EP1888606A2 - Verfahren und neues salz - Google Patents
Verfahren und neues salzInfo
- Publication number
- EP1888606A2 EP1888606A2 EP06727135A EP06727135A EP1888606A2 EP 1888606 A2 EP1888606 A2 EP 1888606A2 EP 06727135 A EP06727135 A EP 06727135A EP 06727135 A EP06727135 A EP 06727135A EP 1888606 A2 EP1888606 A2 EP 1888606A2
- Authority
- EP
- European Patent Office
- Prior art keywords
- acid
- risedronate
- ammonium
- process according
- phosphorous
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Withdrawn
Links
- 238000000034 method Methods 0.000 title claims abstract description 83
- 150000003839 salts Chemical class 0.000 title claims abstract description 80
- IIDJRNMFWXDHID-UHFFFAOYSA-N Risedronic acid Chemical compound OP(=O)(O)C(P(O)(O)=O)(O)CC1=CC=CN=C1 IIDJRNMFWXDHID-UHFFFAOYSA-N 0.000 claims abstract description 149
- 229960000759 risedronic acid Drugs 0.000 claims abstract description 92
- 229940089617 risedronate Drugs 0.000 claims abstract description 53
- 239000000203 mixture Substances 0.000 claims abstract description 8
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 5
- 238000002560 therapeutic procedure Methods 0.000 claims abstract description 4
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 53
- QGZKDVFQNNGYKY-UHFFFAOYSA-O Ammonium Chemical compound [NH4+] QGZKDVFQNNGYKY-UHFFFAOYSA-O 0.000 claims description 47
- ISIJQEHRDSCQIU-UHFFFAOYSA-N tert-butyl 2,7-diazaspiro[4.5]decane-7-carboxylate Chemical compound C1N(C(=O)OC(C)(C)C)CCCC11CNCC1 ISIJQEHRDSCQIU-UHFFFAOYSA-N 0.000 claims description 45
- 238000006243 chemical reaction Methods 0.000 claims description 38
- 239000000725 suspension Substances 0.000 claims description 33
- 239000011541 reaction mixture Substances 0.000 claims description 32
- BPSNETAIJADFTO-UHFFFAOYSA-N 2-pyridinylacetic acid Chemical compound OC(=O)CC1=CC=CC=N1 BPSNETAIJADFTO-UHFFFAOYSA-N 0.000 claims description 30
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical group [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 24
- BHEPBYXIRTUNPN-UHFFFAOYSA-N hydridophosphorus(.) (triplet) Chemical compound [PH] BHEPBYXIRTUNPN-UHFFFAOYSA-N 0.000 claims description 24
- 238000010992 reflux Methods 0.000 claims description 23
- 239000002253 acid Substances 0.000 claims description 19
- 238000011282 treatment Methods 0.000 claims description 18
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 17
- 201000010099 disease Diseases 0.000 claims description 14
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 13
- 238000011065 in-situ storage Methods 0.000 claims description 11
- 238000002844 melting Methods 0.000 claims description 11
- 230000008018 melting Effects 0.000 claims description 11
- 239000003960 organic solvent Substances 0.000 claims description 11
- 239000013078 crystal Substances 0.000 claims description 10
- 238000001228 spectrum Methods 0.000 claims description 10
- 208000001132 Osteoporosis Diseases 0.000 claims description 8
- 238000005033 Fourier transform infrared spectroscopy Methods 0.000 claims description 7
- 210000000988 bone and bone Anatomy 0.000 claims description 7
- 239000003814 drug Substances 0.000 claims description 7
- 238000004519 manufacturing process Methods 0.000 claims description 7
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 claims description 6
- 208000006386 Bone Resorption Diseases 0.000 claims description 6
- 206010006811 Bursitis Diseases 0.000 claims description 6
- 206010020584 Hypercalcaemia of malignancy Diseases 0.000 claims description 6
- 201000002980 Hyperparathyroidism Diseases 0.000 claims description 6
- 206010027452 Metastases to bone Diseases 0.000 claims description 6
- 206010029240 Neuritis Diseases 0.000 claims description 6
- 208000000491 Tendinopathy Diseases 0.000 claims description 6
- 206010043255 Tendonitis Diseases 0.000 claims description 6
- 239000000908 ammonium hydroxide Substances 0.000 claims description 6
- 206010003246 arthritis Diseases 0.000 claims description 6
- 230000004097 bone metabolism Effects 0.000 claims description 6
- 230000024279 bone resorption Effects 0.000 claims description 6
- 230000003913 calcium metabolism Effects 0.000 claims description 6
- 208000008750 humoral hypercalcemia of malignancy Diseases 0.000 claims description 6
- 230000004968 inflammatory condition Effects 0.000 claims description 6
- OJMIONKXNSYLSR-UHFFFAOYSA-N phosphorous acid Chemical compound OP(O)O OJMIONKXNSYLSR-UHFFFAOYSA-N 0.000 claims description 6
- 238000000634 powder X-ray diffraction Methods 0.000 claims description 6
- 201000004415 tendinitis Diseases 0.000 claims description 6
- 150000003863 ammonium salts Chemical group 0.000 claims description 5
- 230000015572 biosynthetic process Effects 0.000 claims description 5
- 238000001816 cooling Methods 0.000 claims description 5
- 238000000411 transmission spectrum Methods 0.000 claims description 5
- 230000001668 ameliorated effect Effects 0.000 claims description 4
- 239000003795 chemical substances by application Substances 0.000 claims description 4
- 125000001309 chloro group Chemical group Cl* 0.000 claims description 4
- 239000003085 diluting agent Substances 0.000 claims description 4
- 239000003937 drug carrier Substances 0.000 claims description 4
- 230000003301 hydrolyzing effect Effects 0.000 claims description 4
- XLYOFNOQVPJJNP-UHFFFAOYSA-M hydroxide Chemical compound [OH-] XLYOFNOQVPJJNP-UHFFFAOYSA-M 0.000 claims description 4
- 239000003112 inhibitor Substances 0.000 claims description 4
- 229910052500 inorganic mineral Inorganic materials 0.000 claims description 4
- 239000011707 mineral Substances 0.000 claims description 4
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 4
- HYFDYHPNTXOPPO-UHFFFAOYSA-L disodium;hydroxy-(1-hydroxy-1-phosphono-2-pyridin-3-ylethyl)phosphinate;pentahydrate Chemical compound O.O.O.O.O.[Na+].[Na+].OP(=O)(O)C(P(O)([O-])=O)(O)CC1=CC=CN=C1.OP(=O)(O)C(P(O)([O-])=O)(O)CC1=CC=CN=C1 HYFDYHPNTXOPPO-UHFFFAOYSA-L 0.000 claims description 3
- 125000005843 halogen group Chemical group 0.000 claims description 3
- 238000010952 in-situ formation Methods 0.000 claims description 3
- 238000002835 absorbance Methods 0.000 claims description 2
- 125000001246 bromo group Chemical group Br* 0.000 claims description 2
- 125000001153 fluoro group Chemical group F* 0.000 claims description 2
- 125000002346 iodo group Chemical group I* 0.000 claims description 2
- 230000001419 dependent effect Effects 0.000 claims 1
- 159000000000 sodium salts Chemical group 0.000 claims 1
- -1 risedronate ammonium salts Chemical class 0.000 abstract description 8
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 57
- 239000000243 solution Substances 0.000 description 27
- 238000002425 crystallisation Methods 0.000 description 15
- 230000008025 crystallization Effects 0.000 description 15
- FAIAAWCVCHQXDN-UHFFFAOYSA-N phosphorus trichloride Chemical compound ClP(Cl)Cl FAIAAWCVCHQXDN-UHFFFAOYSA-N 0.000 description 12
- 230000000717 retained effect Effects 0.000 description 12
- 238000001914 filtration Methods 0.000 description 11
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 10
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 8
- 229910052799 carbon Inorganic materials 0.000 description 8
- 238000002360 preparation method Methods 0.000 description 8
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 6
- 150000007513 acids Chemical class 0.000 description 6
- 239000002904 solvent Substances 0.000 description 6
- 238000001035 drying Methods 0.000 description 5
- 238000010438 heat treatment Methods 0.000 description 5
- XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 description 5
- 238000005406 washing Methods 0.000 description 5
- WGNUNYPERJMVRM-UHFFFAOYSA-N 3-pyridylacetic acid Chemical compound OC(=O)CC1=CC=CN=C1 WGNUNYPERJMVRM-UHFFFAOYSA-N 0.000 description 4
- 239000007864 aqueous solution Substances 0.000 description 4
- 239000002585 base Substances 0.000 description 4
- 238000000113 differential scanning calorimetry Methods 0.000 description 4
- 238000004090 dissolution Methods 0.000 description 4
- 239000000706 filtrate Substances 0.000 description 4
- 238000005259 measurement Methods 0.000 description 4
- 239000000843 powder Substances 0.000 description 4
- 239000007787 solid Substances 0.000 description 4
- 229940122361 Bisphosphonate Drugs 0.000 description 3
- KXDHJXZQYSOELW-UHFFFAOYSA-N Carbamic acid Chemical compound NC(O)=O KXDHJXZQYSOELW-UHFFFAOYSA-N 0.000 description 3
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- 150000004663 bisphosphonates Chemical class 0.000 description 3
- 208000035475 disorder Diseases 0.000 description 3
- 239000007903 gelatin capsule Substances 0.000 description 3
- 239000000463 material Substances 0.000 description 3
- 238000012986 modification Methods 0.000 description 3
- 230000004048 modification Effects 0.000 description 3
- 150000004682 monohydrates Chemical class 0.000 description 3
- 239000000523 sample Substances 0.000 description 3
- 230000001225 therapeutic effect Effects 0.000 description 3
- 241001465754 Metazoa Species 0.000 description 2
- YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical compound C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 description 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
- 239000004480 active ingredient Substances 0.000 description 2
- 229910052783 alkali metal Inorganic materials 0.000 description 2
- 150000001340 alkali metals Chemical class 0.000 description 2
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 2
- 239000001099 ammonium carbonate Substances 0.000 description 2
- 230000008901 benefit Effects 0.000 description 2
- 230000004071 biological effect Effects 0.000 description 2
- 150000001875 compounds Chemical class 0.000 description 2
- 238000004455 differential thermal analysis Methods 0.000 description 2
- 239000002270 dispersing agent Substances 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 235000003599 food sweetener Nutrition 0.000 description 2
- 238000007918 intramuscular administration Methods 0.000 description 2
- 238000001990 intravenous administration Methods 0.000 description 2
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 2
- LXCFILQKKLGQFO-UHFFFAOYSA-N methylparaben Chemical compound COC(=O)C1=CC=C(O)C=C1 LXCFILQKKLGQFO-UHFFFAOYSA-N 0.000 description 2
- 239000012299 nitrogen atmosphere Substances 0.000 description 2
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 2
- QELSKZZBTMNZEB-UHFFFAOYSA-N propylparaben Chemical compound CCCOC(=O)C1=CC=C(O)C=C1 QELSKZZBTMNZEB-UHFFFAOYSA-N 0.000 description 2
- 239000002002 slurry Substances 0.000 description 2
- 241000894007 species Species 0.000 description 2
- 238000007920 subcutaneous administration Methods 0.000 description 2
- 239000003765 sweetening agent Substances 0.000 description 2
- 239000006188 syrup Substances 0.000 description 2
- 235000020357 syrup Nutrition 0.000 description 2
- 238000002411 thermogravimetry Methods 0.000 description 2
- 230000000699 topical effect Effects 0.000 description 2
- GETQZCLCWQTVFV-UHFFFAOYSA-N trimethylamine Chemical compound CN(C)C GETQZCLCWQTVFV-UHFFFAOYSA-N 0.000 description 2
- 239000000080 wetting agent Substances 0.000 description 2
- PUPZLCDOIYMWBV-UHFFFAOYSA-N (+/-)-1,3-Butanediol Chemical compound CC(O)CCO PUPZLCDOIYMWBV-UHFFFAOYSA-N 0.000 description 1
- QCQCHGYLTSGIGX-GHXANHINSA-N 4-[[(3ar,5ar,5br,7ar,9s,11ar,11br,13as)-5a,5b,8,8,11a-pentamethyl-3a-[(5-methylpyridine-3-carbonyl)amino]-2-oxo-1-propan-2-yl-4,5,6,7,7a,9,10,11,11b,12,13,13a-dodecahydro-3h-cyclopenta[a]chrysen-9-yl]oxy]-2,2-dimethyl-4-oxobutanoic acid Chemical compound N([C@@]12CC[C@@]3(C)[C@]4(C)CC[C@H]5C(C)(C)[C@@H](OC(=O)CC(C)(C)C(O)=O)CC[C@]5(C)[C@H]4CC[C@@H]3C1=C(C(C2)=O)C(C)C)C(=O)C1=CN=CC(C)=C1 QCQCHGYLTSGIGX-GHXANHINSA-N 0.000 description 1
- OGSPWJRAVKPPFI-UHFFFAOYSA-N Alendronic Acid Chemical compound NCCCC(O)(P(O)(O)=O)P(O)(O)=O OGSPWJRAVKPPFI-UHFFFAOYSA-N 0.000 description 1
- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 description 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-M Bicarbonate Chemical compound OC([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-M 0.000 description 1
- 206010065687 Bone loss Diseases 0.000 description 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-L Carbonate Chemical compound [O-]C([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-L 0.000 description 1
- 229910016523 CuKa Inorganic materials 0.000 description 1
- 108010010803 Gelatin Proteins 0.000 description 1
- 229920000084 Gum arabic Polymers 0.000 description 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 1
- 241000978776 Senegalia senegal Species 0.000 description 1
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 1
- 229920002472 Starch Polymers 0.000 description 1
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 description 1
- 229930006000 Sucrose Natural products 0.000 description 1
- 239000000205 acacia gum Substances 0.000 description 1
- 235000010489 acacia gum Nutrition 0.000 description 1
- 239000000654 additive Substances 0.000 description 1
- 150000001298 alcohols Chemical class 0.000 description 1
- 229960004343 alendronic acid Drugs 0.000 description 1
- 150000001408 amides Chemical class 0.000 description 1
- 235000012538 ammonium bicarbonate Nutrition 0.000 description 1
- 235000012501 ammonium carbonate Nutrition 0.000 description 1
- 235000011114 ammonium hydroxide Nutrition 0.000 description 1
- 230000002421 anti-septic effect Effects 0.000 description 1
- 229940064004 antiseptic throat preparations Drugs 0.000 description 1
- 239000012736 aqueous medium Substances 0.000 description 1
- 239000007900 aqueous suspension Substances 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 239000011230 binding agent Substances 0.000 description 1
- 230000037396 body weight Effects 0.000 description 1
- 239000006227 byproduct Substances 0.000 description 1
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 1
- 239000000969 carrier Substances 0.000 description 1
- 239000001913 cellulose Substances 0.000 description 1
- 229920002678 cellulose Polymers 0.000 description 1
- MVPPADPHJFYWMZ-IDEBNGHGSA-N chlorobenzene Chemical group Cl[13C]1=[13CH][13CH]=[13CH][13CH]=[13CH]1 MVPPADPHJFYWMZ-IDEBNGHGSA-N 0.000 description 1
- MVPPADPHJFYWMZ-UHFFFAOYSA-N chlorobenzene Substances ClC1=CC=CC=C1 MVPPADPHJFYWMZ-UHFFFAOYSA-N 0.000 description 1
- 238000005056 compaction Methods 0.000 description 1
- 239000012059 conventional drug carrier Substances 0.000 description 1
- 239000006071 cream Substances 0.000 description 1
- 230000003111 delayed effect Effects 0.000 description 1
- 230000002939 deleterious effect Effects 0.000 description 1
- 238000001938 differential scanning calorimetry curve Methods 0.000 description 1
- 150000004683 dihydrates Chemical class 0.000 description 1
- XQRLCLUYWUNEEH-UHFFFAOYSA-N diphosphonic acid Chemical compound OP(=O)OP(O)=O XQRLCLUYWUNEEH-UHFFFAOYSA-N 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- 150000002170 ethers Chemical class 0.000 description 1
- 125000000219 ethylidene group Chemical group [H]C(=[*])C([H])([H])[H] 0.000 description 1
- 239000012467 final product Substances 0.000 description 1
- 239000012530 fluid Substances 0.000 description 1
- 239000008273 gelatin Substances 0.000 description 1
- 229920000159 gelatin Polymers 0.000 description 1
- 235000019322 gelatine Nutrition 0.000 description 1
- 235000011852 gelatine desserts Nutrition 0.000 description 1
- 239000008187 granular material Substances 0.000 description 1
- 229950007593 homonicotinic acid Drugs 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 239000012535 impurity Substances 0.000 description 1
- 150000007529 inorganic bases Chemical class 0.000 description 1
- 239000002050 international nonproprietary name Substances 0.000 description 1
- 238000002955 isolation Methods 0.000 description 1
- 150000002576 ketones Chemical class 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 239000006210 lotion Substances 0.000 description 1
- 235000019359 magnesium stearate Nutrition 0.000 description 1
- 235000010270 methyl p-hydroxybenzoate Nutrition 0.000 description 1
- 239000004292 methyl p-hydroxybenzoate Substances 0.000 description 1
- 229960002216 methylparaben Drugs 0.000 description 1
- 239000003094 microcapsule Substances 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 238000001565 modulated differential scanning calorimetry Methods 0.000 description 1
- PYLWMHQQBFSUBP-UHFFFAOYSA-N monofluorobenzene Chemical group FC1=CC=CC=C1 PYLWMHQQBFSUBP-UHFFFAOYSA-N 0.000 description 1
- 210000004985 myeloid-derived suppressor cell Anatomy 0.000 description 1
- 150000002825 nitriles Chemical class 0.000 description 1
- 239000002674 ointment Substances 0.000 description 1
- 150000007530 organic bases Chemical class 0.000 description 1
- 230000001590 oxidative effect Effects 0.000 description 1
- 238000007911 parenteral administration Methods 0.000 description 1
- 239000008188 pellet Substances 0.000 description 1
- 229920001223 polyethylene glycol Polymers 0.000 description 1
- 229920000642 polymer Polymers 0.000 description 1
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 1
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 1
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 1
- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
- 230000002035 prolonged effect Effects 0.000 description 1
- 230000000069 prophylactic effect Effects 0.000 description 1
- 238000011321 prophylaxis Methods 0.000 description 1
- 235000010232 propyl p-hydroxybenzoate Nutrition 0.000 description 1
- 239000004405 propyl p-hydroxybenzoate Substances 0.000 description 1
- 229960003415 propylparaben Drugs 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- 230000005855 radiation Effects 0.000 description 1
- 239000012429 reaction media Substances 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 239000008247 solid mixture Substances 0.000 description 1
- 230000003595 spectral effect Effects 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 210000002784 stomach Anatomy 0.000 description 1
- 238000003860 storage Methods 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 239000005720 sucrose Substances 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 239000000375 suspending agent Substances 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- 235000012222 talc Nutrition 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 239000004562 water dispersible granule Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
- C07F9/553—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having one nitrogen atom as the only ring hetero atom
- C07F9/576—Six-membered rings
- C07F9/58—Pyridine rings
Definitions
- the present invention relates to a process of preparing risedronic acid, or a pharmaceutically acceptable salt thereof, novel ammonium risedronate salts and pharmaceutical compositions thereof, and the use of such novel salts and compositions in human therapy.
- Risedronic acid is the international non-proprietary name of [l-hydroxy-2-(3- pyridinyl)ethylidene]bisphosphonic acid.
- Risedronic acid has the following structural formula
- a particularly preferred salt of risedronic acid is sodium risedronate.
- Bisphosphonic acids such as risedronic acid, and pharmaceutically acceptable salts thereof, in particular sodium risedronate as referred to above, have been employed in the treatment of diseases of bone and calcium metabolism.
- diseases include osteoporosis, hyperparathyroidism, hypercalcemia of malignancy, ostolytic bone metastases, myosistis ossifcans progressiva, calcinoisis universalis, arthritis, neuritis, bursitis, tendonitis and other inflammatory conditions.
- Bisphosphonic acids tend to inhibit the resorption of bone tissue, which is beneficial to patients suffering from excessive bone loss.
- all bisphosphonates do not exhibit the same degree of biological activity.
- Some bisphosphonates have serious drawbacks with respect to the degree of toxicity in animals and the tolerability or negative side effects in humans.
- the salt and hydrate forms of bisphosphonates alter both their solubility and their bioavailability.
- EP 1243592B describes a process of preparing risedronic acid by reacting 3- pyridylacetic acid with phosphorous acid and phosphorous trichloride in a solvent.
- the solvent is chlorobenzene
- the reaction is carried out at a temperature in the range of 85-100°C.
- the solvent is fluorobenzene
- the reaction is carried out at the reflux temperature of the reaction medium. Isolation of the risedronic acid involves separation thereof from the reaction mixture by treatment with alkali metal or ammonium hydroxide, bicarbonate or carbonate and subsequent treatment of the resulting alkali metal or ammonium risedronic acid salt with a strong mineral acid.
- EP 04949844B also discloses a process of preparing bisphosphonic acids, but not risedronic acid.
- Bisphosphonic acids, in particular alendronic acid, of the following general formula are prepared according to the process of EP 0494844B
- n 2 to 8.
- the process comprises melting a mixture of the corresponding aminocarboxylic acid and phosphorous acid obtained by heating at 90°C in the absence of an organic solvent, adding dropwise phosphorous trihalide under stirring and N 2 atmosphere, adding to the reaction mixture a hydrolyzing agent selected between water and a strong non-oxidizing acid and recovering the diphosphonic acid thus produced.
- the process is described as being characterised in that the molar ratio between the aminocarboxylic acid, phosphorous acid and phosphorous trihalide in the reaction mixture is 1 :3:2 and 1 :20:6.
- WO 01/57052 involves use of molten phosphorous acid, an amino carboxylic acid, phosphorous trihalide and a base in the bisphosphorylation step.
- the base is employed to facilitate bisphosphorylation and can include organic and inorganic bases.
- the more preferred bases are triethylamine, trimethylamine, potassium carbonate, pyridine and morpholine.
- WO 05/063779 describes use of phosphorous oxychloride (POCl 3 ), instead of phosphorous trihalide. More specifically, WO 05/063779 describes reaction of a carboxylic acid with a mixture of phosphorous acid and phosphorous oxychloride, in the absence of solvents. Water, which is formed during bisphosphorylation, reacts with POCl 3 and consequently phosphoric acid (H 3 PO 4 ) is generated. The thus formed phosphoric acid can influence reaction conditions and can also form as an impurity in final product.
- the scheme of the reaction is as follows
- EP 1252170B describes a process for selectively producing sodium risedronate hemipentahydrate or monohydrate comprising the steps of (a) providing an aqueous solution of sodium risedronate, (b) heating the aqueous solution to a temperature from about 45 0 C to about 75 °C, (c) adding a solvent to the aqueous solution, characterised in that the solvent is selected from the group consisting of alcohols, esters, ethers, ketones, amides and nitriles, and (d) optionally cooling the aqueous solution.
- WO 03/086355 describes polymorph forms B, Bl, BB, C, D, E, F, G and H of sodium risedronate and processes of preparing these various polymorphs.
- phosphorous acid is formed in situ in the reaction mixture by the reaction of phosphorous trihalide and water.
- This formation of phosphorous acid in situ preferably occurs as a first step in the process to allow subsequent reaction thereof with pyridylacetic acid, optionally present as a hydrohalide salt.
- the presence of excess phosphorous trihalide in the reaction mixture also allows phosphorous acid to be formed during the reaction process and thus enables continued reaction of the phosphorous acid with pyridylacetic acid, optionally present as a hydrohalide salt, to occur.
- a process according to the present invention provides a reaction mixture comprising (i) pyridylacetic acid, optionally in the form of a hydrohalide salt, (ii) phosphorous acid and (iii) phosphorous trihalide, whereby the phosphorous trihalide present in the reaction mixture allows continued in situ formation of phosphorous acid during the reaction process.
- the present invention provides a process of preparing risedronic acid of formula (I)
- reaction mixture comprising (i) pyridylacetic acid, optionally in the form of a hydrohalide salt, (ii) phosphorous acid and (iii) phosphorous trihalide; reacting (i) and (ii) to yield risedronic acid and recovering the thus formed risedronic acid;
- phosphorous acid is formed in situ in the reaction mixture by the reaction of phosphorous trihalide and water.
- phosphorous acid is formed in situ in the reaction mixture by initial reaction of the phosphorous trihalide and water. It is also preferred that the pyridylacetic acid is employed in the form of a hydrohalide salt.
- a process according to the present invention can be represented by the following reaction scheme
- X denotes halo, which can be bromo, chloro, fluoro or iodo, preferably chloro.
- pyridylacetic acid is employed in the form of the hydrochloride salt.
- the phosphorous trihalide employed is phosphorous trichloride.
- the synthesis starts from preparation of phosphorous acid in situ, where phosphorous trihalide, preferably phosphorous trichloride, is added dropwise to water in step (1).
- phosphorous trihalide preferably phosphorous trichloride
- phosphorous acid is formed until all the water present is consumed (reacted).
- a by product of this reaction is HX, which is degassed.
- Phosphorous trihalide (excess), preferably phosphorous trichloride (excess) is then added continuously and a reaction mixture consisting of phosphorous acid and phosphorous trichloride is prepared according to step (2).
- Pyridylacetic acid in the form of a hydrohalide salt preferably 3 -pyridylacetic acid hydrochloride
- the reaction of phosphorous acid and pyridylacetic acid in the form of a hydrohalide salt, preferably 3 -pyridylacetic acid hydrochloride, in step (3) forms risedronic acid and water.
- Water thus liberated from the reaction spontaneously reacts with the excess of phosphorous trihalide, preferably phosphorous trichloride, present in the reaction mixture so as to form phosphorous acid and HX.
- This phosphorous acid then reacts further with pyridylacetic acid in the form of a hydrohalide salt, preferably 3- pyridylacetic acid hydrochloride, as described in step (3).
- pyridylacetic acid optionally in the form of a hydrohalide salt substantially as hereinbefore described, is added to a reaction mixture comprising phosphorous acid at a temperature in the range of about 1O 0 C to 3O 0 C, preferably at a temperature in the range of about 2O 0 C to 25 0 C.
- the resulting mixture is subsequently heated to a temperature in the range of about 6O 0 C to 100 0 C, preferably at a temperature on the range of about 6O 0 C to 9O 0 C.
- the temperature does not exceed about 9O 0 C during the above reaction process, and in some embodiments it is preferred that the reaction temperature does not exceed about 7O 0 C.
- a process of the present invention which is carried out in the absence of organic solvent and at a low temperature, provides advantages over the prior art processes for the preparation of bisphosphonic acids, which either require the presence of an organic solvent or an elevated process temperature.
- a process according to the present invention further comprises a hydrolysis stage, which is advantageous in obviating the formation of undesirable polymers in the reaction mixture.
- the process further comprises addition of a hydrolysing agent, such as water and / or a strong mineral acid, such as hydrochloric acid, followed by reflux for about 3 to 4 hours.
- reaction mixture is preferably cooled to a temperature in the range of about 7O 0 C to 8O 0 C, followed by the addition of active carbon.
- the resulting suspension is stirred, filtered and the carbon cake washed with water. The filtrate is then collected, evaporated under vacuum and water is added. Crystallization of risedronic acid occurs on cooling.
- Risedronic free acid as prepared by the above described process can be further converted to a pharmaceutically acceptable salt, such as the sodium or ammonium salt.
- a pharmaceutically acceptable salt such as the sodium or ammonium salt.
- a process of preparing a pharmaceutically acceptable salt of risedronic acid comprises providing a reaction mixture comprising (i) pyridylacetic acid, optionally in the form of a hydrohalide salt, (ii) phosphorous acid and (iii) phosphorous trihalide; reacting (i) and (ii) to yield risedronic acid, converting the thus formed risedronic free acid to a pharmaceutically acceptable salt form, and recovering the pharmaceutically acceptable salt of risedronic acid, characterised in that said phosphorous acid is formed in situ in said reaction mixture.
- the above process is further characterised in that the reaction of said pyridylacetic acid with phosphorous acid and phosphorous trihalide is carried out in the absence of an organic solvent.
- Particularly preferred pharmaceutically acceptable salt forms prepared in accordance with the present invention are sodium risedronate and ammonium risedronate.
- a suspension of risedronic free acid and water is heated to a temperature in the range of about 35 0 C to 95 0 C, preferably in the range of about 4O 0 C to 9O 0 C, followed by the addition of a base of the salt forming species, preferably a hydroxide of the salt forming species, for example sodium hydroxide or ammonium hydroxide to form a solution.
- a base of the salt forming species preferably a hydroxide of the salt forming species, for example sodium hydroxide or ammonium hydroxide to form a solution.
- the resulting solution is when required typically heated to reflux, typically at about 100 0 C, and again when required a C ⁇ alcohol, such as methanol or ethanol, is added. Subsequent cooling results in crystallization of the risedronate salt.
- the solution in the case of the preparation of ammonium risedronate, following addition of the hydroxide the solution can be cooled prior to addition of the C 1-4 alcohol resulting in the formation of slurried crystals, which can be heated and subsequently cooled to yield crystals of the ammonium salt which are filtered, washed and dried.
- sodium risedronate this may preferably be provided as the hemipentahydrate form in accordance with carrying out a process according to the present invention.
- the hemipentahydrate is the thermodynamically preferred crystalline form of sodium risedronate under typical processing conditions, based on observations in the art that monohydrate crystals converted to the hemipentahydrate form.
- Sodium risedronate hemipentahydrate is by weight of water from about 11.9% to about 13.9%, more preferably from about 12.5% to about 13.2% and most preferably about 12.9%.
- Ammonium risedronate as provided by the present invention represents a novel salt of risedronic acid. According to the present invention, therefore, there is further provided ammonium risedronate.
- ammonium risedronate preferably refers to the mono-ammonium salt of risedronic acid.
- the di- and tri-ammonium salts are also included within this invention. It is also preferred that the ammonium salt is provided in anhydrous form, although hydrated or other solvated forms (such as the monohydrate, sesquihydrate or dihydrate) of the ammonium salt are also included in this invention.
- Ammonium risedronate as provided by the present invention may exist in more than one polymorphic form, including the amorphous form.
- Another important solid state property of a pharmaceutical compound that can depend on crystal structure is its rate of dissolution in aqueous media.
- the rate of dissolution of an active ingredient in a patient's stomach fluid can have therapeutic consequences because it imposes an upper limit on the rate at which an orally administered active ingredient can reach the patient's bloodstream.
- the rate of dissolution is also a consideration in formulating syrups, elixirs and other liquid medicaments.
- the solid state form of a compound can also affect its behavior on compaction and its storage stability. We have now found that the risedronate ammonium salt provided in accordance with the present invention has advantageous dissolution properties.
- Thermodynamic properties can be used to distinguish between different salt forms and can be measured in the laboratory by such techniques as capillary melting point, thermogravimetric analysis (TGA), differential scanning calorimetry (DSC) and differential thermal analysis (DTA).
- TGA thermogravimetric analysis
- DSC differential scanning calorimetry
- DTA differential thermal analysis
- the melting point measurement varies from method to method.
- Ammonium risedronate as provided by the present invention is characterised as having a melting point in the range of about 221 0 C to about 24O 0 C. It is recognised that the capillary method provides the most precise measurement.
- the melting point of ammonium risedronate as provided by the present invention is in the range of about 233.5°C to about 235.0°C, and more preferably is in the range of about 234.O 0 C to about 234.5°C, when measured in a capillary method according to the standardised method within European Pharmacopoeia 2.2.14.
- ammonium risedronate is characterised as having an X-ray powder diffraction pattern, or substantially the same X-ray powder diffraction pattern, as shown in Figure 1.
- Ammonium risedronate according to the present invention is further characterised as having characteristic peaks (20): 11.94+0.02, 12.93+0.02, 17.03 ⁇ 0.02, 22.05 ⁇ 0.02 and 27.73 ⁇ 0.02.
- Ammonium risedronate according to the present invention is still further characterised by the following other typical peaks (20): 14.37+0.02, 15.19+0.02, 21.47 ⁇ 0.02, 24.05 ⁇ 0.02 and 29.93+0.02°.
- Ammonium risedronate according to the present invention is further characterised as having an FTIR transmission spectrum, or substantially the same FTIR transmission spectrum, as shown in Figure 2. More particularly, ammonium risedronate has characteristic IR absorbance at about 3084 ⁇ 4, 1552 ⁇ 4, 1469+4, 1185+4, 1155+4, 911+4, 892 ⁇ 4, 760 ⁇ 4, 605 ⁇ 4 and 540 ⁇ 4 cm “1 .
- Ammonium risedronate according to the present invention is further characterised as having an FTNIR reflection spectrum, or substantially the same FTNIR reflection spectrum, as shown in Figure 3.
- Ammonium risedronate can be still further characterised by a typical DSC thermograph as shown in Figure 4.
- Ammonium risedronate has a DSC endotherm in the range of about 241 0 C to about 253°C.
- Risedronic acid as prepared by the present invention has therapeutic utility in the treatment of diseases associated with bone resorption disorders and more specifically in the treatment of diseases of bone and calcium metabolism.
- diseases include osteoporosis, hyperparathyroidism, hypercalcemia of malignancy, ostolytic bone metastases, myosistis ossifcans progressiva, calcinoisis universalis, arthritis, neuritis, bursitis, tendonitis and other inflammatory conditions.
- the present invention further provides, therefore, a pharmaceutical composition
- a pharmaceutical composition comprising a therapeutically effective dose of risedronic acid as prepared by the present invention, or a pharmaceutically acceptable salt of risedronic acid as described herein, in particular ammonium risedronate, together with a pharmaceutically acceptable carrier, diluent or excipient therefor.
- Excipients are chosen according to the pharmaceutical form and the desired mode of administration.
- the term "therapeutically effective amount” means an amount of risedronic acid as prepared by the present invention, or a pharmaceutically acceptable salt of risedronic acid as described herein, which is capable of preventing, ameliorating or eliminating a bone resorption disorder.
- pharmaceutically acceptable it is meant that the carrier, diluent or excipient is compatible with risedronic acid as prepared by the present invention, or a pharmaceutically acceptable salt of risedronic acid as described herein, and is not deleterious to a recipient thereof.
- risedronic acid or a pharmaceutically acceptable salt thereof is administered to animals and humans in unit forms of administration, mixed with conventional pharmaceutical carriers, for the prophylaxis or treatment of the above disorders or diseases.
- the appropriate unit forms of administration include forms for oral administration, such as tablets, gelatin capsules, powders, granules and solutions or suspensions to be taken orally, forms for sublingual, buccal, intratracheal or intranasal administration, forms for subcutaneous, intramuscular or intravenous administration and forms for rectal administration.
- risedronic acid or a pharmaceutically acceptable salt thereof can be used in creams, ointments or lotions.
- the dose of risedronic acid or a pharmaceutically acceptable salt thereof can vary between about 0.01 and about 50 mg per kg of body weight per day.
- Each unit dose can contain from about 0.1 to about 1000 mg, preferably about 1 to about 500 mg, of risedronic acid or a pharmaceutically acceptable salt thereof, in combination with a pharmaceutical carrier.
- This unit dose can be administered 1 to 5 times a day so as to administer a daily dosage of about 0.5 to about 5000 mg, preferably about 1 to about 2500 mg.
- risedronic acid or a pharmaceutically acceptable salt thereof is mixed with a pharmaceutical vehicle such as gelatin, starch, lactose, magnesium stearate, talc, gum arabic or the like.
- a pharmaceutical vehicle such as gelatin, starch, lactose, magnesium stearate, talc, gum arabic or the like.
- the tablets can be coated with sucrose, a cellulose derivative or other appropriate substances, or else they can be treated so as to have a prolonged or delayed activity and so as to release a predetermined amount of active principle continuously.
- the use of tablets is generally preferred for administration of risedronic acid or a pharmaceutically acceptable salt thereof, as provided by the present invention.
- a preparation in the form of gelatin capsules can be obtained by mixing risedronic acid or a pharmaceutically acceptable salt thereof, with a diluent and pouring the resulting mixture into soft or hard gelatin capsules.
- a preparation in the form of a syrup or elixir or for administration in the form of drops can contain risedronic acid or a pharmaceutically acceptable salt thereof, typically in conjunction with a sweetener, which is preferably calorie-free, optionally antiseptics such as methylparaben and propylparaben, as well as a flavoring and an appropriate color.
- a sweetener which is preferably calorie-free, optionally antiseptics such as methylparaben and propylparaben, as well as a flavoring and an appropriate color.
- Water-dispersible granules or powders can contain risedronic acid or a pharmaceutically acceptable salt thereof, mixed with dispersants or wetting agents, or suspending agents such as polyvinylpyrrolidone, as well as with sweeteners or taste correctors.
- Rectal administration is effected using suppositories prepared with binders which melt at the rectal temperature, for example polyethylene glycols.
- Parenteral administration is effected using aqueous suspensions, isotonic saline solutions or sterile and injectable solutions which contain pharmacologically compatible dispersants and/or wetting agents, for example propylene glycol or butylene glycol.
- Risedronic acid or a pharmaceutically acceptable salt thereof can also be formulated as microcapsules, with one or more carriers or additives if appropriate.
- risedronic acid as prepared by the present invention, or a pharmaceutically acceptable salt of risedronic acid as described herein, in particular ammonium risedronate, for use in therapy.
- the present invention further provides risedronic acid as prepared by the present invention, or a pharmaceutically acceptable salt of risedronic acid as described herein, in particular ammonium risedronate, for use in the manufacture of a medicament for the treatment of a disease state prevented, ameliorated or eliminated by the administration of an inhibitor of bone resorption.
- the present invention provides risedronic acid as prepared by the present invention, or a pharmaceutically acceptable salt of risedronic acid as described herein, in particular ammonium risedronate, for use in the manufacture of a medicament for the treatment of diseases of bone and calcium metabolism, and even more specifically for the treatment of any one of the following: osteoporosis, hyperparathyroidism, hypercalcemia of malignancy, ostolytic bone metastases, myosistis ossifcans progressiva, calcinoisis universalis, arthritis, neuritis, bursitis, tendonitis and other inflammatory conditions.
- the present invention also provides a method of treating a disease state prevented, ameliorated or eliminated by the administration of an inhibitor of bone resorption in a patient in need of such treatment, which method comprises administering to the patient a therapeutically effective amount of risedronic acid as prepared by the present invention, or a pharmaceutically acceptable salt of risedronic acid as described herein, in particular ammonium risedronate.
- the present invention provides a method of treating diseases of bone and calcium metabolism, such as osteoporosis, hyperparathyroidism, hypercalcemia of malignancy, ostolytic bone metastases, myosistis ossifcans progressiva, calcinoisis universalis, arthritis, neuritis, bursitis, tendonitis and other inflammatory conditions, in a patient in need of such treatment, which method comprises administering to the patient a therapeutically effective amount of risedronic acid as prepared by the present invention, or a pharmaceutically acceptable salt of risedronic acid as described herein, in particular ammonium risedronate.
- diseases of bone and calcium metabolism such as osteoporosis, hyperparathyroidism, hypercalcemia of malignancy, ostolytic bone metastases, myosistis ossifcans progressiva, calcinoisis universalis, arthritis, neuritis, bursitis, tendonitis and other inflammatory conditions
- which method comprises administering to the patient a therapeutically effective amount of
- Figure 1 is an XRPD pattern of ammonium risedronate according to the present invention.
- the XRPD pattern of ammonium risedronate was obtained by using CuKa radiation on a powder sample collected using a PANalytical X'PertPRO powder diffractometer.
- Figure 2 is an FTIR transmission spectrum of ammonium risedronate according to the present invention recorded by KBr disc and resolution 4 cm '1 .
- the FTIR pattern of ammonium risedronate was obtained by using Perkin Elmer Spectrum GX FT-IR Spectrometer (Detector: DTGS, Beam splitter: extended KBr, Spectral Range: 4000- 400cm '1 , Resolution: 4cm "1 , 4 scans, Samples prepared as KBr pellets).
- Figure 3 is an FTNIR reflection spectrum of ammonium risedronate according to the present invention, recorded with solid probe accessories and resolution 8 cm “1 .
- the FTNIR spectrum of ammonium risedronate was obtained by using Bruker NIR Multi Purpose Analyser (MPA).
- MPA Bruker NIR Multi Purpose Analyser
- the spectra were recorded in a diffuse reflectance mode using integrating sphere for collecting reflecting beams. The measurements were carried out over the range 4000 cm “1 - 12000 cm “1 , with a resolution of 8 cm “1 .
- the spectra were averaged over 32 scans.
- the system was governed via the software OPUS that includes routines for acquisition and processing of spectra).
- Figure 4 is a DSC thermogram of ammonium risedronate according to the present invention, recorded at a heat rate of 10°C/min (endotherm temperature onset is at 241 0 C and egzotherm onset is at 253 0 C ).
- the DSC pattern of ammonium risedronate was obtained by using a TA Instruments MDSC QlOOO, where the sample was scanned at 10°C/min in N 2 atmosphere in closed Al pan.
- Example 1 42ml of water were charged to a 500ml four necked flask, to which was added dropwise 116ml of phosphorous trichloride over a period of 2.5 hours. During the dropwise addition of phosphorous trichloride, the reaction temperature was maintained in the range of 10-70 0 C depending on reaction kinetics. At 2O 0 C, 26.6g of pyridylacetic acid hydrochloride were charged to the flask. The reaction was performed by slow heating to 7O 0 C over a period of one hour and maintained for half hour at this temperature. 34ml of water and 50ml of hydrochloric acid were then added dropwise. The solution was heated to reflux (-112 0 C) and maintained at the reflux temperature for four hours.
- Example 5 50ml of water and 15g of risedronic acid were charged to a 250ml three necked flask. The suspension was heated to 6O 0 C and the pH was adjusted with ammonium hydroxide (25%) until a pH of about 4 was achieved. The solution was heated to the reflux ( ⁇ 100°C) and 60ml of methanol were slowly added under reflux. The solution was maintained at the reflux temperature ( ⁇ 77°C) for five minutes, and then allowed to cool. Crystallization of the salt started at about 74 0 C. The suspension was then slowly cooled to 0-5 0 C over a period of two hours and retained for one hour at this temperature. Risedronate ammonium salt, 12.9g, was obtained after filtration, washing with 20ml of a water / methanol cold solution (1 / 1) and drying.
- Melting point was determined to be 234.0 - 234.5 0 C.
- the melting point was determined on a capillary Buchi B-540 machine, according to EurPh. (2.2.14 Melting Point - Capillary method).
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GB0511000A GB0511000D0 (en) | 2005-05-28 | 2005-05-28 | Novel salt |
GB0515775A GB0515775D0 (en) | 2005-07-30 | 2005-07-30 | Process |
PCT/GB2006/001830 WO2006129056A2 (en) | 2005-05-28 | 2006-05-18 | Process and novel salt |
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US8076483B2 (en) | 2006-05-11 | 2011-12-13 | M/S. Ind Swift Laboratories Limited | Process for the preparation of pure risedronic acid or salts |
KR100775440B1 (ko) * | 2006-12-20 | 2007-11-12 | 동우신테크 주식회사 | 리세드로네이트 나트륨 헤미펜타히드레이트의 제조방법 |
WO2011023280A1 (en) * | 2009-08-28 | 2011-03-03 | Synthon B.V. | Process for making 1-hydroxyalkylidene-1,1-biphosphonic acids |
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US6638920B2 (en) * | 2000-07-21 | 2003-10-28 | Merck & Co., Inc. | Compositions and methods of preventing or reducing the risk or incidence of skeletal injuries in horses |
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