EP1963345A2 - Processes for the preparation of pure zoledronic acid - Google Patents
Processes for the preparation of pure zoledronic acidInfo
- 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- Withdrawn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
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- 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)
Abstract
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. Specifically, the invention describes processes to prepare zoledronic acid from imidazol-1-yl acetic acid reacted with phosphorous acid followed by the addition of phosphorus trichloride or phosphorus oxychloride at temperatures below 80C in either an organic solvent or solventless system. The resulting zoledronic acid is tested for purity by HPLC.
Description
PROCESSES FOR THE PREPARATION OF PURE ZOLEDRONIC ACID
Field of the Invention [0001] 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.
Background of the Invention
[0002] Zoledronic acid, a bisphosphonic 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.
FORMULA I
[0003] 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. In general, the process involves the treatment of imidazol-1-yl acetic acid hydrochloride with phosphoric acid and phosphorous trichloride in chlorobenzene as solvent at 1000C. During the reaction, the reaction mass becomes very thick. This leads to incomplete reaction and results in a low overall yield and impure product.
[0004] 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.
[0005] US Application No. 2005/0054616 provides processes for the preparation of crystalline and amorphous forms of zoledronic acid. In general, 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. However, the product is not obtained in high purity.
Summary of the Invention [0006] The present inventors have noticed that 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 800C 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.
[0008] It also was observed by the present inventors that use of phosphorous trichloride is a safety hazard because of the presence of free phosphorous in commercially available phosphorous trichloride. This free phosphorous sublimes and settles at the top surface of the reaction vessel under the reaction conditions. During the aqueous work-up stage, this free phosphorous comes in contact with air and water whereby it ignites leading to generation of fire. This leads to hazardous consequences and therefore great care must be taken in order to prevent this.
[0009] While working on this problem, it was found by the present inventors that phosphorous oxychloride can be used in place of phosphorous trichloride without compromising on safety because commercially available phosphorous oxychloride (POCl3) does not contain free phosphorous. Additionally, the boiling point Of POCl3 is about 1050C, 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 0C or less to obtain a homogeneous solution; adding phosphorous trichloride at 80 0C or less; and isolating the zoledronic acid or salts thereof from the reaction mass thereof.
[0011] Embodiments of the process may include one or more of the following features. For example, 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.
[0014] In another 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 80 0C or less to obtain a homogeneous solution; adding phosphorous oxychloride at 80 0C or less; and isolating the zoledronic acid or salts thereof from the reaction mass thereof.
[0015] Embodiments of the process may include one or more of the following features. For example, 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.
[0016] In another aspect there is provided 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. [0017] The details of one or more embodiments of the inventions are set forth in the description below. Other features, objects and advantages of the inventions will be apparent from the description and claims.
Description of the Drawings
[0018] Figure 1 is an X-Ray Diffraction Pattern of zoledronic acid.
Detailed Description of the Invention
[0019] 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 800C or less to obtain a homogeneous solution;
(b) adding phosphorous trichloride at 800C or less; and
(c) isolating the zoledronic acid or salts thereof from the reaction mass thereof.
[0020] 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 8O0C. This reaction may be carried out in the absence of a solvent. Such reactions are normally termed as "neat reactions". Alternatively, 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. After completion of the reaction, the 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.
[0021] The product may be further or additionally dried to achieve the desired moisture values. For example, the product may be further or additionally dried in a tray drier, dried under vacuum and/or in a Fluid Bed Drier. [0022] 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%. [0023] A second aspect of the present invention provides a process for preparing zoledronic acid or salts thereof. The process includes the steps of:
(a) reacting imidazol-1-yl acetic acid or salt thereof with phosphorous acid at 800C or less to obtain a homogeneous solution;
(b) adding phosphorous oxychloride at 800C or less; and
(c) isolating the zoledronic acid or salts thereof from the reaction mass thereof.
[0024] Imidazole 1-yl acetic acid or salts thereof may be treated with phosphorous acid and mass may be heated to get a homogeneous solution. Phosphorous oxychloride may be added to this homogeneous solution under controlled rate of addition at a temperature less than 8O0C. This reaction may be carried out in the absence of a solvent. Such reactions are normally termed as "neat reactions". Alternatively, 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. After completion of the reaction, the 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. [0025] 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. The hydrolysis of imidazol-1-yl acetate in water gives imidazol-1-yl acetic acid. The alkyl haloacetate can be methyl chloroacetate or ethyl bromoacetate. [0026] 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.
[0027] The reaction of imidazole and alkyl haloacetate may be carried out in the presence of one or more suitable solvents. The term "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. For practical purpose, 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. The aqueous layer can be treated with activated carbon and concentrated under reduced pressure to get a residue, which upon addition of suitable anti-solvent such as methanol or isopropanol gives imidazol-1-yl acetic acid as solid. The solid can be filtered and dried suitably to get imidazol-1-yl acetic acid. [0029] 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.
In general, the solution of zoledronic acid may be obtained by dissolving zoledronic acid in water. Alternatively, such 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 0C to about reflux temperature of the solvent used, for example from about 30 0C to about 100 0C. 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. [0030] The term "obtaining" includes dissolving, slurrying, stirring or a combination thereof. [0031] 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. For example, the product may be further or additionally dried in a tray drier, dried under vacuum and/or in a Fluid Bed Drier. [0032] 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.
[0033] A fifth aspect of the present invention provides a pharmaceutical composition comprising as its active ingredient pure zoledronic acid or salts thereof having purity more than 99.7% by HPLC. With the active ingredient, 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.
[0034] The present invention is further illustrated by the following examples which are provided merely to be exemplary of the invention and do not limit the scope of the invention. Certain modifications and equivalents will be apparent to those skilled in the art and are intended to be included within the scope of the present invention. [0035] Example- 1 : Preparation of methyl imidazol-1-yl acetate
To a suspension of potassium carbonate (400 gm) and potassium iodide (5 gm) in dichloromethane (2 Lit), imidazole (100 gm) was added and the mixture was stirred vigorously. Methyl chloroacetate (205 gm) was added slowly and the mass was stirred further for 30 minutes followed by heating to reflux for 6-8 hours. The mass was cooled to ambient temperature and filtered. The residue was washed with dichloromethane (500 ml) and the washings were combined with the filtrate. The combined dichloromethane layers were distilled under reduced pressure to get methyl imidazole- 1-yl acetate. Yield: 235 gm [0036] 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. The solid obtained was washed with methanol (100 ml) and dried at 70- 8O0C to get imidazol-1-yl acetic acid. Yield: 158 gm [0037] Example- 3: Preparation of zoledronic acid
A mixture of imidazol-1-yl acetic acid (100 gm) and phosphorous acid (324 gm) was heated under stirring to about 60-800C to get a homogeneous solution. Phosphorous trichloride (324 gm) was added slowly at a temperature of about 750C to the homogeneous solution. The resultant mass was stirred for 6 hours and cooled. A solution of hydrochloric acid (9N, 465 ml) was added over 30 minutes and the entire mass was heated at 75-8O0C for about 12 hours, treated with activated carbon (3.8 gm) and filtered. Acetone (1200 ml) was added to the filtrate and the resultant mixture was cooled to 15-2O0C. After complete precipitation of the product, the mass was filtered and the wet cake was washed with acetone (300 ml) and dried at 50-6O0C to get zoledronic acid as a white crystalline solid. Yield: 161 gm
HPLC Purity: 99.92%
[0038] Example- 4: Purification of zoledronic acid
A mixture of zoledronic acid (100 gm) and water (2.4 Lit) was heated at a temperature of about 9O0C. The hot solution was treated with activated charcoal and filtered to remove charcoal. The filtrate was cooled to 5-100C under stirring and filtered. The wet cake was washed with water (100 ml) and dried at 50-600C to get white crystals of pure zoledronic acid.
Yield: 82 gm HPLC Purity: 99.99% [0039] Example-5: Preparation of zoledronic acid
A mixture of imidazol-1-yl acetic acid (100 gm) and phosphorous acid (324 gm) was heated under stirring to about 60-800C to get a homogeneous solution. Phosphorous oxychloride (364 gm) was added slowly at a temperature of about 750C to the homogeneous solution. The resultant mass was stirred for 5 hours and cooled. A solution of hydrochloric acid (9N, 465 ml) was added over 30 minutes and the entire mass was heated at 9O0C for about 12 hours, cooled and filtered. Acetone (1200 ml) was added to the filtrate and the resultant mixture was cooled to 15-2O0C. After complete precipitation of the product, the mass was filtered and the
wet cake was washed with acetone (300 ml) and dried at 50-600C to get crystals of zoledronic acid.
Yield: 170 gm
HPLC Purity: 99.92%
[0040] While the present invention has been described in terms of its specific embodiments, certain modifications and equivalents will be apparent to those skilled in the art and are intended to be included within the scope of the present invention.
Claims
CLAIMS:
We claim: L A process for the preparation of pure zoledronic acid or salts thereof having purity more than 99.7% by HPLC, the process comprising:
(a) reacting imidazol-1-yl acetic acid or salt thereof with phosphorous acid at 8O0C or less to obtain a homogeneous solution;
(b) adding phosphorous trichloride at 800C or less; and (c) isolating the zoledronic acid or salts thereof from the reaction mass thereof.
2. The process of claim 1 , wherein the phosphorous trichloride is added under a controlled rate of addition.
3. The process of claim 1 , wherein the reaction is carried out in the absence of a solvent.
4. The process of claim 1 , wherein the reaction is carried out in the presence of a solvent.
5. The process of claim 4, wherein the solvent comprises one or more of chlorobenzene, toluene, polyethylene glycol, silicon oil or mixtures thereof.
6. The process of claim 1 , wherein the product obtained is zoledronic acid monohydrate.
7. A process for the preparation of pure zoledronic acid or salts thereof having purity more than 99.7% by HPLC, the process comprising:
(a) reacting imidazol-1-yl acetic acid or salt thereof with phosphorous acid at 8O0C or less to obtain a homogeneous solution;
(b) adding phosphorous oxychloride at 800C or less; and
(c) isolating the zoledronic acid or salts thereof from the reaction mass thereof .
8. The process of claim 7, wherein the phosphorous oxychloride is added under a controlled rate of addition.
9. The process of claim 7, wherein the reaction is carried out in the absence of a solvent.
10. The process of claim 7, wherein the reaction is carried out in the presence of a solvent.
11. The process of claim 10, wherein the solvent comprises one or more of chlorobenzene, toluene, polyethylene glycol, silicon oil or mixtures thereof.
12. A process for the preparation of zoledronic acid or salts thereof, the process comprising:
(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.
13. The process of claim 12, wherein the alkyl haloacetate is methyl chloroacetate or ethyl bromoacetate.
14. The process of claim 12, wherein the reaction of imidazole and alkyl haloacetate is carried out in the presence of organic solvent comprising one or more of halogenated hydrocarbons, non-polar aprotic solvents, polar aprotic solvents, or mixtures thereof.
15. A process for the purification of zoledronic acid or salts thereof, the process comprising:
(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.
16. The process of claim 15, wherein removing the solvent comprises one or more of filtration, filtration under vacuum, decantation, centrifugation, distillation and distillation under vacuum.
17. The process of claim 15, wherein the pure zoledronic acid has the X-ray diffraction pattern of Figure 1.
18. Pure zoledronic acid or salts thereof having purity more than 99.7% by HPLC.
19. Pure zoledronic acid or salts thereof having purity more than 99.9% by HPLC.
20. A pharmaceutical composition comprising a therapeutically effective amount of the pure zoledronic acid or a salt thereof having purity more then 99.7% by HPLC; and one or more pharmaceutically acceptable carriers, excipients or diluents.
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 |
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| EP1963345A2 true EP1963345A2 (en) | 2008-09-03 |
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| 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 (en) | 2008-10-31 | 2013-03-29 | Politechnika Gdanska | Method of obtaining of [1-hydroxy-2-(1H-imidazole-1-yl)-ethylidene] bisphosphonic acid |
| AU2010278860B2 (en) | 2009-07-31 | 2016-05-26 | Thar Pharma, Llc | Crystallization method and bioavailability |
| US20160016982A1 (en) | 2009-07-31 | 2016-01-21 | Thar Pharmaceuticals, Inc. | Crystallization method and bioavailability |
| US9169279B2 (en) | 2009-07-31 | 2015-10-27 | Thar Pharmaceuticals, Inc. | Crystallization method and bioavailability |
| US9340565B2 (en) | 2010-11-24 | 2016-05-17 | Thar Pharmaceuticals, Inc. | Crystalline forms |
| CN102070668B (en) * | 2010-12-23 | 2013-07-24 | 蚌埠丰原医药科技发展有限公司 | Method for preparing zoledronic acid and sodium salt thereof by utilizing phase transfer catalyst |
| US10195218B2 (en) | 2016-05-31 | 2019-02-05 | Grunenthal Gmbh | Crystallization method and bioavailability |
| CN106699809A (en) * | 2016-12-07 | 2017-05-24 | 河北仁合益康药业有限公司 | Synthesis process of zoledronic acid |
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| US7038083B2 (en) * | 2002-05-17 | 2006-05-02 | Teva Pharmaceutical Industries, Ltd. | Process for making bisphosphonic acids using diluents other than halogenated hydrocarbons |
| DE602004019881D1 (en) * | 2003-07-03 | 2009-04-23 | Teva Pharma | CRYSTAL FORMS OF ZOLEDRONIC ACID AND THEIR NATRIOUS SALTS, AMORPHIC SODIUM ZOLEDRONATE AND PROCESS FOR THE PRODUCTION THEREOF |
| EP1716161B1 (en) * | 2003-12-23 | 2011-05-04 | Alchymars S.p.A. | Ibandronic acid monosodium salt in the amorphous form |
| WO2005063717A1 (en) * | 2003-12-26 | 2005-07-14 | Natco Pharma Limited | An improved process for the preparation of zoledronic acid |
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