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WO2009034580A1 - Procédé amélioré de préparation de risédronate monosodique hémipentahydraté - Google Patents

Procédé amélioré de préparation de risédronate monosodique hémipentahydraté Download PDF

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Publication number
WO2009034580A1
WO2009034580A1 PCT/IN2007/000601 IN2007000601W WO2009034580A1 WO 2009034580 A1 WO2009034580 A1 WO 2009034580A1 IN 2007000601 W IN2007000601 W IN 2007000601W WO 2009034580 A1 WO2009034580 A1 WO 2009034580A1
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WO
WIPO (PCT)
Prior art keywords
acid
hours
hemipentahydrate
pyridyl
heating
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.)
Ceased
Application number
PCT/IN2007/000601
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English (en)
Inventor
Ravishankar Balasubramaniam
Pulla Rao Polsani
Gowri Naidu Tammireddy
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
FLEMING LABORATORIES Ltd
Original Assignee
FLEMING LABORATORIES Ltd
Priority date (The priority date 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 date listed.)
Filing date
Publication date
Application filed by FLEMING LABORATORIES Ltd filed Critical FLEMING LABORATORIES Ltd
Publication of WO2009034580A1 publication Critical patent/WO2009034580A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
    • A61L27/50—Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
    • A61L27/60—Materials for use in artificial skin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L15/00—Chemical aspects of, or use of materials for, bandages, dressings or absorbent pads
    • A61L15/16—Bandages, dressings or absorbent pads for physiological fluids such as urine or blood, e.g. sanitary towels, tampons
    • A61L15/22—Bandages, dressings or absorbent pads for physiological fluids such as urine or blood, e.g. sanitary towels, tampons containing macromolecular materials
    • A61L15/26—Macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds; Derivatives thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L15/00—Chemical aspects of, or use of materials for, bandages, dressings or absorbent pads
    • A61L15/16—Bandages, dressings or absorbent pads for physiological fluids such as urine or blood, e.g. sanitary towels, tampons
    • A61L15/40—Bandages, dressings or absorbent pads for physiological fluids such as urine or blood, e.g. sanitary towels, tampons containing ingredients of undetermined constitution or reaction products thereof, e.g. plant or animal extracts
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
    • A61L27/14—Macromolecular materials
    • A61L27/18—Macromolecular materials obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
    • A61L27/36—Materials for grafts or prostheses or for coating grafts or prostheses containing ingredients of undetermined constitution or reaction products thereof, e.g. transplant tissue, natural bone, extracellular matrix
    • A61L27/38—Materials for grafts or prostheses or for coating grafts or prostheses containing ingredients of undetermined constitution or reaction products thereof, e.g. transplant tissue, natural bone, extracellular matrix containing added animal cells

Definitions

  • the present invention is directed to an improved, safe and industrially viable process for manufacturing of Risedronic acid (3-pyridyl-l-hydroxyethylidene-l,l-bisphosphonic acid) in the absence of organic solvents.
  • the further aspect of the invention is to provide a cost-effective process for preparation of substantially pure Risedronate sodium hemipentahydrate (3-pyridyl-l- hydroxyethylidene-l,l-bisphosphonic acid sodium hemipentahydrate) in the absence of organic solvents.
  • Osteoporosis is a disease characterized by a progressive loss of bone mineral.
  • 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 fracture.
  • the goal of therapy in treatment of osteoporosis is to improve calcium absorption and decrease urinary excretion of calcium thus reversing secondary hyperparathyroidism.
  • the bisphosphonates for example etidronate, pamidronate, and Risedronate are useful in treating osteoporosis.
  • Risedronate sodium ([l-hydroxy-2(3-pyridinyl)ethylidene]bisphosphonic acid monosodium) salt is marketed under the trade name - Actonel(R) for treatment of osteoporosis.
  • US6410520 discloses selective crystallization of Risedronate sodium as a monohydrate or hemipentahydrate (pseudopolymorphs).
  • the monohydrate and the hemipentahydrate are hydrated forms and the hemipentahydrate is thermodynamically preferred crystalline form.
  • 3-pyridyl-l-hydroxyethylidene-l,l-bisphosphonic acid was reacted with sodium hydroxide in isopropanol and water mixture to give 3-pyridyl-l-hydroxyethylidene-l,l- bisphosphonic acid sodium hemipentahydrate.
  • WO2007042048 discloses a process for selective crystallisation of monosodium Risedronate monohydrate or monosodium Risedronate hemipentahydrate. And the process comprises as follows: Risedronic acid or Risedronic acid monohydrate is treated with sodium in an alcohol (methanol/ethanol) to give Risedronate sodium hemihydrate, which is further treated with excess water to give Risedronate sodium hemipentahydrate.
  • WO2007083243 discloses a process of preparation of the Risedronate sodium hemipentahydrate. The process comprises, converting Risedronic acid into an organic amine salt and the resulting salt was reacted with a base (which is capable of giving sodium ion) in a mixture of water and methanol to give Risedronate sodium hemipentahydrate.
  • WO2005012314 discloses a process for controlling the crystal structure of sodium
  • EPl 86405 (US5583122) describes the preparation of isomer of Risedronic acid by reaction of 2-pyridyl acetic acid with phosphorous acid and phosphorous trichloride in chlorobenzene.
  • EP 1243592 discloses the process of preparation of the Risedronic acid by treating the 3- ⁇ yridylacetic acid or its hydrochloride salt with phosphorous acid, phosphorus trichloride in chlorobenzene or fluorobenzene as a solvent.
  • WO2005044831 discloses the process of preparation of bisphosphonic acid [Risedronic acid] by treating with corresponding carboxylic acid or its hydrochloride salt [3- pyridylacetic acid or its hydrochloride] with phosphorous acid, phosphorous trichloride in sulfolane solvent.
  • carboxylic acid or its hydrochloride salt [3- pyridylacetic acid or its hydrochloride]
  • phosphorous acid, phosphorous trichloride in sulfolane solvent.
  • the main objective of the present invention is to provide a safe and an improved process for the preparation of Risedronic acid in high yield without using any organic solvent, which would be easy to implement on a commercial scale production.
  • the other objective of the present invention is to provide a process for the preparation of sodium Risedronate hemipentahydrate in high yield and high purity without using any organic solvent.
  • A) PREPARATION OF RISEDRONIC ACID (II) a) addition of 3- ⁇ yridyl acetic acid of Formula-I to phosphorous acid in the absence of any organic solvent, b) addition of phosphorous trichloride to the above reaction mixture at a temperature of about 6O 0 C to about 65 0 C, c) heating the reaction mixture at about 7O 0 C to about 75 0 C for about 7 to 9 hours, d) cooling the reaction mixture to 50-60 0 C and removal of unreacted phosphorous trichloride under vacuum, e) addition of water to the reaction mixture and heating to about 9O 0 C to about 95 0 C for about 5 to 7 hours, f) cooling the reaction mixture to about 25 0 C to about 35 0 C, whereby Risedronic acid precipitates as a crystalline white powder, g) isolating the solid material by filtration and dried to give pure crystalline Risedronic acid of Formula-II.
  • the process of the present invention is characterized by two stages, first stage provides the preparation of Risedronic acid and second stage provides the preparation of Risedronate sodium hemipentahydrate.
  • the present invention provides an improved and cost effective process for the preparation of Risedronic acid (3-pyridyl-l-hydroxyethylidene-l,l-bisphosphonic acid) and Risedronate sodiumhemipentahydrate (3-pyridyl-l-hydroxyethylidene-l,l-bisphosphonic acid sodium hemipentahydrate) in the absence of organic solvents.
  • the first stage of the process comprises, reacting 3-pyridylacetic acid with phosphorous acid and phosphorous trichloride and followed by hydrolysis in water. Initially the reaction mixture of 3-pyridylacetic acid and phosphorous acid is heated to about 55 0 C to about 7O 0 C, more preferably from 6O 0 C to 65 0 C.
  • Phosphorous trichloride is added to the above mixture slowly at about 6O 0 C to about 65 0 C. After complete addition of phosphorous trichloride, the reaction mixture is heated to the temperature range from about 7O 0 C to about 75 0 C and maintained for a period of 7 to 9 hours at the same temperature, more preferably 8 hours to provide a good conversion. Reaction mixture is cooled to the temperature range from about 5O 0 C to about 6O 0 C more preferably to 55 0 C and vacuum is applied to remove the unreacted phosphorous trichloride. Water is added to the reaction mass and temperature is raised to about 9O 0 C to about 95 0 C and maintained for 5 to 7 hours more preferably for six hours.
  • the process comprises conversion of Risedronic acid to Risedronate sodium hemipentahydrate by reaction with sodium hydroxide in aqueous medium followed by adjusting the pH with acetic acid.
  • Risedronic acid prepared in first stage is reacted with a base, which is capable of giving sodium ions more specifically sodium hydroxide (NaOH) to adjust the pH to about 6.5 to about 7.0, more preferably to 6.7 in aqueous medium at about 25 0 C to about 35 0 C.
  • Activated carbon is added to the solution and filtered through filter aid bed.
  • pH is adjusted to about 4.0 to about 5.0, more preferably to 4.6 with an acid more preferably with acetic acid at about 25 0 C to about 35 0 C.
  • Crystalline solid of Risedronate sodium hemipentahydrate (3-pyridyl-l-hydroxyethylidene-l,l-bisphosphonic acid sodium hemipentahydrate) is precipitated on stirring for about 3 to about 5 hours more specifically for 4 hours. Isolated the material by known art and dried at about 4O 0 C to about 5O 0 C, more preferably at about 45 0 C to furnish pure crystalline Risedronate sodium hemipentahydrate.
  • 3-pyridylacetic acid hydrochloride 100 gm, 0.576 moles
  • phosphorous acid 103.97 gm, 1.267 moles
  • the reaction mixture was heated to 6O 0 C to 65 0 C and at this temperature phosphorous trichloride (198.12 gm, 1.44 moles) was added slowly in one hour to the reaction mixture. Then the reaction mixture was heated to 7O 0 C to 75 0 C and maintained for 8 hours at the same temperature.
  • Reaction mixture was cooled to 55 0 C and the unreacted phosphorous trichloride was distilled at 5O 0 C to 55 0 C under vacuum.
  • Water (725 ml) was added to the reaction mixture and heated at 9O 0 C to 95 0 C for six hours.
  • Reaction mass was cooled to ambient temperature (25 0 C to 3O 0 C) and stirred for 2 hrs.
  • Product is separated as crystalline solid, which was filtered, and dried at 43 0 C to 45 0 C under vacuum.
  • 3-pyridyl-l-hydroxyethylidene-l,l-bisphosphonic acid (130 gm) prepared in the example- 1 was taken in a four necked round bottom flask and water(520ml) was added to it. The mixture was stirred for ten minutes at ambient temperature (25 0 C to 3O 0 C) and pH was adjusted to 6.7 with 40% aqueous sodium hydroxide (NaOH) to get a clear solution. Activated carbon (5 gm) was added to the solution and stirred for fifteen minutes. Filtered the carbon on filter aid bed and washed with water (10 ml). The clear filtrate was taken in a beaker and pH was adjusted to 4.6 with the addition of acetic acid.
  • the product was formed as white crystalline solid on slow stirring for four hours at ambient temperature (25 0 C to 3O 0 C).
  • the product was filtered, washed with water (10 ml) and dried at 40-45 0 C to get pure Risedronate sodium hemipentahydrate (3- ⁇ yridyl-l-hydroxyethylidene-l,l-bisphosphonic acid sodium hemipentahydrate) Yield : 130 gms (80.90%)

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Epidemiology (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Engineering & Computer Science (AREA)
  • Transplantation (AREA)
  • Oral & Maxillofacial Surgery (AREA)
  • Medicinal Chemistry (AREA)
  • Dermatology (AREA)
  • Biomedical Technology (AREA)
  • Zoology (AREA)
  • Botany (AREA)
  • Hematology (AREA)
  • Materials Engineering (AREA)
  • Cell Biology (AREA)

Abstract

L'invention porte sur le procédé de préparation d'acide risédronique et de risédronate monosodique hémipentahydraté en l'absence de solvants organiques. Le procédé consiste à faire réagir l'acide 3-pyridyl acétique avec de l'acide phosphoreux et du trichlorure de phosphore pour donner de l'acide risédronique qui est ensuite amené à réagir avec de l'hydroxyde de sodium dans un milieu aqueux pour donner du risédronate monosodique hémipentahydraté.
PCT/IN2007/000601 2007-09-11 2007-12-20 Procédé amélioré de préparation de risédronate monosodique hémipentahydraté Ceased WO2009034580A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
IN2029CH2007 2007-09-11
IN2029/CHE/2007 2007-09-11

Publications (1)

Publication Number Publication Date
WO2009034580A1 true WO2009034580A1 (fr) 2009-03-19

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Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/IN2007/000601 Ceased WO2009034580A1 (fr) 2007-09-11 2007-12-20 Procédé amélioré de préparation de risédronate monosodique hémipentahydraté

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8076483B2 (en) 2006-05-11 2011-12-13 M/S. Ind Swift Laboratories Limited Process for the preparation of pure risedronic acid or salts

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2003097655A1 (fr) * 2002-05-17 2003-11-27 Teva Pharmaceutical Industries Ltd. Utilisation de certains diluants pour l'elaboration d'acides bisphosphoniques
US20050026869A1 (en) * 2003-07-30 2005-02-03 The Procter & Gamble Company Process for controlling crystal structure of risedronate
EP1775302A1 (fr) * 2005-10-11 2007-04-18 Sandoz A/S Méthode pour la préparation de risedronate de sodium cristallin
WO2007068678A1 (fr) * 2005-12-13 2007-06-21 Eczacibasi-Zentiva Kimyasal Urunler Sanayi Ve Ticaret A.S. Procede de preparation de l'acide 3-pyridyl-1-hydroxyethylidene-1,1-biphosphonique et de formes hydratees de cet acide

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2003097655A1 (fr) * 2002-05-17 2003-11-27 Teva Pharmaceutical Industries Ltd. Utilisation de certains diluants pour l'elaboration d'acides bisphosphoniques
US20050026869A1 (en) * 2003-07-30 2005-02-03 The Procter & Gamble Company Process for controlling crystal structure of risedronate
EP1775302A1 (fr) * 2005-10-11 2007-04-18 Sandoz A/S Méthode pour la préparation de risedronate de sodium cristallin
WO2007068678A1 (fr) * 2005-12-13 2007-06-21 Eczacibasi-Zentiva Kimyasal Urunler Sanayi Ve Ticaret A.S. Procede de preparation de l'acide 3-pyridyl-1-hydroxyethylidene-1,1-biphosphonique et de formes hydratees de cet acide

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
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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