EP1963345A2 - Verfahren zur herstellung reiner zoledronsäure - Google Patents
Verfahren zur herstellung reiner zoledronsäureInfo
- Publication number
- EP1963345A2 EP1963345A2 EP06831707A EP06831707A EP1963345A2 EP 1963345 A2 EP1963345 A2 EP 1963345A2 EP 06831707 A EP06831707 A EP 06831707A EP 06831707 A EP06831707 A EP 06831707A EP 1963345 A2 EP1963345 A2 EP 1963345A2
- Authority
- EP
- European Patent Office
- Prior art keywords
- zoledronic acid
- salts
- acid
- reaction
- 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- Withdrawn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
- 229960004276 zoledronic acid Drugs 0.000 title claims abstract description 67
- XRASPMIURGNCCH-UHFFFAOYSA-N zoledronic acid Chemical compound OP(=O)(O)C(P(O)(O)=O)(O)CN1C=CN=C1 XRASPMIURGNCCH-UHFFFAOYSA-N 0.000 title claims abstract description 67
- 238000000034 method Methods 0.000 title claims abstract description 48
- 238000002360 preparation method Methods 0.000 title claims abstract description 13
- 150000003839 salts Chemical class 0.000 claims abstract description 45
- QAFBDRSXXHEXGB-UHFFFAOYSA-N imidazol-1-ylacetic acid Chemical compound OC(=O)CN1C=CN=C1 QAFBDRSXXHEXGB-UHFFFAOYSA-N 0.000 claims abstract description 25
- 238000004128 high performance liquid chromatography Methods 0.000 claims abstract description 18
- 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 abstract description 17
- FAIAAWCVCHQXDN-UHFFFAOYSA-N phosphorus trichloride Chemical compound ClP(Cl)Cl FAIAAWCVCHQXDN-UHFFFAOYSA-N 0.000 claims abstract description 14
- XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 claims abstract description 12
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 7
- 239000003960 organic solvent Substances 0.000 claims abstract description 4
- 238000006243 chemical reaction Methods 0.000 claims description 51
- 239000002904 solvent Substances 0.000 claims description 29
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 21
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 claims description 21
- MVPPADPHJFYWMZ-UHFFFAOYSA-N chlorobenzene Chemical compound ClC1=CC=CC=C1 MVPPADPHJFYWMZ-UHFFFAOYSA-N 0.000 claims description 16
- 239000012456 homogeneous solution Substances 0.000 claims description 14
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 13
- 239000000203 mixture Substances 0.000 claims description 11
- -1 alkyl imidazole- 1-yl acetate Chemical compound 0.000 claims description 10
- 125000000217 alkyl group Chemical group 0.000 claims description 8
- 239000002202 Polyethylene glycol Substances 0.000 claims description 7
- XUIMIQQOPSSXEZ-UHFFFAOYSA-N Silicon Chemical compound [Si] XUIMIQQOPSSXEZ-UHFFFAOYSA-N 0.000 claims description 7
- 239000003921 oil Substances 0.000 claims description 7
- 229920001223 polyethylene glycol Polymers 0.000 claims description 7
- 239000010703 silicon Substances 0.000 claims description 7
- 229910052710 silicon Inorganic materials 0.000 claims description 7
- 238000000746 purification Methods 0.000 claims description 5
- 239000003085 diluting agent Substances 0.000 claims description 4
- 238000004821 distillation Methods 0.000 claims description 4
- 238000001914 filtration Methods 0.000 claims description 4
- 239000003880 polar aprotic solvent Substances 0.000 claims description 4
- 238000010438 heat treatment Methods 0.000 claims description 3
- QABLOFMHHSOFRJ-UHFFFAOYSA-N methyl 2-chloroacetate Chemical group COC(=O)CCl QABLOFMHHSOFRJ-UHFFFAOYSA-N 0.000 claims description 3
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 3
- 239000003444 phase transfer catalyst Substances 0.000 claims description 3
- 238000002441 X-ray diffraction Methods 0.000 claims description 2
- 238000005119 centrifugation Methods 0.000 claims description 2
- 238000001816 cooling Methods 0.000 claims description 2
- 238000010908 decantation Methods 0.000 claims description 2
- 239000003937 drug carrier Substances 0.000 claims description 2
- PQJJJMRNHATNKG-UHFFFAOYSA-N ethyl bromoacetate Chemical compound CCOC(=O)CBr PQJJJMRNHATNKG-UHFFFAOYSA-N 0.000 claims description 2
- 150000008282 halocarbons Chemical class 0.000 claims description 2
- 230000003301 hydrolyzing effect Effects 0.000 claims description 2
- FUXFIVRTGHOMSO-UHFFFAOYSA-N (1-hydroxy-2-imidazol-1-yl-1-phosphonoethyl)phosphonic acid;hydrate Chemical compound O.OP(=O)(O)C(P(O)(O)=O)(O)CN1C=CN=C1 FUXFIVRTGHOMSO-UHFFFAOYSA-N 0.000 claims 1
- 229950011303 zoledronic acid monohydrate Drugs 0.000 claims 1
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 14
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 12
- 239000000047 product Substances 0.000 description 11
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 9
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 9
- 239000012296 anti-solvent Substances 0.000 description 6
- 239000000706 filtrate Substances 0.000 description 6
- NLKNQRATVPKPDG-UHFFFAOYSA-M potassium iodide Chemical compound [K+].[I-] NLKNQRATVPKPDG-UHFFFAOYSA-M 0.000 description 6
- 238000003756 stirring Methods 0.000 description 6
- 238000004519 manufacturing process Methods 0.000 description 5
- 238000010992 reflux Methods 0.000 description 5
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 4
- BHEPBYXIRTUNPN-UHFFFAOYSA-N hydridophosphorus(.) (triplet) Chemical compound [PH] BHEPBYXIRTUNPN-UHFFFAOYSA-N 0.000 description 4
- 239000007787 solid Substances 0.000 description 4
- 230000007062 hydrolysis Effects 0.000 description 3
- 238000006460 hydrolysis reaction Methods 0.000 description 3
- 239000010410 layer Substances 0.000 description 3
- 239000011369 resultant mixture Substances 0.000 description 3
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical class O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 2
- 239000004480 active ingredient Substances 0.000 description 2
- 239000003054 catalyst Substances 0.000 description 2
- 239000003610 charcoal Substances 0.000 description 2
- 239000013078 crystal Substances 0.000 description 2
- 239000012530 fluid Substances 0.000 description 2
- BUTAEDDIDXHHEN-UHFFFAOYSA-N imidazol-1-yl acetate Chemical compound CC(=O)ON1C=CN=C1 BUTAEDDIDXHHEN-UHFFFAOYSA-N 0.000 description 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 239000012044 organic layer 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
- 238000001556 precipitation Methods 0.000 description 2
- 239000000725 suspension Substances 0.000 description 2
- LYUUUWIOPMQOQZ-UHFFFAOYSA-N (1-hydroxy-2-imidazol-1-yl-2-phosphonoethyl)phosphonic acid;hydrate Chemical compound O.OP(=O)(O)C(O)C(P(O)(O)=O)N1C=CN=C1 LYUUUWIOPMQOQZ-UHFFFAOYSA-N 0.000 description 1
- QIVUCLWGARAQIO-OLIXTKCUSA-N (3s)-n-[(3s,5s,6r)-6-methyl-2-oxo-1-(2,2,2-trifluoroethyl)-5-(2,3,6-trifluorophenyl)piperidin-3-yl]-2-oxospiro[1h-pyrrolo[2,3-b]pyridine-3,6'-5,7-dihydrocyclopenta[b]pyridine]-3'-carboxamide Chemical compound C1([C@H]2[C@H](N(C(=O)[C@@H](NC(=O)C=3C=C4C[C@]5(CC4=NC=3)C3=CC=CN=C3NC5=O)C2)CC(F)(F)F)C)=C(F)C=CC(F)=C1F QIVUCLWGARAQIO-OLIXTKCUSA-N 0.000 description 1
- JKZJSYXGKHQHRA-UHFFFAOYSA-N 2-imidazol-1-ylacetic acid;hydrochloride Chemical compound Cl.OC(=O)CN1C=CN=C1 JKZJSYXGKHQHRA-UHFFFAOYSA-N 0.000 description 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-M Bicarbonate Chemical class OC([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-M 0.000 description 1
- 208000006386 Bone Resorption Diseases 0.000 description 1
- 206010020584 Hypercalcaemia of malignancy Diseases 0.000 description 1
- 206010027452 Metastases to bone Diseases 0.000 description 1
- 208000034578 Multiple myelomas Diseases 0.000 description 1
- 206010028980 Neoplasm Diseases 0.000 description 1
- 206010035226 Plasma cell myeloma Diseases 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 150000004703 alkoxides Chemical class 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 239000007900 aqueous suspension Substances 0.000 description 1
- 239000002585 base Substances 0.000 description 1
- 238000009835 boiling Methods 0.000 description 1
- 230000024279 bone resorption Effects 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 150000004649 carbonic acid derivatives Chemical class 0.000 description 1
- 238000004040 coloring Methods 0.000 description 1
- 238000006482 condensation reaction Methods 0.000 description 1
- 239000006071 cream Substances 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- 238000001704 evaporation Methods 0.000 description 1
- 230000008020 evaporation Effects 0.000 description 1
- 239000008187 granular material Substances 0.000 description 1
- 231100001261 hazardous Toxicity 0.000 description 1
- 208000008750 humoral hypercalcemia of malignancy Diseases 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-M hydroxide Chemical compound [OH-] XLYOFNOQVPJJNP-UHFFFAOYSA-M 0.000 description 1
- 239000012729 immediate-release (IR) formulation Substances 0.000 description 1
- 239000012535 impurity Substances 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 239000008297 liquid dosage form Substances 0.000 description 1
- 239000006210 lotion Substances 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- 229910001507 metal halide Inorganic materials 0.000 description 1
- 150000005309 metal halides Chemical class 0.000 description 1
- 150000002739 metals Chemical class 0.000 description 1
- 150000004682 monohydrates Chemical group 0.000 description 1
- XULSCZPZVQIMFM-IPZQJPLYSA-N odevixibat Chemical compound C12=CC(SC)=C(OCC(=O)N[C@@H](C(=O)N[C@@H](CC)C(O)=O)C=3C=CC(O)=CC=3)C=C2S(=O)(=O)NC(CCCC)(CCCC)CN1C1=CC=CC=C1 XULSCZPZVQIMFM-IPZQJPLYSA-N 0.000 description 1
- 239000002674 ointment Substances 0.000 description 1
- 230000001599 osteoclastic effect Effects 0.000 description 1
- 239000013618 particulate matter Substances 0.000 description 1
- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 230000035484 reaction time Effects 0.000 description 1
- 239000007909 solid dosage form Substances 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 239000012258 stirred mixture Substances 0.000 description 1
- 238000013268 sustained release Methods 0.000 description 1
- 239000012730 sustained-release form Substances 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- 230000000699 topical effect Effects 0.000 description 1
- 230000035899 viability Effects 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
- 238000010626 work up procedure Methods 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
- C07F9/645—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having two nitrogen atoms as the only ring hetero atoms
- C07F9/6503—Five-membered rings
- C07F9/6506—Five-membered rings having the nitrogen atoms in positions 1 and 3
Definitions
- the field of the invention relates to processes for the preparation of pure zoledronic acid or pharmaceutically acceptable salts thereof.
- the invention also relates to pharmaceutical compositions that include the pure zoledronic acid.
- Zoledronic acid a bisphosphonic acid
- Zoledronic acid is an inhibitor of osteoclastic bone resorption indicated in the treatment of hypercalcemia of malignancy. It is also indicated for the treatment of multiple myeloma and bone metastases of solid tumors.
- Zoledronic acid is chemically, (l-Hydroxy-2-imidazol-l-yl-phosphonoethyl)phosphonic acid monohydrate of structural Formula I.
- a process for the preparation of zoledronic acid is disclosed for example, in U.S. Patent number 4,939,130 and Izv. Akad. Nauk. USSR, Ser. KUm., 1987, 2, 433-437.
- the process involves the treatment of imidazol-1-yl acetic acid hydrochloride with phosphoric acid and phosphorous trichloride in chlorobenzene as solvent at 100 0 C.
- the reaction mass becomes very thick. This leads to incomplete reaction and results in a low overall yield and impure product.
- US Application No. 2004/0230076 provides a process for the purification of zoledronic acid.
- the process includes obtaining a clear solution of crude zoledronic acid by raising the pH of an aqueous suspension; lowering the pH of the solution; and isolating the zoledronic acid from the solution.
- US Application No. 2005/0054616 provides processes for the preparation of crystalline and amorphous forms of zoledronic acid.
- the process involves the use of chlorobenzene or toluene as solvent along with silicon oil, polyethylene glycol or diatomaceous earth compounds such as celite, keisulgurh etc. as diluents to keep the reaction mass stirrable.
- the product is not obtained in high purity.
- zoledronic acid when prepared as per the processes reported in the prior art is not pure and yields are low. It also was observed by the present inventors that the reaction mass becomes thick and is very difficult to stir. [0007] The present inventors have found that there is no need to use solvent in the condensation reaction between imidazole- 1-yl acetic acid or salts thereof and phosphorous acid in presence of phosphorous trichloride to get zoledronic acid. A small excess of phosphorous acid can act as a solvent and the reaction mass remains homogeneous and is easily stirrable. Further, the inventors have also found that the reaction can be accomplished at temperatures less than 80 0 C in less than 10 hours reaction time. The yield of zoledronic acid obtained is about 80% with purity in excess of 99%. This significantly improves the process economics and commercial viability.
- phosphorous oxychloride can be used in place of phosphorous trichloride without compromising on safety because commercially available phosphorous oxychloride (POCl 3 ) does not contain free phosphorous. Additionally, the boiling point Of POCl 3 is about 105 0 C, which is well above the reaction temperature, and therefore the disadvantages such as addition at reflux temperature can also be taken care off. [0010] Accordingly, in one general aspect there is provided a process for preparing pure zoledronic acid or salts thereof having purity more than 99.7% by HPLC.
- the process includes reacting imidazol-1-yl acetic acid or salts thereof with phosphorous acid at 8O 0 C or less to obtain a homogeneous solution; adding phosphorous trichloride at 80 0 C or less; and isolating the zoledronic acid or salts thereof from the reaction mass thereof.
- Embodiments of the process may include one or more of the following features.
- the reaction of imidazol-1-yl acetic acid or salt thereof with phosphorous acid may be carried out without any solvent.
- the reaction may be carried out in the presence of one or more solvents.
- the solvent may be one or more of chlorobenzene, polyethylene glycol, toluene, and silicon oil.
- the process may include further purification of the product obtained. [0012] The process may include further drying of the product obtained. [0013] The process may produce the pure zoledronic acid or salts thereof having purity more than 99.7% by HPLC. In particular, it may produce the pure zoledronic acid or salts thereof having purity more than 99.9% by HPLC.
- a process for preparing pure zoledronic acid or salts thereof having purity more than 99.7% by HPLC includes reacting imidazol-1-yl acetic acid or salts thereof with phosphorous acid at 80 0 C or less to obtain a homogeneous solution; adding phosphorous oxychloride at 80 0 C or less; and isolating the zoledronic acid or salts thereof from the reaction mass thereof.
- Embodiments of the process may include one or more of the following features.
- the reaction of imidazol-1-yl acetic acid or salt thereof with phosphorous acid may be carried out without any solvent.
- the reaction may be carried out in the presence of one or more solvents.
- the solvent may be one or more of chlorobenzene, polyethylene glycol, toluene, and silicon oil.
- a pharmaceutical composition that includes a therapeutically effective amount of pure zoledronic acid or salts thereof having purity more than 99.7% by HPLC; and one or more pharmaceutically acceptable carriers, excipients or diluents.
- Figure 1 is an X-Ray Diffraction Pattern of zoledronic acid. Detailed Description of the Invention
- a first aspect of the present invention provides a process for preparing pure zoledronic acid or salts thereof having purity more than 99.7% by HPLC.
- the process includes the steps of: (a) reacting imidazol-1-yl acetic acid or salt thereof with phosphorous acid at 80 0 C or less to obtain a homogeneous solution;
- Imidazole 1-yl acetic acid or salts thereof may be treated with phosphorous acid and the resultant mass may be heated to get a homogeneous solution.
- Phosphorous trichloride may be added to this homogeneous solution under controlled rate of addition at a temperature less than 8O 0 C.
- This reaction may be carried out in the absence of a solvent. Such reactions are normally termed as "neat reactions".
- the reaction may be carried out in the presence of one or more solvents.
- a suitable solvent may include one or more of chlorobenzene, polyethylene glycol, toluene, and silicon oil.
- the reaction may be continued at the same temperature until completion of the reaction. In general, it may be required to maintain the reaction temperature for about 10 hours.
- reaction mass may be acidified.
- the acidified mixture may be further heated for about 8-15 hours. It may be treated with activated charcoal and filtered.
- the filtrate may be treated with acetone or any other suitable anti-solvent to precipitate zoledronic acid from the solution.
- the precipitated mass may be filtered and dried suitably.
- the product may be further or additionally dried to achieve the desired moisture values.
- the product may be further or additionally dried in a tray drier, dried under vacuum and/or in a Fluid Bed Drier.
- the zoledronic acid has a purity of more than purity 99% when measured by HPLC. More particularly, the purity is more than 99.7%, for example more than 99.9%.
- a second aspect of the present invention provides a process for preparing zoledronic acid or salts thereof. The process includes the steps of:
- Imidazol-1-yl acetic acid to be used as the starting material can be prepared the resultant by any process known in the literature. In particular, it can be prepared by reacting imidazole with alkyl haloacetate in the absence of a phase transfer catalyst to get imidazole- 1-yl acetate.
- a third aspect of the present invention provides a process for preparing zoledronic acid or salt thereof.
- the process includes the steps of: a) reacting imidazole with alkyl haloacetate in one or more organic solvents in the absence of a phase transfer catalyst, to get alkyl imidazole- 1-yl acetate; b) hydrolyzing the alkyl imidazole- 1-yl acetate in water to get imidazol-1-yl acetic acid; c) treating imidazol-1-yl acetic acid or salts thereof with phosphorous acid and phosphorous trichloride optionally in the presence of one or more solvents; and d) isolating the zoledronic acid or salts thereof from the reaction mass thereof.
- the reaction of imidazole and alkyl haloacetate may be carried out in the presence of one or more suitable solvents.
- suitable solvents include, for example, halogenated hydrocarbons, non-polar aprotic solvents, polar aprotic solvents, and mixtures thereof.
- the reaction may also be carried out in the presence of a base.
- the base can be selected from carbonates, bicarbonates, hydroxide or alkoxides of metals. Additionally metal halides such as potassium iodide can be effectively used as catalysts to accelerate the rate of reaction.
- base, imidazole and catalyst are mixed with solvent and to this stirred mixture is added alkyl haloacetate at controlled rate.
- the resultant mass after stirring for approximately 30 to 45 minutes can be heated to reflux. After completion of the reaction, the resultant mass can be cooled to room temperature and filtered to remove inorganics. The organic layer containing the product can be then concentrated under reduced pressure to get crude mass of methyl /ethyl imidazol-1-yl acetate. This crude mass can be purified suitably or can be used as such for its hydrolysis to get imidazol-1-yl acetic acid or salt thereof. [0028]
- the hydrolysis of methyl/ethyl imidazol-1-yl acetate can be carried out under aqueous conditions at higher temperature.
- the ester can be mixed with water and the resultant mass can be heated to reflux for about 4 to 10 hours, and cooled.
- a fourth aspect of the present invention provides a process for the purification of zoledronic acid or salts thereof.
- the process includes the steps of: a) obtaining a solution of zoledronic acid or salts thereof in water by heating; b) cooling the solution; and c) recovering the pure zoledronic acid or salts thereof having purity more than 99.7% from the solution thereof by the removal of water.
- the solution of zoledronic acid may be obtained by dissolving zoledronic acid in water.
- a solution may be obtained directly from a reaction in which zoledronic acid is formed.
- the mixture containing zoledronic acid may be heated to obtain a solution. It can be heated from about 30 0 C to about reflux temperature of the solvent used, for example from about 30 0 C to about 100 0 C.
- the resultant solution can be clarified to remove foreign particulate matter or treated with activated charcoal to remove coloring and other related impurities.
- the clear solution is cooled to a temperature of 30 °C or less and an optionally pre-cooled anti-solvent is added to it.
- the anti-solvent is characterized by the fact that zoledronic acid is insoluble, practically insoluble or very slightly soluble in the anti- solvent.
- the terms insoluble, practically insoluble or very slightly soluble have their ordinary meanings as defined in United States Phamacopoeia 2002.
- the term "obtaining” includes dissolving, slurrying, stirring or a combination thereof.
- the pure zoledronic acid may be recovered from the solution by a technique/which includes, for example, distillation, distillation under vacuum, filtration, filtration under vacuum, evaporation, decantation and centrifugation. The product may be further or additionally dried to achieve the desired moisture values.
- the product may be further or additionally dried in a tray drier, dried under vacuum and/or in a Fluid Bed Drier.
- the zoledronic acid has a purity of more than purity 99.7% when measured by HPLC. More particularly, the purity is more than 99.9%.
- the pure zoledronic acid may be in its monohydrate form and has a moisture content of about 6 to 8% w/w.
- a fifth aspect of the present invention provides a pharmaceutical composition
- a pharmaceutical composition comprising as its active ingredient pure zoledronic acid or salts thereof having purity more than 99.7% by HPLC.
- the pharmaceutical composition includes one or more pharmaceutically acceptable excipients/diluents.
- the pharmaceutical composition of the present invention may be in the form of a solid or liquid dosage forms for oral, parenteral or topical use and may have immediate or sustained release characteristics.-
- the dosage forms possible include tablets, capsules, powders, granules, creams, lotions, ointments, injectables, ophthalmic or otic solutions, suspensions, elixirs, and the like.
- Example- 2 Preparation of imidazol-1-yl acetic acid Water (500 ml) was added to methyl imidazol-1-yl acetate (235 gm) and the resultant mass was refluxed for 4 to 8 hours. After completion of the reaction, it was cooled. The organic layer was separated and discarded. The aqueous layer was treated with activated charcoal, filtered to remove charcoal and concentrated under reduced pressure to get a residue. The residue obtained was treated with methanol (250 ml) and the resultant mixture was stirrejl for 2 hours and filtered.
- Example- 4 Purification of zoledronic acid
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Biochemistry (AREA)
- General Health & Medical Sciences (AREA)
- Molecular Biology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
IN1584MU2005 | 2005-12-16 | ||
IN278MU2006 | 2006-02-28 | ||
PCT/IB2006/003603 WO2007069049A2 (en) | 2005-12-16 | 2006-12-14 | Processes for the preparation of pure zoledronic acid |
Publications (1)
Publication Number | Publication Date |
---|---|
EP1963345A2 true EP1963345A2 (de) | 2008-09-03 |
Family
ID=38163283
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
EP06831707A Withdrawn EP1963345A2 (de) | 2005-12-16 | 2006-12-14 | Verfahren zur herstellung reiner zoledronsäure |
Country Status (2)
Country | Link |
---|---|
EP (1) | EP1963345A2 (de) |
WO (1) | WO2007069049A2 (de) |
Families Citing this family (10)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US8071574B2 (en) | 2005-02-22 | 2011-12-06 | John Dennis Bobyn | Implant improving local bone formation |
WO2007125521A2 (en) * | 2006-05-02 | 2007-11-08 | Ranbaxy Laboratories Limited | Polymorphic form of zoledronic acid and processes for their preparation |
PL213599B1 (pl) | 2008-10-31 | 2013-03-29 | Politechnika Gdanska | Sposób otrzymywania kwasu [1-hydroksy-2-(1H-imidazol-1-ilo)-etylideno] bisfosfonowego |
PT2459176T (pt) | 2009-07-31 | 2017-12-11 | Gruenenthal Gmbh | Método de cristalização e biodisponibilidade |
US9169279B2 (en) | 2009-07-31 | 2015-10-27 | Thar Pharmaceuticals, Inc. | Crystallization method and bioavailability |
US20160016982A1 (en) | 2009-07-31 | 2016-01-21 | Thar Pharmaceuticals, Inc. | Crystallization method and bioavailability |
WO2012071517A2 (en) | 2010-11-24 | 2012-05-31 | Thar Pharmaceuticals, Inc. | Novel crystalline forms |
CN102070668B (zh) * | 2010-12-23 | 2013-07-24 | 蚌埠丰原医药科技发展有限公司 | 一种利用相转移催化剂制备唑来膦酸及其钠盐的方法 |
US10195218B2 (en) | 2016-05-31 | 2019-02-05 | Grunenthal Gmbh | Crystallization method and bioavailability |
CN106699809A (zh) * | 2016-12-07 | 2017-05-24 | 河北仁合益康药业有限公司 | 一种唑来膦酸的合成工艺 |
Family Cites Families (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CA2485443C (en) * | 2002-05-17 | 2010-04-06 | Teva Pharmaceutical Industries Ltd | Use of aromatic hydrocarbons and silicone fluids for making bisphosphonic acids |
EP1612212A1 (de) * | 2003-07-03 | 2006-01-04 | Teva Pharmaceutical Industries Ltd | Kristalleformen der Zoledronsäure und deren Natrioumsalze, Amorphes Natriumzoledronat und Verfahren zu deren Herstellung |
CA2551230A1 (en) * | 2003-12-23 | 2005-07-14 | Lyogen Limited | A process for the preparation of alkyl- and aryl-diphosphonic acids and salts thereof |
WO2005063717A1 (en) * | 2003-12-26 | 2005-07-14 | Natco Pharma Limited | An improved process for the preparation of zoledronic acid |
-
2006
- 2006-12-14 EP EP06831707A patent/EP1963345A2/de not_active Withdrawn
- 2006-12-14 WO PCT/IB2006/003603 patent/WO2007069049A2/en active Application Filing
Non-Patent Citations (1)
Title |
---|
See references of WO2007069049A2 * |
Also Published As
Publication number | Publication date |
---|---|
WO2007069049A2 (en) | 2007-06-21 |
WO2007069049A3 (en) | 2009-04-16 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
WO2007069049A2 (en) | Processes for the preparation of pure zoledronic acid | |
AU2015260762B2 (en) | N-[5-(aminosulfonyl)-4-methyl-1,3-thiazol-2-yl]-n-methyl-2-[4-(2-pyridinyl)phenyl]acetamide mesylate monohydrate | |
US8759515B2 (en) | Process for the preparation of tenofovir disoproxil fumarate | |
JP5535082B2 (ja) | ボセンタン、その多形形態及びその塩の合成方法 | |
JP6267213B2 (ja) | 5−(2,6−ジ−4−モルホリニル−4−ピリミジニル)−4−トリフルオロメチルピリジン−2−アミンを製造するための改良された方法 | |
US8329905B2 (en) | Synthesis of diethyl{[5-(3-fluorophenyl)-pyridine-2yl]methyl}phosphonate | |
JP2015107976A (ja) | 結晶形態のテノホビルジソプロキシル及びその製造方法 | |
WO2007083240A2 (en) | An improved process for the preparation of bisphosphonic acids | |
EP1931326A1 (de) | Kristallines trihydrat von zoledronsäure | |
JP2013512893A (ja) | デフェラシロクスの調製方法、及びデフェラシロクスの多形体 | |
WO2013072745A1 (en) | Process for the preparation of tenofovir | |
JP2004520446A (ja) | ロサルタンカリウムの結晶化方法 | |
WO2014091386A2 (en) | An improved process for preparation of minodronic acid | |
JP2010508376A (ja) | ビホスホン酸、及びその塩の製造方法 | |
KR20100092960A (ko) | Hiv 역전사 효소 억제제의 제조 방법 | |
CN101522664B (zh) | 3-(1h-吲哚-3-基)-4-[2-(4-甲基-哌嗪-1-基)-喹唑啉-4-基]-吡咯-2,5-二酮的晶型 | |
KR101316653B1 (ko) | 헤테로고리 화합물의 제조방법 | |
KR20090005206A (ko) | 순수한 리세드론산 또는 염의 제조 방법 | |
EP1888606A2 (de) | Verfahren und neues salz | |
CN1693308A (zh) | 唑来膦酸制备方法 | |
US20100317859A1 (en) | Process for the Preparation of Risedronate Sodium | |
JP3385208B2 (ja) | ヘテロ環ビス(フォスフォン酸)誘導体の新規製造法 | |
US7012150B2 (en) | Method of manufacturing bis(cyclopentadienly)ruthenium and bis(cyclopentadienyl)ruthenium manufactured by the same | |
JP3539152B2 (ja) | シトシンの製法 | |
JP2976493B2 (ja) | 塩素化ピラゾールカルボン酸誘導体の製造方法 |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
PUAI | Public reference made under article 153(3) epc to a published international application that has entered the european phase |
Free format text: ORIGINAL CODE: 0009012 |
|
AK | Designated contracting states |
Kind code of ref document: A2 Designated state(s): AT BE BG CH CY CZ DE DK EE ES FI FR GB GR HU IE IS IT LI LT LU LV MC NL PL PT RO SE SI SK TR |
|
AX | Request for extension of the european patent |
Extension state: AL BA HR MK RS |
|
R17D | Deferred search report published (corrected) |
Effective date: 20090416 |
|
RIC1 | Information provided on ipc code assigned before grant |
Ipc: C07F 9/38 20060101ALI20090518BHEP Ipc: A61K 31/675 20060101AFI20090518BHEP |
|
STAA | Information on the status of an ep patent application or granted ep patent |
Free format text: STATUS: THE APPLICATION IS DEEMED TO BE WITHDRAWN |
|
18D | Application deemed to be withdrawn |
Effective date: 20091017 |