberlite.RTM.. Amberlite.RTM.
comprises, for example, a matrix formed of styrene-divinylbenzene
having active or functional groups such as quaternary ammonium
groups, bezyldimethyl (2-hydroxyethyl) ammonium groups or
dimethylethanolamine groups. Other anion exchange media which can
be used are known for example, under the trade name Dowex.RTM..
Dowex.RTM. comprises, for example, a matrix formed of
styrene-divinylbenzene which may have active or functional groups
such as trimethylbenzylammonium.
[0033] In yet another aspect of the present invention, the
particles entrapped in the membrane of the invention are based on
vinylimidazolium methochloride vinylpyrrolidone copolymers, known,
for example, as Luviquat.RTM..
[0034] According to yet another aspect of the present invention,
the particles may be uncharged, hydrophobic particles, such as
styrenic polymers like DOWEX.TM. OPTIPORE.TM. L493 and V493 or
Amberlite.RTM. XAD.RTM.-2, polydivinylbenzene polymers or
styrene-divinylbenzene copolymers (e.g. Amberlite.RTM. XAD4 or
Amberchrom.TM.CG161), poly(l-phenylethene-1,2-diyl) (Thermocole),
or hydrophobic silica, which is silica that has hydrophobic groups
chemically bonded to the surface, or combinations thereof.
Hydrophobic silica can be made both from fumed and precipitated
silica. Hydrophobic silica can be made both from fumed and
precipitated silica. Hydrophobic groups that can be used are, for
example, alkyl or polydimethylsiloxane chains. Another hydrophobic
material which can be used is known as Ujotit, a copolymer of
styrene and divinylbenzene without any functional groups, which is
available as Ujotit PA-30, Ujotit PA-40 or Ujotit PA-20. Activated
carbon particles which may be used according to the invention can
be derived, for example, from carbon such as Printex.RTM. XE2
(Degussa AG) or Norit.RTM. GAC 1240 PLUS A (Norit Nederland
BV).
[0035] Cation exchange particles which may be used are generally
based on matrices of agarose, cellulose, dextran, methacrylate,
polystyrene or are polyacrylic acid. They are generally known and
commercially available, for example, under trade names such as
Sepharose.RTM. CM, Sephadex, Toyopearl.RTM., Amberlite.RTM.,
Diaion.TM., Purolite.RTM., Dowex.RTM. and Duolite.RTM. SO.sub.3H,
respectively.
[0036] In order to obtain the doped membranes of the present
invention, it is important to provide a method of grinding which
allows the preparation of particles with an average particle size
of below 20 .mu.m or below 15 .mu.m, e.g. of between 0.1 and 10
.mu.m, wherein the particles will not re-form or agglomerate into
larger particles during or after grinding and during the formation
of the spinning solution and/or the spinning process itself. In
other words, the method of grinding and subsequent formation of a
spinning solution must ensure the maintenance of particles with
said average size of about 0.1 to 15 .mu.m.
[0037] According to one aspect of the present invention, the
particles used are based on gel ion exchange material (gel resins).
For example, Dowex.RTM. 1.times.2-Cl is provided as a gel with a
particle size of between 100 and 200 mesh. The general particle
size of, for example, the before-mentioned anion exchange material
is in the range of 20 to 400 mesh (.mu.m) depending on the specific
starting material. Most ion exchange materials such as anion
exchange material are provided as gels. Gel resins generally have
higher ion capacity compared to e.g. microporous resins. Such ion
exchange resins are hygroscopic, wherein the amount of moisture
hydrated by the material depends on the cross-linking and the type
of functional group. Low cross-linking gel resins with functional
groups such as quaternary ammonium contain large amounts of water
resulting in swelling. The addition and removal of water thus
results in swelling and contraction. The hygroscopic and swelling
properties of the material severely influence the grinding process
and especially the formation of the spinning solution and the
following spinning process. Tests could show that the dry grinding
of the ion exchange material which was done in the absence of
additional water resulted in fine particles in the desired range of
about 1 to 7 .mu.m. However, the particles swelled upon addition to
a standard polymer solution comprising, among other components,
water. In addition, the particles were shown to agglomerate,
especially upon adding the particles to spinning solutions which
contain water. The particles finally present in the polymer
solution were found to have a size of again up to 20-30 .mu.m and
were deposited in such size in the membrane during spinning (see
Examples 1, 2.2, 3 and 6), even if the addition of the particles to
the spinning solution or vice versa was done very slowly. As a
consequence, the spinning of the membranes is difficult and often
is interrupted as the nozzles get clogged by the larger particles,
in which case the spinning is interrupted and the fiber is torn. In
the resulting membranes, the particles are well visible within a
cavity or void formed by the water which is abundant in the
particle, as can be seen in the SEM as shown in FIG. 3.
Furthermore, the large particles being close to or penetrating the
outer or inner surface of the membrane destabilize the membrane and
are prone to be washed out of the membrane structure. The efficacy
and usefulness of such membranes for removing or adsorbing the
targeted substances from a liquid is thus limited.
[0038] It could now be shown that it is important for avoiding such
problems to perform the grinding of the particles in an aqueous
solution or in a solution comprising water and an organic solvent.
The organic solvent usually will be the organic solvent also used
for forming the spinning solution. As a result, a suspension
comprising particles, water and, optionally, organic solvent, is
formed. The amount of water used for forming the suspension may
vary.
[0039] According to one aspect of the present invention, water
should be added in an amount which corresponds to the amount of
water which is needed for forming the spinning solution. In other
words, the complete amount of water which would otherwise be a
component of the spinning solution is already added to the ion
exchange material for grinding. Any influence of water which is
added at a later stage, for example during the formation of the
final spinning solution, is thus avoided. However, it is also
possible to add only a portion of the complete amount of water to
the grinding process, as long as the amount of water sustains the
forming and maintenance of the particles of the intended size
according to the invention and avoids further swelling and/or
agglomeration of the particles.
[0040] According to another aspect of the invention, the water is
supplemented by an organic solvent, wherein the solvent is chosen
according to the organic solvent which is otherwise used for
forming the membrane spinning solution. Such organic solvent can be
chosen from the group comprising, for example,
N-alkyl-2-pyrrolidones (NAP) such as N-methyl-2-pyrrolidone (NMP),
N-ethyl-2-pyrrolidone (NEP), N-octyl-2-pyrrolidone (NOP); dimethyl
acetamid (DMAc); dimethylformamide (DMF); dimethylsulfoxide (DMSO);
formamide; THF; butyrolactone; especially 4-butyrolactone; and
.epsilon.-caprolactam or mixtures thereof. However, any other
organic solvent may be used in the process which is also used as an
organic solvent for the preparation of synthetic membranes. Such
organic solvents are generally known in the art. According to one
aspect of the present invention, a mixture of water and NMP is used
for grinding the ion exchange material.
[0041] According to another aspect of the invention,
polyvinylpyrrolidone (PVP) can be added to the grinding solution in
addition to the water and the optional organic solvent. The PVP
concentration may vary. In general, the PVP concentration will be
determined by the composition of the final polymer spinning
solution. Particles for doped membranes based on polymer
compositions which comprise PVP can thus be grinded in a solution
which may include PVP in a concentration of up to the total amount
of PVP which will be added to the polymer spinning solution. For
example, a membrane without particles may consist of 80-99% by
weight of a hydrophobic polymer, such as polyethersulfone, and
1-20% by weight of a hydrophilic polymer, such as
polyvinylpyrrolidone. The PVP consists of a high (.gtoreq.100 kD)
and low (<100 kD) molecular component, wherein the PVP consists
of 10-45 weight-%, based on the total weight of PVP in the
membrane, of a high molecular weight component, and of 55-90
weight-%, based on the total weight of PVP in the membrane, of a
low molecular weight component. The spinning solution for preparing
a membrane according to the present invention comprises, for
example, between 12 and 19 weight-% of a hydrophobic polymer and 5
to 12 weight-% of PVP, wherein said PVP consists of a low and a
high molecular PVP component. Examples for high and low molecular
weight PVP are, for example, PVP K85/K90 and PVP K30, respectively.
PVP was found to stabilize the grinding suspension and foster the
maintenance of the particles at the desired size.
[0042] It is another aspect of the present invention that the
grinding time can be significantly reduced by such grinding
process. In addition, the energy expenditure is also significantly
reduced as, surprisingly, the softer material proved to be grinded
more readily in a process according to the invention. Usually,
brittle or recalcitrant material is better suited for grinding.
[0043] Various grinding mills can be used for a grinding process
according to the invention. Such mills should be able to control
pressure, temperature and energy input. Agitator bead mills are
commercially available, for example, from manufacturers such as
Nitzsch, Hosokawa Alpine or WAB. For example, the LABSTAR mills of
Nitzsch, which are generally used for laboratory scale
applications, can be used in accordance with the present invention.
The achieved process data for the specific grinded material can
then be used for a scale up and may be applied for production
machines available from the same producer.
[0044] According to one aspect of the present invention, the
membrane may effectively be used for removing or purifying from a
liquid substances which bind to or are adsorbed to the material
which is entrapped in the membrane according to the invention.
According to one aspect, the membranes of the invention are used
for the removal or purification of nucleic acids from a liquid.
According to another aspect, the membranes of the invention are
used for the removal or purification of certain target substances,
comprising endogenous and/or exogenous toxins, from a liquid. Such
liquid may comprise, for example, whole blood, blood products such
as, for example, blood fractions like blood plasma, cell culture
suspensions or their supernatant and/or any fractions thereof, and
solutions based on water, organic solvents or mixtures thereof and
from which one or more compounds are to be removed or purified from
and which will bind or adsorb to the hydrophobic or hydrophilic
material, such as ion exchange or activated carbon particles, with
which the membrane has been doped. The material to be entrapped in
the membrane will have to be chosen according to the target
compounds which shall be removed or purified from the liquid in
question.
[0045] The membranes of the invention may be prepared and used in
various geometries, such as, for example in hollow fiber geometry.
The membranes may also be prepared as flat sheet membranes. It is
also possible to prepare solid membranes. According to one aspect
of the invention, the wall thickness of the hollow fiber membrane
is below 150 .mu.m. In another aspect of the invention, the inner
diameter of a solid or hollow fiber membrane is below 400 .mu.m,
generally between 250 .mu.m and 400 .mu.m.
[0046] According to another aspect of the invention, the membrane
is used for the removal, adsorption, isolation and/purification of
certain compounds from blood or blood products, such as, for
example, blood plasma. According to yet another aspect of the
invention, the membrane is used for the removal, adsorption,
isolation and/purification of certain compounds from aqueous
solutions, such as, for example, water or dialysate.
[0047] According to one aspect of the invention, the membranes are
characterized in that they have particles entrapped therein,
wherein the particles may consist of activated carbon particles
and/or hydrophobic particles based on styrene-divinylbenzene
copolymers and/or ion exchange material, such as cation exchange
material or anion exchange material, for example anion exchange
material based on polyquaternary ammonium functionalized styrene
divinylbenzene copolymers.
[0048] According to another aspect, the invention relates to
membranes which are characterized in that they have particles
entrapped therein, wherein the particles consist of basic anion
exchange material based on polyquaternary ammonium functionalized
vinylimidazolium methochloride vinylpyrrolidone copolymers, such
as, for example, Luviquat.RTM..
[0049] According to a further aspect of the present invention, the
polyquaternary ammonium functionalized styrene divinylbenzene
copolymers and vinylimidazolium methochloride vinylpyrrolidone
copolymers are functionalized with at least one quaternary ammonium
selected from the group consisting of dimethyl(2-hydroxyethyl)
ammonium, trimethylbenzyl ammonium, dimethylethanolbenzyl ammonium,
dimethylethanol ammonium and benzyltriethyl ammonium. According to
yet another aspect of the present invention, the functionalized
polyquaternary ammonium copolymer is used in its chloride form for
preparing and providing the membrane of the invention.
[0050] According to another aspect of the present invention the
particles make up for 5-40 wt.-% of the total membrane mass.
According to yet another aspect of the present invention, the
particles are present in an amount of between 20 to 35 wt.-% of the
total membrane.
[0051] According to another aspect of the present invention, the
particles have an average size of below 15 .mu.m in diameter.
According to yet another aspect of the present invention, the
particles have an average size of between 0.1 and 10 .mu.m in
diameter. According to yet another aspect of the present invention,
the particles have an average size of between 0.1 and 1.0 .mu.m in
diameter.
[0052] According to a further aspect of the present invention, the
membrane is otherwise comprised of at least one hydrophobic polymer
selected from the group consisting of polysulfones,
polyethersulfones, polyamides and polyacrylonitriles and at least
one hydrophilic polymer. According to yet another aspect of the
present invention, the hydrophilic polymer is selected from the
group consisting of polyvinylpyrrolidone (PVP), polyethylene glycol
(PEG), polyglycolmonoester, water soluble cellulosic derivates,
polysorbate and polyethylene-polypropylene oxide copolymers. The
particle content in the polymer spinning solution may vary.
According to one aspect, the particle content is from about 0.1 to
12 wt.-% of the spinning solution. According to another aspect, the
particle content in the spinning solution is from 1 to 10 wt.-% of
the spinning solution. According to yet another aspect of the
invention, the particle content is from 1 to 8 wt.-% of the
spinning solution.
[0053] According to one aspect of the present invention, the doped
membranes of the invention are microporous membranes. Microporous
membranes are known in the art and can be prepared, for example,
according to what is disclosed in EP 1 875 957 A1, incorporated
herein by reference. The expression "microporous" as used herein
refers to membranes which are characterized by an average pore
diameter of the selective separation layer in the membrane in the
range of 0.1 to 10 .mu.m, preferably 0.1 to 1.0 .mu.m.
[0054] According to one aspect of the present invention, doped
microporous hollow fibre membranes can be prepared in a process
comprising the steps of extruding a polymer solution through the
outer ring slit of a hollow fibre spinning nozzle, simultaneously
extruding a centre fluid through the inner bore of the hollow fibre
spinning nozzle, into a precipitation bath, whereby the polymer
solution contains 0.1 to 10 wt.-% of hydrophobic and/or ion
exchange particles, 10 to 26 wt-% of a hydrophobic polymer, such as
polysulfone (PSU), polyethersulfone (PES) or polyarylethersulfone
(PAES), 8 to 15 wt-% polyvinylpyrrolidone (PVP), 55 to 75 wt-% of a
solvent such as, for example, NMP, and 3 to 9 wt-% water. The
centre fluid contains 70 to 90 wt-% of a solvent such as, for
example, NMP, and 10 to 30 wt-% water, and the precipitation bath
contains 0 to 20 wt-% of a solvent such as, for example, NMP, and
80 to 100 wt-% water.
[0055] According to another aspect of the present invention, the
doped membranes of the invention are ultrafiltration membranes.
Membranes of this type can be characterized by a pore size, on the
selective layer, of from about 2 to 6 nm as determined from dextran
sieving experiments. The preparation of ultrafiltration membranes
is known in the art and are described in detail, for example, in
U.S. Pat. No. 4,935,141, U.S. Pat. No. 5,891,338 and EP 1 578 521
A1, all of which are incorporated herein by reference. According to
one aspect of the invention, doped ultrafiltration membranes
according to the invention are prepared from a polymer mixture
comprising particles and hydrophobic and hydrophilic polymers in
amounts such that the fraction of hydrophobic polymer in the
polymer solution used to prepare the membrane is from 5 to 20% by
weight and the fraction of the hydrophilic polymer is from 2 to 13%
by weight.
[0056] According to another aspect of the present invention, the
polymer solution for preparing a membrane according to the
invention comprises from 0.1-8 wt.-% of ion exchange and/or
hydrophobic particles, 11 to 19 wt.-% of a first polymer selected
from the group consisting of polysulfone (PS), polyethersulfone
(PES) and polyarylethersulfone (PAES), from 0.5 to 13 wt.-% of a
second polymer such as polyvinylpyrrolidone (PVP), from 0 wt.-% to
5 wt.-%, preferably from 0.001 to 5 wt.-% of a polyamide (PA), from
0 to 7 wt.-% of water and, the balance to 100 wt.-%, of a solvent
selected from the group consisting of N-methyl-2-pyrrolidone (NMP),
which is preferred, N-ethyl-2-pyrrolidone (NEP),
N-octyl-2-pyrrolildone (NOP), dimethyl acetamide, dimethyl
formamide (DMF), dimethyl sulfoxide (DMSO) and gammabutyrolactone
(GBL).
[0057] In yet another aspect of the present invention, the polymer
solution used to prepare the membrane of the invention comprises in
addition to the particles contained in the doped membrane from 12
to 15 wt.-% polyethersulfone or polysulfone as hydrophobic polymer
and from 5 to 10 wt.-% PVP, wherein said PVP consists of a low and
a high molecular PVP component. The total PVP contained in the
spinning solution consists of from 22 to 34 wt.-%, preferably of
from 25 to 30 wt.-%, of a high molecular weight (>100 kDa)
component and from 66 to 78 wt.-%, preferably from 70 to 75 wt.-%
of a low molecular weight (<=100 kDa) component. Examples for
high and low molecular weight PVP are, for example, PVP K85/K90 and
PVP K30, respectively. The polymer solution used in the process of
the present invention preferably further comprises from 66 to 86
wt.-% of solvent and from 1 to 5 wt.-% suitable additives. Suitable
additives are, for example, water, glycerol and/or other alcohols.
Water is especially preferred and, when used, is present in the
spinning solution in an amount of from 1 to 8 wt.-%, preferably
from 2 to 5 wt.-%. The solvent used in the process of the present
invention preferably is chosen from N-methylpyrrolidone (NMP),
dimethyl acetamide (DMAC), dimethyl sulfoxide (DMSO), dimethyl
formamide (DMF), butyrolactone and mixtures of said solvents. NMP
is especially preferred. The center fluid or bore liquid which is
used for preparing the membrane comprises at least one of the
above-mentioned solvents and a precipitation medium chosen from
water, glycerol and other alcohols. Most preferably, the center
fluid consists of 45 to 70 wt.-% precipitation medium and 30 to 55
wt.-% of solvent. Preferably, the center fluid consists of 51 to 57
wt.-% of water and 43 to 49 wt.-% of NMP. Methods for preparing
such membranes are disclosed in detail in European Patent
Application No. 08008229, incorporated herein by reference.
[0058] According to yet another aspect of the present invention,
the doped membranes of the invention are so called protein
separation membranes, sometimes also referred to as "plasma
purification or "plasma fractionation membrane". Such membrane is
characterized by allowing the passage of .gtoreq.90% of molecules
having a molecular weight of below 100 kD, while molecules having a
molecular weight of >1000 kD will pass the membrane wall only to
a very limited extend (.ltoreq.10%). The membrane thus allows to
separate plasma in fractions with mainly larger proteins/lipids and
smaller proteins, such as, for example, albumin. Membranes of this
type are known and also commercially available, for example the
"Monet.RTM." filter (Fresenius Medical Care Deutschland GmbH).
[0059] According to one aspect of the present invention, the
membranes have hollow fiber geometry. According to another aspect
of the present invention, the membranes have flat sheet
geometry.
[0060] It is another object of the present invention to provide a
method for preparing the membrane of the invention in hollow fiber
geometry, wherein the method comprises (a) grinding the particles
to an average size of up to 15 .mu.m in an aqueous solution which
optionally also comprises PVP and/or an organic solvent; (b)
optionally further suspending the grinded particles in an organic
solvent; (c) combining the at least one hydrophilic and the at
least one hydrophobic polymer with the suspension of step (a) or
(b); (d) stirring the polymer particle suspension to obtain a
polymer solution wherein the particles are suspended; (e) degassing
the polymer particle suspension; (f) extruding the polymer solution
together with the suspended particles through an outer ring slit of
a nozzle with two concentric openings, wherein a center fluid is
extruded through the inner opening of the nozzle; (g) optionally
exposing the polymer solution on the outside of the precipitating
fiber to a humid steam/air mixture comprising a solvent in a
content of between 0 and 10% by weight related to the water
content; (h) immersing the precipitating fiber in a bath of
non-solvent; (i) washing and optionally drying and sterilizing the
membrane.
[0061] It is another object of the present invention to provide a
method for preparing the membrane of the invention in flat sheet
geometry, wherein the method comprises (a) grinding the particles
to an average size of up to 15 .mu.m in an aqueous solution,
optionally in the presence of PVP and/or an organic solvent; (b)
optionally further suspending the particle solution in organic
solvent; (c) combining the at least one hydrophilic and the at
least one hydrophobic polymer with the suspension of step (a) or
(b); (d) stirring the polymer particle suspension to obtain a
polymer solution wherein the particles are suspended; (e) degassing
the polymer particle suspension; (f) casting the polymer solution
together with the suspended particles as an uniform film onto a
smooth surface; (g) washing the membrane and optionally drying
and/or sterilizing the membrane.
[0062] In yet another aspect of the present invention, it is of
course possible to create hollow fiber membranes based on the
present invention, wherein the membranes have multiple layers which
are concentrically arranged and wherein at least one of the layers
comprises 5-40 wt.-% of particles having an average particles size
of below 15 .mu.m entrapped in the membrane according to the
invention. The layer adjacent to the layer containing ion exchange
and/or carbon particles is preferably the one which contacts the
blood in applications which involve the treatment of blood or blood
components, e.g. in an extracorporeal system. Like that, the risk
of any particles being washed out of the membrane is minimized. It
is also possible to have adjacent layers to the outer and inner
surface of the particle containing layer. The multi layer membranes
can be produced in analogy to what is disclosed in WO 2006/019293
A1, which is incorporated herein by reference.
EXAMPLES
Example 1
Grinding of Ion Exchange Resin in the Presence and Absence of
Water
[0063] Grinding was performed with a LabStar LS1 grinding mill of
Netzsch. Dowex.RTM. 1.times.2 anion exchanger was grinded in two
separate batches A and B in the presence of water and NMP as an
organic solvent (see also FIGS. 4A and 4B, corresponding to Batch B
and Batch A, respectively). Batch C was grinded in the absence of
water. Table I summarizes the settings for the grinding
procedure.
TABLE-US-00001 TABLE I Batch A Batch B Batch C (RF070205A)
(RF070207A) (RF061106A) Ion exchange Dowex .RTM. Dowex .RTM. Dowex
.RTM. material 1x2-Cl, 1x2-Cl, 1x2-Cl, 1000 g 500 g 500 g Solvent
Water/NMP Water/NMP NMP (247.1 g/1300 g) (247.1 g/1300 g) (2000 g)
Agitator 3000 1/min 3000 1/min 3000 1/min speed Throughput 74 kg/h
76 kg/h 60 kg/h Energy input 3.99 kWh 1.81 kWh 7.96 kWh Grinding
Zirconium Zirconium Zirconium material oxide oxide Oxide Filler 90%
90% 90% Loading Treatment 120 min 60 min 300 min time Particle
diam- d99 = 7.6 .mu.m d99 = 5.9 .mu.m d99 = 8.0 .mu.m eter on cu-
mulative %
[0064] The process data were collected for controlling energy
input, pump speed and the resulting average size of the grinded
particles. FIG. 4 shows the results for the above batches of Table
I. As can be seen, Batch A resulted in particles with q99%:7.6
.mu.m. Batch B resulted in particles with q99%:5.9 .mu.m. A
considerable portion of the particles in Batches A and B, in the
presence of water, have a diameter of well below 1 .mu.m.
[0065] Comparative Batch C (see also FIG. 5) resulted in particles
with q99%:8.0 .mu.m, which per se was a satisfying result with
regard to the goal of having particles of at least below 15 .mu.m.
However, the resulting particles of Batches A and B were already
swollen. The particles of Batch C, however, had not yet been
contacted with the water present in the spinning solution (see
Example 2.2).
Example 2
2.1 Preparation of a Spinning Solution which Contains Particles
Grinded in the Presence of Water
[0066] The particles of Batch A (see Example 1) were used for the
preparation of a spinning solution for preparing a microporous
doped membrane. The polymer composition was chosen to be a
combination of hydrophobic polyethersulfone (PES) and a mixture of
polyvinylpyrrolidone having high molecular weight (PVP K85) and low
molecular weight (PVP K30). The spinning solution further comprised
NMP as a solvent and water.
[0067] Batch A (2414.48 g) was comprised, after grinding, of anion
exchange particles (19.88%), NMP (65.21%) and H.sub.2O (14.91%).
This suspension was filled into a glass reactor and 1362.97 g NMP
were added. The suspension was stirred at U=600 min.sup.-1 until
the suspension was homogenous. This was followed by a one hour
treatment, under stirring, with an ultrasonic device of Hielscher
(UP 400S) for the homogenization and deagglomeration of the
suspension. The UP 400S was set to Cycle 1, Amplitude 45% and an
energy input of 150 W.
[0068] PVP K85 (180 g) was then added to the suspension and the
stirrer was set to 1000 min.sup.-1. The PVP K85 was dissolved under
stirring and ultrasound for one hour. 360 g PVP K30 were then added
and also dissolved under stirring and ultrasound. 960 g PES were
then added and after 15 minutes the ultrasound device was removed.
The stirring velocity was adapted to the apparent viscosity of the
suspension. After the PES had completely been solved the average
particle size was determined in a particle counter. To this end,
100 .mu.l of the solution were taken and added to 600 ml NMP in a
glass bottle. The sample was stirred for about 15 to 20 minutes.
The particle counter was set as follows. Channel setting: 16/2-100
.mu.m, sample volume; 5 ml; flow rate: 60 ml/min; number of runs:
9; dilution factor: 1.0; discard first run. No particles larger
than about 15 .mu.m could be detected in the spinning solution.
[0069] The spinning solution ready for spinning was comprised of
(wt.-%) grinded Dowex.RTM. 1.times.2 anion exchanger: 8%; NMP: 61%;
PVP K85: 3%; PVP K30: 6%; PES: 16%; H.sub.2O: 6%.
[0070] The spinning solution comprising the particles of Batch B
was prepared accordingly. Batch (1622.9 g) B contained, after
grinding, grinded Dowex.RTM. 1.times.2 particles (17.75%, NMP:
68.87% and water (13.35%). NMP (1083.82 g) was added to the
suspension which was treated as described above for Batch A and PVP
K85 (108.27 g), PVP K30 (216.54 g) and PES (577.44 g) were added.
No particles larger than about 15 .mu.m could be detected in the
spinning solution. The spinning solution ready for spinning was
comprised of (wt.-%) grinded Dowex.RTM. 1.times.2 anion exchanger:
8%; NMP: 61%; PVP K85: 3%; PVP K30: 6%; PES: 16%; H.sub.2O: 6%.
2.2 Preparation of a Comparative Spinning Solution which Contains
Particles Grinded in the Presence of Organic Solvent
[0071] The anion exchanger particle suspension of Example 2 (Batch
C) after grinding contained NMP (222.07) and 25 wt.-% of the anion
exchange particles (191.92 g). The suspension was treated with
ultrasound as described in Example 2.1 for 1 h. Several batches
were treated (separately) in order to guarantee an optimal
homogenization and deagglomeration. The treated suspensions were
then transferred to a three-necked flask. The final content of NMP
in the flask was set to a total of 1830 g NMP (61 wt.-% of the
final polymer solution) and 239.9 g of the anion exchange material
(8% of the final polymer solution). PVP K85 (90 g) was slowly added
to the solution (3% of the final polymer solution), followed by the
careful addition of 180 g PVP K30 (6% of the final polymer
solution). Ultrasound treatment was applied until the PVP
components had completely dissolved. Then PES (480 g) was added
slowly (16% of the final polymer solution) at a temperature of
45.degree. C. Finally, H.sub.2O (180 g) was carefully added (6% of
the final polymer solution).
[0072] The control of the particle size after each step gave the
following results: (1) after mixing particles and NMP: d99=20
.mu.m; (2) after addition of PVP K85: d99=30 .mu.m; (3) after
addition of PVP K30: d99=30 .mu.m; (4) after addition of PES:
d99=25 .mu.m; (5) after complete addition of water: d99=30 .mu.m.
The polymer solution was then used for spinning.
Example 3
Preparation of Doped Hollow Fiber Membranes
[0073] Spinning of hollow fibers was done as described in the art
for all polymer solutions of Example 2. The polymer and solvent
components used for the various membranes are set forth again in
Table II, wherein samples 2-3a were prepared with the spinning
solution containing Batch A particles (Ex. 1 and 2.1) and samples
4-5 were prepared with the spinning solution containing Batch B
particles (Ex. 1 and 2.1). Sample 1 was prepared from a spinning
solution according to Ex. 2.2 comprising particles as described in
Ex. 1 (Batch C). Table II also shows the composition of the center
fluid which was used for the spinning process.
TABLE-US-00002 TABLE II Polymer solution PVP PVP DOWEX Center PES
K85 K30 1X2 H.sub.2O NMP Viscosity H.sub.2O NMP Samples % % % % % %
cP % % 1 16 3 6 8 6 61 ~200000 22 78 2-3a 110000 4-5 112200
[0074] For the spinning process, the respective polymer solutions
of Example 2 were transferred into stable stainless steel
containers. The containers were closed and vacuum was applied for
degassing the solutions. The solution was degassed and then heated
to 50.degree. C. and passed through a spinning die
(1200.times.440.times.220 .mu.m) into the precipitation bath. As
center fluid, a mixture of 22% H.sub.2O and 78% NMP was used (Table
II). The temperature of the die (SD) and of the spinning shaft (SS)
can be derived from Table III. The hollow fiber membrane was formed
at a spinning speed of between 13.0 and 13.2 m/min (see Table III).
The liquid fiber leaving the die was passed into a heated
precipitation (water) bath having a temperature of about 65.degree.
C. (see Table III). The fiber, at leaving the die, was surrounded
by water vapor from the precipitation bath. The distance between
the exit of the die and the precipitation bath was 7 to cm (see
Table III). The precipitated fiber was guided through several water
baths and subjected to online-drying followed by undulation of the
fiber. The fibers were transferred into bundles.
[0075] The resulting hollow fiber membranes had an inner diameter
of between 375 and 388 .mu.m and a wall thickness of between 116
and 122 .mu.m (see Table IV).
TABLE-US-00003 TABLE III Spinning Parameters Distance Precipitation
Spinning to Water Bath Temperature Speed Bath T NMP Spinning
Spinning Sample [m/min] [cm] [.degree. C.] [%] Nozzle Shaft 1 13
8.sup.1 55 0 50 50 2 13 8.sup.1 ca. 65 0 46 52-54 3 13.2 7.sup.2
ca. 65 0 47 54 3a 13.2 7.sup.2 ca. 64 0 46 53 4 13.2 7.sup.2 ca. 65
0 47 54 5 13.2 7.sup.2 ca. 65 0 48 54 .sup.1Spinning shaft with 1
cm distance to water surface. .sup.2Spinning shaft directly on
water surface.
TABLE-US-00004 TABLE IV Dimensions Inner diameter Wall thickness
Sample .mu.m .mu.m 1 380 120 2 385 118 3 383 116 3a 380 115 4 375
122 5 388 118
Example 4
Preparation of Hollow Fiber Membranes Doped with Amberlite.RTM. IRA
410 or PEI, Dowex.RTM. 1.times.2 Anion Exchanger Plus Carbon
Particles
[0076] Doped microporous hollow fiber membranes were prepared
according to Example 3, wherein polyethyleneimine (PEI, see Samples
1-12, 14-16 in Table Va) and both grinded Dowex.RTM. 1.times.2
anion exchange particles and highly conductive carbon black
particles Printex.RTM. XE2 (Degussa AG), see Samples 13, 17-24 in
Table V, were entrapped in the membrane. The preparation of the
spinning solution was done as described before in Example 2.1. The
polymer composition was as set forth in Table V. Table VI
summarizes the spinning parameters which were applied for the
production of this double-doped membrane. Samples 1-16 were online
dried and subjected to an undulation of the fibers. For Samples
1-16 standard 500.times.350.times.170 .mu.m were used. For the
rest, 1200.times.440.times.220 .mu.m spinning nozzles were
used.
TABLE-US-00005 TABLE V Polymer Solution PVP PVP DOWEX .RTM. Center
PAES K85 K30 1X2 PRINTEX .RTM. H.sub.2O NMP PEI H.sub.2O NMP Sample
% % % % XE2 % % % % % 1 17.75 3 8 0 0 0.96 69.99 0.3 46 54 2 17.75
3 8 0 0 0.96 69.99 0.3 44 56 3 17.75 3 8 0 0 0.96 69.99 0.3 42 58 4
17.75 3 8 0 0 0.96 69.99 0.3 40 60 5-12, 17.75 3 8 0 0 0.96 69.99
0.3 38.5 61.5 14-16 13, 17 3.25 7 4 0 6 62.75 0 22 78 17-19 20-22
16 3 6 8 0 6 61 0 22 78 23, 24 16 3 6 7 1 6 61 0 22 78
[0077] Hollow fiber membranes which contained Amberlite.RTM.
IRA-410 particles were prepared accordingly, based on the following
polymer compositions (Table Vb). Samples 10-13 were prepared for
comparative reasons without any Amberlite.RTM. IRA-410 particles.
Triple spinnerets were used for Samples 10-16. Other spinnerets
used were a 600.times.305.times.170 .mu.m spinneret for Samples 2
and 6-9, a 500.times.350.times.170 .mu.m spinneret for Sample 1 and
a 1200.times.440.times.220 for Samples 3-5. Spinning was done as
summarized in Table VIb. Inner diameter and wall thickness are also
shown in Table VIb. DNA retention capability (adsorption) was
measured with salmon sperm DNA (c=40 .mu.g/ml, dialysate, RT, Q=1.9
ml/min, t=50 min). The results are shown in FIG. 8 in comparison to
a membrane without any entrapped Amberlite.RTM. IRA-410. It can be
seen that the presence of the ion-exchanger leads to a clear
reduction of the DNA concentration.
TABLE-US-00006 TABLE Vb Polymer Solution Center PVP PVP Amberlite
.RTM. PVP PES K90 K30 IRA-410 H.sub.20 NMP H.sub.20 K90 NMP Sample
[%] [%] [%] [%] [%] [%] [%] [%] [%] 1 13.1 1.9 4.8 3.9 2.9 73.4 56
0 44 2 13.5 1.5 5 1.3 3 75.7 56 0 44 3 13.3 1.5 4.9 2.7 2.9 74.7 56
0 44 4 13.3 1.5 4.9 2.7 2.9 74.7 56 0 44 5 13.3 1.5 4.9 2.7 2.9
74.7 56 0 44 6 13.1 1.5 4.8 3.9 2.9 73.8 56 0 44 7 13.1 1.5 4.8 3.9
2.9 73.8 56 0 44 8 13.1 1.5 4.8 3.9 2.9 73.8 56 0 44 9 17.1 2.9 6.6
5.1 0 68.3 43 0 57 10 13.6 2 5 0 3 76.4 56 0 44 11 13.6 2 5 0 3
76.4 56 0 44 12 13.6 2 5 0 3 76.4 56 0 44 13 13.6 2 5 0 3 76.4 56 0
44 14 13.6 2 5 1.36 3 75.04 56 0 44 15 13.6 2 5 1.36 3 75.04 56 0
44 16 13.6 2 5 1.36 3 75.04 56 0 44
TABLE-US-00007 TABLE VI Spinning Conditions Precipitation Distance
to bath Temperature v.sub.ab water bath T NMP SK SS Sample [m/min]
[cm] [.degree. C.] [%] .degree. C. .degree. C. 1 10 4 30 80 60 -- 2
10 4 30 80 60 -- 3 10 4 31 80 60 -- 4 10 4 31 80 60 -- 5 10 4 31 80
57 -- 6 10 4 31 80 60 -- 7 10 4 31 80 63 -- 8 10 4 31 80 66 -- 9 10
4 30 80 49 -- 10 10 4 30 80 51 -- 11 10 4 30 80 53 -- 12 10 4 30 80
56 -- 13 13 .sup. 8.sup.1 51 0 50 ~46 14 10 4 30 80 55 -- 15 10 4
30 80 57 -- 16 10 4 30 80 59 -- 17 13 .sup. 8.sup.1 51 0 50 ~45 18
13 .sup. 8.sup.1 51 0 50 ~45 19 13 .sup. 8.sup.1 51 0 50 ~45 20 13
.sup. 8.sup.1 52 0 50 ~46 21 13 .sup. 8.sup.1 57 0 50 ~48 22 13
.sup. 8.sup.1 56 0 50 ~48 23 13 .sup. 8.sup.1 51 0 50 ~45 24 13
.sup. 8.sup.1 57 0 50 ~49 .sup.1hot precipitation bath with 1 cm
distance to the bath
[0078] The dimensions of the fibers with Dowex.RTM. 1.times.2 and
Printex.RTM. XE2 particles are shown in Table VII. It was possible
to reduce the wall thicknesses to about 50 .mu.m for fibers with
PEI and to about 70 to 80 .mu.m for fibers with Dowex.RTM.
1.times.2 anion exchange particles and carbon black particles
Printex.RTM. XE2.
TABLE-US-00008 TABLE VIb Temper- Temper- Dimensions Distance ature
ature Inner Wall to precip. Spinning Spinning Diam- Thick- Sam-
bath v.sub.ab Nozzle Shaft eter ness ple [cm] [m/min] [.degree. C.]
[.degree. C.] [.mu.m] [.mu.m] 1 100 20 51 45 nd nd 2 100 20 51 45
254 53 3 100 17 51 45 270 88 4 100 17 51 45 274 92 5 100 17 53 48
265 92 6 100 17 51 45 256 75 7 100 18 53 48 257 73 8 100 18 53 48
243 70 9 68 17 47 45 318 50 10 100 45 55 50 212 48 11 100 45 55 50
212 48 12 100 37 57 52 211 74 13 100 37 57 52 211 74 14 80 37 58 55
213 71 15 80 37 58 55 213 71 16 100 45 55 50 211 53
TABLE-US-00009 TABLE VII Dimensions Inner diameter Wall thickness
Sample .mu.m .mu.m 1 214 50 2 218 50 3 213 50 4 216 51 5 215 51 6
218 52 7 215 48 8 218 50 9 217 51 10 217 52 11 215 51 12 213 51 13
320 50 14 219 50 15 213 52 16 215 50 17 321 50 18 323 79 19 321 50
20 318 77 21 317 78 22 258 80 23 321 78 24 326 77
Example 5
Preparation of Flat Sheet Membranes Containing Luviquat.RTM. FC 370
Particles
[0079] Doped flat sheet membranes containing Luviquat.RTM. FC 370
(BASF AG) particles (poly[(3-methyl-1-vinylimidazolium
chloride)-co-(1-vinylpyrrolidone)]polyquaternium), were prepared.
The polymer solution contained 13.6 wt.-% PEAS, 2.0 wt.-% PVP K90,
5.0 wt.-% PVP K30 and 79.4 wt.-% NMP. All components were dissolved
in NMP and stirred at 60.degree. C. The suspension was additionally
filtered (50 .mu.m). The precipitation solution, having a
temperature of 50.degree. C., contained 56 wt.-% water and 44 wt.-%
NMP. The final polymer solution was cast as uniform film onto a
smooth surface (glass slide) which acted as supporting area by
utilizing a special coating knife. First, the polymer solution at
60.degree. C. was directly applied steady-going onto the glass
slide using a syringe. The coating knife was driven with a constant
velocity, thus creating a uniform polymer film. This glass slide
with the thin polymer film was quickly dipped into the
precipitation bath. Subsequently, the precipitated membrane was
taken out, stored in non-solvent until all membranes of a series
were prepared and then cut into a defined size. After cutting, the
membranes were washed with distilled water, dried and finally
packed in special bags used for sterilization.
Example 6
Preparation of Flat Sheet Membranes Doped with Amberlite.RTM.
IRA-410 (Comparative Example)
[0080] Doped flat sheet membranes were prepared according to
Example 5, wherein Amberlite.RTM. IRA-410 (chloride form) particles
were entrapped in the membrane at different concentrations (0%, 30%
and 50%). The Amberlite.RTM. particles were suspended in water and
grinded and the material was passed through a PE net (50 .mu.m and
20 .mu.m) in order to remove particles with a size of above 20
.mu.m. The excess water was then removed in a vacuum rotary
evaporator and NMP was added, followed by another treatment with
the vacuum rotary evaporator for the removal of remaining water.
The other components of the polymer solution were then added to the
NMP suspension (see Table VIII). An agglutination of the particles
was visible at that stage already.
Example 7
[0081] Preparation of Membranes Doped with Modified
Poly(p-phenylene ether) (PPE)
[0082] Doped microporous hollow fiber membranes were prepared
according to Example 3, wherein modified PPE was added to the
membrane as anion-exchanger. The modified PPE (FUMA-Tech GmbH, St.
Ingbert, 5 or 15% solution) was produced by bromination of PPE,
dissolving it in NMP and reacting it with N-methylimidazole. The
resulting structure is as follows:
##STR00001##
[0083] The polymer composition was as set forth in Tables VIII.
Table VIII (a) shows the composition for preparing an
ultrafiltration membrane with (a1-a3) and without (a4) anion
exchange component. The resulting membrane was prepared as shown in
Table VIII (b). The inner diameter was about 213-217 .mu.m and the
wall thickness about 48-50 .mu.m. Then, the DNA retention was
compared (Table VIII (c)) with the help of mini-modules. Again,
salmon sperm DNA (40 mg/1) was used, dead end filtration at 2
ml/min, t=100 min. The retention of DNA could be improved by the
anion exchanger.
TABLE-US-00010 TABLE VIII(a) Polymer Center mod. PVP PVP PVP Sam-
PAES PPE K90 K30 H.sub.20 NMP H.sub.20 K30 NMP ple % % % % % % % %
% a1 13.72 0.28 2 5 2 77.0 56 1 43 a2 13.72 0.28 2 5 2 77.0 55 1 44
a3 13.72 0.28 2 5 2 77.0 54 1 45 a4* 13.55 0 2 5 3 76.4 56 1 43
*with 0.05% polyamide
TABLE-US-00011 TABLE VIII (b) Distance Temperature v.sub.ab to
water Spinning Spinning Sample [m/min] bath [cm] Nozzle Shaft a1 45
100 55 50 a2 45 100 58 53 a3 45 100 58 53 a4 45 100 54.5 48.5
TABLE-US-00012 TABLE VIII(c) Sample DNA-Adsorption [%] a1 50 a4
28
[0084] Table VIII (d) shows the composition for preparing a
microporous membrane with modified PPE (Table VIII (e)). The inner
diameters were 258 and 259 .mu.m for b1 and b2, respectively, with
a wall thickness of 40 and 42 .mu.m. The DNA retention was again
assessed (Table VIII (f)) with mini-modules as described before and
compared with the ultrafiltration membrane a4 which was prepared as
described before in Tables VIII (a) and (b). Again, the DNA
retention capability was clearly improved.
TABLE-US-00013 TABLE VIII(d) Polymer Center mod. PVP PVP PVP Sam-
PAES PPE K90 K30 H.sub.20 NMP H.sub.20 K30 NMP ple % % % % % % % %
% b1 16.7 1.3 3.25 8 0 70.75 43 0 57 b2 16.7 1.3 3.25 8 0 70.75 43
0 57
TABLE-US-00014 TABLE VIII(e) Distance Temperature v.sub.ab to water
Spinning Spinning Sample [m/min] bath [cm] Nozzle Shaft b1 28 60 45
43 b2 28 60 47 45
TABLE-US-00015 TABLE VIII(f) Sample DNA-Adsorption [%] b2 73 a4
30
Example 8
Preparation of Hand Bundles and Mini-Modules
[0085] The preparation of a membrane bundle after the spinning
process is necessary to prepare the fiber bundle for following
performance tests. The first process step is to cut the fiber
bundles to a defined length of 23 cm. The next process step
consists of melting the ends of the fibers. An optical control
ensures that all fibers are well melted. Then, the ends of the
fiber bundle are transferred into a potting cap. The potting cap is
fixed mechanically and a potting tube is put over the potting caps.
Then the fibers are potted with polyurethane. After the
polyurethane has hardened, the potted membrane bundle is cut to a
defined length and stored dry before it is used for the different
performance tests.
[0086] Mini-modules [=fiber bundles in a housing] are prepared in a
similar manner. The mini-modules ensure protection of the fibers
and are used for steam-sterilization. The manufacturing of the
mini-modules comprises the following specific steps: [0087] (A) The
number of fibers required is calculated for an effective surface A
of 360 cm.sup.2 according to equation (1)
[0087] A=.pi..times.d.sub.i.times.l.times.n[cm.sup.2] (1) [0088]
Wherein d.sub.i is the inner diameter of fiber [cm], n represents
the amount of fibers, and 1 represents the effective fiber length
[cm]. [0089] (B) The fiber bundle is cut to a defined length of 20
cm. [0090] (C) The fiber bundle is transferred into the housing
before the melting process
[0091] The mini-module is put into a vacuum drying oven over night
before the potting process.
Example 9
Determining the Liquid Permeability (Lp) of a Membrane
[0092] The permeability was determined with either a hand bundle as
described in Example 8 or with flat sheet membranes. For
determining the Lp of a given hand bundle, said hand bundle is
sealed at one end and a defined amount of water passes through the
bundle under a certain pressure. This process will take a certain
time. Based on said time, the membrane surface area, the pressure
used and the volume of the water which has passed the membrane, the
Lp can be calculated. The equation used is
Lp = V p .times. A .times. t = V .pi. .times. d .times. l .times. n
.times. p .times. t ##EQU00001##
wherein Lp is the convective permeability [10.sup.-4 cm/bars], V is
the water volume [cm.sup.3], p is the pressure [bar], t is the
time, and A is the effective membrane surface of the bundle with
A=.pi.dln. The pressure used was 400 mmHg. For determining the Lp
of a flat sheet membrane, a water bath and test solution (water,
dest.) is heated to 37.degree. C. The membrane (A=27.5 cm.sup.2) is
soaked in the test solution for at least 30 minutes. The soaked
membrane is inserted into the measuring device. A maximum pressure
of 600 mmHg (0.8 bar) is applied. The time needed for the passage
of 1 ml water is determined. The equation used is
Lp = V ( ml ) .times. 750 A ( cm 2 ) .times. p ( mmHg ) .times. t (
s ) . ##EQU00002##
* * * * *