WO2008044245A2 - A process for the preparation of risedronate sodium hemipentahydrate - Google Patents
A process for the preparation of risedronate sodium hemipentahydrate Download PDFInfo
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- WO2008044245A2 WO2008044245A2 PCT/IN2007/000470 IN2007000470W WO2008044245A2 WO 2008044245 A2 WO2008044245 A2 WO 2008044245A2 IN 2007000470 W IN2007000470 W IN 2007000470W WO 2008044245 A2 WO2008044245 A2 WO 2008044245A2
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- WIPO (PCT)
- Prior art keywords
- hemipentahydrate
- pyridyl
- preparation
- sodium
- risedronate sodium
- Prior art date
Links
- 238000000034 method Methods 0.000 title claims abstract description 21
- 238000002360 preparation method Methods 0.000 title claims abstract description 17
- 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 title abstract description 10
- 229940026199 risedronate sodium hemi-pentahydrate Drugs 0.000 title abstract description 10
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 20
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 16
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 16
- 239000002253 acid Substances 0.000 claims description 13
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 12
- MVPPADPHJFYWMZ-UHFFFAOYSA-N chlorobenzene Chemical compound ClC1=CC=CC=C1 MVPPADPHJFYWMZ-UHFFFAOYSA-N 0.000 claims description 12
- 239000013078 crystal Substances 0.000 claims description 9
- 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 7
- 239000000203 mixture Substances 0.000 claims description 7
- 239000011734 sodium Substances 0.000 claims description 7
- 229910052708 sodium Inorganic materials 0.000 claims description 7
- 239000007787 solid Substances 0.000 claims description 7
- WGNUNYPERJMVRM-UHFFFAOYSA-N 3-pyridylacetic acid Chemical compound OC(=O)CC1=CC=CN=C1 WGNUNYPERJMVRM-UHFFFAOYSA-N 0.000 claims description 6
- 229950007593 homonicotinic acid Drugs 0.000 claims description 6
- 239000003960 organic solvent Substances 0.000 claims description 6
- 239000011541 reaction mixture Substances 0.000 claims description 6
- ISIJQEHRDSCQIU-UHFFFAOYSA-N tert-butyl 2,7-diazaspiro[4.5]decane-7-carboxylate Chemical compound C1N(C(=O)OC(C)(C)C)CCCC11CNCC1 ISIJQEHRDSCQIU-UHFFFAOYSA-N 0.000 claims description 6
- 238000001816 cooling Methods 0.000 claims description 5
- XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 claims description 5
- 159000000000 sodium salts Chemical class 0.000 claims description 5
- 238000010899 nucleation Methods 0.000 claims description 4
- 230000003301 hydrolyzing effect Effects 0.000 claims description 3
- 239000002904 solvent Substances 0.000 abstract description 9
- IIDJRNMFWXDHID-UHFFFAOYSA-N Risedronic acid Chemical compound OP(=O)(O)C(P(O)(O)=O)(O)CC1=CC=CN=C1 IIDJRNMFWXDHID-UHFFFAOYSA-N 0.000 description 30
- 229960000759 risedronic acid Drugs 0.000 description 27
- 238000006243 chemical reaction Methods 0.000 description 9
- 210000000988 bone and bone Anatomy 0.000 description 8
- 229910052588 hydroxylapatite Inorganic materials 0.000 description 6
- XYJRXVWERLGGKC-UHFFFAOYSA-D pentacalcium;hydroxide;triphosphate Chemical compound [OH-].[Ca+2].[Ca+2].[Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O XYJRXVWERLGGKC-UHFFFAOYSA-D 0.000 description 6
- 208000001132 Osteoporosis Diseases 0.000 description 5
- 238000004519 manufacturing process Methods 0.000 description 4
- 238000010992 reflux Methods 0.000 description 4
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- 239000010410 layer Substances 0.000 description 3
- 150000004682 monohydrates Chemical class 0.000 description 3
- 210000002997 osteoclast Anatomy 0.000 description 3
- 239000000243 solution Substances 0.000 description 3
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 2
- 201000002980 Hyperparathyroidism Diseases 0.000 description 2
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 2
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 2
- 230000004097 bone metabolism Effects 0.000 description 2
- 239000011575 calcium Substances 0.000 description 2
- 229910052791 calcium Inorganic materials 0.000 description 2
- 150000001875 compounds Chemical class 0.000 description 2
- 238000011109 contamination Methods 0.000 description 2
- 238000002425 crystallisation Methods 0.000 description 2
- 230000008025 crystallization Effects 0.000 description 2
- 201000010099 disease Diseases 0.000 description 2
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 2
- 230000007062 hydrolysis Effects 0.000 description 2
- 238000006460 hydrolysis reaction Methods 0.000 description 2
- 238000010956 selective crystallization Methods 0.000 description 2
- 208000010392 Bone Fractures Diseases 0.000 description 1
- 208000006386 Bone Resorption Diseases 0.000 description 1
- DBVJJBKOTRCVKF-UHFFFAOYSA-N Etidronic acid Chemical compound OP(=O)(O)C(O)(C)P(O)(O)=O DBVJJBKOTRCVKF-UHFFFAOYSA-N 0.000 description 1
- 206010020584 Hypercalcaemia of malignancy Diseases 0.000 description 1
- 206010061218 Inflammation Diseases 0.000 description 1
- 206010029240 Neuritis Diseases 0.000 description 1
- 208000000491 Tendinopathy Diseases 0.000 description 1
- 206010043255 Tendonitis Diseases 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 229940037127 actonel Drugs 0.000 description 1
- 230000001476 alcoholic effect Effects 0.000 description 1
- 150000001298 alcohols Chemical class 0.000 description 1
- 150000001408 amides Chemical class 0.000 description 1
- 230000000123 anti-resoprtive effect Effects 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 206010003246 arthritis Diseases 0.000 description 1
- 230000024279 bone resorption Effects 0.000 description 1
- 230000003913 calcium metabolism Effects 0.000 description 1
- 230000001413 cellular effect Effects 0.000 description 1
- 238000012512 characterization method Methods 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 230000006866 deterioration Effects 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- 150000002170 ethers Chemical class 0.000 description 1
- 229940009626 etidronate Drugs 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- -1 hemipentahydrate Chemical compound 0.000 description 1
- 208000008750 humoral hypercalcemia of malignancy Diseases 0.000 description 1
- 230000004968 inflammatory condition Effects 0.000 description 1
- 230000004054 inflammatory process Effects 0.000 description 1
- 239000004615 ingredient Substances 0.000 description 1
- 229910052500 inorganic mineral Inorganic materials 0.000 description 1
- 238000002955 isolation Methods 0.000 description 1
- 150000002576 ketones Chemical class 0.000 description 1
- 210000003041 ligament Anatomy 0.000 description 1
- 239000011159 matrix material Substances 0.000 description 1
- 230000001404 mediated effect Effects 0.000 description 1
- 239000011707 mineral Substances 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 150000002825 nitriles Chemical class 0.000 description 1
- 230000006911 nucleation Effects 0.000 description 1
- 239000012044 organic layer Substances 0.000 description 1
- 238000010979 pH adjustment Methods 0.000 description 1
- WRUUGTRCQOWXEG-UHFFFAOYSA-N pamidronate Chemical compound NCCC(O)(P(O)(O)=O)P(O)(O)=O WRUUGTRCQOWXEG-UHFFFAOYSA-N 0.000 description 1
- 229940046231 pamidronate Drugs 0.000 description 1
- FAIAAWCVCHQXDN-UHFFFAOYSA-N phosphorus trichloride Chemical compound ClP(Cl)Cl FAIAAWCVCHQXDN-UHFFFAOYSA-N 0.000 description 1
- 238000000634 powder X-ray diffraction Methods 0.000 description 1
- 229940089617 risedronate Drugs 0.000 description 1
- 238000013341 scale-up Methods 0.000 description 1
- 239000012056 semi-solid material Substances 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 201000004415 tendinitis Diseases 0.000 description 1
- 210000002435 tendon Anatomy 0.000 description 1
- 210000001519 tissue Anatomy 0.000 description 1
- 230000036325 urinary excretion Effects 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
- C07F9/553—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having one nitrogen atom as the only ring hetero atom
- C07F9/576—Six-membered rings
- C07F9/58—Pyridine rings
Definitions
- This invention in general, relates to a process for preparing 3-pyridyl-l- hydroxyethylidine-l,l-bisphosphonic acid sodium hemipentahydrate (Risedronate sodium hemipentahydrate). More specifically, but without restriction to the particular embodiment herein after described in accordance with the best mode of practice, the present invention provides a novel process for preparation of Risedronate sodium hemipentahydrate employing a novel crystallizing solvent system.
- Risedronate sodium (3-pyridyl-l-hydroxyethylidene-l,l-biphosphonic acid mono sodium salt), the subject of present invention under the trade name Actonel ® is used for the treatment of osteoporosis.
- the chemical structure of Risedronate sodium is the following:
- Biphosphonates such as 3-pyridyl-l-hydroxyethylidene-l,l-biphosphonic acid (Risedronate) are therapeutically used in the treatment of diseases of bone and calcium metabolism.
- diseases include osteoporosis, hyperparathyroidism, hypercalcemia of malignancy, arthritis, neuritis, tendonitis and other inflammatory conditions.
- Risedronate sodium inhibits osteoclast-mediated bone resorption and modulates bone metabolism.
- Risedronate sodium has an affinity for hydroxyapatite crystals in bone and acts as an antiresorptive agent (Hydroxyapatite is the major component, and an essential ingredient, of normal bone and teeth. It is hydroxyapatite that makes up bone mineral and the matrix of teeth. Hydroxyapatite molecules can group together (crystallize) to form microscopic clumps, called hydroxyapatite crystals. Tiny crystals of hydroxyapatite sometimes form in or around joints and can cause inflammation of joints and tissues around the joints, such as tendons and ligaments). At the cellular level, risedronate sodium inhibits osteoclasts. The osteoclasts adhere normally to the bone surface, but show evidence of reduced active resorption (e.g.
- Osteoporosis is also characterized by low bone mass and architectural deterioration of bone tissue leading to enhanced bone fragility and increase in the risk of bone fracture.
- Biphosphonates treatment is to achieve the goal in the treatment of osteoporosis and is to improve calcium absorption and decrease urinary excretion of calcium thus reversing hyperparathyroidism.
- Other biphosphonates are etidronate and pamidronate which are also useful in treating osteoporosis.
- US Patent No. 6,410,520 discloses the polymorphic forms of risedronate sodium i.e. hemipentahydrate, monohydrate and anhydrous form.
- hemipentahydrate and monohydrate is prepared by selective crystallization. The characterization data for these forms are not reported in the said patent.
- the patent also discloses selective crystallization of mono and hemipentahydrates by heating an aqueous solution of Risedronate sodium from about 45-75 0 C and crystallization of product by the addition of isopropanol and cooling the reaction mixture with different ramp.
- US Patent Application No. 20030195170 discloses various crystalline forms e.g. B, C, D, E, F, G and H of risedronate sodium and methods for their preparation.
- the patent discloses PXRD, TGA and IR of various forms of Risedronate sodium prepared by different ratio of alcoholic solvents in water.
- PCT Application No. WO 2005012314 discloses a process for controlling the crystal form of risedronate sodium hemipentahydrate. The process employs a pH adjustment step to induce the proper hydrate form and thereby avoiding inadvertent nucleation of undesired hydrate forms.
- PCT Application No. WO 2006051553 discloses a process for the preparation of risedronate sodium Form A (hemipentahydrate) and Form B (monohydrate) using the organic solvents selected from the group comprising alcohols, amides, esters, ethers, ketones or nitriles by employing in appropriate ratio.
- the present invention discloses a convenient, industrially feasible and efficient process for the preparation of pure polymorphic form of risedronate sodium i.e. hemipentahydrate without the contamination of other forms.
- the process comprises of selecting the suitable solvent system for obtaining the polymorphic form of risedronate sodium.
- a novel process for preparing a pure form of polymorph of 3 -pyridyl-1 -hydroxyethylidine- 1,1 -bisphosphonic acid sodium salt comprising of treating 3-pyridyl acetic acid with phosphorous acid and phosphorous oxychloride in the presence of a solvent such as chlorobenzene, hydrolyzing the same using water, followed by acetone addition and collecting the solid as Risedronic acid and suspending the solid Risedronic acid in water and dimethylsulfoxide mixture and adding sodium base into the same to obtain the pure polymorphic form of risedronate sodium.
- the present invention describes a convenient, industrially feasible and efficient process for the preparation of polymorphic form of monosodium salt of Risedronic acid, without the contamination of other forms.
- the present invention provides the process for the preparation of polymorphic form of risedronate sodium specifically hemipentahydrate by treating the 3-pyridyl acetic acid with phosphorous acid and phosphorous oxychloride in the presence of a solvent such as chlorobenzene, hydrolyzing the same using water, followed by acetone addition and collecting the solid as Risedronic acid, further followed by preparation of sodium salt in mixture of water and water miscible solvent and then isolation from it at room temperature to reflux temperature.
- a solvent such as chlorobenzene
- risedronate sodium is also a preferred mode of the present invention, wherein the process comprises the step of stirring a combination of Risedronic acid, a sodium base in water and a water miscible solvent preferably dimethylsulfoxide at room temperature to reflux temperature preferably 25-75 0 C optionally seeding with the crystalline risedronate sodium hemipentahydrate.
- the present invention describes the preparation of Risedronoic acid by reacting 3-pyridyl acetic acid with phosphorous acid in chlorobenzene and phosphorous oxychloride at about 80-95 0 C for 2hrs followed by hydrolysis with water.
- the aqueous and organic layers are separated and aqueous layer is heated to reflux for 10 hrs and cooled to about 20-30 0 C, followed by the addition of acetone to get crystalline compound of Risedronoic acid.
- the compound is filtered and washed with water followed by acetone.
- the crystalline Risedronic acid is taken in a mixture of water and DMSO at ambient temperature and heated to about 55 to 75 0 C followed by the slow addition of sodium hydroxide solution and maintained for lhr. Cooled the reaction mass to 40-50 0 C, and the reaction mixture is optionally seeded with the crystals of risedronate sodium hemipentahydrate and the reaction is maintained for lhr. Reaction mass is cooled to 0-5 C and maintained for 3 hrs to get the pure crystalline Risedronate Sodium hemipentahydrate.
- 3-Pyridyl acetic acid (100.0 gm) was taken in chlorobenzene (720.0 ml) and phosphorous acid (209.0 gm) was added at 25-30 0 C and maintained at this temperature for 5 min. Heated the reaction mass to 80-85 0 C and followed by the addition of phosphorous oxychloride (203.7 ml, 335.09 gm) in 3 hrs. Temperature was raised to 90-95 0 C and maintained for 2 hrs. The reaction mass was cooled to 60-65 0 C and water (720 ml) was added followed by further cooling to 25-30 0 C.
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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)
- Pyridine Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
- Hydrogenated Pyridines (AREA)
Abstract
The present invention provides an improved process for the preparation of Risedronate sodium hemipentahydrate by employing novel solvent system.
Description
A Process for the preparation of Risedronate Sodium hemipentahydrate
Field of the Invention
This invention, in general, relates to a process for preparing 3-pyridyl-l- hydroxyethylidine-l,l-bisphosphonic acid sodium hemipentahydrate (Risedronate sodium hemipentahydrate). More specifically, but without restriction to the particular embodiment herein after described in accordance with the best mode of practice, the present invention provides a novel process for preparation of Risedronate sodium hemipentahydrate employing a novel crystallizing solvent system.
Background of the Invention
Risedronate sodium (3-pyridyl-l-hydroxyethylidene-l,l-biphosphonic acid mono sodium salt), the subject of present invention under the trade name Actonel® is used for the treatment of osteoporosis. The chemical structure of Risedronate sodium is the following:
Biphosphonates such as 3-pyridyl-l-hydroxyethylidene-l,l-biphosphonic acid (Risedronate) are therapeutically used in the treatment of diseases of bone and calcium metabolism. Such diseases include osteoporosis, hyperparathyroidism, hypercalcemia of malignancy, arthritis, neuritis, tendonitis and other inflammatory conditions. Risedronate sodium inhibits osteoclast-mediated bone resorption and modulates bone metabolism.
Risedronate sodium has an affinity for hydroxyapatite crystals in bone and acts as an antiresorptive agent (Hydroxyapatite is the major component, and an essential ingredient, of normal bone and teeth. It is hydroxyapatite that makes up bone mineral and the matrix of teeth. Hydroxyapatite molecules can group together (crystallize) to form microscopic clumps, called hydroxyapatite crystals. Tiny crystals of hydroxyapatite sometimes form in or around joints and can cause inflammation of joints and tissues around the joints, such as tendons and ligaments).
At the cellular level, risedronate sodium inhibits osteoclasts. The osteoclasts adhere normally to the bone surface, but show evidence of reduced active resorption (e.g. lack of ruffled border). Osteoporosis is also characterized by low bone mass and architectural deterioration of bone tissue leading to enhanced bone fragility and increase in the risk of bone fracture. Biphosphonates treatment is to achieve the goal in the treatment of osteoporosis and is to improve calcium absorption and decrease urinary excretion of calcium thus reversing hyperparathyroidism. Other biphosphonates are etidronate and pamidronate which are also useful in treating osteoporosis.
US Patent No. 5,583,122 describe the preparation of risedronic acid by reaction of 3- pyridyl acetic acid with phosphorous acid and phosphorous trichloride in chlorobenzene to obtain the oily to viscous semi solid material which on hydrolysis in presence of water followed by the crystallization of product by adding methanol to obtain only 52% yield. This process is complicated, as the reaction mixture being in semi solid form, which creates difficulty in safe scale up.
US Patent No. 6,410,520 discloses the polymorphic forms of risedronate sodium i.e. hemipentahydrate, monohydrate and anhydrous form. In this patent hemipentahydrate and monohydrate is prepared by selective crystallization. The characterization data for these forms are not reported in the said patent. The patent also discloses selective crystallization of mono and hemipentahydrates by heating an aqueous solution of Risedronate sodium from about 45-750C and crystallization of product by the addition of isopropanol and cooling the reaction mixture with different ramp.
US Patent Application No. 20030195170 discloses various crystalline forms e.g. B, C, D, E, F, G and H of risedronate sodium and methods for their preparation. The patent discloses PXRD, TGA and IR of various forms of Risedronate sodium prepared by different ratio of alcoholic solvents in water.
PCT Application No. WO 2005012314 discloses a process for controlling the crystal form of risedronate sodium hemipentahydrate. The process employs a pH adjustment step to induce the proper hydrate form and thereby avoiding inadvertent nucleation of undesired hydrate forms.
PCT Application No. WO 2006051553 discloses a process for the preparation of risedronate sodium Form A (hemipentahydrate) and Form B (monohydrate) using the organic solvents selected from the group comprising alcohols, amides, esters, ethers, ketones or nitriles by employing in appropriate ratio.
The present invention discloses a convenient, industrially feasible and efficient process for the preparation of pure polymorphic form of risedronate sodium i.e. hemipentahydrate without the contamination of other forms.
Summary of the Invention
In accordance with the principal aspect of the present invention, there is provided a novel process for preparing a pure form of risedronate sodium to improve upon limitations in the prior art. The process comprises of selecting the suitable solvent system for obtaining the polymorphic form of risedronate sodium.
In accordance with another aspect of the present invention, there is provided a novel process for preparing pure polymorphic form of 3 -pyridyl-1 -hydroxy ethylidene- 1,1- bisphosphonic acid sodium salt (Risedronate sodium), in particular to prepare the polymorphic form hemipentahydrate employing novel solvent system comprising a mixture of organic solvent such as dimethylsulfoxide with water.
In accordance with still another aspect, there is provided a novel process for preparing a pure form of polymorph of 3 -pyridyl-1 -hydroxyethylidine- 1,1 -bisphosphonic acid sodium salt (Risedronate sodium), wherein the process comprises of treating 3-pyridyl acetic acid with phosphorous acid and phosphorous oxychloride in the presence of a solvent such as chlorobenzene, hydrolyzing the same using water, followed by acetone addition and collecting the solid as Risedronic acid and suspending the solid Risedronic acid in water and dimethylsulfoxide mixture and adding sodium base into the same to obtain the pure polymorphic form of risedronate sodium.
Detailed Description of the Invention
The present invention describes a convenient, industrially feasible and efficient process for the preparation of polymorphic form of monosodium salt of Risedronic acid, without the contamination of other forms.
The present invention provides the process for the preparation of polymorphic form of risedronate sodium specifically hemipentahydrate by treating the 3-pyridyl acetic acid with phosphorous acid and phosphorous oxychloride in the presence of a solvent such as chlorobenzene, hydrolyzing the same using water, followed by acetone addition and collecting the solid as Risedronic acid, further followed by preparation of sodium salt in mixture of water and water miscible solvent and then isolation from it at room temperature to reflux temperature.
The preparation of risedronate sodium described herein is also a preferred mode of the present invention, wherein the process comprises the step of stirring a combination of Risedronic acid, a sodium base in water and a water miscible solvent preferably dimethylsulfoxide at room temperature to reflux temperature preferably 25-750C optionally seeding with the crystalline risedronate sodium hemipentahydrate.
The present invention describes the preparation of Risedronoic acid by reacting 3-pyridyl acetic acid with phosphorous acid in chlorobenzene and phosphorous oxychloride at about 80-950C for 2hrs followed by hydrolysis with water. The aqueous and organic layers are separated and aqueous layer is heated to reflux for 10 hrs and cooled to about 20-300C, followed by the addition of acetone to get crystalline compound of Risedronoic acid. The compound is filtered and washed with water followed by acetone.
The crystalline Risedronic acid is taken in a mixture of water and DMSO at ambient temperature and heated to about 55 to 750C followed by the slow addition of sodium hydroxide solution and maintained for lhr. Cooled the reaction mass to 40-500C, and the reaction mixture is optionally seeded with the crystals of risedronate sodium hemipentahydrate and the reaction is maintained for lhr. Reaction mass is cooled to 0-5 C and maintained for 3 hrs to get the pure crystalline Risedronate Sodium hemipentahydrate.
The examples mentioned below explain all the aspects of the present invention. The examples are given to illustrate the details of the invention and should not be construed to limit the scope of the present invention.
Example 1
Preparation of Risedronic acid
3-Pyridyl acetic acid (100.0 gm) was taken in chlorobenzene (720.0 ml) and phosphorous acid (209.0 gm) was added at 25-300C and maintained at this temperature for 5 min. Heated the reaction mass to 80-850C and followed by the addition of phosphorous oxychloride (203.7 ml, 335.09 gm) in 3 hrs. Temperature was raised to 90-950C and maintained for 2 hrs. The reaction mass was cooled to 60-650C and water (720 ml) was added followed by further cooling to 25-300C. Both the layers were separated and the aqueous layer was heated to reflux for lOhrs followed by cooling to 25-350C and then acetone (600 ml) was added. The reaction mass was maintained for 2hrs to get crystalline Risedronoic acid. Filtered the crystals and washed with DM water (1330 ml) .Washed the wet cake with acetone (100 ml) and dried.
Example 2 Preparation of Risedronate Sodium hemipentahydrate
Risedronic acid (100.0 gm) was taken in a mixture of DM water (500 ml) and DMSO (25.0 ml) at 25-350C and heated the solution to 60-700C. Aqueous NaOH solution (1.41 gm in 30 ml of water) was added slowly and maintained for lhr. The reaction mass was filtered and cooled to 40-500C. The reaction mass was seeded with the crystals of hemipentahydrate (1.0 gm) and maintained for lhr. The reaction mixture was further cooled to 0-50C and maintained for 3hrs. Filtered and washed the product with acetone (100 ml). Dried the wet product for 6hrs below 500C.
Certain modifications and improvements of the disclosed invention will occur to those skilled in the art without departing from the scope of invention, which is limited only by the appended claims.
Claims
1. A process for the preparation of 3 -pyridyl- 1 -hydroxyethylidine- 1 , 1 -bisphosphonic acid sodium salt hemipentahydrate comprising:
(a) taking 3 -pyridyl- 1 -hydroxyethylidine- 1,1 -bisphosphonic acid in a mixture of water and organic solvent;
(b) adding a sodium base to the resulting solution;
(c) optionally seeding with the hemipentahydrate crystals;
(d) cooling the resultant solution to 0-50C; and
(e) isolating the resultant solid.
2. The process according to claim 1, organic solvent used herein is dimethylsulfoxide.
3. The process according to claim 1, wherein sodium base used is sodium hydroxide.
4. A process for the preparation of 3 -pyridyl- 1 -hydroxyethylidine- 1,1 -bisphosphonic acid sodium salt hemipentahydrate comprising:
(a) reacting 3-pyridyl acetic acid with phosphorous acid in presence of phosphorous oxychloride and chlorobenzene; (b) hydrolyzing the reaction mixture with water;
(c) adding acetone to the reaction mixture to get 3 -pyridyl- 1 - hydroxyethylidine- 1,1 -bisphosphonic acid as a solid; . (d) taking 3 -pyridyl- 1 -hydroxyethylidine- 1,1 -bisphosphonic acid in a mixture of water and organic solvent; (e) adding a sodium base to the resulting solution;
(f) optionally seeding with the hemipentahydrate crystals;
(g) cooling the resultant solution to 0-50C; and (h) isolating the resultant solid.
5. The process according to claim 4, organic solvent used herein is dimethylsulfoxide.
6. The process according to claim 4, wherein sodium base used is sodium hydroxide.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| IN1870CH2006 | 2006-10-10 | ||
| IN1870/CHE/2006 | 2006-10-10 |
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| Publication Number | Publication Date |
|---|---|
| WO2008044245A2 true WO2008044245A2 (en) | 2008-04-17 |
| WO2008044245A3 WO2008044245A3 (en) | 2008-10-16 |
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| PCT/IN2007/000470 WO2008044245A2 (en) | 2006-10-10 | 2007-10-09 | A process for the preparation of risedronate sodium hemipentahydrate |
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| WO (1) | WO2008044245A2 (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
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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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| WO2001056983A2 (en) * | 2000-02-01 | 2001-08-09 | The Procter & Gamble Company | Selective crystallization of 3-pyridyl-1-hydroxyethylidene-1,1-bisphosphonic acid sodium as the hemipentahydrate or monohydrate |
| WO2003097655A1 (en) * | 2002-05-17 | 2003-11-27 | Teva Pharmaceutical Industries Ltd. | Use of certain diluents for making bisphosphonic acids |
| US20050026869A1 (en) * | 2003-07-30 | 2005-02-03 | The Procter & Gamble Company | Process for controlling crystal structure of risedronate |
| WO2006071128A1 (en) * | 2004-12-28 | 2006-07-06 | Zaklady Farmaceutyczne Polpharma S.A. | Process for the preparation of [1-hydroxy-2-(3-pyridinyl)ethyliden] bisphosphonic acid and hemi-pentahydrate monosodium salt thereof |
| EP1775302A1 (en) * | 2005-10-11 | 2007-04-18 | Sandoz A/S | Method for preparing crystalline sodium risedronate |
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| CA2590046A1 (en) * | 2004-11-09 | 2006-05-18 | Jubilant Organosys Limited | Process for preparing a pure polymorphic form of 3-pyridyl-1-hydroxyethylidine-1,1-bisphosphonic acid sodium salt |
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| WO2001056983A2 (en) * | 2000-02-01 | 2001-08-09 | The Procter & Gamble Company | Selective crystallization of 3-pyridyl-1-hydroxyethylidene-1,1-bisphosphonic acid sodium as the hemipentahydrate or monohydrate |
| US20020002282A1 (en) * | 2000-02-01 | 2002-01-03 | Cazer Frederick Dana | Selective crystallization of 3-pyridyl-1-hydroxyethylidene-1,1-bisphosphonic acid sodium as the hemipentahydrate or monohydrate |
| WO2003097655A1 (en) * | 2002-05-17 | 2003-11-27 | Teva Pharmaceutical Industries Ltd. | Use of certain diluents for making bisphosphonic acids |
| US20050026869A1 (en) * | 2003-07-30 | 2005-02-03 | The Procter & Gamble Company | Process for controlling crystal structure of risedronate |
| WO2006071128A1 (en) * | 2004-12-28 | 2006-07-06 | Zaklady Farmaceutyczne Polpharma S.A. | Process for the preparation of [1-hydroxy-2-(3-pyridinyl)ethyliden] bisphosphonic acid and hemi-pentahydrate monosodium salt thereof |
| EP1775302A1 (en) * | 2005-10-11 | 2007-04-18 | Sandoz A/S | Method for preparing crystalline sodium risedronate |
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| Publication number | Priority date | Publication date | Assignee | Title |
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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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| WO2008044245A3 (en) | 2008-10-16 |
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