WO1999047587A1

WO1999047587A1 - Continuous crosslinking of polymer gels

Info

Publication number: WO1999047587A1
Application number: PCT/US1999/005662
Authority: WO
Inventors: W. Harry Mandeville, Iii; Stephen Randall Holmes-Farley
Original assignee: Geltex Pharmaceuticals, Inc.
Priority date: 1998-03-19
Filing date: 1999-03-15
Publication date: 1999-09-23
Also published as: AU3005599A

Abstract

The present invention relates to a method for producing a cross-linked polymer gel. The method comprises the steps of (1) contacting a polymer with a cross-linking agent in a chamber under conditions suitable for producing a cross-linked polymer gel; and extruding the cross-linked polymer gel from the chamber. The method can, optionally, further include the step of fragmenting the cross-linked polymer gel of step (1) within the chamber to form cross-linked polymer gel particles. The cross-linked polymer gel particles can then be extruded from the chamber.

Description

CONTINUOUS CROSSLINKING OF POLYMER GELS

BACKGROUND OF THE INVENTION

Crosslinked polymer gels are of interest in a variety of applications. For example, U.S. Patent No. 5,624,963 describes the use of certain crosslinked polymer gels for the removal of bile salts from the body of a patient, as a mechanism for lowering the patient's serum cholesterol level. U.S. Patent Nos. 5,496,545 and 5,667,775 describe the use of certain crosslinked amine polymer gels for lowering the serum phosphate level of a patient.

Despite the increasing interest in crosslinked polymer gels, known methods for the large scale manufacture of these gels are hampered by several disadvantages. For example, the preparation of crosslinked polymer gels using batch reactions results in the formation of a block gel, which must be fragmented into pieces of manageable size and then transported to the final processing steps. Moreover, the physical properties of block gels often hinder processing. For example, poor heat transfer through a gel can lead to poor thermal control of the gel and significantly slow the curing rate of the gel. Such processing difficulties can be a significant disadvantage in the production of large quantities of a polymer gel when product consistency is critical.

It is clear that the need exists for a method for producing crosslinked polymer gels which overcomes the above-stated limitations of prior art methods.

SUMMARY OF THE INVENTION

The present invention relates to a method for producing a crosslinked polymer gel. The method comprises the steps of (1) contacting a polymer with a crosslinking agent in a chamber under conditions suitable for producing a crosslinked polymer gel; and extruding the crosslinked polymer gel from the chamber. The method can, optionally, further include the step of fragmenting the crosslinked polymer gel of step (1) within the chamber to form crosslinked polymer gel particles. The crosslinked polymer gel particles can then be extruded from the chamber. The crosslinking agent is a compound which comprises two or more moieties which are reactive with functional groups on the polymer backbone or polymer side chains.

In one embodiment, the polymer is characterized by a polymerized amino monomer and the crosslinking agent is a compound comprising two or more functional groups which are reactive with amino groups to form a covalent bond. For example, the crosslinking agent can comprise two or more electrophilic functional groups.

In one embodiment, the method of the invention further includes the step of washing the crosslinked polymer gel following extrusion. The polymer gel can be washed, for example, by a continuous filtration process, such as elutriation, by batch washing multiple times or by belt washing.

The present method offers several advantages compared to methods disclosed in the prior art. For example, the method allows the continuous production of a crosslinked polymer gel, thereby avoiding the production of large block gels and the associated process difficulties.

DETAILED DESCRIPTION OF THE INVENTION

The present invention provides an improved process for producing a crosslinked polymer gel. The method comprises the steps of (1) contacting a polymer with a crosslinking agent in a chamber under conditions suitable for producing a crosslinked polymer gel; and (2) extruding the crosslinked polymer gel from the chamber.

In a preferred embodiment, the method further comprises the step of fragmenting the crosslinked polymer gel of step (1) to form crosslinked polymer gel particles. For example, the crosslinked polymer gel can be fragmented within the chamber, producing crosslinked polymer gel particles within the chamber which are then extruded from the chamber. The crosslinked polymer gel can also be fragmented following extrusion of the gel from the chamber. Optionally, the crosslinked polymer gel can be fragmented both within the chamber and following extrusion. For example, in one embodiment, the crosslinked polymer gel is fragmented within the chamber to produce crosslinked polymer gel particles, which are then further fragmented following extrusion from the chamber

The polymer to be crosslinked can be any polymer which is capable of post- polymerization crosslinking. Such polymers preferably comprise functional groups which can be used as reactive sites for crosslinking. The crosslinking reaction results in the formation of a bridging unit which connects reactive sites on two or more adjacent polymer strands.

As used herein, the term "crosslinking agent" refers to a compound capable of crosslinking a pre-polymerized polymer. Such crosslinking agents include at least two functional groups which are capable of reacting with functional groups on the polymer to form covalent bonds. For example, the polymer can comprise nucleophilic functional groups and the crosslinking agent can include electrophilic functional groups which are reactive with the polymer functional groups.

In a preferred embodiment, the polymer is characterized by a polymerized amine monomer. An amine monomer comprises one or more amino groups, such as primary, secondary or tertiary amino groups. The amino groups can be incorporated within the polymer backbone or pendant from the polymer backbone, i.e., incorporated in a polymer side chain. Suitable examples of such amino monomers include allylamine, vinylamine, diallylamine, diallylmethylamine and ethyleneimine.

The polymer to be crosslinked can be a homopolymer or a copolymer. Suitable homopolymers include polymers include poly(allylamine), poly(diallylamine), poly(vinylamine), poly(diallylmethylamine) and poly(ethyleneimine). The polymer can also be a copolymer characterized by a polymerized amino monomer and one or more additional polymerized co- monomers. The comonomer or comonomers can be any suitable monomer which copolymerizes with the amino monomer and can, optionally, also include an amino group. In one embodiment, the polymer is characterized by two polymerized amine monomers which differ only in the substitution of the amino nitrogen atom. Preferably, the polymer is not crosslinked, i.e. the polymer is a linear polymer. However, polymers which are crosslinked to an extent which is not sufficient for gelation can also be used as the starting polymer in the present process. Such crosslinked polymers can, for example, be characterized by a multifunctional comonomer, such as a compound comprising two or more vinyl groups. Suitable multifunctional co-monomers include diacrylates, triacrylates, tetraacrylates, dimethacrylates, diacrylamides, diallylacrylamide, di(methacrylamides), triallylamine and tetraallylammonium ion. Specific examples include ethylene glycol diacrylate, propylene glycol diacrylate, butylene glycol diacrylate, ethylene glycol dimethacrylate, butylene glycol dimethacrylate, methylene bis(methacrylamide), ethylene bis(acrylamide), ethylene bis(methacrylamide), ethylidene bis(acrylamide), ethylidene bis(methacrylamide), pentaerythritol tetraacrylate, trimethylolpropane triacrylate, bisphenol A dimethacrylate, and bisphenol A diacrylate. Other suitable multifunctional monomers include polyvinylarenes, such as divinylbenzene.

Polymers comprising amino groups can be crosslinked by reacting the polymer with a suitable crosslinking agent to form bridging units which covalently link amino groups on adjacent polymer strands. Suitable bridging units include straight chain or branched, substituted or unsubstituted alkylene groups, diacylalkylene groups, diacylarene groups and alkylene bis(carbamoyl) groups. Examples of suitable bridging units include -(CH₂)_n-, wherein n is an integer from about 2 to about 20; -CH₂-CH(OH)-CH₂-; -C(O)CH₂CH₂C(O)-; -CH₂-CH(OH)-O- (CH₂)_m-O-CH(OH)-CH₂-, wherein m is an integer from about 2 to about 4; -C(O)- (C₆H,(COOH)₂)-C(O)- and -C(O)NH(CH₂)_pNHC(O)-, wherein p is an integer from about 2 to about 20.

Suitable crosslinking agents have two or more functional groups which react with functional groups on the polymer to form links between adjacent polymer strands. When the polymer comprises amino groups, the crosslinking agent preferably includes two or more electrophilic groups which react with amine groups to form a covalent bond. Crosslinking in this case can occur, for example, via nucleophilic attack of the polymer amino groups on the electrophilic groups, resulting in the formation of a bridging unit which links two or more amino nitrogen atoms from different polymer strands. Suitable crosslinking agents of this type include compounds having two or more groups selected from among epoxide, acyl- X and alkyl-X, wherein X- is a suitable leaving group, such as a halide, carboxylate, tosylate or mesylate group. Examples of such compounds include epichlorohydrin, succinyl dichloride, butanedioldiglycidyl ether, ethanedioldiglycidyl ether, pyromellitic dianhydride and dihaloalkanes. The crosslinking agent can also be an ,ω-alkylene diisocyanate, for example OCN(CH₂)_pNCO, wherein p is an integer from about 2 to about 20. The polymer can be reacted with an amount of crosslinking agent equal to from about 0.5 to 40 mole percent relative to the amino groups within the polymer, depending upon the extent of crosslinking desired.

In a preferred embodiment, the chamber in which crosslinking occurs is the interior of an extruder, a device which is well known in the art. A typical extruder comprises a heated tube which includes one or more entrance ports and an extrusion nozzle. An extruder can, optionally, include an internal screw which can be turned to transport viscous material through the tube. A variety of extruder configurations is known in the art. For example, an extruder can have multiple inlet ports throughout the length of the tube and multiple heating zones which can be controlled at different temperatures. A variety of screw designs is also possible for optimal mixing as are various outlet configurations. The polymer can be injected into the extruder in liquid form or as a solution in a suitable solvent. For example, water- soluble polymers, such as an amino polymer or an acid salt thereof, can be injected into the extruder as a concentrated aqueous solution. In one embodiment, the polymer and the crosslinking agent are mixed in solution. This polymer/cross-linking agent solution is then injected into an extruder. Optionally, the solution is maintained under conditions sufficient for at least partial crosslinking of the polymer before the solution is directed to the extruder.

In a preferred embodiment, the crosslinking agent and the polymer or polymer solution are co-injected into the extruder. The crosslinking agent can be injected into the extruder as a neat liquid or in a solution in a suitable solvent. In this embodiment, the crosslinking reaction can occur within the extruder if the reaction is sufficiently fast, and conditions such as temperature, and concentration of reactants can be controlled to achieve crosslinking and polymer gelation at a desired point within the extruder. The gel which forms within the extruder can then be fragmented by the rotating the screw within the extruder barrel. Optionally, a die can be placed at the exit nozzle of the extruder to further reduce the size of the gel particles emerging from the exit nozzle.

In a particularly preferred embodiment, the polymer is polyallylamine or a salt of polyallylamine with a suitable acid, such as HC1, and the crosslinking agent is epichlorohydrin. For example, poly(allylamine hydrochloride) as a 20% (w/w) solution can be partially neutralized and treated with epichlorohydrin under a wide range of conditions. Preferably, the reaction is performed at basic pH and a temperature of about 25 °C or greater. For continuous processing, it is preferred that crosslinking be carried out under conditions which lead to rapid reaction. For example, at about pH 12 and 80°C, the polymer will gel in a matter of seconds.

The method of the present invention can, optionally, further include the step of washing the crosslinked polymer gel or gel particles. The gel can be washed by any suitable method known in the art. For example, the gel can be collected on a filter and washed with a suitable volume of a wash liquid. Gel particles can also be dispersed in a suitable wash liquid, for example, water, and the resulting dispersion can be agitated or stirred. The washed gel particles can then be collected by filtration. This process can also be repeated one or more times until the gel is of the desired degree of purity.

Preferably, the gel is washed via a continuous process. For example, the gel particles can be washed using a continuous filtration process. This method comprises continuously adding crude gel particles to the top of a tall column, for example, directly from an extruder. The gel particles then fall to the bottom of the column under the force of gravity while a wash liquid, such as water, is flowed upward from the bottom of the column and through the descending gel particles. The column size and wash solvent flow rate should be suitable for obtaining gel particles of sufficient purity at the bottom of the column. The purified gel particles can then be removed from the bottom of the column and filtered, if necessary.

In another embodiment, the gel particles flow through multiple columns multiple columns arranged in series to increase the distance the gel particles flow. In this embodiment, the gel particles are applied to the top of a first column. After the particles have reached the bottom of the first column, they are pumped to the top of a second column. This process continues until the particles reach the bottom of the last column, from which they are removed. The flow of the wash liquid is opposite that of the gel particles. The wash liquid flows upward from the bottom of the last column. Upon reaching the top of this column, the wash liquid is fed to the bottom of the penultimate column and flows to the top of this column. This process continues until the wash liquid reaches the top of the first column, from which it is removed from the system.

In another embodiment, the polymer gel is washed using a vacuum belt filter. In this process, the gel or gel particles are applied to the surface of a porous moving belt. The opposite side of the belt is held under reduced pressure. A wash liquid is sprayed onto the gel and forced through the gel and the underlying belt by the pressure difference across the belt. The used wash liquid can then be discarded. At the end of the belt, the washed polymer gel is removed.

In each of the gel washing procedures described above, the wash liquid can be any solvent which does not dissolve the polymer gel but which does dissolve compounds which are suspected contaminants of the newly formed crosslinked polymer gel. Such contaminants can include unreacted crosslinking agent. When the gel is a crosslinked poly(allylamine) gel, for example, epichlorohydrin- crosslinked poly(allylamine) gel, the preferred wash liquid is water.

While this invention has been particularly shown and described with references to preferred embodiments thereof, it will be understood by those skilled in the art that various changes in form and details may be made therein without departing from the spirit and scope of the invention as defined by the appended claims.

Claims

CLAIMSWhat is claimed is:

1. A method for producing a crosslinked polymer gel, comprising the steps of:

(a) contacting a polymer with a crosslinking agent in a chamber under conditions suitable for producing a crosslinked polymer gel; and

(b) extruding the crosslinked polymer gel from the chamber.

2. The method of Claim 1, further including the step of fragmenting the crosslinked polymer gel of step (a), thereby forming crosslinked polymer gel particles.

3. The method of Claim 1 wherein the polymer is characterized by a polymerized amine monomer.

4. The method of Claim 3 wherein the amine monomer is selected from the group consisting of allylamine, vinylamine, diallylamine, diallylmethylamine and ethyleneimine.

5. The method of Claim 3 wherein the polymer is a homopolymer.

6. The method of Claim 5 wherein the polymer is selected from the group consisting of poly(allylamine), poly (vinylamine), poly(diallylamine), poly(diallylmmethylamine) and poly(ethyleneimine).

7. The method of Claim 3 wherein the polymer is further characterized by a polymerized comonomer.

8. The method of Claim 3 wherein the crosslinking agent comprises having two or more groups selected from the group consisting of epoxide, isocyanate, acyl-X and alkyl-X, wherein X- is a leaving group.

9. The method of Claim 8 wherein X- is a halide, a carboxylate, tosylate or mesylate.

10. The method of Claim 8 wherein the crosslinking agent is selected from the group consisting of epichlorohydrin, succinyl dichloride, butanedioldiglycidyl ether, ethanedioldiglycidyl ether, pyromellitic dianhydride, a,w-alkylene diisocyanates and dihaloalkanes.

11. The method of Claim 2 wherein the chamber is the interior of an extruder.

12. The method of Claim 11 wherein the extruder comprises two or more inlet ports.

13. The method of Claim 12 wherein the extruder further comprises an internal screw.

14. The method of Claim 13 wherein the crosslinked polymer gel is fragmented by rotating the screw.

15. The method of Claim 12 wherein the polymer is contacted with the crosslinking agent by mixing a first solution comprising the polymer with a second solution comprising the crosslinking agent.

16. A method of producing a crosslinked poly(allylamine) gel, comprising the steps of

(a) contacting poly(allylamine) or a salt thereof with a suitable acid with a crosslinking agent in a chamber under conditions suitable for producing a crosslinked poly(allylamine) gel;

(b) fragmenting the crosslinked poly(allyamine) gel, thereby producing crosslinked poly(allylamine) gel particles; and

(c) extruding the crosslinked poly(allylamine) gel particles from the chamber.

17. The method of Claim 16 wherein crosslinking agent is epichlorohydrin.

18. The method of Claim 16 further comprising the step of washing the crosslinked poly(allylamine) gel particles with water.

19. A method for producing a crosslinked polymer gel, comprising the steps of: (a) contacting a polymer with a crosslinking agent in solution, thereby forming a solution comprising the polymer and the crosslinking agent;

(b) directing the solution into a chamber;

(c) maintaining the solution under conditions suitable for producing a crosslinked polymer gel; and

(d) extruding the crosslinked polymer gel from the chamber.

20. The method of Claim 19 wherein the solution of step (a) is maintained under conditions suitable for partial crosslinking of the polymer prior to directing the solution into the chamber.

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