EP2018392A1 - Sels pharmaceutiquement acceptables et formes polymorphes - Google Patents
Sels pharmaceutiquement acceptables et formes polymorphesInfo
- Publication number
- EP2018392A1 EP2018392A1 EP07712850A EP07712850A EP2018392A1 EP 2018392 A1 EP2018392 A1 EP 2018392A1 EP 07712850 A EP07712850 A EP 07712850A EP 07712850 A EP07712850 A EP 07712850A EP 2018392 A1 EP2018392 A1 EP 2018392A1
- Authority
- EP
- European Patent Office
- Prior art keywords
- tetra
- sodium risedronate
- sodium
- alkali metal
- risedronic
- 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- Withdrawn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
- 150000003839 salts Chemical class 0.000 title claims abstract description 43
- IIDJRNMFWXDHID-UHFFFAOYSA-N Risedronic acid Chemical class OP(=O)(O)C(P(O)(O)=O)(O)CC1=CC=CN=C1 IIDJRNMFWXDHID-UHFFFAOYSA-N 0.000 claims abstract description 58
- 229960000759 risedronic acid Drugs 0.000 claims abstract description 58
- 229910052783 alkali metal Inorganic materials 0.000 claims abstract description 43
- 238000000034 method Methods 0.000 claims abstract description 35
- 238000011282 treatment Methods 0.000 claims abstract description 20
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 5
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical group [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 33
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 23
- 239000002253 acid Substances 0.000 claims description 22
- 238000001228 spectrum Methods 0.000 claims description 20
- 238000010992 reflux Methods 0.000 claims description 19
- 238000005033 Fourier transform infrared spectroscopy Methods 0.000 claims description 17
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 17
- 239000000725 suspension Substances 0.000 claims description 17
- 238000000634 powder X-ray diffraction Methods 0.000 claims description 16
- 238000000411 transmission spectrum Methods 0.000 claims description 16
- 150000001340 alkali metals Chemical class 0.000 claims description 14
- 201000010099 disease Diseases 0.000 claims description 14
- 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 claims description 8
- 208000001132 Osteoporosis Diseases 0.000 claims description 8
- 229910052708 sodium Inorganic materials 0.000 claims description 8
- 239000011734 sodium Substances 0.000 claims description 8
- 210000000988 bone and bone Anatomy 0.000 claims description 7
- 238000001914 filtration Methods 0.000 claims description 7
- 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
- 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
- 239000003814 drug Substances 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
- 238000004519 manufacturing process Methods 0.000 claims description 6
- 201000004415 tendinitis Diseases 0.000 claims description 6
- 238000001816 cooling Methods 0.000 claims description 5
- 230000001668 ameliorated effect Effects 0.000 claims description 4
- 239000003085 diluting agent Substances 0.000 claims description 4
- 239000003937 drug carrier Substances 0.000 claims description 4
- 238000010438 heat treatment Methods 0.000 claims description 4
- 239000003112 inhibitor Substances 0.000 claims description 4
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 4
- 150000008044 alkali metal hydroxides Chemical class 0.000 claims description 3
- 238000002560 therapeutic procedure Methods 0.000 claims description 2
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 claims 1
- 229910052700 potassium Inorganic materials 0.000 claims 1
- 239000011591 potassium Substances 0.000 claims 1
- 230000001225 therapeutic effect Effects 0.000 abstract description 4
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 48
- 239000000243 solution Substances 0.000 description 13
- 238000006243 chemical reaction Methods 0.000 description 11
- BHEPBYXIRTUNPN-UHFFFAOYSA-N hydridophosphorus(.) (triplet) Chemical compound [PH] BHEPBYXIRTUNPN-UHFFFAOYSA-N 0.000 description 7
- 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 description 7
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 6
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 6
- 238000002425 crystallisation Methods 0.000 description 6
- 230000008025 crystallization Effects 0.000 description 6
- XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 description 6
- 229940089617 risedronate Drugs 0.000 description 6
- 239000002904 solvent Substances 0.000 description 6
- 238000002360 preparation method Methods 0.000 description 5
- 150000007513 acids Chemical class 0.000 description 4
- 238000004458 analytical method Methods 0.000 description 4
- 239000007864 aqueous solution Substances 0.000 description 4
- 238000001938 differential scanning calorimetry curve Methods 0.000 description 4
- 239000011541 reaction mixture Substances 0.000 description 4
- 239000000523 sample 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
- 239000002585 base Substances 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
- 239000000203 mixture Substances 0.000 description 3
- 238000012986 modification Methods 0.000 description 3
- 230000004048 modification Effects 0.000 description 3
- -1 risedronic acid Chemical class 0.000 description 3
- 239000007787 solid Substances 0.000 description 3
- BPSNETAIJADFTO-UHFFFAOYSA-N 2-pyridinylacetic acid Chemical compound OC(=O)CC1=CC=CC=N1 BPSNETAIJADFTO-UHFFFAOYSA-N 0.000 description 2
- 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
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 2
- 239000001099 ammonium carbonate Substances 0.000 description 2
- 230000004071 biological effect Effects 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
- 150000004682 monohydrates Chemical class 0.000 description 2
- 239000012299 nitrogen atmosphere Substances 0.000 description 2
- OJMIONKXNSYLSR-UHFFFAOYSA-N phosphorous acid Chemical compound OP(O)O OJMIONKXNSYLSR-UHFFFAOYSA-N 0.000 description 2
- FAIAAWCVCHQXDN-UHFFFAOYSA-N phosphorus trichloride Chemical compound ClP(Cl)Cl FAIAAWCVCHQXDN-UHFFFAOYSA-N 0.000 description 2
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 2
- 239000000843 powder Substances 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
- 230000000717 retained effect Effects 0.000 description 2
- 238000007920 subcutaneous administration Methods 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 239000003765 sweetening agent Substances 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
- WGNUNYPERJMVRM-UHFFFAOYSA-N 3-pyridylacetic acid Chemical compound OC(=O)CC1=CC=CN=C1 WGNUNYPERJMVRM-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
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-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
- QXNVGIXVLWOKEQ-UHFFFAOYSA-N Disodium Chemical class [Na][Na] QXNVGIXVLWOKEQ-UHFFFAOYSA-N 0.000 description 1
- 108010010803 Gelatin Proteins 0.000 description 1
- 229920000084 Gum arabic Polymers 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
- 229910019213 POCl3 Inorganic materials 0.000 description 1
- 241000978776 Senegalia senegal Species 0.000 description 1
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical class [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 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
- 239000000908 ammonium hydroxide Substances 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
- 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
- 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
- 239000003795 chemical substances by application Substances 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
- 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
- XQRLCLUYWUNEEH-UHFFFAOYSA-N diphosphonic acid Chemical compound OP(=O)OP(O)=O XQRLCLUYWUNEEH-UHFFFAOYSA-N 0.000 description 1
- 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 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
- 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
- 230000003301 hydrolyzing effect Effects 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-M hydroxide Chemical compound [OH-] XLYOFNOQVPJJNP-UHFFFAOYSA-M 0.000 description 1
- 239000012535 impurity Substances 0.000 description 1
- 238000011065 in-situ storage Methods 0.000 description 1
- 150000007529 inorganic bases Chemical class 0.000 description 1
- 229910052500 inorganic mineral Inorganic materials 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
- 239000006210 lotion Substances 0.000 description 1
- 235000019359 magnesium stearate Nutrition 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 238000002844 melting Methods 0.000 description 1
- 230000008018 melting Effects 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
- 239000011707 mineral Substances 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 238000001565 modulated differential scanning calorimetry Methods 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
- 239000003960 organic solvent Substances 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
- 150000004686 pentahydrates Chemical class 0.000 description 1
- 229920001223 polyethylene glycol 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
- 159000000001 potassium salts Chemical class 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
- 239000012429 reaction media Substances 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 159000000000 sodium salts Chemical class 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
- 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
- 239000006188 syrup Substances 0.000 description 1
- 235000020357 syrup Nutrition 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
- 150000004684 trihydrates Chemical class 0.000 description 1
- HRXKRNGNAMMEHJ-UHFFFAOYSA-K trisodium citrate Chemical compound [Na+].[Na+].[Na+].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O HRXKRNGNAMMEHJ-UHFFFAOYSA-K 0.000 description 1
- 239000004562 water dispersible granule Substances 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/66—Phosphorus compounds
- A61K31/662—Phosphorus acids or esters thereof having P—C bonds, e.g. foscarnet, trichlorfon
- A61K31/663—Compounds having two or more phosphorus acid groups or esters thereof, e.g. clodronic acid, pamidronic acid
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P19/00—Drugs for skeletal disorders
-
- 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 is concerned with new risedronate salts and new polymorphic forms thereof, processes of preparing the same, pharmaceutical compositions containing the same, therapeutic uses thereof and methods of treatment employing the same.
- 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 0 C.
- the solvent is fmorobenzene
- 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 (POCI 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 POCI 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 0 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 04/037252 discloses crystalline hydrated forms of sodium risedronate, which contain from 6.4 up to 22 weight % of sodium based on the anhydrous substance, and in the case where the sodium content is lower than 7.5 weight %, then 15 to 23 weight % of crystalline water is present, or in the case where the sodium content is higher than 7.5 weight %, then 4.5 to 18 weight % of crystalline water is present.
- the pentahydrate of the monosodium salt which contains from 5.5 to 7.5 weight % of sodium and 20 to 23 weight % of crystalline water
- the trihydrate of the trisodium salt which contains from 19 to 21 weight % of sodium and 12 to 14 weight % of crystalline water
- the monohydrate of the disodium salt which contains from 13 to 15 weight % of sodium and 4.5 to 6.5 weight % of crystalline water.
- WO 03/086355 describes polymorph forms B, Bl 5 BB, C, D, E, F 5 G and H of sodium risedronate and processes of preparing these various polymorphs.
- Pharmaceutically acceptable alkali metal salts include sodium and potassium salts. Specifically, there is provided by the present invention terra-sodium risedronate.
- the present invention also provides tetra-sodium risedronate as tetra-sodium risedronate Form I, tetra-sodium risedronate Form II and tetra-sodium risedronate Form III.
- Tetra-sodium risedronate Form I as provided by the present invention can be characterised as having an X-ray powder diffraction pattern, or substantially the same X-ray powder diffraction pattern, as shown in Figure 1.
- Tetra-sodium risedronate Form I is further characterised as having characteristic peaks (2 ⁇ ): 6.33, 9.76, 11.05, 12.15, 12.65, 15.13, 16.77, 17.0, 18.99, 22.23, 22.61 and 30.53°.
- Tetra-sodium risedronate Form I is further characterised as having an FTIR transmission spectrum, or substantially the same FTIR transmission spectrum, as shown in Figure 2.
- Tetra-sodium risedronate Form I is further characterised as having an FTNIR reflection spectrum, or substantially the same FTNIR reflection spectrum, as shown in Figure 3.
- Tetra-sodium risedronate Form I can be still further characterised by a typical DSC thermograph as shown in Figure 4.
- Tetra-sodium risedronate Form I has a DSC endotherm temperature onset of about 175°C.
- Tetra-sodium risedronate Form II as provided by the present invention can be characterised as having an X-ray powder diffraction pattern, or substantially the same X-ray powder diffraction pattern, as shown in Figure 5.
- Tetra-sodium risedronate Form II is further characterised as having characteristic peaks (2 ⁇ ): 4.33, 5.03, 5.48, 6.94, 9.94, 11.06, 11.89, 12.94, 13.16, 14.14, 16.63, 21.38 and 22.20°.
- Tetra-sodium risedronate Form II is further characterised as having an FTIR transmission spectrum, or substantially the same FTIR transmission spectrum, as shown in Figure 6.
- Tetra-sodium risedronate Form II 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 7.
- Tetra-sodium risedronate Form II can be still further characterised by a typical DSC thermograph as shown in Figure 8. Tetra-sodium risedronate Form II has a DSC endotherm temperature onset of about 120°C.
- Tetra-sodium risedronate Form III as provided by the present invention can be characterised as having an X-ray powder diffraction pattern, or substantially the same X-ray powder diffraction pattern, as shown in Figure 9.
- Tetra-sodium risedronate Form III according to the present invention is further characterised as having characteristic peaks (2 ⁇ ): 5.17, 5.57 and 7.06°.
- Tetra-sodium risedronate Form III 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 10.
- Tetra-sodium risedronate Form III 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 11.
- Tetra-sodium risedronate Form III can be still further characterised by a typical DSC thermograph as shown in Figure 12. Tetra-sodium risedronate Form III has a DSC endotherm temperature onset of about 80°C.
- the present invention also provides a process of preparing a tetra-(alkali metal) salt of risedronic acid according to the present invention substantially as hereinbefore described, which comprises contacting risedronic free acid with a source of a pharmaceutically acceptable alkali metal and thus converting the free acid to a tetra- (alkali metal) salt of risedronic acid. More particularly, a process according to the present invention comprises contacting a suspension of risedronic free acid with a source of a pharmaceutically acceptable alkali metal, adjusting the pH to about 13 to 14, preferably about 13.4, and thereby converting the risedronic free acid to a tetra- (alkali metal) salt of risedronic acid according to the present invention substantially as hereinbefore described.
- the source of the pharmaceutically acceptable alkali metal is the corresponding alkali metal hydroxide, preferably sodium hydroxide, whereby addition of the hydroxide achieves adjustment to the above referred to pH range of 13 to 14.
- the reaction scheme can be illustrated as follows.
- a process as described herein prepares tetra-sodium risedronate as any one of Forms I, II or III as described herein.
- a suspension of risedronic free acid and water is maintained at about 2O 0 C, followed by the addition of sodium hydroxide to form a solution.
- the pH is adjusted to about 13.4.
- a C 1-4 alcohol such as methanol or ethanol, is added at a temperature of up to about 3O 0 C, followed by crystallization of tetra-sodium risedronate Form I according to the present invention.
- a suspension of risedronic free acid and water is maintained at about 2O 0 C, followed by the addition of sodium hydroxide to form a solution.
- the pH is adjusted to about 13.4.
- the solution is heated to reflux and preferably a C 1-4 alcohol, such as methanol or ethanol, is added under reflux. Crystallization of tetra-sodium risedronate starts under reflux followed by cooling and filtration to obtain tetra-sodium risedronate Form II according to the present invention.
- a suspension of risedronic free acid and water is maintained at about 2O 0 C, followed by the addition of sodium hydroxide to form a solution.
- the pH is adjusted to about 13.4.
- the solution is heated to reflux and preferably a C 1 ⁇ alcohol, such as methanol or ethanol, is added under reflux. Crystallization of tetra-sodium risedronate starts under reflux followed by cooling, further addition of a C 1-4 alcohol and filtration to obtain tetra- sodium risedronate Form III according to the present invention.
- risedronic acid as employed in the above reactions is prepared by the reaction of phosphorous acid with pyridylacetic acid, optionally present as a hydrohalide salt.
- the reaction is also carried out in the presence of phosphorous trihalide and phosphorous acid is formed in situ in the reaction mixture by the reaction of phosphorous trihalide and water. This can be represented by the following reaction scheme. (1) PX 3 (excess) + H 2 O
- pyridylacetic acid is employed in the form of the hydrochloride salt and the phosphorous trihalide employed is phosphorous trichloride.
- a tetra-(alkali metal) salt of risedronic acid as provided 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 a tetra-(alkali metal) salt of risedronic acid, together with a pharmaceutically acceptable carrier, diluent or excipient therefor.
- Excipients are chosen according to the pharmaceutical form and the desired mode of administration.
- therapeutically effective amount means an amount a tetra- (alkali metal) salt of risedronic acid as prepared by the present invention, 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 a tetra-(alkali metal) salt of risedronic acid as prepared by the present invention and is not deleterious to a recipient thereof.
- a tetra-(alkali metal) salt of risedronic acid 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.
- a tetra- (alkali metal) salt of risedronic acid can be used in creams, ointments or lotions.
- the dose of a tetra-(alkali metal) salt of risedronic acid 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 a tetra-(alkali metal) salt of risedronic acid, 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.
- a tetra-(alkali metal) salt of risedronic acid 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 a tetra-(alkali metal) salt of risedronic acid as provided by the present invention.
- a preparation in the form of gelatin capsules can be obtained by mixing a tetra-(alkali metal) salt of risedronic acid 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 a tetra-(alkali metal) salt of risedronic acid, 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 a tetra-(alkali metal) salt of risedronic acid 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.
- a tetra-(alkali metal) salt of risedronic acid can also be formulated as microcapsules, with one or more carriers or additives if appropriate.
- tetra-(alkali metal) salt of risedronic acid for use in therapy.
- the present invention further provides a tetra-(alkali metal) salt of risedronic acid, 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. More specifically, the present invention provides a tetra-(alkali metal) salt of risedronic acid, 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 a tetra-(alkali metal) salt of risedronic acid.
- 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 a tetra- (alkali metal) salt of risedronic acid.
- 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.
- Figure 1 is an XRPD pattern of tetra-sodium risedronate Form I according to the present invention.
- Figure 2 is an FTIR transmission spectrum of tetra-sodium risedronate Form I according to the present invention recorded by KBr disc and resolution 4 cm "1 .
- Figure 3 is an FTNIR reflection spectrum of tetra-sodium risedronate Form I according to the present invention, recorded with solid probe accessories and resolution 8 cm “1 .
- Figure 4 is a DSC thermogram of tetra-sodium risedronate Form I according to the present invention, recorded at a heat rate of 10°C/min (endotherm temperature onset is at 175 0 C ).
- Figure 5 is an XRPD pattern of tetra-sodium risedronate Form II according to the present invention.
- Figure 6 is an FTIR transmission spectrum of tetra-sodium risedronate Form II according to the present invention recorded by KBr disc and resolution 4 cm “1 .
- Figure 7 is an FTNIR reflection spectrum of tetra-sodium risedronate Form II according to the present invention, recorded with solid probe accessories and resolution 8 cm “1 .
- Figure 8 is a DSC thermogram of tetra-sodium risedronate Form II according to the present invention, recorded at a heat rate of 10°C/min (endotherm temperature onset is at 12O 0 C ).
- Figure 9 is an XRPD pattern of tetra-sodium risedronate Form III according to the present invention.
- Figure 10 is an FTIR transmission spectrum of tetra-sodium risedronate Form III according to the present invention recorded by KBr disc and resolution 4 cm “1 .
- Figure 11 is an FTNIR reflection spectrum of tetra-sodium risedronate Form III according to the present invention, recorded with solid probe accessories and resolution 8 cm “1 .
- Figure 12 is a DSC thermogram of tetra-sodium risedronate Form III according to the present invention, recorded at a heat rate of 10°C/min (endotherm temperature onset is at 8O 0 C ).
- the above referenced FTIR transmission spectra for each of polymorphs I, II and III were obtained by using Perkin Elmer Spectrum GX FT-IR Spectrometer (Detector: DTGS, Beam splitter: extended KBr, Spectral Range: 4000-400Cm "1 , Resolution: 4cm " ⁇ 4 scans, Samples prepared as KBr pellets).
- the above referenced FTNIR reflection spectra for each of polymorphs I 5 II and III were obtained by using Bruker NIR Multi Purpose Analyser (MPA). (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).
- risedronate tetra-sodium salt 21.17 g, was obtained after filtration, washed with 100ml of a water / methanol solution (1 / 4) and dried. Analysis carried out confirmed the risedronate tetra-sodium salt thus prepared to be tetra-sodium risedronate form I.
- risedronate tetra-sodium salt 19.58 g, was obtained after filtration, washed with 100ml of a water / methanol cold solution (1 / 4) and dried. Analysis carried out confirmed the risedronate tetra-sodium salt thus prepared to be tetra-sodium risedronate form II.
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Abstract
La présente invention concerne de nouveaux sels risedronates et de nouvelles formes polymorphes de ceux-ci, notamment un sel pharmaceutiquement acceptable de tétra-(métal alcalin) de l'acide risedronique et de nouvelles formes polymorphes de celui-ci, des procédés permettant de les préparer, des compositions pharmaceutiques les contenant, leurs utilisations thérapeutiques et des procédés de traitement les employant.
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
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GBGB0609465.0A GB0609465D0 (en) | 2006-05-12 | 2006-05-12 | Pharmaceutically acceptable salts and polymorphic forms |
PCT/GB2007/000792 WO2007132138A1 (fr) | 2006-05-12 | 2007-03-06 | Sels pharmaceutiquement acceptables et formes polymorphes |
Publications (1)
Publication Number | Publication Date |
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EP2018392A1 true EP2018392A1 (fr) | 2009-01-28 |
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EP07712850A Withdrawn EP2018392A1 (fr) | 2006-05-12 | 2007-03-06 | Sels pharmaceutiquement acceptables et formes polymorphes |
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EP (1) | EP2018392A1 (fr) |
CA (1) | CA2649489A1 (fr) |
EA (1) | EA200870525A1 (fr) |
GB (1) | GB0609465D0 (fr) |
WO (1) | WO2007132138A1 (fr) |
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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 |
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CZ20023574A3 (en) * | 2002-10-25 | 2004-04-14 | Léčiva, A.S. | New crystalline form of the sodium salt of 3-pyridyl-1-hydroxyehtylidene-1,1-bisphosphonic acid |
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2006
- 2006-05-12 GB GBGB0609465.0A patent/GB0609465D0/en active Pending
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2007
- 2007-03-06 EP EP07712850A patent/EP2018392A1/fr not_active Withdrawn
- 2007-03-06 WO PCT/GB2007/000792 patent/WO2007132138A1/fr active Application Filing
- 2007-03-06 CA CA002649489A patent/CA2649489A1/fr not_active Abandoned
- 2007-03-06 EA EA200870525A patent/EA200870525A1/ru unknown
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EA200870525A1 (ru) | 2009-04-28 |
CA2649489A1 (fr) | 2007-11-22 |
GB0609465D0 (en) | 2006-06-21 |
WO2007132138A1 (fr) | 2007-11-22 |
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