WO1984000885A1 - Ammonia scavenger - Google Patents
Ammonia scavenger Download PDFInfo
- Publication number
- WO1984000885A1 WO1984000885A1 PCT/US1983/001365 US8301365W WO8400885A1 WO 1984000885 A1 WO1984000885 A1 WO 1984000885A1 US 8301365 W US8301365 W US 8301365W WO 8400885 A1 WO8400885 A1 WO 8400885A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- product
- water
- slurry
- value
- phosphate
- Prior art date
Links
- 229940121848 Ammonia scavenger Drugs 0.000 title description 3
- 239000004137 magnesium phosphate Substances 0.000 claims abstract description 94
- 235000010994 magnesium phosphates Nutrition 0.000 claims abstract description 94
- GVALZJMUIHGIMD-UHFFFAOYSA-H magnesium phosphate Chemical compound [Mg+2].[Mg+2].[Mg+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O GVALZJMUIHGIMD-UHFFFAOYSA-H 0.000 claims abstract description 66
- 229960002261 magnesium phosphate Drugs 0.000 claims abstract description 63
- 229910000157 magnesium phosphate Inorganic materials 0.000 claims abstract description 63
- 238000000034 method Methods 0.000 claims abstract description 61
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 claims abstract description 57
- XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Chemical compound NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 claims abstract description 56
- 239000004202 carbamide Substances 0.000 claims abstract description 56
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 41
- 229910001868 water Inorganic materials 0.000 claims abstract description 39
- 229910021529 ammonia Inorganic materials 0.000 claims abstract description 29
- 108010046334 Urease Proteins 0.000 claims abstract description 25
- -1 ammonium ions Chemical class 0.000 claims abstract description 18
- 238000000502 dialysis Methods 0.000 claims abstract description 13
- 239000007864 aqueous solution Substances 0.000 claims abstract description 11
- 238000002360 preparation method Methods 0.000 claims abstract description 11
- 230000003134 recirculating effect Effects 0.000 claims abstract description 8
- 239000012530 fluid Substances 0.000 claims abstract description 7
- 239000002002 slurry Substances 0.000 claims description 38
- 229910001862 magnesium hydroxide Inorganic materials 0.000 claims description 21
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 claims description 21
- VTHJTEIRLNZDEV-UHFFFAOYSA-L magnesium dihydroxide Chemical compound [OH-].[OH-].[Mg+2] VTHJTEIRLNZDEV-UHFFFAOYSA-L 0.000 claims description 19
- 239000000347 magnesium hydroxide Substances 0.000 claims description 19
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 claims description 18
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical group [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 18
- 229940085991 phosphate ion Drugs 0.000 claims description 18
- 238000003756 stirring Methods 0.000 claims description 18
- 239000000203 mixture Substances 0.000 claims description 17
- 239000000872 buffer Substances 0.000 claims description 16
- 241000220451 Canavalia Species 0.000 claims description 14
- 235000010520 Canavalia ensiformis Nutrition 0.000 claims description 14
- 239000011777 magnesium Substances 0.000 claims description 14
- 238000006243 chemical reaction Methods 0.000 claims description 13
- 230000036571 hydration Effects 0.000 claims description 13
- 238000006703 hydration reaction Methods 0.000 claims description 13
- 235000012054 meals Nutrition 0.000 claims description 13
- 239000012528 membrane Substances 0.000 claims description 13
- 239000003153 chemical reaction reagent Substances 0.000 claims description 11
- 229910000147 aluminium phosphate Inorganic materials 0.000 claims description 8
- 239000002245 particle Substances 0.000 claims description 8
- CURLTUGMZLYLDI-UHFFFAOYSA-N Carbon dioxide Chemical compound O=C=O CURLTUGMZLYLDI-UHFFFAOYSA-N 0.000 claims description 6
- 150000008044 alkali metal hydroxides Chemical class 0.000 claims description 6
- 229910002092 carbon dioxide Inorganic materials 0.000 claims description 6
- 239000000395 magnesium oxide Substances 0.000 claims description 6
- CPLXHLVBOLITMK-UHFFFAOYSA-N magnesium oxide Inorganic materials [Mg]=O CPLXHLVBOLITMK-UHFFFAOYSA-N 0.000 claims description 6
- 238000002156 mixing Methods 0.000 claims description 6
- 229920000515 polycarbonate Polymers 0.000 claims description 6
- 239000004417 polycarbonate Substances 0.000 claims description 6
- 229910000318 alkali metal phosphate Inorganic materials 0.000 claims description 5
- AXZKOIWUVFPNLO-UHFFFAOYSA-N magnesium;oxygen(2-) Chemical compound [O-2].[Mg+2] AXZKOIWUVFPNLO-UHFFFAOYSA-N 0.000 claims description 4
- 239000001488 sodium phosphate Substances 0.000 claims description 4
- 229910000162 sodium phosphate Inorganic materials 0.000 claims description 4
- RYFMWSXOAZQYPI-UHFFFAOYSA-K trisodium phosphate Chemical group [Na+].[Na+].[Na+].[O-]P([O-])([O-])=O RYFMWSXOAZQYPI-UHFFFAOYSA-K 0.000 claims description 4
- 239000001856 Ethyl cellulose Substances 0.000 claims description 3
- ZZSNKZQZMQGXPY-UHFFFAOYSA-N Ethyl cellulose Chemical compound CCOCC1OC(OC)C(OCC)C(OCC)C1OC1C(O)C(O)C(OC)C(CO)O1 ZZSNKZQZMQGXPY-UHFFFAOYSA-N 0.000 claims description 3
- 229910019142 PO4 Inorganic materials 0.000 claims description 3
- 239000001569 carbon dioxide Substances 0.000 claims description 3
- 238000001035 drying Methods 0.000 claims description 3
- 229920001249 ethyl cellulose Polymers 0.000 claims description 3
- 235000019325 ethyl cellulose Nutrition 0.000 claims description 3
- 239000010452 phosphate Substances 0.000 claims description 2
- 239000002243 precursor Substances 0.000 claims description 2
- 238000005406 washing Methods 0.000 claims description 2
- 238000013019 agitation Methods 0.000 claims 1
- 229910000166 zirconium phosphate Inorganic materials 0.000 abstract description 39
- LEHFSLREWWMLPU-UHFFFAOYSA-B zirconium(4+);tetraphosphate Chemical compound [Zr+4].[Zr+4].[Zr+4].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O LEHFSLREWWMLPU-UHFFFAOYSA-B 0.000 abstract description 39
- 239000000243 solution Substances 0.000 abstract description 16
- 230000007062 hydrolysis Effects 0.000 abstract description 9
- 238000006460 hydrolysis reaction Methods 0.000 abstract description 9
- 239000000463 material Substances 0.000 abstract description 9
- 239000002516 radical scavenger Substances 0.000 abstract description 6
- QGZKDVFQNNGYKY-UHFFFAOYSA-O Ammonium Chemical compound [NH4+] QGZKDVFQNNGYKY-UHFFFAOYSA-O 0.000 abstract description 2
- 230000007071 enzymatic hydrolysis Effects 0.000 abstract 2
- 238000006047 enzymatic hydrolysis reaction Methods 0.000 abstract 2
- 150000001413 amino acids Chemical class 0.000 abstract 1
- 230000002255 enzymatic effect Effects 0.000 abstract 1
- 238000000338 in vitro Methods 0.000 abstract 1
- 238000001727 in vivo Methods 0.000 abstract 1
- 108090000623 proteins and genes Proteins 0.000 abstract 1
- 102000004169 proteins and genes Human genes 0.000 abstract 1
- 239000000047 product Substances 0.000 description 49
- 210000003734 kidney Anatomy 0.000 description 10
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 9
- 239000002775 capsule Substances 0.000 description 9
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical class CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 9
- 230000008569 process Effects 0.000 description 9
- 238000011282 treatment Methods 0.000 description 9
- 210000004369 blood Anatomy 0.000 description 8
- 239000008280 blood Substances 0.000 description 8
- 210000004379 membrane Anatomy 0.000 description 8
- 208000037157 Azotemia Diseases 0.000 description 6
- 238000001631 haemodialysis Methods 0.000 description 6
- 230000000322 hemodialysis Effects 0.000 description 6
- 239000003094 microcapsule Substances 0.000 description 6
- 239000007787 solid Substances 0.000 description 6
- 208000009852 uremia Diseases 0.000 description 6
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 5
- QCWXUUIWCKQGHC-UHFFFAOYSA-N Zirconium Chemical compound [Zr] QCWXUUIWCKQGHC-UHFFFAOYSA-N 0.000 description 5
- 235000011007 phosphoric acid Nutrition 0.000 description 5
- 229910052700 potassium Inorganic materials 0.000 description 5
- 239000011591 potassium Substances 0.000 description 5
- 239000000126 substance Substances 0.000 description 5
- 229910052726 zirconium Inorganic materials 0.000 description 5
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 4
- 230000008901 benefit Effects 0.000 description 4
- 239000011575 calcium Substances 0.000 description 4
- 229910052791 calcium Inorganic materials 0.000 description 4
- 238000002474 experimental method Methods 0.000 description 4
- 210000001035 gastrointestinal tract Anatomy 0.000 description 4
- 210000000056 organ Anatomy 0.000 description 4
- 238000002560 therapeutic procedure Methods 0.000 description 4
- LWIHDJKSTIGBAC-UHFFFAOYSA-K tripotassium phosphate Chemical compound [K+].[K+].[K+].[O-]P([O-])([O-])=O LWIHDJKSTIGBAC-UHFFFAOYSA-K 0.000 description 4
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 description 3
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 3
- 239000006096 absorbing agent Substances 0.000 description 3
- 210000001124 body fluid Anatomy 0.000 description 3
- 239000010839 body fluid Substances 0.000 description 3
- 239000008367 deionised water Substances 0.000 description 3
- 229910021641 deionized water Inorganic materials 0.000 description 3
- 238000011161 development Methods 0.000 description 3
- LOKCTEFSRHRXRJ-UHFFFAOYSA-I dipotassium trisodium dihydrogen phosphate hydrogen phosphate dichloride Chemical compound P(=O)(O)(O)[O-].[K+].P(=O)(O)([O-])[O-].[Na+].[Na+].[Cl-].[K+].[Cl-].[Na+] LOKCTEFSRHRXRJ-UHFFFAOYSA-I 0.000 description 3
- 239000006185 dispersion Substances 0.000 description 3
- 238000004519 manufacturing process Methods 0.000 description 3
- 239000002207 metabolite Substances 0.000 description 3
- 239000012071 phase Substances 0.000 description 3
- 239000008363 phosphate buffer Substances 0.000 description 3
- 239000002953 phosphate buffered saline Substances 0.000 description 3
- 230000002000 scavenging effect Effects 0.000 description 3
- 239000011734 sodium Substances 0.000 description 3
- 238000012360 testing method Methods 0.000 description 3
- 210000001519 tissue Anatomy 0.000 description 3
- 238000012546 transfer Methods 0.000 description 3
- 238000004065 wastewater treatment Methods 0.000 description 3
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- 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 2
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 2
- 239000002202 Polyethylene glycol Substances 0.000 description 2
- XKMRRTOUMJRJIA-UHFFFAOYSA-N ammonia nh3 Chemical compound N.N XKMRRTOUMJRJIA-UHFFFAOYSA-N 0.000 description 2
- 239000002585 base Substances 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 210000003736 gastrointestinal content Anatomy 0.000 description 2
- 230000036541 health Effects 0.000 description 2
- 238000011835 investigation Methods 0.000 description 2
- 229910052749 magnesium Inorganic materials 0.000 description 2
- 210000000885 nephron Anatomy 0.000 description 2
- 239000012074 organic phase Substances 0.000 description 2
- 239000012466 permeate Substances 0.000 description 2
- 235000021317 phosphate Nutrition 0.000 description 2
- 229920001223 polyethylene glycol Polymers 0.000 description 2
- 229910000160 potassium phosphate Inorganic materials 0.000 description 2
- 235000011009 potassium phosphates Nutrition 0.000 description 2
- 239000011541 reaction mixture Substances 0.000 description 2
- 238000011160 research Methods 0.000 description 2
- 238000000926 separation method Methods 0.000 description 2
- 239000010865 sewage Substances 0.000 description 2
- 229910052708 sodium Inorganic materials 0.000 description 2
- 210000002784 stomach Anatomy 0.000 description 2
- 206010070817 Bone decalcification Diseases 0.000 description 1
- 229920000623 Cellulose acetate phthalate Polymers 0.000 description 1
- 229910019440 Mg(OH) Inorganic materials 0.000 description 1
- 229910017958 MgNH Inorganic materials 0.000 description 1
- 208000001647 Renal Insufficiency Diseases 0.000 description 1
- 102000004142 Trypsin Human genes 0.000 description 1
- 108090000631 Trypsin Proteins 0.000 description 1
- PNNCWTXUWKENPE-UHFFFAOYSA-N [N].NC(N)=O Chemical compound [N].NC(N)=O PNNCWTXUWKENPE-UHFFFAOYSA-N 0.000 description 1
- 206010000059 abdominal discomfort Diseases 0.000 description 1
- 238000002835 absorbance Methods 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 229940009868 aluminum magnesium silicate Drugs 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 238000013459 approach Methods 0.000 description 1
- 239000008346 aqueous phase Substances 0.000 description 1
- 238000003556 assay Methods 0.000 description 1
- 230000001580 bacterial effect Effects 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 150000001768 cations Chemical class 0.000 description 1
- 229940081734 cellulose acetate phthalate Drugs 0.000 description 1
- 230000001684 chronic effect Effects 0.000 description 1
- 230000001010 compromised effect Effects 0.000 description 1
- 229920001577 copolymer Polymers 0.000 description 1
- 238000012937 correction Methods 0.000 description 1
- 230000001627 detrimental effect Effects 0.000 description 1
- 239000000385 dialysis solution Substances 0.000 description 1
- 229940075110 dibasic magnesium phosphate Drugs 0.000 description 1
- MHJAJDCZWVHCPF-UHFFFAOYSA-L dimagnesium phosphate Chemical compound [Mg+2].OP([O-])([O-])=O MHJAJDCZWVHCPF-UHFFFAOYSA-L 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 230000008030 elimination Effects 0.000 description 1
- 238000003379 elimination reaction Methods 0.000 description 1
- 239000000839 emulsion Substances 0.000 description 1
- 238000005538 encapsulation Methods 0.000 description 1
- 239000002702 enteric coating Substances 0.000 description 1
- 238000009505 enteric coating Methods 0.000 description 1
- 239000003337 fertilizer Substances 0.000 description 1
- 230000002496 gastric effect Effects 0.000 description 1
- INIGCWGJTZDVRY-UHFFFAOYSA-N hafnium zirconium Chemical compound [Zr].[Hf] INIGCWGJTZDVRY-UHFFFAOYSA-N 0.000 description 1
- YPDKFMYSITXPDU-UHFFFAOYSA-B hafnium(4+) tetraphosphate Chemical class [Hf+4].[Hf+4].[Hf+4].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O YPDKFMYSITXPDU-UHFFFAOYSA-B 0.000 description 1
- 150000004679 hydroxides Chemical class 0.000 description 1
- 230000002452 interceptive effect Effects 0.000 description 1
- 230000000968 intestinal effect Effects 0.000 description 1
- 210000000936 intestine Anatomy 0.000 description 1
- 238000005342 ion exchange Methods 0.000 description 1
- 150000002500 ions Chemical class 0.000 description 1
- 201000006370 kidney failure Diseases 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 229910001386 lithium phosphate Inorganic materials 0.000 description 1
- 210000004185 liver Anatomy 0.000 description 1
- HCWCAKKEBCNQJP-UHFFFAOYSA-N magnesium orthosilicate Chemical compound [Mg+2].[Mg+2].[O-][Si]([O-])([O-])[O-] HCWCAKKEBCNQJP-UHFFFAOYSA-N 0.000 description 1
- 239000000391 magnesium silicate Substances 0.000 description 1
- 229910052919 magnesium silicate Inorganic materials 0.000 description 1
- 235000019792 magnesium silicate Nutrition 0.000 description 1
- 238000012423 maintenance Methods 0.000 description 1
- 229940127554 medical product Drugs 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- AHKZTVQIVOEVFO-UHFFFAOYSA-N oxide(2-) Chemical compound [O-2] AHKZTVQIVOEVFO-UHFFFAOYSA-N 0.000 description 1
- TWNQGVIAIRXVLR-UHFFFAOYSA-N oxo(oxoalumanyloxy)alumane Chemical compound O=[Al]O[Al]=O TWNQGVIAIRXVLR-UHFFFAOYSA-N 0.000 description 1
- 238000010979 pH adjustment Methods 0.000 description 1
- 230000010412 perfusion Effects 0.000 description 1
- 210000004303 peritoneum Anatomy 0.000 description 1
- 230000035699 permeability Effects 0.000 description 1
- 150000003013 phosphoric acid derivatives Chemical class 0.000 description 1
- 239000011148 porous material Substances 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 230000000063 preceeding effect Effects 0.000 description 1
- 230000001376 precipitating effect Effects 0.000 description 1
- 230000022558 protein metabolic process Effects 0.000 description 1
- 238000007789 sealing Methods 0.000 description 1
- 210000002966 serum Anatomy 0.000 description 1
- AJPJDKMHJJGVTQ-UHFFFAOYSA-M sodium dihydrogen phosphate Chemical compound [Na+].OP(O)([O-])=O AJPJDKMHJJGVTQ-UHFFFAOYSA-M 0.000 description 1
- 229910001415 sodium ion Inorganic materials 0.000 description 1
- GQJPVGNFTLBCIQ-UHFFFAOYSA-L sodium;zirconium(4+);carbonate Chemical compound [Na+].[Zr+4].[O-]C([O-])=O GQJPVGNFTLBCIQ-UHFFFAOYSA-L 0.000 description 1
- 238000005063 solubilization Methods 0.000 description 1
- 230000007928 solubilization Effects 0.000 description 1
- 239000002594 sorbent Substances 0.000 description 1
- 239000006228 supernatant Substances 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 229920001169 thermoplastic Polymers 0.000 description 1
- 239000004416 thermosoftening plastic Substances 0.000 description 1
- TWQULNDIKKJZPH-UHFFFAOYSA-K trilithium;phosphate Chemical compound [Li+].[Li+].[Li+].[O-]P([O-])([O-])=O TWQULNDIKKJZPH-UHFFFAOYSA-K 0.000 description 1
- 239000012588 trypsin Substances 0.000 description 1
- 239000012905 visible particle Substances 0.000 description 1
- 239000002699 waste material Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C02—TREATMENT OF WATER, WASTE WATER, SEWAGE, OR SLUDGE
- C02F—TREATMENT OF WATER, WASTE WATER, SEWAGE, OR SLUDGE
- C02F1/00—Treatment of water, waste water, or sewage
- C02F1/28—Treatment of water, waste water, or sewage by sorption
- C02F1/281—Treatment of water, waste water, or sewage by sorption using inorganic sorbents
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01D—SEPARATION
- B01D15/00—Separating processes involving the treatment of liquids with solid sorbents; Apparatus therefor
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
- B01J20/00—Solid sorbent compositions or filter aid compositions; Sorbents for chromatography; Processes for preparing, regenerating or reactivating thereof
- B01J20/02—Solid sorbent compositions or filter aid compositions; Sorbents for chromatography; Processes for preparing, regenerating or reactivating thereof comprising inorganic material
- B01J20/04—Solid sorbent compositions or filter aid compositions; Sorbents for chromatography; Processes for preparing, regenerating or reactivating thereof comprising inorganic material comprising compounds of alkali metals, alkaline earth metals or magnesium
- B01J20/048—Solid sorbent compositions or filter aid compositions; Sorbents for chromatography; Processes for preparing, regenerating or reactivating thereof comprising inorganic material comprising compounds of alkali metals, alkaline earth metals or magnesium containing phosphorus, e.g. phosphates, apatites, hydroxyapatites
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
- B01J20/00—Solid sorbent compositions or filter aid compositions; Sorbents for chromatography; Processes for preparing, regenerating or reactivating thereof
- B01J20/28—Solid sorbent compositions or filter aid compositions; Sorbents for chromatography; Processes for preparing, regenerating or reactivating thereof characterised by their form or physical properties
- B01J20/28014—Solid sorbent compositions or filter aid compositions; Sorbents for chromatography; Processes for preparing, regenerating or reactivating thereof characterised by their form or physical properties characterised by their form
- B01J20/28026—Particles within, immobilised, dispersed, entrapped in or on a matrix, e.g. a resin
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
- B01J20/00—Solid sorbent compositions or filter aid compositions; Sorbents for chromatography; Processes for preparing, regenerating or reactivating thereof
- B01J20/30—Processes for preparing, regenerating, or reactivating
- B01J20/3085—Chemical treatments not covered by groups B01J20/3007 - B01J20/3078
-
- C—CHEMISTRY; METALLURGY
- C01—INORGANIC CHEMISTRY
- C01B—NON-METALLIC ELEMENTS; COMPOUNDS THEREOF; METALLOIDS OR COMPOUNDS THEREOF NOT COVERED BY SUBCLASS C01C
- C01B25/00—Phosphorus; Compounds thereof
- C01B25/16—Oxyacids of phosphorus; Salts thereof
- C01B25/26—Phosphates
- C01B25/32—Phosphates of magnesium, calcium, strontium, or barium
- C01B25/34—Magnesium phosphates
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
- B01J2220/00—Aspects relating to sorbent materials
- B01J2220/50—Aspects relating to the use of sorbent or filter aid materials
- B01J2220/62—In a cartridge
Definitions
- AMMONIA SCAVENGER BACKGROUND OF THE INVENTION * 1.
- Field of the Invention relates to the preparation of (in certain instances novel) magnesium phosphates (MGP) and their exploitation in the medical field, to-wit, their use in recirculating dialysis systems and other systems having the purpose of removing urea/ammonia from body fluids and in waste water treatment to remove ammonium ions (NH. ) .
- MGP magnesium phosphates
- the novel magnesium phosphate product can be utilized as a replacement for the older zirconium phosphate (ZP) materials which • in combination with an artificial kidney can be used to effect removal of urea/ammonia from the dialysate solution employed within the artificial kidney prior to the dialysate solution being reconducted through the artificial kidney.
- ZP zirconium phosphate
- the instant invention also relates to the field of encapsulated medical products for human consumption in eliminating urea present in the gastrointestinal tract.
- Uremia is present in blood, intestinal contents and other body fluids of normal as well as uremic patients. Uremia is a clinical term describing the condition in which the level of urea in a patient's blood is elevated above the normal levels of about 20 to about 40 milligrams per deciliter (mg/dl) . Uremia is due to the nephron function being inadequate to excrete the urea generated by protein metabolism.
- Excess urea can be removed by: (1) mass transfer across a membrane from blood to another low urea content fluid as in hemodialysis; (2) mass transfer across the membranes of the peritoneum into a low urea content fluid as in peritoneal dialysis; or (3) strongly
- urea/ammonia from the blood and other body tissues and organs we mean more precisely the removal of ammonium ions from solution, the source of the NH. ions being the hydrolysis of urea, either catalyzed by an exogenous urease enzyme such as jack bean meal urease or by an endogenous urease or by non-catalyzed hydrolysis of urea. Also, NH. is produced by bacterial activity in
- the progeny of the '880 patent discloses much investigation toward the preparation of various zirconium hydrous oxide ion exchangers comprising amorphous or microcrystalline solids containing zirconium or zirconium plus other oxides or hydroxides in various amounts of water.
- the recirculating dialysis systems utilize disposable cartridges containing layers of urease and ZP separate from other layers of aluminum oxide and magnesium silicate. See U.S. Patent No. 3,989,622 and Figure No.
- a very recent development to the gastrointestinal approach utilizes an enzyme urease from jack beans, encapsulated along with an ammonia absorber, ZP.
- the capsules are swallowed by the uremic patient and act to remove urea as ammonia. The removal of urea is completed when the capsules are voided in the patient's stools.
- This treatment while not a complete replacement for dialysis, is useful to postpone the onset or reduce the number of expensive and debilitating extracorporeal treatments. See Carl M. Kjellstrand et al. , “On the Clinical Use of Microencapsulated Zirconium Phosphate-Urease, the Treatment of Chronic Uremia", TRANS. AMER. SOC ARTIF. INT. ORGANS 27 at 24-29, (1981) and the pioneering microencapsulation work of Gardner and coworkers at Battelle Memorial Institute, Columbus, Ohio, in articles cited therein. In these articles, ZP is again the ammonia absorber of choice.
- ZP/urease capsules needs to be ingested by the patient because of low-binding capacity for ammonia and the low specificity for ammonium ions of the ZP material.
- the need to take such large quantities of this material may lead to stomach upset and the patient's refusal to adhere to this therapy regimen.
- a new and useful particulate magnesium phosphate product has been found which acts as a remarkably effective scavenger to bind ammonia (here, "ammonia” in our context shall mean, of course, ammonia ions) in aqueous systems.
- ammonia in our context shall mean, of course, ammonia ions
- the novel particulate magnesium phosphate product is substantially water insoluble (by
- substantially water insoluble we mean in an aqueous solution that when the MGP product . is added to said aqueous solution at a pH of about 4 to 9, the solubility of the MGP is less than about 70 g/dl.) , and when slurried, yields a pH of approximately 7.4, said product having an empirical composition exclusive of water of hydration, as follows:
- MGP magnesium phosphate
- MGP has the advantage of reacting chemically with the ammonia as opposed to less specific ion exchange as is traditionally criticized with the use of zirconium phosphate.
- Use of MGP would, therefore, lead to the advantage of avoiding calcium, magnesium, and potassium absorbance from the patient as is the case with zirconium phosphate.
- MGP unlike zirconium phosphate, does not release any sodium ions back into the dialysate solution, or when employed in encapsulated product, back into the patient.
- a method for treating a solution containing ammonium ions comprising contacting said solution with an ammonium-removing effective amount of the novel particulate magnesium phosphate product of the above formula.
- Urea is normally present in the intestinal contents in the concentration of 40-60 mg/dl, and it is recommended that the instant novel MGP product be utilized in amounts roughly one-third that of the traditional zirconium phosphate for removal of the hydrolysis product NH. + from urea. In like fashion, this MGP can also replace ZP in recirculating dialysate systems.
- magnesium phosphate product made in accordance with the present invention include use for sewage waste water treatment and process water effluents. After such treatments the resulting MgNH.PO. may be removed and used as a fertilizer.
- a method for the preparation of the novel particulate magnesium phosphate product comprising the steps of:
- the novel magnesium phosphate product is dried at about 150°F overnight to obtain a readily commercially useful product for encapsulation or for replacement of ZP in disposable cartridges.
- the present invention relates to a method for producing a particulate substantially water-soluble magnesium phosphate product, which when slurried has a pH of from about 6.5 to about 8.5, having an empirical composition exclusive of water of hydration of the formula:
- step (b) slowly adding H-PO. to the slurry of step (a) to form a particulate substantially water-insoluble magnesium phosphate product having an empirical composition exclusive of water of hydration of the formula: wherein x is from about 0.75 to about 1.4, y is from about 0.2 to about 1.5, and z is 1; and
- substantially water-soluble means that the magnesium phosphate product has a solubility of less than about 70 mg/dl when the product is added to an aqueous solution at a pH of about 4 to about 9.
- the phosphate ion-containing buffer is normally an alkali metal phosphate such as sodium phosphate, potassium phosphate, or lithium phosphate. Sodium phosphate is preferred. Any phosphate ion-containing buffer can be used as long as it is capable of providing phosphate ions in an aqueous solution and can provide by itself or by adjustment a pH ranging from about 6.5 to about 8.5. A pH of about 7.4 is preferred.
- the phosphate ion-containing buffer may also contain an alkali metal hydroxide to provide for pH range control.
- Typical alkali metal hydroxides include sodium hydroxide, potassium hydroxide, and lithium hydroxide. Sodium hydroxide is preferred.
- the phosphate ion-containing buffer having a pH of from about 6.5 to about 8.5 in the second step of the process may be added in this step to assure a control on the pH range.
- the make-up of the phosphate ion-containing buffer in this step may be the same as the make-up in the first step and again the preferred pH is 7.4.
- the H-PO. must be slowly added in the second step of the process since the reaction is highly exothermic and the reaction temperature should be kept under control. This is best achieved by removing heat from the reaction vessel and this can be accomplished by surrounding the reaction vessel with a water bath.
- the process of the present invention is especially useful in forming a magnesium phosphate product where x and y are both 1.0.
- the product is normally dried at a temperature of about 50°C to about 55°C Drying is usually carried out overnight.
- the magnesium phosphate product of the present invention is a useful alternative to ZP in removing urea, actually ammonium ions, from body fluids.
- a microencapsulated product for removing ammonia and/or urea from aqueous solutions comprising one or more particles, each having a water-insoluble, membranous wall which is permeable to urea, ammonia, and water and impermeable to urease enzyme, which membranous wall surrounds a core of a composition comprising urease and the novel particulate magnesium phosphate product of the empirical formula mentioned above.
- the particles are enterically coated on the outside in the manner traditionally done for medically consumable icrocapsules to prevent solubilization of the novel particulate magnesium phosphate product while passing through the stomach which has a pH of about 2.
- the ratio of the novel magnesium phosphate product to the jack bean meal be at least in the weight ratio of 10:1.
- the novel microencapsulated MGP removes urea from the gut by absorbing ammonium ions simultaneously generated by the hydrolysis of urea by urease contained in the jack bean meal, as well as removing NH. generated by other means.
- novel magnesium phosphate product includes its usage for sewage waste water treatment and process water effluents, as well as in systems for the treatment of the recirculated dialysate liquids, e.g., the REDY TM system by Organon
- FIG. 1 comprises an illustration showing the effectiveness of the novel magnesium phosphate (MGP) product for our encapsulated embodiment.
- MGP novel magnesium phosphate
- Figure No. 2 shows the efficiency of MGP in treating urea in terms of time.
- Figure No. 3 comprises an illustration showing the test to prove the effectiveness of microencapsulated MGP.
- Figure No. 4 comprises a chart showing the effectiveness of the microencapsulated MGP.
- Our enteric system consists of urease in jack bean meal or purified urease and MGP encased in capsules of a partially permeable membrane.
- the permeability of the capsule wall or membrane must be such that urea can readily permeate the membrane but larger molecules such as urease (about 240,000 daltons) or trypsin (about 24,000 daltons) cannot permeate.
- One suitable membrane is a polycarbonate dialysis membrane supplied by Enka A.G.
- a magnesium phosphate (“MGP") scavenger is generally prepared by reacting magnesium hydroxide (Mg(OH) 2 - Cat. No. MS55 obtained from MCB ("MCB”) Manufacturing Chemists, Inc. , (associate of E. Merck, Darmstadt, West Germany, 2909 Highland Avenue, Cincinnati, Ohio 45212) or magnesium oxide (MgO - Cat. No. ' 1-2480, J. T. Baker Chem. Co., Phillipsburg, New Jersey 08865) with orthophosphoric acid (H_PO. -MCB, Cat. No. PX100) in the presence of excess water.
- a slurry of insoluble MGP is formed from this reaction and the pH of the slurry is adjusted with the above reagents until the final pH is from 7.4 to 7.5.
- the reaction vessel shouli be cover>i ⁇ i to prevent atmospheric carbon dioxide frcrn dissolving in and reacting with the product MGP and the basic reagents. If carbon dioxide is not excluded, the pH will continue to drift downward and the M.GP quality may be compromised.
- o_..r ⁇ is stabilized, stirring is stopped and the solids are allowed to settle out. The supernatant is decanted and the solids are collected on several layers of absorbant paper. When the bulk of the water has been absorbed, the solid MGP is transferred to another fresh layer of paper and dried in an oven at about 150°F.
- magnesium orthophosphate from Pfaltz & Bauer (exact composition unknown Cat. No. M00540, Pfaltz & Bauer, Inc., Research Chemicals Division, Stamford, Connecticut 06902) was dissolved in water with a resulting pH of about 3.
- the pH was adjusted to 7.4 with sodium hydroxide, the resulting product lacked ammonia scavenging capacity.
- the pH adjustment was made with magnesium hydroxide, the insoluble product formed had very good ammonia scavenging properties.
- Figure No. 1 illustrates the effectiveness of the novel magnesium phosphate product of Example I for ammonium ion scavenging.
- a polycarbonate dialysis membrane pouch (Enka GmbH, Wuppertal, West Germany) was made by heat-sealing "shrunk” polycarbonate membrane.
- the pouch contained 500 mg of the novel magnesium phosphate product of Example I and 50 mg of the novel magnesium phosphate product of Example I and 50 mg of jack bean meal (Cat. No. J-0125 - Sigma Chemical Co., P. 0. Box 124508, St. Louis, Missouri 63178) as the urease source.
- the pouch was placed into 250 ml of a 0.01M phosphate buffer (sodium plus potassium phosphate) at a pH of about 7.4.
- the solution also contained about 50mg/dl of urea, ASC Reagent - (MCB above. Cat. No. UX65) for total of about 125 mg of urea. The entire contents were maintained at about 37°C with stirring. Samples were taken periodically and analyzed for urea using a blood urea nitrogen ("BUN") test kit. Cat. No. 64667 Provided by HARLECO , a division of EM Industries, Inc., Gibbstown, New Jersey 08027, and for ammonia using Nessler's Reagent (See pages 9095 of Capps Colorimetric Chemical Analytical Methods, Ninth Edition, by L. C Thomas, et al..
- EXAMPLE V Preparation of microencapsulated MGP: (a) A 5-percent solution of ethyl cellulose in toluene was prepared. This was further diluted to 3 percent ethyl cellulose with additional toluene so that about 200 ml of solution were used for the process. This phase represented the organic, wall material containing phase.
- the capsules are resuspended in fresh phosphate buffered saline and held until testing was performed.
- microencapsulated MGP and jack bean meal for removing urea from solution is demonstrated.
- Microcapsules were prepared as in Example V except that 0.5 grams of MGP and 0.05 grams of jack bean meal were used.
- Figure No. 3 shows the laboratory setup.
Abstract
A new and useful particulate magnesium phosphate product (MGP) and method of use therefor for removing ammonia from aqueous solutions, e.g., recirculating dialysate solutions and intragastrointestinal fluids as may result from the hydrolysis of urea. This particulate magnesium phosphate product (MGP) acts as a remarkably effective scavenger wherein under equilibrium conditions only about six (6) grams of the novel product are required to bind the ammonia (more exactly, ammonium ions) liberated from one (1) gram of the urea, a result far superior to traditional zirconium phosphate (ZP) prior art materials which under ideal conditions require about 17-20 grams of ZP per gram of urea. The novel particulate magnesium phosphate product can be exploited in one embodiment as a replacement for the older ZP materials used to remove ammonia produced by enzymatic hydrolysis of urea in recirculating dialysis systems utilizing disposable cartridges. In another embodiment, in a new encapsulated product (comprising a water-insoluble, membranous wall, permeable to urea and/or ammonia and water, while impermeable to urease enzyme, wherein the wall surrounds a core of urease and the novel particulate magnesium phosphate product) is disclosed, which can also be used as in in vivo or in vitro scavenger. This particulate MGP product can also be used for the removal of ammonium ions either produced by enzymatic or non-enzymatic hydrolysis of urea or proteins or amino acids or available as NH4+ from its native source. Two methods are also disclosed for the preparation of the particulate magnesium phosphate product.
Description
AMMONIA SCAVENGER BACKGROUND OF THE INVENTION * 1. Field of the Invention The subject matter of this application relates to the preparation of (in certain instances novel) magnesium phosphates (MGP) and their exploitation in the medical field, to-wit, their use in recirculating dialysis systems and other systems having the purpose of removing urea/ammonia from body fluids and in waste water treatment to remove ammonium ions (NH. ) . As one of the embodiments of the invention, the novel magnesium phosphate product can be utilized as a replacement for the older zirconium phosphate (ZP) materials which • in combination with an artificial kidney can be used to effect removal of urea/ammonia from the dialysate solution employed within the artificial kidney prior to the dialysate solution being reconducted through the artificial kidney. The instant invention also relates to the field of encapsulated medical products for human consumption in eliminating urea present in the gastrointestinal tract.
2. Description of the Prior Art and Other Information Urea is present in blood, intestinal contents and other body fluids of normal as well as uremic patients. Uremia is a clinical term describing the condition in which the level of urea in a patient's blood is elevated above the normal levels of about 20 to about 40 milligrams per deciliter (mg/dl) . Uremia is due to the nephron function being inadequate to excrete the urea generated by protein metabolism.
Excess urea can be removed by: (1) mass transfer across a membrane from blood to another low urea content fluid as in hemodialysis; (2) mass transfer across the membranes of the peritoneum into a low urea content fluid as in peritoneal dialysis; or (3) strongly
gfR__Al5*
absorbing urea or its hydrolysis products, especially ammonia, from the intestinal tract. see Kjellstrand, infra.
In the last several decades, systems have been developed to treat people who might otherwise die of kidney failure due to the inability of the kidney to remove metabolites, e.g., urea/ammonia from the blood and other body tissues and organs. By the removal of
"urea/ammonia from the blood and other body tissues and organs", we mean more precisely the removal of ammonium ions from solution, the source of the NH. ions being the hydrolysis of urea, either catalyzed by an exogenous urease enzyme such as jack bean meal urease or by an endogenous urease or by non-catalyzed hydrolysis of urea. Also, NH. is produced by bacterial activity in
** + the intestine. Normally, this NH is converted to urea by the liver. Thus, by removing NH. which is or is not the product of urease-catalyzed hydrolysis of urea, the net effect is to reduce the amount of urea which would have to be removed by other means.
Over a period of time, variations on these basic methods of removing urea have been made. In the field of hemodialysis, artificial kidneys were developed following the initial disclosure of the first suggestion for an effective mass transfer exchanger to treat a patient's blood through mass exchange with a treating solution. See Mahon, U.S. Patent No. 3,228,886 and 3,228,887.
Commencing with the pioneer invention of Marantz and co-workers of a recirculation dialysate system for use with artificial kidney machines, U.S. Patent No. 3,669,880, much investigation and development has ensued in the marketing of various portable systems whereby artificial kidneys can be employed at locations other than the hospital in order to reduce the cost and to increase convenience to the patients. See U.S. Patents No. 3,697,410; 3,697,418; 3,703,959; 3,850,835;
OVFI
3,989,622; 4,164,437; 4,212,738; and 4,256,718. Presently, such an advanced recirculation dialysate system for use with artificial kidneys is marketed under the trademark REDY TM by Organon Teknika Corporation of
Oklahoma City, Oklahoma. Following the disclosure of
U.S. Patent No. 3,332,737 to Kraus, much study has been made toward the development of materials suitable for removing metabolites, e.g., urea/ammonia from the blood and from various body tissues and organs. Early on, it was discovered that zirconium phosphate was effective for removing these metabolites. See U.S. Patent No.
3,669,880, Column 2, lines 54-67. Of course, zirconium phosphate was old at the time of the '880 invention. F.
Hevesey and K. Kimura, J. AM. CHEM. SOC, £7 at 2540, et seq. , (1925) examined zirconium and hafnium phosphates looking for ways to separate them, and methods of preparation and solubility were examined. R. Ried and
J. ithrow, J. AM. CHEM. SOC, 5JL at 1311 (1929) did an extensive study on methods of quantitatively precipitating zirconium phosphate using various phosphate mixtures. Chemical abstracts list several references to zirconium-hafnium separations employing phosphates. Note Z. ANORG. ALLGEM. CHEM., 165 at 1-15,
21-30 (1927), U.S. Patent No. 1,636,493 and Dutch
Patents No. 16,508; 16,510; 16,955, and 16,956.
The progeny of the '880 patent discloses much investigation toward the preparation of various zirconium hydrous oxide ion exchangers comprising amorphous or microcrystalline solids containing zirconium or zirconium plus other oxides or hydroxides in various amounts of water. In addition, the recirculating dialysis systems utilize disposable cartridges containing layers of urease and ZP separate from other layers of aluminum oxide and magnesium silicate. See U.S. Patent No. 3,989,622 and Figure No.
1 therein.
In the above cited art, '880, etc., ZP has been used as the preferred ammonia absorbant.
A very recent development to the gastrointestinal approach utilizes an enzyme urease from jack beans, encapsulated along with an ammonia absorber, ZP. The capsules are swallowed by the uremic patient and act to remove urea as ammonia. The removal of urea is completed when the capsules are voided in the patient's stools. This treatment, while not a complete replacement for dialysis, is useful to postpone the onset or reduce the number of expensive and debilitating extracorporeal treatments. See Carl M. Kjellstrand et al. , "On the Clinical Use of Microencapsulated Zirconium Phosphate-Urease, the Treatment of Chronic Uremia", TRANS. AMER. SOC ARTIF. INT. ORGANS 27 at 24-29, (1981) and the pioneering microencapsulation work of Gardner and coworkers at Battelle Memorial Institute, Columbus, Ohio, in articles cited therein. In these articles, ZP is again the ammonia absorber of choice.
3. The Problems Associated with Zirconium Phosphate and Replacing It
In 1981, and at the time of this invention, more than 56,000 Americans were being keep alive by maintenance peritoneal dialysis or hemodialysis at an annual expenditure of over $1.2 billion. Because of its extraordinary cost, however, three out of four people around the world will have no chance of receiving contemporary uremia therapy should their kidneys fail. Health planners in developed countries, distressed by the advancing expense of uremia therapy, are exploring shortened, more efficient hemodialysis and/or the potential benefits of Continuous Ambulatory Peritoneal Dialysis (CAPD) to contain costs. Also, to reduce the volume and cost of dialysate fluid and to improve the mobility of hemodialysis equipment, recirculating
dialysate systems have been introduced and are being used by uremic patients.
Unfortunately, however, all of these recirculation-looped, artifical kidney hemodialysis systems rely on the use of zirconium phosphate - a relatively expensive material whose precursors are only available from a few sources in the world, e.g. , the
Union of Soviet Socialist Republics and the Union of
South Africa - presenting supply difficulties. In addition, because of its relative ineffectiveness in removing ammonia/urea from dialysis solutions and body cavities, i.e., because of its nonspecificity and
4. limited binding capacity for NH. , ZP has had to be employed in relatively great quantities and has even been shown to remove serum potassium, calcium, and magnesium during microencapsulation treatment. Removing potassium and calcium from patients is detrimental because (1) potassium is needed by the patient for proper sodium/potassium balance and (2) calcium loss is increased in uremic patients due to accumulated phosphate ion concentration. This leads to bone decalcification, a serious problem for uremic patients.
See Kjellstrand, supra. Also, a large volume of
ZP/urease capsules needs to be ingested by the patient because of low-binding capacity for ammonia and the low specificity for ammonium ions of the ZP material. The need to take such large quantities of this material may lead to stomach upset and the patient's refusal to adhere to this therapy regimen.
The great expense of manufacturing ZP, poor availability worldwide, and its nonspecificity have long been criticized in its use for the treatment of uremia.
Notwithstanding numerous investigational studies attempting to obtain solutions to exploit alternatives to ZP in disposable cartridges and in the gut as substitute nephrons, including administration of oral
sorbent and intestinal perfusion, no practical commercial successor to ZP has been found.
While it is clear that the strategies described in the preceeding background sections were, for their time, attempts to provide improved, lower cost treatment and improve the clinical course of uremic patients, it is also apparent that the use of ZP in these therapies has limited their ability to reach the goal of better patient health. In order to measurably advance the art, a successor to ZP is needed.
SUMMARY OF THE INVENTION
A new and useful particulate magnesium phosphate product has been found which acts as a remarkably effective scavenger to bind ammonia (here, "ammonia" in our context shall mean, of course, ammonia ions) in aqueous systems. The novel particulate magnesium phosphate product is substantially water insoluble (by
"substantially water insoluble", we mean in an aqueous solution that when the MGP product . is added to said aqueous solution at a pH of about 4 to 9, the solubility of the MGP is less than about 70 g/dl.) , and when slurried, yields a pH of approximately 7.4, said product having an empirical composition exclusive of water of hydration, as follows:
wherein when "z", if
alue 1, "x" has a value from about 1.1 to about 1.3, and "y" has a value of from about 0.4 to about 0.8. An especially effective magnesium phosphate ("MGP") product (z=l) has been found having the formula:
i1-6_4/!Hr0.._6r-7r3-_pO4Λ-
For the binding to the novel magnesium phosphate product (MGP) , it has been discovered that under equilibrim conditions only about six (6) grams of the novel MGP is required per gram of hydrolyzed urea. This is far
C'-I
superior to traditional zirconium phosphate (ZP) reagents, which reagents require about 17-20 grams of ZP per gram of hydrolyzed urea to be removed, even when ZP is tested under almost ideal conditions not involving other cations always present in practical applications. We believe our novel MGP product treats patient urea in the following way: 0
/I
1) NH2-C - H2 + H20 urease ^ 2 H3 + C02 (urea
(urea) hydrolysis)
2) H3 + C02 + H2O^NH4 + + HC03~
3) H4 + + (Mg)χ(H)y(P04)z-,MgNH4P04 + H+
In summary, urea and water liberate ammonium ions (NH. ) , and our novel MGP consumes the ammonium ions.
In addition, we believe the novel MGP has the advantage of reacting chemically with the ammonia as opposed to less specific ion exchange as is traditionally criticized with the use of zirconium phosphate. Use of MGP would, therefore, lead to the advantage of avoiding calcium, magnesium, and potassium absorbance from the patient as is the case with zirconium phosphate. Further, MGP, unlike zirconium phosphate, does not release any sodium ions back into the dialysate solution, or when employed in encapsulated product, back into the patient.
A method for treating a solution containing ammonium ions has also been found, comprising contacting said solution with an ammonium-removing effective amount of the novel particulate magnesium phosphate product of the above formula.
Urea is normally present in the intestinal contents in the concentration of 40-60 mg/dl, and it is recommended that the instant novel MGP product be
utilized in amounts roughly one-third that of the traditional zirconium phosphate for removal of the hydrolysis product NH.+ from urea. In like fashion, this MGP can also replace ZP in recirculating dialysate systems.
Other applications for the magnesium phosphate product made in accordance with the present invention include use for sewage waste water treatment and process water effluents. After such treatments the resulting MgNH.PO. may be removed and used as a fertilizer.
A method is also disclosed for the preparation of the novel particulate magnesium phosphate product, comprising the steps of:
(a) mixing a given amount of magnesium hydroxide with an effective amount of water sufficient only to yield a highly fluid slurry having a pH of about 9.5 to about 10.5;
(b) gradually adding and stirring phosphoric acid to said slurry, sufficient to lower the pH of said slurry to about 7.4;
(c) adding and stirring one or more of the components selected from the group consisting of magnesium hydroxide, magnesium oxide, and phosphoric acid for a time sufficient to stabilize the pH of said slurry to about 7.4 to produce a substantially water-insoluble magnesium phosphate product of the aforementioned empirical formula; and
(d) separating said magnesium phosphate product from said slurry.
Preferably, after the magnesium phosphate product is separated, the novel magnesium phosphate product is dried at about 150°F overnight to obtain a readily commercially useful product for encapsulation or for replacement of ZP in disposable cartridges.
In another aspect, the present invention relates to a method for producing a particulate substantially water-soluble magnesium phosphate product, which when
slurried has a pH of from about 6.5 to about 8.5, having an empirical composition exclusive of water of hydration of the formula:
(Mg)χ(H)y(P04)z wherein x is from about 0.75 to about 1.4, y is from about 0.2 to about 1.5, and z is 1 comprising the steps of:
(a) mixing magnesium hydroxide with water containing a phosphate ion-containing buffer having a pH of from about 6.5 to about 8.5 to form a slurry,
(b) slowly adding H-PO. to the slurry of step (a) to form a particulate substantially water-insoluble magnesium phosphate product having an empirical composition exclusive of water of hydration of the formula:
wherein x is from about 0.75 to about 1.4, y is from about 0.2 to about 1.5, and z is 1; and
(c) separating the magnesium phosphate product from the slurry.
The term "substantially water-soluble" means that the magnesium phosphate product has a solubility of less than about 70 mg/dl when the product is added to an aqueous solution at a pH of about 4 to about 9.
The phosphate ion-containing buffer is normally an alkali metal phosphate such as sodium phosphate, potassium phosphate, or lithium phosphate. Sodium phosphate is preferred. Any phosphate ion-containing buffer can be used as long as it is capable of providing phosphate ions in an aqueous solution and can provide by itself or by adjustment a pH ranging from about 6.5 to about 8.5. A pH of about 7.4 is preferred.
The phosphate ion-containing buffer may also contain an alkali metal hydroxide to provide for pH
range control. Typical alkali metal hydroxides include sodium hydroxide, potassium hydroxide, and lithium hydroxide. Sodium hydroxide is preferred.
Although not absolutely required for a successful practice of the invention, it is also possible to add the phosphate ion-containing buffer having a pH of from about 6.5 to about 8.5 in the second step of the process to assure a control on the pH range. The make-up of the phosphate ion-containing buffer in this step may be the same as the make-up in the first step and again the preferred pH is 7.4.
The H-PO. must be slowly added in the second step of the process since the reaction is highly exothermic and the reaction temperature should be kept under control. This is best achieved by removing heat from the reaction vessel and this can be accomplished by surrounding the reaction vessel with a water bath.
The process of the present invention is especially useful in forming a magnesium phosphate product where x and y are both 1.0.
After separation of the magnesium phosphate product from the slurry, the product is normally dried at a temperature of about 50°C to about 55°C Drying is usually carried out overnight.
The magnesium phosphate product of the present invention is a useful alternative to ZP in removing urea, actually ammonium ions, from body fluids.
Also disclosed is a microencapsulated product for removing ammonia and/or urea from aqueous solutions, comprising one or more particles, each having a water-insoluble, membranous wall which is permeable to urea, ammonia, and water and impermeable to urease enzyme, which membranous wall surrounds a core of a composition comprising urease and the novel particulate magnesium phosphate product of the empirical formula mentioned above. The particles are enterically coated on the outside in the manner traditionally done for
medically consumable icrocapsules to prevent solubilization of the novel particulate magnesium phosphate product while passing through the stomach which has a pH of about 2. It is preferred that the ratio of the novel magnesium phosphate product to the jack bean meal be at least in the weight ratio of 10:1. Again, the novel microencapsulated MGP removes urea from the gut by absorbing ammonium ions simultaneously generated by the hydrolysis of urea by urease contained in the jack bean meal, as well as removing NH. generated by other means.
Other potential applications for the novel magnesium phosphate product include its usage for sewage waste water treatment and process water effluents, as well as in systems for the treatment of the recirculated dialysate liquids, e.g., the REDY TM system by Organon
Teknika Corporation, aforementioned.
SUMMARY OF THE DRAWINGS
Figure No. 1 comprises an illustration showing the effectiveness of the novel magnesium phosphate (MGP) product for our encapsulated embodiment.
Figure No. 2 shows the efficiency of MGP in treating urea in terms of time.
Figure No. 3 comprises an illustration showing the test to prove the effectiveness of microencapsulated MGP.
Figure No. 4 comprises a chart showing the effectiveness of the microencapsulated MGP.
DESCRIPTION OF THE PREFERRED EMBODIMENTS
One proposed use for our novel particulate magnesium phosphate product is as a scavenger for ammonium ions (NH. ) released by the hydrolysis of urea, which reaction is catalyzed by the presence of urease in
jack bean meal or purified urease. See U.S. Patent No. 3,669,878 and especially Column 3, lines 35-52, which are incorporated herein by reference. Such application operates as a replacement for zirconium phosphate (ZP) , or its progeny. Preferably, it is employed with a phosphate ion absorber, e.g., the state-of-the-art sodium zirconium carbonate product of the formula
(Na)A(Zr)B(C03)c, wherein "A" has the value of from about 0.8 to about 1.2, and "C" , measured as C02, has the value of from about 0.8 to about 1.2 when "B: , measured as Zr02, is assigned the value "1". However, our primary interest is for the use of the MGP in a system to be ingested by uremic patients for the enteric elimination of urea.
Our enteric system consists of urease in jack bean meal or purified urease and MGP encased in capsules of a partially permeable membrane. The permeability of the capsule wall or membrane must be such that urea can readily permeate the membrane but larger molecules such as urease (about 240,000 daltons) or trypsin (about 24,000 daltons) cannot permeate. The capsules must further be provided with an enteric coating as known in the pharmaceutical art, such as cellulose acetate phthalate, to prevent the MGP from contacting media with low pH (e.g. , pH=2 as in the stomach) . One suitable membrane is a polycarbonate dialysis membrane supplied by Enka A.G. Research Institute, Obernburg, West Germany, (experimental product of Enka A.G., Wuppertal, West Germany) ; it consists of a copolymer of polycarbonate and polyethyleneglycol (PEG) , and has a molecular weight of 200,000, which has boor, "shrunk" by washing with water and drying in order to produce the appropriate pore size. This polycarbonate dialysis ■membrane has the advantage of being heat-sealable since it is thermoplastic and pouches are easily formed.
Many methods for microencapsulating substances in partially permeable, water-insoluble membranes exist.
C'TI
■
It is beyond the scope of this invention to enumerate and describe all of them here. However, a variety of such techniques are described in Microencapsulation, ed. by J. R. Nixon from DRUGS AND THE PHARMACEUTICAL SCIENCES Series, Vol. 3 (Dekker; 1976); and MICRONENCAPSULATION: PROCESSES AND APPLICATIONS, ed. by Jan E. Vandergren, (Plenum Pub., 1974) .
While preferred embodiments and applications of the invention have been shown and described, it will be more apparent to those skilled in the art that many more modifications are possible without departing from the inventive concepts herein described. For example, other novel magnesium phosphate products could be formed and utilized for encapsulated particles as replacements for ZP. Similarly, other uses such as waste or process effluent treatment may be envisioned. The invention, therefore, is not to be restricted except as is necessary by the prior art and by the spirit of the appended claims.
EXAMPLE I A magnesium phosphate ("MGP") scavenger is generally prepared by reacting magnesium hydroxide (Mg(OH)2 - Cat. No. MS55 obtained from MCB ("MCB") Manufacturing Chemists, Inc. , (associate of E. Merck, Darmstadt, West Germany, 2909 Highland Avenue, Cincinnati, Ohio 45212) or magnesium oxide (MgO - Cat. No. ' 1-2480, J. T. Baker Chem. Co., Phillipsburg, New Jersey 08865) with orthophosphoric acid (H_PO. -MCB, Cat. No. PX100) in the presence of excess water. A slurry of insoluble MGP is formed from this reaction and the pH of the slurry is adjusted with the above reagents until the final pH is from 7.4 to 7.5.
Specifically, we first prepared batches of MGP scavenger as follows:
One mole (58.3 grams) of the aforementioned Mg(OH)2 is dispersed in about 400 ml of deionized water. To this slurry, one mole of 85-percent H3PO. (115.3
grams) was added while stirring with a magnetic stirbar. Care should be exercised to add the mentioned H.,PO. gradually since the reaction is exothermic and rapid addition can result in splashing. We have found that the reaction mixture will reach about 65°C during the H.-PO. addition. Vigorous stirring should continue throughout the procedure since otherwise the solids will settle out and form concretions.
After the reaction mix has cooled to about 30°C to 35°C a pH electrode was inserted. We have found that the pH at this point is about 3.5. Mg(OH)2 or MgO is added in very small increments to raise the pH. While we have attempted on many occasions to judiciously add the base, invariably the pH exceeded the target of 7.4-7.5. In this case, H PO. was added to lower the pH. Since the reactions at this point are occurring at the surface and perhaps throughout the particles of solid, the reaction rates are very slow. It was not unusual, therefore, to titrate with acid and base back and forth several times before achieving the final stable pH value between 7.4 and 7.5. In one experiment a total of 68.42 grams of Mg(OH) (1.174 moles) and 116.34 of 85-percent H-.PO. (1.009 moles) were used. Variations in the H..PO. content of the phosphoric acid solution supplied by chemical supply firms will result in the requirement to adjust the amount of phosphoric acid solution used. The normal range of assay for H-5 PO ι from commercial suppliers is 85-88%. Corrections for variations within this range are required.
The reaction vessel shouli be cover>i<i to prevent atmospheric carbon dioxide frcrn dissolving in and reacting with the product MGP and the basic reagents. If carbon dioxide is not excluded, the pH will continue to drift downward and the M.GP quality may be compromised.
Stirring is continued until the pH of the slurry changes by less than 0.03 within 2 hours. After the pH
o_..rι
is stabilized, stirring is stopped and the solids are allowed to settle out. The supernatant is decanted and the solids are collected on several layers of absorbant paper. When the bulk of the water has been absorbed, the solid MGP is transferred to another fresh layer of paper and dried in an oven at about 150°F.
EXAMPLE II
In another experiment, the reagents (Mg(0H)2 and
H-PO.) were added to water in amounts proportional to the final total quantity of each used in the preceding experiment. Initially, the pH was 4.12. Stirring was continued overnight in a closed vessel and the pH after about 18 hours was 7.90. We believe that the final pH must always be adjusted with Mg(0H)2 until a final value of 7.4 to 7.5 is obtained. To our best knowledge, in the expected application as an enteric ammonia scavenger, the expected surrounding medium will have a pH of about 7.4-7.5.
EXAMPLE III
In another experiment, magnesium orthophosphate from Pfaltz & Bauer (exact composition unknown Cat. No. M00540, Pfaltz & Bauer, Inc., Research Chemicals Division, Stamford, Connecticut 06902) was dissolved in water with a resulting pH of about 3. When the pH was adjusted to 7.4 with sodium hydroxide, the resulting product lacked ammonia scavenging capacity. However, when the pH adjustment was made with magnesium hydroxide, the insoluble product formed had very good ammonia scavenging properties.
EXAMPLE IV
Figure No. 1 illustrates the effectiveness of the novel magnesium phosphate product of Example I for ammonium ion scavenging. A polycarbonate dialysis membrane pouch (Enka GmbH, Wuppertal, West Germany) was
made by heat-sealing "shrunk" polycarbonate membrane. The pouch contained 500 mg of the novel magnesium phosphate product of Example I and 50 mg of the novel magnesium phosphate product of Example I and 50 mg of jack bean meal (Cat. No. J-0125 - Sigma Chemical Co., P. 0. Box 124508, St. Louis, Missouri 63178) as the urease source. The pouch was placed into 250 ml of a 0.01M phosphate buffer (sodium plus potassium phosphate) at a pH of about 7.4. The solution also contained about 50mg/dl of urea, ASC Reagent - (MCB above. Cat. No. UX65) for total of about 125 mg of urea. The entire contents were maintained at about 37°C with stirring. Samples were taken periodically and analyzed for urea using a blood urea nitrogen ("BUN") test kit. Cat. No. 64667 Provided by HARLECO , a division of EM Industries, Inc., Gibbstown, New Jersey 08027, and for ammonia using Nessler's Reagent (See pages 9095 of Capps Colorimetric Chemical Analytical Methods, Ninth Edition, by L. C Thomas, et al.. The Tintometer Ltd., Salisbury, England, (1980), incorporated herein). The Nessler's Reagent we used was obtained from Ricca Chemical Co., Arlington, Texas 76012, Cat. No. 5250. The results were shown in the graph of Figure No. 2. All quantities are expressed as mg of urea. The data of Figure No. 2 indicate that 500 mg of the novel magnesium phosphate of Example I inside the pouch was sufficient to consume the ammonia liberated from 120 mg of urea rapidly, and without interfering with the urease enzyme. These results disclose that use of the MGP of the present invention represents an enormous advance n the ar over the capacity of zirconium phosphate, and related reagents.
EXAMPLE V Preparation of microencapsulated MGP: (a) A 5-percent solution of ethyl cellulose in toluene was prepared. This was further diluted to 3 percent ethyl cellulose with additional toluene so that
about 200 ml of solution were used for the process. This phase represented the organic, wall material containing phase.
(b) An aqueous dispersion was then made of magnesium phosphate, as previously described, and jack bean meal. We used about 1 gram of magnesium phosphate and 0.10 gram of jack bean meal.
(c) The two above solutions and dispersions were next combined in a beaker containing a magnetic stirbar, placed on a magnetic stirplate, and stirred with a velocity such that the droplets of aqueous dispersion were formed in the non-aqueous, wall material bearing, phase.
(d) Mixed hexanes were then gradually (dropwise) added to the stirred suspension (pseudo-emulsion) until visible particle formation was seen. This usually required approximately 300-400 ml of mixed hexanes.
(e) At this point, stirring was halted and the soft microcapsules were allowed to settle to the bottom of the vessel. The supernatent organic phase consisting of hexane and toluene was decanted and an additional 300 ml of mixed hexanes were added.
(f) Stirring with the magnetic stirbar (but very gently) was resumed at this point and continued for about 20 minutes.
(g) Once again, stirring was stopped and the microcapsules were allowed to settle to the bottom of the vessel. The organic phase was decanted and the paste-like, densely packed microcapsules were spread on a bibulous layer and allowed to dry for at least 2 hours at room conditions.
(h) The microcapsules so prepared were resuspended in an aqueous phase consisting of phosphate buffered saline at pH=7.4 and then separated to wash away any unencapsulated urease enzymes.
(i) The capsules are resuspended in fresh phosphate buffered saline and held until testing was performed.
EXAMPLE VI
In this example, the use of microencapsulated MGP and jack bean meal for removing urea from solution is demonstrated.
Microcapsules were prepared as in Example V except that 0.5 grams of MGP and 0.05 grams of jack bean meal were used.
The microcapsules were added to 250 ml of phosphate buffered saline containing 125 mg of urea (=50 mg/dl) and stirred with a magnetic stirbar. Figure No. 3 shows the laboratory setup.
Samples were taken periodically and analyzed for urea and ammonia using the methods of Example IV. The results are shown in Figure No. 4. The data indicate that the capsules resulting from the above microencapsulation process were sufficient to consume 112 mg of urea, an enormous advance in the art over the capacity of ZP/urease capsules.
The following examples are representative of the second method of preparation.
EXAMPLE VII
In a 5 liter round bottom flask, 200 g of magnesium hydroxide (U.S.P. powder, Mallinckrodt 5984) was slurried with a variable speed stirrer in approximately 2 liters of 0.12 N phosphate buffer (pH 7.4; 8.3 g/1 sodium phosphate monobasic and sodium hydroxide) . The flask was immersed in a large volume room temperature water bath to aid in controlling the temperature of the exothermic reaction. While the magnesium hydroxide slurry was vigorously stirred, 292 g of H3 04 (85%; MCB 100-5) diluted with about 2 liters of 0.12 N phosphate buffer (pH 7.4) was pumped into the
flask at a rate of about 30 ml/min. Both temperature and pH were monitored throughout the reaction. After the temperature of the slurry re-equilibrated to room temperature and the pH restabilized at 7.4 (a period of about one to two hours) , the slurry was decant washed four times with 2 liters of deionized water, filtered, and rinsed with 12 liters of deionized water. The resulting wet cake magnesium phosphate product was then spread on trays and dried overnight to free flowing in a 50°C dehumidified forced air cabinet. The percent moisture normally ranged from 30% to 40%.
EXAMPLES VIII TO XVI A number of magnesium phosphate products produced in accordance with the present invention were tested for ammonia-nitrogen capacity on both a wet and a dry basis. The results appear below which also include values of the percentage yield as dibasic magnesium phosphate (MgHPO.) and percentage moisture.
Example Ammonia-Nitrogen Capacityt %Yield as % No. Wet Dry MgHPO. Moisture
VIII 52 89 67.6 41.4
IX 58 88 65.4 34.2
X 54 90 63.0 40.4
XI 50 93 63.0 46.5
XII 55 76 87.0 . 28.2
XIII 60 103 52.9 42.3
XIV 51 87 73.7 41.3
XV 55 94 81.9 41.3
XVI 59 83 66.8 28.2
t measured in terms of mg nitrogen /g magnesium phosphate product
ϋU.O-»
Claims
1. A particulate magnesium phosphate product which is substantially water insoluble, and when slurried, yields a pH of about 7.4, said product having an empirical composition exclusive of water of hydration, as follows:
(Mg)χ(H)y(P04)z wherein when "z" has an assigned value of 1, "x" has a value of about 1.1 to about 1.3, and "y" has a value from about 0.4 to about 0.8.
2. The magnesium phosphate product of claim 1, wherein "x" has a value from about 1.14 to about 1.18 and "y" has a value from about" 0.72 to about 0.64, respectivel .
3. The magnesium phosphate product of claim 1, wherein "x" is 1.164 and "y" is 0.673.
4. A method for treating an aqueous solution containing ammonium ions, comprising: contacting an aqueous solution containing ammonium ions with an ammonium-removing effective amount of a particulate magnesium phosphate product, which product is substantially water-insoluble, and when slurried yields a pH of about 7.4, said product having an empirical composition exclusive of water of hydration, as follows:
(Mg)χ(H)y(P04)2 wherein "z" has an assigned value of 1, "x" has a value of about 1.1 to about 1.3, and "y" has a value of from about 0.4 to about 0.8.
5. The method of claim 4, wherein "x" has a value of from about 1.14 to about 1.18, and "y" has a value of from about 0.72 to about 0.64, respectively.
6. The method of claim 4, wherein "x" is 1.164 and "y" is 0.673.
7. The method of claims 4, 5, or 6 when such contact takes place in a recirculating dialysis system.
MPI
8. The method of claims 4, 5, or 6 when such contact takes place by means of encapsulated particles containing said particulate magnesium phosphate product.
9. The method of claim 7", wherein said recirculating dialysis system utilizes a disposable cartridge containing microencapsulated particles comprising said particulate magnesium phosphate product.
10. The method -of claim 9, wherein said microencapsulated particles contain urease which is provided by jack bean meal, or purified urease enzyme.
11. A method for the preparation of a particulate magnesium phosphate product which is substantially water-insoluble, and when slurried yields a pH of about
7.4, said product having an empirical composition exclusive of water of hydration, as follows:
(Mg) (H) (PO.) ' x y 4 z wherein when "z" has an assigned value of 1, "x" has a value of from about 1.1 to about 1.3 and "y" has a value of about 0.4 to about 0.8, said method comprising the steps of:
(a) mixing and stirring a given amount of magnesium hydroxide with an effective amount of water sufficient only to yield a highly fluid slurry having a pH of about 9.5 to about 10.5;
(b) gradually adding and stirring H_PO. to said slurry sufficient to lower the pH of said slurry to about 7.4;
(c) adding and stirring one or more of the components selected from the group consisting of magnesium hydroxide, magnesium oxide, and phosphoric acid for a time sufficient to stabilize the pH of said slurry to about 7.4 to produce a water-insoluble, magnesium phosphate product having an empirical formula of:
(Mg)χ(H)y(P04)z
wherein when "z" has an assigned value of 1, "x" is from about 1.1 to about 1.3 and "y" has a value from about 0.4 to about 0.8; and
(d) separating said magnesium phosphate product from said slurry.
12. The method of claim 11, wherein "x" has a value of from about 1.14 to about 1.18 and "y" has a value of from about 0.72 to about 1.18.
13. The method of claim 11, wherein "x" is 1.164 and "y" is 0.673.
14. The method of claims 11, 12 or 13 wherein said separated magnesium phosphate product is dried at a temperature of 150°F.
15. The method of claims 11, 12, or 13, in which the water mixed with the magnesium hydroxide in step (a) , is deionized.
16. The method of claims 11, 12, or 13, in which the slurry of step (b) is cooled to about 30°C prior to adding one or more of the components of step (c) .
17. The method of claims 11, 12, or 13, in which said method is conducted in a blanketed reaction vessel to prevent atmospheric carbon dioxide from dissolving in and reacting with the particulate magnesium phosphate product or the precursor reagents.
18. The method of claims 11, 12, or 13, wherein the reagents magnesium hydroxide and phosphoric acid in steps (a) and (b) respectively, are added to water in amounts proportional to the final total quantity.
19. The method of claims 11, 12, or 13, wherein magnesium ortho phosphate is added to the magnesium hydroxide of step (a) .
20. A method for the preparation of a particulate magnesium phosphate product-containing slurry, which product is substantially water-insoluble, and when slurried yields a pH of about 7.4, said product having an empirical composition exclusive of water of hydration, as follows:
(Mg)χ(H)y(P04)z wherein when "z" has an assigned value of 1", "x" has a value from about 1.1 to about 1.3, and "y" has a value of about 0.4 to about 0.8, said method comprising steps of:
(a) mixing and stirring a given amount of magnesium hydroxide in an effective amount of water sufficient only to yield a highly fluid slurry having a pH of about 9.5 to about 10.5;
(b) gradually adding and stirring phosphoric acid to said slurry sufficient to lower the pH of said slurry to about 7.4;
(c) stirring one or more of the components selected from the group consisting of magnesium hydroxide, magnesium oxide, and phosphoric acid for a time sufficient to stabilize the pH of said slurry to about 7.4 to produce a substantially water-soluble, magnesium phosphate product having an empirical formula of:
(Mg)χ(H)y(P04)z, wherein when "z" has an assigned value of 1, "x" is from about 1.1 to about 1.3 and "y" has a value from about 0.4 to about 0.8 in order to form a magnesium phosphate product-containing slurry.
21. The slurry of claim 20, wherein "x" has a value of from about 1.14 to about 1.18 and "y" has a value of from about 0.72 to about 0.64.
22. The slurry of claim 20, wherein "x" is 1.164 and "y" is 0.673.
23. A microencapsulated product for removing ammonia and/or urea from aqueous solutions, comprising: one or more particles each having a water-insoluble wall permeable to urea, ammonia and water and impermeable to urease enzyme, surrounding a core composition comprising urease and a particulate magnesium phosphate product which is substantially water-insoluble, and when slurried yields a pH of about
O.'PI
~,.ii'θ
7.4, said product having an empirical composition exclusive of water of hydration, as follows:
(Mg)χ(H)y(P04)z wherein when "z" has an assigned value of 1, "x" is from about 1.1 to about 1.3 and "y" is from about 0.4 to 0.8.
24. The microencapsulated product of claim 23, wherein "x" has a value of from about 1.14 to about 1.18 and "y" has a value of from about 0.72 to about 0.64, respectivel .
25. The microencapsulated product of claim 23, wherein "x" is 1.164 and "y" is 0.673.
26. The microencapsulated product of claims 23, 24, or 25 wherein the membrane comprises a polycarbonate dialysis membrane shrunk by washing and subsequent drying.
27. The microencapsulated product of claims 23, 24, or 25 wherein the composition core comprises said particulate magnesium phosphate product and jack bean meal.
28. The microencapsulated product of claims 23, 24, or 25 wherein the weight ratio of particulate magnesium phosphate product to jack bean meal is about 10 to about 1.
29. The microencapsulated product of claims 23, 24, or 25 wherein the membranous wall comprises ethyl cellulose.
30. The microencapsulated product of claims 23, 24, 25, 26, 27, 28, or 29, which is enterically coated.
31. A method for the preparation of a particulate substantially water-insoluble nagnesi rr. phosphate product, which when slurried has a pH cf frcrr. about 6.5 to about 8.5, having an empirical composition exclusive of water hydration of the formula:
(Mg) (H) (PO.) ^ x y 4 z wherein x is from about 0.75 to about 1.4, y is from about 0.2 to about 1.5, and z is 1
comprising the steps of
(a) mixing magnesium hydroxide with water containing a phosphate ion-containing buffer having a pH of from about 6.5 to about 8.5 to form a slurry;
(b) slowly adding H,PO. to the slurry of step (a) to form a particulate substantially water-insoluble magnesium phosphate product having an empirical composition exclusive of water of hydration of the formula:
wherein x is from about 0.75 to about 1.4, y is from about 0.2 to about 1.5, and z is 1, and
(c) separating said magnesium phosphate product from said slurry.
32. The method of claim 31 wherein said phosphate ion-containing buffer has a pH of about 7.4.
33. The method of claim 31 wherein said phosphate ion-containing buffer contains an alkali metal phosphate.
34. The method of claim 33 wherein said alkali metal phosphate is sodium phosphate.
35. The method of claim 33 wherein said phosphate ion-containing buffer contains an alkali metal hydroxide.
36. The method of claim 35 wherein said alkali metal hydroxide is sodium hydroxide.
37. The method of claim 31 wherein x and y are 1.0.
38. The method of claim 31 wherein a phosphate ion-containing buffer having a pH of from about 6.5 to about 8.5 is added to the slurry in step (b) .
39. The method of claim 38 wherein said phosphate ion-containing buffer added to the slurry in step (b) has a pH of about 7.4.
40. The method of claim 31 wherein step (b) is carried out under stirring.
41. The method of claim 40 wherein step (b) is carried out under agitation.
42. A method for treating an aqueous solution containing ammonium ions comprising: contacting an aqueous solution containing ammonium ions with an ammonium-removing effective amount of a particulate substantially water-insoluble magnesium phosphate product, which when slurried has a pH from about 6.5 to about 8.5, having an empirical formula exclusive of water of hydration of the formula:
(Mg)χ(H)y(P04)z wherein x is from about 0.75 to about 1.4, y is from about 0.2 to about 1.5, and z is 1.
43. The method of "claim 42 wherein x and y and 1.0.
44. A method for the preparation of a particulate substantially water-insoluble magnesium phosphate product containing slurry having a pH of from about 6.5 to about 8.5, said product having an empirical composition exclusive of water of hydration of the formula:
(a) mixing magnesium hydroxide wL'- water containing a phosphate ion-containing buffer having a pH of from about 6.5 to about 8.5 to form a slurry, and
(b) slowly adding H-PO. to the slurry of step (a) to form a particulate substantially water-insoluble magnesium phosphate product having an empirical composition exclusive of water of hydration of the formula:
(Mg)χ(H)y(P04)z wherein x is from about 0.75 to about 1.4, y is from about 0.2 to about 1.5, and z is 1.
45. The method of claim 44 wherein x and y are 1.0.
46. The method of claim 44 wherein said phosphate ion-containing buffer has a pH of about 7.4.
47. The method of claim 44 wherein said phosphate-ion containing buffer contains an alkali metal phosphate.
48. The method of claim 47 wherein said alkali metal phosphate is sodium phosphate.
49. The method of claim 47 wherein said phosphate ion-containing buffer contains an alkali metal hydroxide.
50. The method of claim 49 wherein said alkali metal hydroxide is sodium hydroxide.
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
AU20366/83A AU2036683A (en) | 1982-09-09 | 1983-09-09 | Ammonia scavenger |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US06/416,771 US4650587A (en) | 1982-09-09 | 1982-09-09 | Ammonia scavenger |
US06/526,311 US4460555A (en) | 1983-08-25 | 1983-08-25 | Ammonia scavenger |
Publications (1)
Publication Number | Publication Date |
---|---|
WO1984000885A1 true WO1984000885A1 (en) | 1984-03-15 |
Family
ID=27023476
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/US1983/001365 WO1984000885A1 (en) | 1982-09-09 | 1983-09-09 | Ammonia scavenger |
Country Status (2)
Country | Link |
---|---|
EP (1) | EP0118548A1 (en) |
WO (1) | WO1984000885A1 (en) |
Cited By (10)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
DE3732896A1 (en) * | 1986-11-07 | 1988-08-25 | Schulze Rettmer Rainer | Process for eliminating ammonia and phosphate from waste water and process water |
EP0282218A2 (en) * | 1987-03-09 | 1988-09-14 | Mobil Oil Corporation | Layered divalent metal compositions |
DE3834543A1 (en) * | 1988-10-11 | 1990-04-12 | Passavant Werke | METHOD FOR THE DISPOSAL OF A HIGH AMOUNT OF AMMONIUM-NITROGEN-RELATED WASTEWATERS |
EP0490396A1 (en) * | 1990-12-14 | 1992-06-17 | DEUTSCHE NALCO-CHEMIE GmbH | Process for recovery of ammonia from process and waste waters |
WO1993015746A1 (en) * | 1992-02-18 | 1993-08-19 | Urecap Corporation | Compositions for the treatment of pylori and dermatitis |
WO2002061107A2 (en) * | 2001-01-31 | 2002-08-08 | Dsm Ip Assets B.V. | Process for the preparation of enantiomer-enriched amino acids |
US8012118B2 (en) | 2006-03-08 | 2011-09-06 | Fresenius Medical Care Holdings, Inc. | Artificial kidney dialysis system |
US8241239B2 (en) | 2006-08-24 | 2012-08-14 | Fresenius Medical Care Holdings, Inc. | Device for removing fluid from blood in a patient |
US8715221B2 (en) | 2006-03-08 | 2014-05-06 | Fresenius Medical Care Holdings, Inc. | Wearable kidney |
US8777892B2 (en) | 2008-11-03 | 2014-07-15 | Fresenius Medical Care Holdings, Inc. | Portable peritoneal dialysis system |
Citations (21)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US1251742A (en) * | 1917-06-21 | 1918-01-01 | Carroll Allen | Process of treating phosphate material. |
US1816051A (en) * | 1928-05-21 | 1931-07-28 | Chemical Products Company | Method for treating phosphate material |
US2036760A (en) * | 1934-07-21 | 1936-04-07 | Victor Chemical Works | Manufacture of calcium phosphates |
US2121208A (en) * | 1935-03-30 | 1938-06-21 | American Agricultural Chem Co | Production of monocalcium phosphate |
GB896660A (en) * | 1959-07-13 | 1962-05-16 | Thorn Electrical Ind Ltd | Improvements in the preparation of phosphates of bivalent metals |
CA704951A (en) * | 1965-03-02 | Woitas Gotz-Dieter | Process for production of very finely divided orthophosphates | |
BE675741A (en) * | 1965-01-29 | 1966-05-16 | ||
US3294486A (en) * | 1963-09-16 | 1966-12-27 | Knapsack Ag | Manufacture of dicalcium phosphate, dihydrate |
US3495988A (en) * | 1968-03-06 | 1970-02-17 | Leslie L Balassa | Encapsulation of aromas and flavors |
US3723308A (en) * | 1970-11-16 | 1973-03-27 | D Breck | Process for removal of ammonia from waste water streams |
US3989622A (en) * | 1970-12-30 | 1976-11-02 | Cci Life Systems, Inc. | Urease in insoluble form for converting urea present in a liquid |
US4205060A (en) * | 1978-12-20 | 1980-05-27 | Pennwalt Corporation | Microcapsules containing medicament-polymer salt having a water-insoluble polymer sheath, their production and their use |
US4218541A (en) * | 1978-03-30 | 1980-08-19 | Ackerman Roy A | Converting urea with bacteria |
US4247393A (en) * | 1979-01-11 | 1981-01-27 | Wallace Richard A | Hemodialysis assist device |
JPS5688812A (en) * | 1979-12-21 | 1981-07-18 | Hitachi Zosen Corp | Preparation of phosphoric acid by wet process |
US4294808A (en) * | 1978-09-20 | 1981-10-13 | Hoechst Aktiengesellschaft | Production of anticorrosive pigments containing phosphorus |
JPS56161886A (en) * | 1980-05-13 | 1981-12-12 | Burando Kenkyusho:Kk | Separation and recovery of phosphate from phosphate- containing. waste water |
JPS5712892A (en) * | 1980-06-25 | 1982-01-22 | Ebara Infilco Co Ltd | Disposal of phosphate ion-containing waste water |
US4344857A (en) * | 1975-12-22 | 1982-08-17 | The United States Of America As Represented By The Secretary Of Agriculture | Encapsulation by entrapment |
US4344851A (en) * | 1974-07-15 | 1982-08-17 | Union Carbide Corporation | Phillipsite-type zeolites for ammonia adsorption |
US4392963A (en) * | 1980-03-26 | 1983-07-12 | Sartorius Gmbh | Resorcinol or phloroglucinol condensation product for aqueous mixture purification |
-
1983
- 1983-09-09 EP EP19830903058 patent/EP0118548A1/en not_active Withdrawn
- 1983-09-09 WO PCT/US1983/001365 patent/WO1984000885A1/en unknown
Patent Citations (23)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CA704951A (en) * | 1965-03-02 | Woitas Gotz-Dieter | Process for production of very finely divided orthophosphates | |
US1251742A (en) * | 1917-06-21 | 1918-01-01 | Carroll Allen | Process of treating phosphate material. |
US1816051A (en) * | 1928-05-21 | 1931-07-28 | Chemical Products Company | Method for treating phosphate material |
US2036760A (en) * | 1934-07-21 | 1936-04-07 | Victor Chemical Works | Manufacture of calcium phosphates |
US2121208A (en) * | 1935-03-30 | 1938-06-21 | American Agricultural Chem Co | Production of monocalcium phosphate |
GB896660A (en) * | 1959-07-13 | 1962-05-16 | Thorn Electrical Ind Ltd | Improvements in the preparation of phosphates of bivalent metals |
US3294486A (en) * | 1963-09-16 | 1966-12-27 | Knapsack Ag | Manufacture of dicalcium phosphate, dihydrate |
BE675741A (en) * | 1965-01-29 | 1966-05-16 | ||
DE1224716B (en) * | 1965-01-29 | 1966-09-15 | Knapsack Ag | Process for the production of magnesium hydrogen phosphate trihydrate |
US3433586A (en) * | 1965-01-29 | 1969-03-18 | Knapsack Ag | Process for the manufacture of magnesium hydrogen-phosphate trihydrate |
US3495988A (en) * | 1968-03-06 | 1970-02-17 | Leslie L Balassa | Encapsulation of aromas and flavors |
US3723308A (en) * | 1970-11-16 | 1973-03-27 | D Breck | Process for removal of ammonia from waste water streams |
US3989622A (en) * | 1970-12-30 | 1976-11-02 | Cci Life Systems, Inc. | Urease in insoluble form for converting urea present in a liquid |
US4344851A (en) * | 1974-07-15 | 1982-08-17 | Union Carbide Corporation | Phillipsite-type zeolites for ammonia adsorption |
US4344857A (en) * | 1975-12-22 | 1982-08-17 | The United States Of America As Represented By The Secretary Of Agriculture | Encapsulation by entrapment |
US4218541A (en) * | 1978-03-30 | 1980-08-19 | Ackerman Roy A | Converting urea with bacteria |
US4294808A (en) * | 1978-09-20 | 1981-10-13 | Hoechst Aktiengesellschaft | Production of anticorrosive pigments containing phosphorus |
US4205060A (en) * | 1978-12-20 | 1980-05-27 | Pennwalt Corporation | Microcapsules containing medicament-polymer salt having a water-insoluble polymer sheath, their production and their use |
US4247393A (en) * | 1979-01-11 | 1981-01-27 | Wallace Richard A | Hemodialysis assist device |
JPS5688812A (en) * | 1979-12-21 | 1981-07-18 | Hitachi Zosen Corp | Preparation of phosphoric acid by wet process |
US4392963A (en) * | 1980-03-26 | 1983-07-12 | Sartorius Gmbh | Resorcinol or phloroglucinol condensation product for aqueous mixture purification |
JPS56161886A (en) * | 1980-05-13 | 1981-12-12 | Burando Kenkyusho:Kk | Separation and recovery of phosphate from phosphate- containing. waste water |
JPS5712892A (en) * | 1980-06-25 | 1982-01-22 | Ebara Infilco Co Ltd | Disposal of phosphate ion-containing waste water |
Cited By (14)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
DE3732896A1 (en) * | 1986-11-07 | 1988-08-25 | Schulze Rettmer Rainer | Process for eliminating ammonia and phosphate from waste water and process water |
EP0282218A2 (en) * | 1987-03-09 | 1988-09-14 | Mobil Oil Corporation | Layered divalent metal compositions |
EP0282218A3 (en) * | 1987-03-09 | 1990-05-23 | Mobil Oil Corporation | Layered divalent metal compositions |
DE3834543A1 (en) * | 1988-10-11 | 1990-04-12 | Passavant Werke | METHOD FOR THE DISPOSAL OF A HIGH AMOUNT OF AMMONIUM-NITROGEN-RELATED WASTEWATERS |
EP0490396A1 (en) * | 1990-12-14 | 1992-06-17 | DEUTSCHE NALCO-CHEMIE GmbH | Process for recovery of ammonia from process and waste waters |
US5409903A (en) * | 1992-02-18 | 1995-04-25 | Urecap Corporation | Method and compositions for the treatment of H. pylori and dermatitis |
WO1993015746A1 (en) * | 1992-02-18 | 1993-08-19 | Urecap Corporation | Compositions for the treatment of pylori and dermatitis |
WO2002061107A2 (en) * | 2001-01-31 | 2002-08-08 | Dsm Ip Assets B.V. | Process for the preparation of enantiomer-enriched amino acids |
WO2002061107A3 (en) * | 2001-01-31 | 2003-12-31 | Dsm Ip Assets Bv | Process for the preparation of enantiomer-enriched amino acids |
US8012118B2 (en) | 2006-03-08 | 2011-09-06 | Fresenius Medical Care Holdings, Inc. | Artificial kidney dialysis system |
US8715221B2 (en) | 2006-03-08 | 2014-05-06 | Fresenius Medical Care Holdings, Inc. | Wearable kidney |
US8241239B2 (en) | 2006-08-24 | 2012-08-14 | Fresenius Medical Care Holdings, Inc. | Device for removing fluid from blood in a patient |
US9138521B2 (en) | 2006-08-24 | 2015-09-22 | Fresenius Medical Care Holdings, Inc. | Device for removing fluid from blood in a patient |
US8777892B2 (en) | 2008-11-03 | 2014-07-15 | Fresenius Medical Care Holdings, Inc. | Portable peritoneal dialysis system |
Also Published As
Publication number | Publication date |
---|---|
EP0118548A1 (en) | 1984-09-19 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
US4650587A (en) | Ammonia scavenger | |
US4460555A (en) | Ammonia scavenger | |
US6332985B1 (en) | Process for removing toxins from bodily fluids using zirconium or titanium microporous compositions | |
Pavelić et al. | Medical applications of zeolites | |
JP3665345B2 (en) | Adsorbents for phosphates from aqueous media, their manufacture and use | |
CA2427985C (en) | Cartridges useful in cleaning dialysis solutions | |
US7135156B2 (en) | Method for processing a zirconium oxide composition in crystalline form | |
US20200078507A1 (en) | Sorbent for a dialysis device and dialysis system | |
WO1984000885A1 (en) | Ammonia scavenger | |
CN103038195A (en) | Device and method for solubilizing, separating, removing and reacting carboxylic acids in oils, fats, aqueous or organic solutions by means of micro- or nanoemulsification | |
US20040105895A1 (en) | Monovalent-selective cation exchangers as oral sorbent therapy | |
US4244816A (en) | Liquid membrane capsule systems resistant to coalescence by means of an irreversible coating | |
US4952323A (en) | B2 microglobulin adsorbent | |
Chen et al. | Preparation and characterization of urease immobilized onto porous chitosan beads for urea hydrolysis | |
WO1997026903A1 (en) | Microencapsulated genetically engineered microorganisms for clinical application | |
US4218541A (en) | Converting urea with bacteria | |
Wolfe et al. | Orally ingested microencapsulated urease and an adsorbent, zirconium phosphate, to remove urea in kidney failure | |
US20200040323A1 (en) | Urease Purification And Purified Urease Products Thereof And Sorbent Cartridges, Systems And Methods Using The Same | |
CN1169612C (en) | Adsorbent based on montmorillonite for purifying blood and its preparing method | |
US9585913B2 (en) | Clay mineral for reducing inorganic phosphates, in particular in renal replacement therapy | |
EP1307270A1 (en) | Process for removing toxins from bodily fluids using zirconium or titanium microporous compositions | |
Prakash et al. | Artificial cell microcapsules containing genetically engineered E. coli dhs cells for in-vitro lowering of plasma potassium, phosphate, magnesium, sodium, chloride, uric acid, cholesterol, and creatinine: a preliminary report | |
Spengler et al. | Characterization and extracorporeal application of a new phosphate-binding agent | |
RU1836138C (en) | Synthetic carbon material of spherical granulation intended for sorption of substances from solution and method | |
Maeda et al. | Problems with activated charcoal and alumina as sorbents for medical use |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
AK | Designated states |
Designated state(s): AU BR DK FI JP MC NO |
|
AL | Designated countries for regional patents |
Designated state(s): AT BE CH DE FR GB LU NL SE |