CA2601236A1 - An improved process for the preparation of crosslinked polyallylamine polymer - Google Patents
An improved process for the preparation of crosslinked polyallylamine polymer Download PDFInfo
- Publication number
- CA2601236A1 CA2601236A1 CA002601236A CA2601236A CA2601236A1 CA 2601236 A1 CA2601236 A1 CA 2601236A1 CA 002601236 A CA002601236 A CA 002601236A CA 2601236 A CA2601236 A CA 2601236A CA 2601236 A1 CA2601236 A1 CA 2601236A1
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- Prior art keywords
- improved process
- organic solvent
- range
- crosslinked
- polyallylamine
- Prior art date
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- Abandoned
Links
- 238000000034 method Methods 0.000 title claims abstract description 51
- 229920000642 polymer Polymers 0.000 title claims description 30
- 229920000083 poly(allylamine) Polymers 0.000 title claims description 27
- 238000002360 preparation method Methods 0.000 title claims description 7
- 229920002518 Polyallylamine hydrochloride Polymers 0.000 claims abstract description 46
- 239000003960 organic solvent Substances 0.000 claims abstract description 26
- 239000002245 particle Substances 0.000 claims abstract description 25
- 239000007864 aqueous solution Substances 0.000 claims abstract description 17
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 15
- 239000004094 surface-active agent Substances 0.000 claims abstract description 13
- 239000003513 alkali Substances 0.000 claims abstract description 6
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 57
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 32
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 27
- 239000000243 solution Substances 0.000 claims description 24
- 239000007863 gel particle Substances 0.000 claims description 20
- 238000001914 filtration Methods 0.000 claims description 16
- 102000006335 Phosphate-Binding Proteins Human genes 0.000 claims description 15
- 108010058514 Phosphate-Binding Proteins Proteins 0.000 claims description 15
- 239000003431 cross linking reagent Substances 0.000 claims description 12
- 239000006185 dispersion Substances 0.000 claims description 12
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 claims description 12
- PRXRUNOAOLTIEF-ADSICKODSA-N Sorbitan trioleate Chemical compound CCCCCCCC\C=C/CCCCCCCC(=O)OC[C@@H](OC(=O)CCCCCCC\C=C/CCCCCCCC)[C@H]1OC[C@H](O)[C@H]1OC(=O)CCCCCCC\C=C/CCCCCCCC PRXRUNOAOLTIEF-ADSICKODSA-N 0.000 claims description 11
- 238000001035 drying Methods 0.000 claims description 11
- 238000006243 chemical reaction Methods 0.000 claims description 10
- 239000002904 solvent Substances 0.000 claims description 10
- 238000009826 distribution Methods 0.000 claims description 9
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 8
- ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-Butanone Chemical compound CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 claims description 6
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 6
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 6
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 6
- 238000005406 washing Methods 0.000 claims description 6
- YNQLUTRBYVCPMQ-UHFFFAOYSA-N Ethylbenzene Chemical compound CCC1=CC=CC=C1 YNQLUTRBYVCPMQ-UHFFFAOYSA-N 0.000 claims description 4
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 claims description 4
- 229910019142 PO4 Inorganic materials 0.000 claims description 4
- 150000001338 aliphatic hydrocarbons Chemical class 0.000 claims description 4
- 229910001854 alkali hydroxide Inorganic materials 0.000 claims description 4
- 150000008044 alkali metal hydroxides Chemical class 0.000 claims description 4
- 239000008346 aqueous phase Substances 0.000 claims description 4
- 150000004945 aromatic hydrocarbons Chemical class 0.000 claims description 4
- SNRUBQQJIBEYMU-UHFFFAOYSA-N dodecane Chemical compound CCCCCCCCCCCC SNRUBQQJIBEYMU-UHFFFAOYSA-N 0.000 claims description 4
- 150000002148 esters Chemical class 0.000 claims description 4
- 150000002576 ketones Chemical class 0.000 claims description 4
- 239000012074 organic phase Substances 0.000 claims description 4
- 239000011541 reaction mixture Substances 0.000 claims description 4
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 claims description 3
- 239000008096 xylene Substances 0.000 claims description 3
- NTIZESTWPVYFNL-UHFFFAOYSA-N Methyl isobutyl ketone Chemical compound CC(C)CC(C)=O NTIZESTWPVYFNL-UHFFFAOYSA-N 0.000 claims description 2
- UIHCLUNTQKBZGK-UHFFFAOYSA-N Methyl isobutyl ketone Natural products CCC(C)C(C)=O UIHCLUNTQKBZGK-UHFFFAOYSA-N 0.000 claims description 2
- XBDQKXXYIPTUBI-UHFFFAOYSA-M Propionate Chemical compound CCC([O-])=O XBDQKXXYIPTUBI-UHFFFAOYSA-M 0.000 claims description 2
- KXKVLQRXCPHEJC-UHFFFAOYSA-N acetic acid trimethyl ester Natural products COC(C)=O KXKVLQRXCPHEJC-UHFFFAOYSA-N 0.000 claims description 2
- 238000013019 agitation Methods 0.000 claims description 2
- 125000003158 alcohol group Chemical group 0.000 claims description 2
- 238000001816 cooling Methods 0.000 claims description 2
- DGRJJZRTEGNKON-UHFFFAOYSA-N decane;octane Chemical compound CCCCCCCC.CCCCCCCCCC DGRJJZRTEGNKON-UHFFFAOYSA-N 0.000 claims description 2
- 229940032007 methylethyl ketone Drugs 0.000 claims description 2
- 230000003472 neutralizing effect Effects 0.000 claims description 2
- 239000012188 paraffin wax Substances 0.000 claims description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 claims description 2
- 239000010452 phosphate Substances 0.000 claims description 2
- 239000011369 resultant mixture Substances 0.000 claims description 2
- 238000004132 cross linking Methods 0.000 abstract description 30
- BRLQWZUYTZBJKN-UHFFFAOYSA-N Epichlorohydrin Chemical compound ClCC1CO1 BRLQWZUYTZBJKN-UHFFFAOYSA-N 0.000 abstract description 11
- 238000001879 gelation Methods 0.000 abstract description 4
- 239000011324 bead Substances 0.000 abstract 2
- 238000003756 stirring Methods 0.000 description 24
- 239000000499 gel Substances 0.000 description 17
- 239000007787 solid Substances 0.000 description 15
- 239000000203 mixture Substances 0.000 description 12
- 239000000047 product Substances 0.000 description 12
- VVJKKWFAADXIJK-UHFFFAOYSA-N Allylamine Chemical compound NCC=C VVJKKWFAADXIJK-UHFFFAOYSA-N 0.000 description 9
- 239000008367 deionised water Substances 0.000 description 7
- 239000002609 medium Substances 0.000 description 7
- ZBNRGEMZNWHCGA-SZOQPXBYSA-N [(2s)-2-[(2r,3r,4s)-3,4-bis[[(z)-octadec-9-enoyl]oxy]oxolan-2-yl]-2-hydroxyethyl] (z)-octadec-9-enoate Chemical compound CCCCCCCC\C=C/CCCCCCCC(=O)OC[C@H](O)[C@H]1OC[C@H](OC(=O)CCCCCCC\C=C/CCCCCCCC)[C@H]1OC(=O)CCCCCCC\C=C/CCCCCCCC ZBNRGEMZNWHCGA-SZOQPXBYSA-N 0.000 description 6
- -1 amine hydrochloride Chemical class 0.000 description 6
- 150000001412 amines Chemical class 0.000 description 6
- 230000015572 biosynthetic process Effects 0.000 description 5
- 229920006037 cross link polymer Polymers 0.000 description 5
- 238000004519 manufacturing process Methods 0.000 description 5
- 150000003839 salts Chemical class 0.000 description 5
- MVPPADPHJFYWMZ-UHFFFAOYSA-N chlorobenzene Chemical compound ClC1=CC=CC=C1 MVPPADPHJFYWMZ-UHFFFAOYSA-N 0.000 description 4
- 239000002612 dispersion medium Substances 0.000 description 4
- 239000005662 Paraffin oil Substances 0.000 description 3
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 3
- 239000000017 hydrogel Substances 0.000 description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-M hydroxide Chemical compound [OH-] XLYOFNOQVPJJNP-UHFFFAOYSA-M 0.000 description 3
- 238000006386 neutralization reaction Methods 0.000 description 3
- 235000021317 phosphate Nutrition 0.000 description 3
- 238000001694 spray drying Methods 0.000 description 3
- 238000003786 synthesis reaction Methods 0.000 description 3
- OCJBOOLMMGQPQU-UHFFFAOYSA-N 1,4-dichlorobenzene Chemical compound ClC1=CC=C(Cl)C=C1 OCJBOOLMMGQPQU-UHFFFAOYSA-N 0.000 description 2
- QCQCHGYLTSGIGX-GHXANHINSA-N 4-[[(3ar,5ar,5br,7ar,9s,11ar,11br,13as)-5a,5b,8,8,11a-pentamethyl-3a-[(5-methylpyridine-3-carbonyl)amino]-2-oxo-1-propan-2-yl-4,5,6,7,7a,9,10,11,11b,12,13,13a-dodecahydro-3h-cyclopenta[a]chrysen-9-yl]oxy]-2,2-dimethyl-4-oxobutanoic acid Chemical compound N([C@@]12CC[C@@]3(C)[C@]4(C)CC[C@H]5C(C)(C)[C@@H](OC(=O)CC(C)(C)C(O)=O)CC[C@]5(C)[C@H]4CC[C@@H]3C1=C(C(C2)=O)C(C)C)C(=O)C1=CN=CC(C)=C1 QCQCHGYLTSGIGX-GHXANHINSA-N 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- 239000000654 additive Substances 0.000 description 2
- 150000008280 chlorinated hydrocarbons Chemical class 0.000 description 2
- 239000011362 coarse particle Substances 0.000 description 2
- 229940117389 dichlorobenzene Drugs 0.000 description 2
- 230000009477 glass transition Effects 0.000 description 2
- 150000003013 phosphoric acid derivatives Chemical class 0.000 description 2
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 description 1
- YHRUOJUYPBUZOS-UHFFFAOYSA-N 1,3-dichloropropane Chemical compound ClCCCCl YHRUOJUYPBUZOS-UHFFFAOYSA-N 0.000 description 1
- DBGSRZSKGVSXRK-UHFFFAOYSA-N 1-[2-[5-[2-(2,3-dihydro-1H-inden-2-ylamino)pyrimidin-5-yl]-1,3,4-oxadiazol-2-yl]acetyl]-3,6-dihydro-2H-pyridine-4-carboxylic acid Chemical compound C1C(CC2=CC=CC=C12)NC1=NC=C(C=N1)C1=NN=C(O1)CC(=O)N1CCC(=CC1)C(=O)O DBGSRZSKGVSXRK-UHFFFAOYSA-N 0.000 description 1
- AOBIOSPNXBMOAT-UHFFFAOYSA-N 2-[2-(oxiran-2-ylmethoxy)ethoxymethyl]oxirane Chemical compound C1OC1COCCOCC1CO1 AOBIOSPNXBMOAT-UHFFFAOYSA-N 0.000 description 1
- SHKUUQIDMUMQQK-UHFFFAOYSA-N 2-[4-(oxiran-2-ylmethoxy)butoxymethyl]oxirane Chemical compound C1OC1COCCCCOCC1CO1 SHKUUQIDMUMQQK-UHFFFAOYSA-N 0.000 description 1
- 239000004971 Cross linker Substances 0.000 description 1
- MUXOBHXGJLMRAB-UHFFFAOYSA-N Dimethyl succinate Chemical compound COC(=O)CCC(=O)OC MUXOBHXGJLMRAB-UHFFFAOYSA-N 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 description 1
- 125000003277 amino group Chemical group 0.000 description 1
- 239000003613 bile acid Substances 0.000 description 1
- 238000009835 boiling Methods 0.000 description 1
- IRXBNHGNHKNOJI-UHFFFAOYSA-N butanedioyl dichloride Chemical compound ClC(=O)CCC(Cl)=O IRXBNHGNHKNOJI-UHFFFAOYSA-N 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 238000000576 coating method Methods 0.000 description 1
- 230000003413 degradative effect Effects 0.000 description 1
- 229910021641 deionized water Inorganic materials 0.000 description 1
- 230000001627 detrimental effect Effects 0.000 description 1
- 238000000502 dialysis Methods 0.000 description 1
- 230000007613 environmental effect Effects 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 239000012467 final product Substances 0.000 description 1
- 239000008394 flocculating agent Substances 0.000 description 1
- 238000000227 grinding Methods 0.000 description 1
- 229920001519 homopolymer Polymers 0.000 description 1
- 239000003999 initiator Substances 0.000 description 1
- 238000005342 ion exchange Methods 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 239000000178 monomer Substances 0.000 description 1
- 239000004570 mortar (masonry) Substances 0.000 description 1
- 238000001728 nano-filtration Methods 0.000 description 1
- 239000002736 nonionic surfactant Substances 0.000 description 1
- 238000006116 polymerization reaction Methods 0.000 description 1
- 150000003254 radicals Chemical class 0.000 description 1
- 230000035484 reaction time Effects 0.000 description 1
- 230000000717 retained effect Effects 0.000 description 1
- 238000005549 size reduction Methods 0.000 description 1
- 239000002002 slurry Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 239000007921 spray Substances 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- DVKJHBMWWAPEIU-UHFFFAOYSA-N toluene 2,4-diisocyanate Chemical compound CC1=CC=C(N=C=O)C=C1N=C=O DVKJHBMWWAPEIU-UHFFFAOYSA-N 0.000 description 1
- 238000000108 ultra-filtration Methods 0.000 description 1
- 238000009736 wetting Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08F—MACROMOLECULAR COMPOUNDS OBTAINED BY REACTIONS ONLY INVOLVING CARBON-TO-CARBON UNSATURATED BONDS
- C08F8/00—Chemical modification by after-treatment
- C08F8/18—Introducing halogen atoms or halogen-containing groups
-
- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08F—MACROMOLECULAR COMPOUNDS OBTAINED BY REACTIONS ONLY INVOLVING CARBON-TO-CARBON UNSATURATED BONDS
- C08F2810/00—Chemical modification of a polymer
- C08F2810/20—Chemical modification of a polymer leading to a crosslinking, either explicitly or inherently
Abstract
The present invention provides a process for crosslinking of polyallylamine hydrochloride wherein an aqueous solution of polyallylamine hydrochloride is partly neutralized with alkali and epichlorohydrin is added. The aqueous solution is dispersed in an organic medium containing a surfactant. This leads to gelation in individual droplets. The crosslinking in individual gel beads is completed by raising the temperature. The resulting beads are then separated, washed with water, treated with an organic solvent and dried. The method maximizes the yield of crosslinked polyallylamine hydrochloride particles in the range 60 - 100 mesh.
Description
AN IMPROVED PROCESS FOR THE PREPARATION OF CROSSLINKED
POLYALLYLAMINE POLYMER.
Field of Invention The present invention relates to an improved process for the preparation of crosslinked polyallylamine. More specifically the present invention relates to a process for crosslinking of aqueous polyallylamine dispersed in an organic medium so as to maximize the yield of crosslinked product in the desired particle size range of 60 to 100 mesh.
Background of the Invention Polyallylamine is a polymer of allylamine. The amine group of the polymer can be functionalized further. The polymer finds a wide range of applications such as flocculants, coatings and additives. It is well known that the monomer mono allyl amine does not polymerize readily as it undergoes degradative chain transfer. Allylamine is therefore converted into its salt such as hydrochloride or sulfate and polymerized in the presence of a free radical initiator. The polymerization of salts of allylamine is described adequately in US
patents 6,303,723, 6,787,587, 6,579,933, 6,509,013, 6,083,495, 5,667,775, 5,496,545, which are cited herein by way of reference.
Polyallylamine hydrochloride solutions are then partly neutralized and crosslinked using a wide range of crosslinking agents described in US patents 6,509,013, 6,083,495, 5,667,775, 5,496,545, 4,605,701, which are cited herein by way of reference. The crosslinkers typically used are epichlorohydrin, 1,4 butane diol diglycidyl ether, 1,2 ethane diol diglycidyl ether, 1,3 dichloropropane, 1,2 dichloroethane, succinyl dichloride, dimethyl succinate and toluene diisocyanate. More specifically the partly neutralized polymer of allylamine hydrochloride is crosslinked using epichlorohydrin.
The use of crdsslinked polymer for binding phosphates and bile acids is disclosed in US
patents 5,496,545, 6,667,775, 6,083,495, 6,509,013, 6,696,087, 6,433,026, 6,423,754, 6,294,163, 6,203,785, 6,190,649, 6,083,497, 6,066,678, 6,060,517, 5,981,693, 5,925,379, 5,919,832, 5,969,090, 5,917,007, 5,840,766, 5,703,188, 5,679,717, 5,607,669.
The crosslinked polymers are formulated in tablets as described in US patents 6,696,087 and 6,733,780. The methods of making phosphate binding polymers for oral administration are described in US patents 6,509,013, 6,083,495, 5,496,545, 5,667,775, more particularly the US patents 5,496,545, 5,667,775, 6,083,495, 6,509,013, 4,605,701 , which are cited herein by way of reference.
According to the teaching of the US patent 6,083,495, the method of crosslinking involves reacting for about 15 minutes polyallylamine with a difunctional crosslinking agent in an aqueous solution as to form a gel and allowing the gel to cure for 18 hours at room temperature. The gel is then fragmented into gel particles in a blender in the presence of isopropanol. The gel particles are then washed repeatedly with water and then suspended in isopropanol, filtered and dried in vacuum oven for 18 hours.
The process of crosslinking in aqueous solution described in above patents, leads to gelation.
Curing at room temperature takes a long time. The gel is difficult to break into gel particles and needs application of high shear in special equipments. The gel particles swell when repeatedly extracted with water and need to be treated with isopropanol again prior to drying.
The process also consumes large excess of water and isopropanol. The gel particles need to be dried in a vacuum oven for long time.
This is because polymeric gels adhere to each other and equipment surfaces. In order to overcome problems associated, drying is carried out in presence of additives, which are either azeotrope forming solvents or agents which influence surface wetting of the gel particles.
The US patent 6,600,011 describes the spray drying technique for drying of crosslinked polyallylamine, which is claimed to avoid damage to shear sensitive polymer gels, and also enables improved particle size control. The patent also describes the use of a Ystral three stage disperser to achieve the desired particle size.
Drying of the aqueous slurry by spray drying , needs careful control of the feed pressure and temperature. Especially the feed temperature depends on the nature of the feed in that the feed temperature has to be below the glass transition temperature of the hydrogel and needs to be so adjusted as not to degrade the hydrogel. The US patents 6,362,266 and 6,180,754 describe a process for producing a crosslinked polyallylamine polymer having reduced cohesiveness. According to the teachings of the said patents the crosslinking reaction is carried out in a specially designed reactor, which can handle highly viscous solutions and can break the gel into small pieces after gelation. Typically a LIST- Discotherm B
reactor is suitable for carrying out the crosslinking reaction which generates easy to handle clumps of gel. The application of high. shear is detrimental as it leads to the formation of soluble oligomers.
The dried crosslinked polymer is further ground using a mortar and pestle, a Retsch mill or a Fritz mill. The patents further describe that during the drying stage the hydrogel becomes highly cohesive, which leads to high power consumption to rotate the agitator. The addition of a surfactant is recommended to reduce the cohesiveness during drying.
In summary, the crosslinking of polyallylamine in aqueous solution leads to gelation. The gel is then fragmented in blenders into gel particles, which are then treated with water and isopropanol and then dried. It is also reported that the application of high shear contributes to soluble oligomers, which are undesirable. Hence methods have been proposed to minimize the oligomer content in the final product. Also the use of specific equipments like LIST
Discotherm B reactor has been suggested for carrying out crosslinking and spray driers for drying the crosslinked polymers. Especially spray drying is a critical operation in that the feed temperature has to be below the glass transition temperature of the crosslinked polymer.
The existing methods of crosslinking polyallylamine polymer need specialized equipments for converting the gel into gel particles and /or drying the gel particles formed.
The polyallylamine hydrochloride salt used for crosslinking in the present invention is reported extensively in the literature. More specifically the synthesis of the polyallylamine hydrochloride polymer is disclosed in the patents 6,083,495, 5,667,775, 5,496,545, 6,303,723, 4,605,701, 6,509,013, the disclosures of which are incorporated herein by reference.
The polyallylamine hydrochloride polymer used for crosslinking is partly neutralized prior to crosslinking. This is achieved by dissolving the polymer in water and by adding a calculated amount of alkali such as sodium hydroxide or potassium hydroxide either as a solid or as an aqueous solution.
US patent 6,362,266 reports ion exchange, dialysis nano filtration or ultrafiltration as methods to remove the salt. In the crosslinking processes described in US
patents 6,509,013, 5,496,545, 5,667,775, 6,083,495 the salts are removed by extraction with water after the crosslinked polyallylamine polymer obtained in the form of gel is fragmented into gel particles by treatment with isopropanol in a blender. This process involves the treatment of gel mass in blenders in presence of solvents and is not easy to operate.
The process described by the present invention leads to the formation of gel particles, which can be more readily washed either with an organic solvent or water in order to extract the salts. Furthermore, the gel particles formed as a result of the process described herein, do not readily agglomerate and hence can be washed with water and solvent readily and can also be dried more easily.
The crosslinking agents used for the crosslinking of the polyallylamine hydrochloride are extensively described in the US patents 6,362,266, 6,509,013, 5,496,545, 5,667,775, 6,083,495. In the above patents, the crosslinking agent is added to the partly neutralized polyallylamine hydrochloride at room temperature and the crosslinking reaction is allowed to proceed as such. In contrast, according to the procedure described in this invention, it is desirable to cool the neutralized polyallylamine hydrochloride solution in the range 4 C-10 C
POLYALLYLAMINE POLYMER.
Field of Invention The present invention relates to an improved process for the preparation of crosslinked polyallylamine. More specifically the present invention relates to a process for crosslinking of aqueous polyallylamine dispersed in an organic medium so as to maximize the yield of crosslinked product in the desired particle size range of 60 to 100 mesh.
Background of the Invention Polyallylamine is a polymer of allylamine. The amine group of the polymer can be functionalized further. The polymer finds a wide range of applications such as flocculants, coatings and additives. It is well known that the monomer mono allyl amine does not polymerize readily as it undergoes degradative chain transfer. Allylamine is therefore converted into its salt such as hydrochloride or sulfate and polymerized in the presence of a free radical initiator. The polymerization of salts of allylamine is described adequately in US
patents 6,303,723, 6,787,587, 6,579,933, 6,509,013, 6,083,495, 5,667,775, 5,496,545, which are cited herein by way of reference.
Polyallylamine hydrochloride solutions are then partly neutralized and crosslinked using a wide range of crosslinking agents described in US patents 6,509,013, 6,083,495, 5,667,775, 5,496,545, 4,605,701, which are cited herein by way of reference. The crosslinkers typically used are epichlorohydrin, 1,4 butane diol diglycidyl ether, 1,2 ethane diol diglycidyl ether, 1,3 dichloropropane, 1,2 dichloroethane, succinyl dichloride, dimethyl succinate and toluene diisocyanate. More specifically the partly neutralized polymer of allylamine hydrochloride is crosslinked using epichlorohydrin.
The use of crdsslinked polymer for binding phosphates and bile acids is disclosed in US
patents 5,496,545, 6,667,775, 6,083,495, 6,509,013, 6,696,087, 6,433,026, 6,423,754, 6,294,163, 6,203,785, 6,190,649, 6,083,497, 6,066,678, 6,060,517, 5,981,693, 5,925,379, 5,919,832, 5,969,090, 5,917,007, 5,840,766, 5,703,188, 5,679,717, 5,607,669.
The crosslinked polymers are formulated in tablets as described in US patents 6,696,087 and 6,733,780. The methods of making phosphate binding polymers for oral administration are described in US patents 6,509,013, 6,083,495, 5,496,545, 5,667,775, more particularly the US patents 5,496,545, 5,667,775, 6,083,495, 6,509,013, 4,605,701 , which are cited herein by way of reference.
According to the teaching of the US patent 6,083,495, the method of crosslinking involves reacting for about 15 minutes polyallylamine with a difunctional crosslinking agent in an aqueous solution as to form a gel and allowing the gel to cure for 18 hours at room temperature. The gel is then fragmented into gel particles in a blender in the presence of isopropanol. The gel particles are then washed repeatedly with water and then suspended in isopropanol, filtered and dried in vacuum oven for 18 hours.
The process of crosslinking in aqueous solution described in above patents, leads to gelation.
Curing at room temperature takes a long time. The gel is difficult to break into gel particles and needs application of high shear in special equipments. The gel particles swell when repeatedly extracted with water and need to be treated with isopropanol again prior to drying.
The process also consumes large excess of water and isopropanol. The gel particles need to be dried in a vacuum oven for long time.
This is because polymeric gels adhere to each other and equipment surfaces. In order to overcome problems associated, drying is carried out in presence of additives, which are either azeotrope forming solvents or agents which influence surface wetting of the gel particles.
The US patent 6,600,011 describes the spray drying technique for drying of crosslinked polyallylamine, which is claimed to avoid damage to shear sensitive polymer gels, and also enables improved particle size control. The patent also describes the use of a Ystral three stage disperser to achieve the desired particle size.
Drying of the aqueous slurry by spray drying , needs careful control of the feed pressure and temperature. Especially the feed temperature depends on the nature of the feed in that the feed temperature has to be below the glass transition temperature of the hydrogel and needs to be so adjusted as not to degrade the hydrogel. The US patents 6,362,266 and 6,180,754 describe a process for producing a crosslinked polyallylamine polymer having reduced cohesiveness. According to the teachings of the said patents the crosslinking reaction is carried out in a specially designed reactor, which can handle highly viscous solutions and can break the gel into small pieces after gelation. Typically a LIST- Discotherm B
reactor is suitable for carrying out the crosslinking reaction which generates easy to handle clumps of gel. The application of high. shear is detrimental as it leads to the formation of soluble oligomers.
The dried crosslinked polymer is further ground using a mortar and pestle, a Retsch mill or a Fritz mill. The patents further describe that during the drying stage the hydrogel becomes highly cohesive, which leads to high power consumption to rotate the agitator. The addition of a surfactant is recommended to reduce the cohesiveness during drying.
In summary, the crosslinking of polyallylamine in aqueous solution leads to gelation. The gel is then fragmented in blenders into gel particles, which are then treated with water and isopropanol and then dried. It is also reported that the application of high shear contributes to soluble oligomers, which are undesirable. Hence methods have been proposed to minimize the oligomer content in the final product. Also the use of specific equipments like LIST
Discotherm B reactor has been suggested for carrying out crosslinking and spray driers for drying the crosslinked polymers. Especially spray drying is a critical operation in that the feed temperature has to be below the glass transition temperature of the crosslinked polymer.
The existing methods of crosslinking polyallylamine polymer need specialized equipments for converting the gel into gel particles and /or drying the gel particles formed.
The polyallylamine hydrochloride salt used for crosslinking in the present invention is reported extensively in the literature. More specifically the synthesis of the polyallylamine hydrochloride polymer is disclosed in the patents 6,083,495, 5,667,775, 5,496,545, 6,303,723, 4,605,701, 6,509,013, the disclosures of which are incorporated herein by reference.
The polyallylamine hydrochloride polymer used for crosslinking is partly neutralized prior to crosslinking. This is achieved by dissolving the polymer in water and by adding a calculated amount of alkali such as sodium hydroxide or potassium hydroxide either as a solid or as an aqueous solution.
US patent 6,362,266 reports ion exchange, dialysis nano filtration or ultrafiltration as methods to remove the salt. In the crosslinking processes described in US
patents 6,509,013, 5,496,545, 5,667,775, 6,083,495 the salts are removed by extraction with water after the crosslinked polyallylamine polymer obtained in the form of gel is fragmented into gel particles by treatment with isopropanol in a blender. This process involves the treatment of gel mass in blenders in presence of solvents and is not easy to operate.
The process described by the present invention leads to the formation of gel particles, which can be more readily washed either with an organic solvent or water in order to extract the salts. Furthermore, the gel particles formed as a result of the process described herein, do not readily agglomerate and hence can be washed with water and solvent readily and can also be dried more easily.
The crosslinking agents used for the crosslinking of the polyallylamine hydrochloride are extensively described in the US patents 6,362,266, 6,509,013, 5,496,545, 5,667,775, 6,083,495. In the above patents, the crosslinking agent is added to the partly neutralized polyallylamine hydrochloride at room temperature and the crosslinking reaction is allowed to proceed as such. In contrast, according to the procedure described in this invention, it is desirable to cool the neutralized polyallylamine hydrochloride solution in the range 4 C-10 C
prior to the addition of the crosslinking agent so that the polymer solution does not undergo substantial crosslinking before the dispersion of the aqueous solution into the organic medium is complete and the dispersion of the aqueous phase in the organic phase is readily achieved. The dispersion of the aqueous phase comprising partly neutralized polyallylamine hydrochloride salt and crosslinking agent, in an organic medium is more readily achieved by incorporating a suitable surfactant such as SPAN 85 in the organic medium.
According to the teaching of the patents 5,667,775, 5,496,545, 6,083,495, 6,509,013, the aqueous polyallylamine solutions to which the crosslinking agent is added, gel in about 15 minutes and the gel is then allowed to cure for 18 hrs at room temperature.
The gel is then broken into pieces by putting into a blender with isopropanol. While this treatment can be carried out on the scales described in these patents, these operations are more difficult to carry out on large scales. US patent 6,362,266 describes the use of LIST-Discotherm B
reactor to process high viscosity materials and break the gel into small gel particles.
According to the method of the present invention, the polymer solution containing the crosslinking agent is dispersed in an organic medium before substantial crosslinking takes place. Since the polymer solution is crosslinked in individual liquid droplets to form gel particles, which are suspended in an organic phase, the viscosity of the resulting dispersion is much lower than the viscosity of gel formed when crosslinking is carried out according to the methods previously reported in the literature. The crosslinking of polyallylamine hydrochloride as described herein can be readily carried out in conventional batch reactors provided with stirrers commonly used in the chemical industry.
US patent 4,605,701 describes the use of chlorobenzene and dichlorobenzene as an organic solvent and a non ionic surfactant sorbitane sesquioleate. However, the use of chlorinated hydrocarbons is being discouraged in view of the environmental damage caused by the chlorinated hydrocarbons. Also high boiling points of solvents such as chlorobenzene and dichlorobenzene render the removal of solvents from the polymer difficult.
Accordingly the present invention envisages the use of non chlorinated solvents as organic medium.
Further, the above patent claims the crosslinked homopolymer of monoallylamine having a particle size not more than 2 mm. However, the said patent does not deal any further with the particle size and its distribution and more particularly the importance of the particle size in relation to the properties and applications of the polymer in phosphate binding .
In a surprising development the inventors of the present invention have observed that the phosphate binding capacity of the crosslinked polyallylamine hydrochloride, which is indicative of the ability of the crosslinked polymer to bind with the phosphates in the body, also depends upon the particle size of the dried product. The crosslinking of the polyallylamine hydrochloride in the dispersion medium results in a distribution of the particle sizes. The coarse particles exhibit a lower phosphate binding capacity. The finer particles exhibit a higher phosphate binding capacity. While the coarse particle generated during the process can be further ground to yield product in the desired size range in 60-100 mesh, the grinding process also produces fines, which pass through a 100 mesh sieve.
While the phosphate binding capacity of the fines is not significantly different than the particles in the size range 60-100 mesh, the fines are not particularly suitable for the preparation of tablets. It is therefore desirable that the crosslinking of polyallylamine hydrochloride be carried out under conditions wherein the particle size of the crosslinked product produced in the reactor is in the range 60-100 mesh, so that no further processing is required.
There is therefore a need to develop a method for the synthesis of crosslinked polyallylamine which will simplify the manufacturing method, minimize the need for specialized equipments, bring down the need for wash solvents and will thus bring down the manufacturing costs.
According to the method of the present invention, the crosslinking is carried out in the dispersion medium in the presence of a suitable surfactant and the choice of the stirrer and stirring speed such that the yield of the crosslinked product in the size range 60 - 100 mesh is maximized. If the yield of the product which passes through the 100 mesh sieve and which is retained over 60 mesh sieve is minimized, only a small portion of the product of the reactor will have to be subjected to size reduction and the loss of fines will also be minimum.
Objectives of the Invention The main object of this invention is a simplified process for the synthesis of crosslinked polyallylamine hydrochloride.
Another object of this invention is to provide a process which could maximize the yield of the crosslinked polyallylamine llydrochloride having particle size distribution in the range 60 -100 mesh.
Yet another object of this invention is to provide a process which avoids the need of specialized equipments for the manufacture of the said product and thus reduces the manufacturing cost.
Summary of the Invention The present invention provides a process for producing a crosslinked poiyallylamine polymer directly in the form of the gel particles. The process comprises mixing a crosslinking agent with a chilled aqueous solution of partly neutralized polyallylamine hydrochloride, dispersing the aqueous solution in an organic solvent containing surfactant , maintaining the dispersion at room temperature , while stirring continuously, raising the temperature and maintaining the dispersion at this temperature so as to complete the crosslinking reaction, separating the gel particles from the organic medium, washing with water and finally with a solvent and drying the crosslinked polyallylamine. The method maximizes the yield of crosslinked polyallylamine hydrochloride particles in the size range 60 - 100 mesh.
Detailed Description of the Invention Accordingly the present invention provides an improved process for the preparation of crosslinked polyallylamine polymer having particle size in the range 60 to 100 meshs which comprises partly neutralizing polyallylamine hydrochloride in the range of 58 to 90 % with an alkali in an aqueous solution, chilling the above said solution to a temperature in the range of 4 to 10 C, adding a crosslinking agent to the above said chilled solution and dispersing the resultant mixture in an organic solvent containing a surfactant, under agitation, at a speed of 800 to 1200 rpm, allowing the reaction to occur initially at a temperature in the range of 25-30 C, for a period of about 10 minutes and further increasing the reaction temperature to a maximum of about 80 C and allowing the reaction to continue for at least three hours, cooling the above said reaction mixture to a temperature in the range of 25-30 C, filtering the above said reaction mixture to separate the gel particles, washing the above said gel particles with water and finally with a water miscible organic solvent and removing the excess solvent followed by drying under vacuum to obtain the desired crosslinked polyallylamine polymer.
In an embodiment of the present invention the alkali used is an alkali hydroxide.
In another embodiment of the present invention the alkali hydroxide used is sodium hydroxide .
In another embodiment the surfactant used is commercially available SPAN-85.
In yet another embodiment the concentration of the surfactant used is ranging between 0.25 to 1%(v/v) of the organic solvent.
In yet another embodiment the ratio of the aqueous phase to organic phase used is in the range 1:3.3 to 1:8.
In yet another embodiment the organic solvent used for dispersion is selected from aromatic and aliphatic hydrocarbon.
In yet another embodiment the organic solvent used for dispersion is aromatic hydrocarbon selected from the group consisting of toluene, xylene and ethyl benzene.
In yet another embodiment the organic solvent used for dispersion is aliphatic hydrocarbon selected from the group consisting of hexane, heptane, octane decane, dodecane and paraffin.
According to the teaching of the patents 5,667,775, 5,496,545, 6,083,495, 6,509,013, the aqueous polyallylamine solutions to which the crosslinking agent is added, gel in about 15 minutes and the gel is then allowed to cure for 18 hrs at room temperature.
The gel is then broken into pieces by putting into a blender with isopropanol. While this treatment can be carried out on the scales described in these patents, these operations are more difficult to carry out on large scales. US patent 6,362,266 describes the use of LIST-Discotherm B
reactor to process high viscosity materials and break the gel into small gel particles.
According to the method of the present invention, the polymer solution containing the crosslinking agent is dispersed in an organic medium before substantial crosslinking takes place. Since the polymer solution is crosslinked in individual liquid droplets to form gel particles, which are suspended in an organic phase, the viscosity of the resulting dispersion is much lower than the viscosity of gel formed when crosslinking is carried out according to the methods previously reported in the literature. The crosslinking of polyallylamine hydrochloride as described herein can be readily carried out in conventional batch reactors provided with stirrers commonly used in the chemical industry.
US patent 4,605,701 describes the use of chlorobenzene and dichlorobenzene as an organic solvent and a non ionic surfactant sorbitane sesquioleate. However, the use of chlorinated hydrocarbons is being discouraged in view of the environmental damage caused by the chlorinated hydrocarbons. Also high boiling points of solvents such as chlorobenzene and dichlorobenzene render the removal of solvents from the polymer difficult.
Accordingly the present invention envisages the use of non chlorinated solvents as organic medium.
Further, the above patent claims the crosslinked homopolymer of monoallylamine having a particle size not more than 2 mm. However, the said patent does not deal any further with the particle size and its distribution and more particularly the importance of the particle size in relation to the properties and applications of the polymer in phosphate binding .
In a surprising development the inventors of the present invention have observed that the phosphate binding capacity of the crosslinked polyallylamine hydrochloride, which is indicative of the ability of the crosslinked polymer to bind with the phosphates in the body, also depends upon the particle size of the dried product. The crosslinking of the polyallylamine hydrochloride in the dispersion medium results in a distribution of the particle sizes. The coarse particles exhibit a lower phosphate binding capacity. The finer particles exhibit a higher phosphate binding capacity. While the coarse particle generated during the process can be further ground to yield product in the desired size range in 60-100 mesh, the grinding process also produces fines, which pass through a 100 mesh sieve.
While the phosphate binding capacity of the fines is not significantly different than the particles in the size range 60-100 mesh, the fines are not particularly suitable for the preparation of tablets. It is therefore desirable that the crosslinking of polyallylamine hydrochloride be carried out under conditions wherein the particle size of the crosslinked product produced in the reactor is in the range 60-100 mesh, so that no further processing is required.
There is therefore a need to develop a method for the synthesis of crosslinked polyallylamine which will simplify the manufacturing method, minimize the need for specialized equipments, bring down the need for wash solvents and will thus bring down the manufacturing costs.
According to the method of the present invention, the crosslinking is carried out in the dispersion medium in the presence of a suitable surfactant and the choice of the stirrer and stirring speed such that the yield of the crosslinked product in the size range 60 - 100 mesh is maximized. If the yield of the product which passes through the 100 mesh sieve and which is retained over 60 mesh sieve is minimized, only a small portion of the product of the reactor will have to be subjected to size reduction and the loss of fines will also be minimum.
Objectives of the Invention The main object of this invention is a simplified process for the synthesis of crosslinked polyallylamine hydrochloride.
Another object of this invention is to provide a process which could maximize the yield of the crosslinked polyallylamine llydrochloride having particle size distribution in the range 60 -100 mesh.
Yet another object of this invention is to provide a process which avoids the need of specialized equipments for the manufacture of the said product and thus reduces the manufacturing cost.
Summary of the Invention The present invention provides a process for producing a crosslinked poiyallylamine polymer directly in the form of the gel particles. The process comprises mixing a crosslinking agent with a chilled aqueous solution of partly neutralized polyallylamine hydrochloride, dispersing the aqueous solution in an organic solvent containing surfactant , maintaining the dispersion at room temperature , while stirring continuously, raising the temperature and maintaining the dispersion at this temperature so as to complete the crosslinking reaction, separating the gel particles from the organic medium, washing with water and finally with a solvent and drying the crosslinked polyallylamine. The method maximizes the yield of crosslinked polyallylamine hydrochloride particles in the size range 60 - 100 mesh.
Detailed Description of the Invention Accordingly the present invention provides an improved process for the preparation of crosslinked polyallylamine polymer having particle size in the range 60 to 100 meshs which comprises partly neutralizing polyallylamine hydrochloride in the range of 58 to 90 % with an alkali in an aqueous solution, chilling the above said solution to a temperature in the range of 4 to 10 C, adding a crosslinking agent to the above said chilled solution and dispersing the resultant mixture in an organic solvent containing a surfactant, under agitation, at a speed of 800 to 1200 rpm, allowing the reaction to occur initially at a temperature in the range of 25-30 C, for a period of about 10 minutes and further increasing the reaction temperature to a maximum of about 80 C and allowing the reaction to continue for at least three hours, cooling the above said reaction mixture to a temperature in the range of 25-30 C, filtering the above said reaction mixture to separate the gel particles, washing the above said gel particles with water and finally with a water miscible organic solvent and removing the excess solvent followed by drying under vacuum to obtain the desired crosslinked polyallylamine polymer.
In an embodiment of the present invention the alkali used is an alkali hydroxide.
In another embodiment of the present invention the alkali hydroxide used is sodium hydroxide .
In another embodiment the surfactant used is commercially available SPAN-85.
In yet another embodiment the concentration of the surfactant used is ranging between 0.25 to 1%(v/v) of the organic solvent.
In yet another embodiment the ratio of the aqueous phase to organic phase used is in the range 1:3.3 to 1:8.
In yet another embodiment the organic solvent used for dispersion is selected from aromatic and aliphatic hydrocarbon.
In yet another embodiment the organic solvent used for dispersion is aromatic hydrocarbon selected from the group consisting of toluene, xylene and ethyl benzene.
In yet another embodiment the organic solvent used for dispersion is aliphatic hydrocarbon selected from the group consisting of hexane, heptane, octane decane, dodecane and paraffin.
In yet another embodiment the organic solvent used for washing the crosslinked polyallylamine polymer is selected from alcohol, ketone and ester In yet another embodiment the organic solvent used is an alcohol selected from the group consisting of methanol, ethanol and isopropanol.
In yet another embodiment the organic solvent used is a ketone selected from the group consisting of acetone, methyl ethylketone, methyl isobutyl ketone.
In yet another embodiment the organic solvent used is an ester selected from methyl acetate and ethyl acetate.
In yet another embodiment 70 to 90% of the crosslinked polyallylamine obtained has particle size distribution in the range of 60-100 mesh.
In still another embodiment the phosphate binding capacity of the crosslinked polyallylamine obtained is in the range 2.9-3.25 meq phosphate/g.
The novelty of the present invention lies in the preparation of controlled particle size crosslinked polyallylamine polymer having particle size distribution in the range of 60-100 mesh in high yield.
The invention is now described in details by reference to the following examples, which are purely illustrative in nature and shall in no way limit the scope of the invention.
Example 1 15 g of polyallylamine hydrochloride of intrinsic viscosity 0.18 dl/g in 0.1 N
NaCl solution was partly neutralized with aqueous solution of sodium hydroxide as shown in table I to convert part of amine hydrochloride to free amine. The resulting mixture was cooled to 5 C.
To a jacketed kettle equipped with mechanical stirrer and condenser was added toluene (120 ml) and sorbitane trioleate (0.6 ml) (Span 85). Epichlorohydrin (1.8 ml) was added all at once to the partly neutralized polyallylamine hydrochloride solution. This solution was immediately dispersed in toluene with stirring. The mixture was heated to 60 C
and stirred for 3 hrs. Toluene was decanted. The crosslinked polyallylamine hydrochloride formed was washed 3 times by suspending in 150 ml of de-ionized water stirring magnetically for 45 min.
followed by filtration. The crosslinked solid was rinsed once by suspending it in isopropanol (200 ml) stirring for 45 min followed by filtration. The solid was dried under vacuum for 8 hrs.
Table-I illustrates the degree of neutralization and corresponding phosphate binding capacities of crosslinked polyallylamine hydrochloride polymers as a function of degree of neutralization.
In yet another embodiment the organic solvent used is a ketone selected from the group consisting of acetone, methyl ethylketone, methyl isobutyl ketone.
In yet another embodiment the organic solvent used is an ester selected from methyl acetate and ethyl acetate.
In yet another embodiment 70 to 90% of the crosslinked polyallylamine obtained has particle size distribution in the range of 60-100 mesh.
In still another embodiment the phosphate binding capacity of the crosslinked polyallylamine obtained is in the range 2.9-3.25 meq phosphate/g.
The novelty of the present invention lies in the preparation of controlled particle size crosslinked polyallylamine polymer having particle size distribution in the range of 60-100 mesh in high yield.
The invention is now described in details by reference to the following examples, which are purely illustrative in nature and shall in no way limit the scope of the invention.
Example 1 15 g of polyallylamine hydrochloride of intrinsic viscosity 0.18 dl/g in 0.1 N
NaCl solution was partly neutralized with aqueous solution of sodium hydroxide as shown in table I to convert part of amine hydrochloride to free amine. The resulting mixture was cooled to 5 C.
To a jacketed kettle equipped with mechanical stirrer and condenser was added toluene (120 ml) and sorbitane trioleate (0.6 ml) (Span 85). Epichlorohydrin (1.8 ml) was added all at once to the partly neutralized polyallylamine hydrochloride solution. This solution was immediately dispersed in toluene with stirring. The mixture was heated to 60 C
and stirred for 3 hrs. Toluene was decanted. The crosslinked polyallylamine hydrochloride formed was washed 3 times by suspending in 150 ml of de-ionized water stirring magnetically for 45 min.
followed by filtration. The crosslinked solid was rinsed once by suspending it in isopropanol (200 ml) stirring for 45 min followed by filtration. The solid was dried under vacuum for 8 hrs.
Table-I illustrates the degree of neutralization and corresponding phosphate binding capacities of crosslinked polyallylamine hydrochloride polymers as a function of degree of neutralization.
TABLE I
Sr. No. Sodium Degree of Phosphate binding Hydroxide (g) neutralization (%) capacity meq /g A 3.8 59.2 3.87 B 4.2 65.4 3.17 C 4.8 74.8 2.42 D 5.3 82.5 1.55 E 5.7 88.8 0.89 Example 2 15 g of polyallylamine hydrochloride was neutralized with aqueous solution of sodium hydroxide (4.2 g) to convert part of amine hydrochloride to free amine. The resulting mixture was cooled to 5 C. To a jacketed kettle equipped with mechanical stirrer and condenser was added toluene (120 ml) and sorbitane trioleate (0.6 ml) (Span 85).
Epichlorohydrin (1.8 ml), was added all at once to the partly neutralized polyallylamine hydrochloride solution. This solution was immediately dispersed in toluene with stirring. The mixture was heated to 60 C
and stirred for 3 hr. Toluene was decanted. The crosslinked polyallylamine hydrochloride formed was washed 3 times by suspending in 150 ml of de-ionized water stirring magnetically for 45 min. followed by filtration. The crosslinked solid was rinsed once by suspending it in isopropanol (200 ml) stirring for 45 min followed by filtration. The solid was dried under vacuum for 8 hrs.
Table 2 illustrates crosslinking of polyallylamine hydrochloride polymer differing in intrinsic viscosity.
Sr. No. Intrinsic viscosity dl/g Phosphate binding capacity meq /g A 0.18 3.17 B 0.20 3.12 C 0.22 3.12 D 0.24 2.98 Example 3 15 g of polyallylamine hydrochloride was neutralized with aqueous solution of sodium hydroxide (4.2 g) to convert part of amine hydrochloride to free amine. The resulting mixture was cooled to 7 C. To a jacketed kettle equipped with mechanical stirrer and condenser was added toluene (120 ml) and sorbitane trioleate (0.6 ml) (SPAN 85).
Epichlorohydrin, crosslinking agent was added all at once to the partly neutralized polyallylamine hydrochloride solution. This solution was immediately dispersed in toluene with stirring. The mixture was heated to 60 C and stirred for 3 hrs. Toluene was decanted. The crosslinked polyallylamine hydrochloride formed was washed 3 times by suspending in 150 ml of de-ionized water stirring magnetically for 45 min. followed by filtration. The crosslinked solid was rinsed by suspending it in isopropanol (200 ml) stirring for 45 min followed by filtration.
The solid was dried under vacuum for 8 hrs.
Table 3 describes crosslinking of polyallylamine hydrochloride using different quantities of epichlorohydrin.
Sr. No. Epichlorohydrin ml Phosphate binding capacity meq/g A 0.8 2.47 B 1.2 2.91 C 1.8 3.17 D 2.4 5.03 Example 4 15 g of polyallylamine hydrochloride was neutralized with aqueous solution of sodium hydroxide (4.2 g ) to convert part of amine hydrochloride to free amine. The resulting mixture was cooled to 5 C. To a jacketed kettle equipped with mechanical stirrer and condenser was added toluene (120 ml) and sorbitane trioleate (0.6 ml) (SPAN
85).
Epichlorohydrin (1.8 ml), was added all at once to the partly neutralized polyallylamine hydrochloride solution. This solution was immediately dispersed in organic solvent with stirring. The mixture was heated to 60 C and stirred for 3 hrs. The organic solvent was decanted. The crosslinked polyallylamine hydrochloride formed was washed 3 times by suspension in 150 ml of deionized water stirring magnetically for 45 min.
followed by filtration. The crosslinked solid was rinsed by suspending it in isopropanol (200 ml) stirring for 45 min followed by filtration. The solid was dried under vacuum for 8 hrs.
Table 4 describes crosslinking of polyallylamine hydrochloride carried out in different dispersion media.
In example D paraffin oil was decanted. Trace amount of paraffin oil was removed washing it with. hexane. The crosslinked polyallylamine hydrochloride was washed 3 times by suspending in 150 ml of de-ionized water stirring magnetically for 45 min.
followed by filtration. The crosslinked solid was rinsed by suspending it in isopropanol (200m1) stirring for 45 min followed by filtration. The solid was dried under vacuum for 8 hrs.
Sr.No. Dispersion medium Phosphate binding capacity meq/g A Toluene 3.17 B Hexane 3.16 C Xylene 3.22 D Paraffin oil 3.18 Example 5 g of polyallylamine hydrochloride was neutralized with aqueous solution of sodium hydroxide (4.2 g) to convert part of amine hydrochloride to free amine. The resulting mixture 15 was cooled to 5 C. To a jacketed kettle equipped with mechanical stirrer and condenser was added toluene (120 ml) and sorbitane trioleate (SPAN 85). Epichlorohydrin (1.8 ml), was added all at once to the partly neutralized polyallylamine hydrochloride solution. This solution was immediately dispersed in toluene with stirring. The mixture was heated to 60 C
and stirred for 3 hrs. Toluene was decanted. The crosslinked polyallylamine hydrochloride was washed 3 times by suspending in 150 ml of de-ionized water stirring magnetically for 45 min. followed by filtration. The crosslinked solid was rinsed by suspending it in isopropanol (200 ml) stirring for 45 min followed by filtration. The solid was dried under vacuum for 8 hrs.
Table 5 describes crosslinking of polyallylamine hydrochloride using different amounts of surfactant (SPAN -85).
The particle size distribution of the product obtained and the phosphate binding capacities are summarized below:
Sr SPAN -85 % Above 60 % 60-100 mesh % Below100 mesh No. Conc. mesh (meq P04/g) (meq P04/g) (%) (meq P04/g) 15.14 72.58 12.28 (2.23) (2.96) (3.22) 32.38 60.00 7.62 B 0.5 (2.38)) (3.0) (3.31) 34.22 59.02 6.76 C 0.25 (2.57) (3.18) (3.26) No 94.94 4.67 0.39 D
surfactant (2.76) (3.17) (3.31) The above data indicate the need to control the particle size distribution so as to maximize the yield of the product in the size range 60-100 mesh and minimize the yield of the product in the size range which passes through 100 mesh sieve.
Example 6 15 g of polyallylamine hydrochloride was neutralized with aqueous solution of sodium hydroxide (4.2 g) to convert part of amine hydrochloride to free amine. The resulting mixture was cooled to 5 C. To a jacketed kettle equipped with mechanical stirrer and condenser was added toluene (120 ml) and 0.6 ml sorbitane trioleate (SPAN 85).
Epichlorohydrin (1.8 ml), was added all at once to the partly neutralized polyallylamine hydrochloride solution. This solution was immediately dispersed in toluene with stirring using a stirrer, which has four blades at the bottom, two blades at the center and two blades above the blades at the center.
The mixture was heated to 60 C and stirred at a predetermined speed for 3 hrs.
Toluene was decanted. The crosslinked polyallylamine hydrochloride formed was washed 3 times by suspending in 150 ml of de-ionized water stirring magnetically for 45 min.
followed by filtration. The crosslinked solid was rinsed by suspending it in isopropanol (200 ml) stirring for 45 min followed by filtration. The solid was dried under vacuum for 8 hrs.
The particle size distribution of the product obtained and the phosphate binding capacities are summarized below.
Table 6 describes the crosslinking of polyallylamine hydrochloride under different stirring conditions.
Sr. RPM %Above 60 % 60-100 %Below 100 No. mesh mesh mesh (meq P04/g) (meq P04/g) (meq P04/g) 58.36 39.19 2.45 (2.73) (3.0) (3.29) 32.38 60.00 7.81 (2.38) (3.0) (3.31) 19.2 70.6 10.20 (2.69) (3.12) (3.40) The above data indicates that an optimal stirring speed results in maximizing the yield of crosslinked polyallylamine hydrochloride in the particle size range 60-100 mesh and minimizing the yield of fines which pass through 100 mesh sieve.
The advantages of the present invention are:
1) The present invention is a simplified crosslinking process.
2.) The present invention provides a maximum yield of particles of crosslinked polyallylamine in the size ranging from 60-100 mesh.
3) The present process eliminates the need of specialized and expensive equipments for manufacturing and can be completed in shorter reaction time.
Sr. No. Sodium Degree of Phosphate binding Hydroxide (g) neutralization (%) capacity meq /g A 3.8 59.2 3.87 B 4.2 65.4 3.17 C 4.8 74.8 2.42 D 5.3 82.5 1.55 E 5.7 88.8 0.89 Example 2 15 g of polyallylamine hydrochloride was neutralized with aqueous solution of sodium hydroxide (4.2 g) to convert part of amine hydrochloride to free amine. The resulting mixture was cooled to 5 C. To a jacketed kettle equipped with mechanical stirrer and condenser was added toluene (120 ml) and sorbitane trioleate (0.6 ml) (Span 85).
Epichlorohydrin (1.8 ml), was added all at once to the partly neutralized polyallylamine hydrochloride solution. This solution was immediately dispersed in toluene with stirring. The mixture was heated to 60 C
and stirred for 3 hr. Toluene was decanted. The crosslinked polyallylamine hydrochloride formed was washed 3 times by suspending in 150 ml of de-ionized water stirring magnetically for 45 min. followed by filtration. The crosslinked solid was rinsed once by suspending it in isopropanol (200 ml) stirring for 45 min followed by filtration. The solid was dried under vacuum for 8 hrs.
Table 2 illustrates crosslinking of polyallylamine hydrochloride polymer differing in intrinsic viscosity.
Sr. No. Intrinsic viscosity dl/g Phosphate binding capacity meq /g A 0.18 3.17 B 0.20 3.12 C 0.22 3.12 D 0.24 2.98 Example 3 15 g of polyallylamine hydrochloride was neutralized with aqueous solution of sodium hydroxide (4.2 g) to convert part of amine hydrochloride to free amine. The resulting mixture was cooled to 7 C. To a jacketed kettle equipped with mechanical stirrer and condenser was added toluene (120 ml) and sorbitane trioleate (0.6 ml) (SPAN 85).
Epichlorohydrin, crosslinking agent was added all at once to the partly neutralized polyallylamine hydrochloride solution. This solution was immediately dispersed in toluene with stirring. The mixture was heated to 60 C and stirred for 3 hrs. Toluene was decanted. The crosslinked polyallylamine hydrochloride formed was washed 3 times by suspending in 150 ml of de-ionized water stirring magnetically for 45 min. followed by filtration. The crosslinked solid was rinsed by suspending it in isopropanol (200 ml) stirring for 45 min followed by filtration.
The solid was dried under vacuum for 8 hrs.
Table 3 describes crosslinking of polyallylamine hydrochloride using different quantities of epichlorohydrin.
Sr. No. Epichlorohydrin ml Phosphate binding capacity meq/g A 0.8 2.47 B 1.2 2.91 C 1.8 3.17 D 2.4 5.03 Example 4 15 g of polyallylamine hydrochloride was neutralized with aqueous solution of sodium hydroxide (4.2 g ) to convert part of amine hydrochloride to free amine. The resulting mixture was cooled to 5 C. To a jacketed kettle equipped with mechanical stirrer and condenser was added toluene (120 ml) and sorbitane trioleate (0.6 ml) (SPAN
85).
Epichlorohydrin (1.8 ml), was added all at once to the partly neutralized polyallylamine hydrochloride solution. This solution was immediately dispersed in organic solvent with stirring. The mixture was heated to 60 C and stirred for 3 hrs. The organic solvent was decanted. The crosslinked polyallylamine hydrochloride formed was washed 3 times by suspension in 150 ml of deionized water stirring magnetically for 45 min.
followed by filtration. The crosslinked solid was rinsed by suspending it in isopropanol (200 ml) stirring for 45 min followed by filtration. The solid was dried under vacuum for 8 hrs.
Table 4 describes crosslinking of polyallylamine hydrochloride carried out in different dispersion media.
In example D paraffin oil was decanted. Trace amount of paraffin oil was removed washing it with. hexane. The crosslinked polyallylamine hydrochloride was washed 3 times by suspending in 150 ml of de-ionized water stirring magnetically for 45 min.
followed by filtration. The crosslinked solid was rinsed by suspending it in isopropanol (200m1) stirring for 45 min followed by filtration. The solid was dried under vacuum for 8 hrs.
Sr.No. Dispersion medium Phosphate binding capacity meq/g A Toluene 3.17 B Hexane 3.16 C Xylene 3.22 D Paraffin oil 3.18 Example 5 g of polyallylamine hydrochloride was neutralized with aqueous solution of sodium hydroxide (4.2 g) to convert part of amine hydrochloride to free amine. The resulting mixture 15 was cooled to 5 C. To a jacketed kettle equipped with mechanical stirrer and condenser was added toluene (120 ml) and sorbitane trioleate (SPAN 85). Epichlorohydrin (1.8 ml), was added all at once to the partly neutralized polyallylamine hydrochloride solution. This solution was immediately dispersed in toluene with stirring. The mixture was heated to 60 C
and stirred for 3 hrs. Toluene was decanted. The crosslinked polyallylamine hydrochloride was washed 3 times by suspending in 150 ml of de-ionized water stirring magnetically for 45 min. followed by filtration. The crosslinked solid was rinsed by suspending it in isopropanol (200 ml) stirring for 45 min followed by filtration. The solid was dried under vacuum for 8 hrs.
Table 5 describes crosslinking of polyallylamine hydrochloride using different amounts of surfactant (SPAN -85).
The particle size distribution of the product obtained and the phosphate binding capacities are summarized below:
Sr SPAN -85 % Above 60 % 60-100 mesh % Below100 mesh No. Conc. mesh (meq P04/g) (meq P04/g) (%) (meq P04/g) 15.14 72.58 12.28 (2.23) (2.96) (3.22) 32.38 60.00 7.62 B 0.5 (2.38)) (3.0) (3.31) 34.22 59.02 6.76 C 0.25 (2.57) (3.18) (3.26) No 94.94 4.67 0.39 D
surfactant (2.76) (3.17) (3.31) The above data indicate the need to control the particle size distribution so as to maximize the yield of the product in the size range 60-100 mesh and minimize the yield of the product in the size range which passes through 100 mesh sieve.
Example 6 15 g of polyallylamine hydrochloride was neutralized with aqueous solution of sodium hydroxide (4.2 g) to convert part of amine hydrochloride to free amine. The resulting mixture was cooled to 5 C. To a jacketed kettle equipped with mechanical stirrer and condenser was added toluene (120 ml) and 0.6 ml sorbitane trioleate (SPAN 85).
Epichlorohydrin (1.8 ml), was added all at once to the partly neutralized polyallylamine hydrochloride solution. This solution was immediately dispersed in toluene with stirring using a stirrer, which has four blades at the bottom, two blades at the center and two blades above the blades at the center.
The mixture was heated to 60 C and stirred at a predetermined speed for 3 hrs.
Toluene was decanted. The crosslinked polyallylamine hydrochloride formed was washed 3 times by suspending in 150 ml of de-ionized water stirring magnetically for 45 min.
followed by filtration. The crosslinked solid was rinsed by suspending it in isopropanol (200 ml) stirring for 45 min followed by filtration. The solid was dried under vacuum for 8 hrs.
The particle size distribution of the product obtained and the phosphate binding capacities are summarized below.
Table 6 describes the crosslinking of polyallylamine hydrochloride under different stirring conditions.
Sr. RPM %Above 60 % 60-100 %Below 100 No. mesh mesh mesh (meq P04/g) (meq P04/g) (meq P04/g) 58.36 39.19 2.45 (2.73) (3.0) (3.29) 32.38 60.00 7.81 (2.38) (3.0) (3.31) 19.2 70.6 10.20 (2.69) (3.12) (3.40) The above data indicates that an optimal stirring speed results in maximizing the yield of crosslinked polyallylamine hydrochloride in the particle size range 60-100 mesh and minimizing the yield of fines which pass through 100 mesh sieve.
The advantages of the present invention are:
1) The present invention is a simplified crosslinking process.
2.) The present invention provides a maximum yield of particles of crosslinked polyallylamine in the size ranging from 60-100 mesh.
3) The present process eliminates the need of specialized and expensive equipments for manufacturing and can be completed in shorter reaction time.
Claims (15)
1. An improved process for the preparation of crosslinked polyallylamine polymer having particle size of 60 to 100 meshs which comprises partly neutralizing polyallylamine hydrochloride in the range of 58 to 90 % with an alkali in an aqueous solution, chilling the above said solution to a temperature in the range of 4 to 10 °C, adding a crosslinking agent to the above said chilled solution and dispersing the resultant mixture in an organic solvent containing a surfactant, under agitation, at a speed of 800 to 1200 rpm, allowing the reaction to occur initially at a temperature in the range of 25-30°C, for a period of about 10 minutes and further increasing the reaction temperature to a maximum of about 80°C and allowing the reaction to continue for at least three hours, cooling the above said reaction mixture to a temperature in the range of 25-30°C, filtering the above said reaction mixture to separate the gel particles, washing the above said gel particles with water and finally with a water miscible organic solvent and removing the excess solvent followed by drying under vacuum to obtain the desired crosslinked polyallylamine polymer.
2. An improved process as claimed in claim 1 wherein the alkali used is an alkali hydroxide.
3. An improved process as claimed in claims 1&2, wherein the alkali hydroxide used is Sodium hydroxide.
4. An improved process as claimed in claims 1-3, wherein the surfactant used is commercially available SPAN-85.
5. An improved process as claimed in claims 1-4, wherein the concentration of the surfactant used is ranging between 0.25 to 1% (v/v) of the organic solvent.
6. An improved process as claimed in claims 1-5, wherein the ratio of the aqueous phase to organic phase used is in the range 1:3.3 to 1:8.
7. An improved process as claimed in claims 1-6, wherein the organic solvent used for dispersion is selected from aromatic and aliphatic hydrocarbon.
8. An improved process as claimed in claims 1-7, wherein the organic solvent used for dispersion is aromatic hydrocarbon selected from the group consisting of toluene, xylene and ethyl benzene.
9. An improved process as claimed in claims 1-8, wherein the organic solvent used for dispersion is aliphatic hydrocarbon selected from the group consisting of hexane, heptane, octane decane, dodecane and paraffin.
10. An improved process as claimed in claims 1-9, wherein the organic solvent used for washing the crosslinked polyallylamine polymer is selected from alcohol, ketone and ester.
11. An improved process as claimed in claims 1-10, wherein the organic solvent used is alcohol selected from the group consisting of methanol, ethanol and isopropanol.
12. An improved process as claimed in claims 1-11, wherein the organic solvent used is ketone selected from the group consisting of acetone, methyl ethylketone, methyl isobutyl ketone.
13. An improved process as claimed in claims 1-12, wherein the organic solvent used is ester selected from methyl acetate and ethyl acetate.
14. An improved process as claimed in claims 1-13, wherein 70 to 90% of the crosslinked polyallylamine obtained has particle size distribution in the range of 60-100 mesh.
15. A process as claimed in claims 1-14, wherein the phosphate binding capacity of the crosslinked polyallylamine obtained is in the range 2.9-3.25 meq phosphate/g.
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IN568DE2005 | 2005-03-16 | ||
PCT/IN2005/000375 WO2006097942A1 (en) | 2005-03-16 | 2005-11-22 | An improved process for the preparation of crosslinked polyallylamine polymer. |
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EP (1) | EP1869090A1 (en) |
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US6733780B1 (en) | 1999-10-19 | 2004-05-11 | Genzyme Corporation | Direct compression polymer tablet core |
US7985418B2 (en) | 2004-11-01 | 2011-07-26 | Genzyme Corporation | Aliphatic amine polymer salts for tableting |
US8986669B2 (en) | 2005-09-02 | 2015-03-24 | Genzyme Corporation | Method for removing phosphate and polymer used therefore |
JP5595660B2 (en) | 2005-09-15 | 2014-09-24 | ジェンザイム コーポレーション | Sachet formulation for amine polymer |
EP2441779A1 (en) * | 2006-09-01 | 2012-04-18 | USV Limited | Process for the preparation of sevelamer hydrochloride and formulation thereof |
US7964182B2 (en) * | 2006-09-01 | 2011-06-21 | USV, Ltd | Pharmaceutical compositions comprising phosphate-binding polymer |
US8425887B2 (en) | 2006-09-29 | 2013-04-23 | Genzyme Corporation | Amide dendrimer compositions |
JP2010513271A (en) | 2006-12-14 | 2010-04-30 | ゲンズイメ コーポレーション | Amide-amine polymer composition |
US8389640B2 (en) | 2008-04-15 | 2013-03-05 | Lupin Limited | Process for the preparation of cross-linked polyallylamine polymer |
AU2010209293A1 (en) * | 2009-01-22 | 2011-09-08 | Usv Limited | Pharmaceutical compositions comprising phosphate-binding polymer |
BRPI1012076A2 (en) | 2009-06-16 | 2019-04-16 | Watson Pharma Private Ltd | processes for preparation of sevelamer carbonate |
WO2011099038A2 (en) * | 2010-02-15 | 2011-08-18 | Sun Pharmaceutical Industries Limited | Process for preparing crosslinked allylamine polymer |
CN102858817B (en) * | 2010-02-24 | 2015-09-02 | 瑞立普萨公司 | As the cross-linked polyvinylamine of bile acid chelating agent, polyallylamine and ethyleneimine |
JP5479235B2 (en) * | 2010-06-11 | 2014-04-23 | 国立大学法人豊橋技術科学大学 | POLYALLYLAMINE POLYMER, POLYMER PARTICLE, AND METHOD FOR PRODUCING POLYMER PARTICLE |
WO2012042542A1 (en) | 2010-10-01 | 2012-04-05 | Usv Limited | Process for preparation of crosslinked polymer |
EP3564292B1 (en) * | 2016-12-28 | 2021-06-16 | FUJIFILM Corporation | Emulsion of nitrogen atom-containing polymer or salt thereof, production method therefor, and production method for particles |
WO2019078198A1 (en) | 2017-10-16 | 2019-04-25 | 富士フイルム株式会社 | Hyperphosphatemia treatment agent, and particles |
TW201922267A (en) | 2017-10-16 | 2019-06-16 | 日商富士軟片股份有限公司 | Hyperphosphatemia treatment agent |
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JPS6090243A (en) * | 1983-10-25 | 1985-05-21 | Nitto Boseki Co Ltd | Small spherical crosslinked monoallylamine polymer and its preparation |
JPS60106804A (en) * | 1983-11-15 | 1985-06-12 | Nitto Boseki Co Ltd | New active resin |
US5900475A (en) * | 1994-06-10 | 1999-05-04 | Geltex Pharmaceuticals, Inc. | Hydrophobic sequestrant for cholesterol depletion |
US5703188A (en) * | 1993-06-02 | 1997-12-30 | Geltex Pharmaceuticals, Inc. | Process for removing bile salts from a patient and compositions therefor |
US5607669A (en) * | 1994-06-10 | 1997-03-04 | Geltex Pharmaceuticals, Inc. | Amine polymer sequestrant and method of cholesterol depletion |
US5667775A (en) * | 1993-08-11 | 1997-09-16 | Geltex Pharmaceuticals, Inc. | Phosphate-binding polymers for oral administration |
US5496545A (en) * | 1993-08-11 | 1996-03-05 | Geltex Pharmaceuticals, Inc. | Phosphate-binding polymers for oral administration |
TW474813B (en) * | 1994-06-10 | 2002-02-01 | Geltex Pharma Inc | Alkylated composition for removing bile salts from a patient |
US6203785B1 (en) * | 1996-12-30 | 2001-03-20 | Geltex Pharmaceuticals, Inc. | Poly(diallylamine)-based bile acid sequestrants |
US5925379A (en) * | 1997-03-27 | 1999-07-20 | Geltex Pharmaceuticals, Inc. | Interpenetrating polymer networks for sequestration of bile acids |
TW592727B (en) * | 1997-04-04 | 2004-06-21 | Chugai Pharmaceutical Co Ltd | Phosphate-binding polymer preparations |
US6423754B1 (en) * | 1997-06-18 | 2002-07-23 | Geltex Pharmaceuticals, Inc. | Method for treating hypercholesterolemia with polyallylamine polymers |
EP1024151B1 (en) * | 1997-10-13 | 2004-07-28 | Nitto Boseki Co., Ltd. | Process for producing low-molecular-weight allylamine polymers or addition salts thereof |
US6083497A (en) * | 1997-11-05 | 2000-07-04 | Geltex Pharmaceuticals, Inc. | Method for treating hypercholesterolemia with unsubstituted polydiallylamine polymers |
US6294163B1 (en) * | 1998-10-02 | 2001-09-25 | Geltex Pharmaceuticals, Inc. | Polymers containing guanidinium groups as bile acid sequestrants |
WO2000024791A1 (en) * | 1998-10-28 | 2000-05-04 | Penn State Research Foundation | Process for polymerization of allylic compounds |
DE69931369T2 (en) * | 1999-03-03 | 2007-05-03 | Nitto Boseki Co., Ltd. | PROCESS FOR PREPARING AN AQUEOUS SOLUTION OF MONOALLYLAMINE POLYMER |
ATE366264T1 (en) * | 1999-04-16 | 2007-07-15 | Abbott Lab | METHOD FOR PRODUCING CROSS-LINKED POLYALLYAMIN DERIVATIVES |
US6190649B1 (en) * | 1999-04-23 | 2001-02-20 | Geltex Pharmaceuticals, Inc. | Polyether-based bile acid sequestrants |
US6180754B1 (en) * | 1999-09-03 | 2001-01-30 | The Dow Chemical Company | Process for producing cross-linked polyallylamine polymer |
US6362266B1 (en) * | 1999-09-03 | 2002-03-26 | The Dow Chemical Company | Process for reducing cohesiveness of polyallylamine polymer gels during drying |
US6733780B1 (en) * | 1999-10-19 | 2004-05-11 | Genzyme Corporation | Direct compression polymer tablet core |
AT409630B (en) * | 2000-12-13 | 2002-09-25 | Dsm Fine Chem Austria Gmbh | ALKYLATION OF N-BZW. CROSSLINKED POLYMERS CONTAINING AMINO OR AMMONIUM GROUPS |
JP2002300594A (en) * | 2001-03-30 | 2002-10-11 | Nec Viewtechnology Ltd | Color purity correcting method |
US6600011B2 (en) * | 2001-10-09 | 2003-07-29 | Genzyme Corporation | Process for purification and drying of polymer hydrogels |
AT411463B (en) * | 2002-09-03 | 2004-01-26 | Dsm Fine Chem Austria Gmbh | High yield production of alkylated nitrogen containing crosslinked polymer gels, e.g. epichlorohydrin crosslinked poly allylamine hydrochloride, comprises washing with methanol, sodium chloride and water |
-
2005
- 2005-11-22 CA CA002601236A patent/CA2601236A1/en not_active Abandoned
- 2005-11-22 WO PCT/IN2005/000375 patent/WO2006097942A1/en not_active Application Discontinuation
- 2005-11-22 EP EP05817960A patent/EP1869090A1/en not_active Withdrawn
- 2005-11-22 JP JP2008501490A patent/JP2008533272A/en active Pending
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US7388056B2 (en) | 2008-06-17 |
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