WO2005080332A1 - Nouvelle formule de fluvastatine sodique - Google Patents

Nouvelle formule de fluvastatine sodique Download PDF

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Publication number
WO2005080332A1
WO2005080332A1 PCT/IN2005/000018 IN2005000018W WO2005080332A1 WO 2005080332 A1 WO2005080332 A1 WO 2005080332A1 IN 2005000018 W IN2005000018 W IN 2005000018W WO 2005080332 A1 WO2005080332 A1 WO 2005080332A1
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WO
WIPO (PCT)
Prior art keywords
fluvastatin sodium
pure water
under vacuum
fluvastatin
water
Prior art date
Application number
PCT/IN2005/000018
Other languages
English (en)
Inventor
Jalpa L. Patel
Manish H. Vakil
Parva Y. Purohit
Rajivkumar Sharma
Virendra Kumar Agarwal
Original Assignee
Cadila Healthcare Limited
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 Cadila Healthcare Limited filed Critical Cadila Healthcare Limited
Publication of WO2005080332A1 publication Critical patent/WO2005080332A1/fr

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/10—Indoles; Hydrogenated indoles with substituted hydrocarbon radicals attached to carbon atoms of the hetero ring
    • C07D209/18—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D209/24—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals with an alkyl or cycloalkyl radical attached to the ring nitrogen atom
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
    • A61K31/404—Indoles, e.g. pindolol
    • A61K31/405—Indole-alkanecarboxylic acids; Derivatives thereof, e.g. tryptophan, indomethacin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/04—Anorexiants; Antiobesity agents

Definitions

  • the present invention relates to a novel form of Fluvastatin sodium.
  • the present invention also relates to a novel process for the crystallization of Fluvastatin sodium from water. More particularly, the present invention relates to a simple and industrially feasible process for the preparation of a novel form of Fluvastatin sodium comprising a technique of crystallization from water. The product thus obtained is free from residual solvents used in manufacturing.
  • Fluvastatin is a member of a class of drugs commonly refer red to as HMG-CoA reductase inhibitors (also called "statins"). The statins are used to reduce blood cholesterol levels in patients in need of such treatment.
  • the compound is represented by following structural formula (I) and is chemically known as (E)-(+)-7-[3-(4- fluorophenyl)-l-(methylethyl)-lH-indol-2-yl]-3,5-dihydroxy-6-heptenoic acid sodium salt. It is a racemic mixture of (3R, 5S) and (3S, 5R) enantiomers, which is disclosed in EP-0114027.
  • U.S. Patent No. 6,124,340 discloses the use of lyophilization technique to prepare Fluvastatin sodium, which leads to a mixture of crystalline as well as amorphous material.
  • the amorphous form is designated as form A and crystalline form which is a monohydrate, is designated as form B.
  • the inventor has also claimed to convert form A into form B in the various solvent-water systems.
  • the Form A earlier disclosed in U.S. Patent No. 6,124,340 and WO 02/36563 was obtained by freeze drying of aqueous solution of Fluvastatin sodium. While according to U.S. Patent Application No. 2003/0032666 Al, form A of Fluvastatin sodium can be converted into form C, D, E and F by exposing form A in atmosphere of defined relative humidity.
  • Form E of both the enantiomers of Fluvastatin sodium (3R, 5S) and (3S, 5R) are prepared separately by freeze drying of the suspension or of the precipitated product.
  • Form E of Fluvastatin sodium can also be converted into Form A, BI, B2, C and D by exposing in atmosphere having defined relative humidity.
  • the lyophilization technique mentioned in prior art as well as the technique of spray-drying to produce powders from feed stocks is also well known.
  • the spray- drying technique is useful in the applications ranging from powdered milk to bulk chemicals and pharmaceuticals as disclosed in U.S. Patent No. 4, 187,617.
  • Fluvastatin sodium is very slightly water-soluble. It has been found that the solubility of Fluvastatin sodium in water is 3-4% (w/w) at ambient temperature. Hence, handling of large scale operations for the preparation of Fluvastatin sodium as disclosed in prior-arts by the technique of lyophilization and other techniques such as spray- drying which requires preparation of feedstock, poses great difficulty to handle a huge volume of water, solvent or water -solvent system.
  • Fluvastatin sodium by dissolving any form of Fluvastatin sodium in pure water through heating to achieve and maintain complete dissolution without any remaining solid.
  • the present invention provides a novel form of Fluvastatin sodium having characteristic peaks on X-ray powder diffractogram at 2 ⁇ 7.0 ⁇ 0.2°, 10.5 ⁇ 0.2°, 12.7°, 13.6 ⁇ 0.2°, 20.5 ⁇ 0.2°, 22.2 ⁇ 0.2°.
  • said novel form of Fluvastatin sodium has characteristic peaks on Infrared spectroscopic studies at 1572, 1569, 1560, and 1400 cm '1 .
  • the present invention also provides a process for the manufacture a novel form of Fluvastatin sodium by the crystallization of known forms of Fluvastatin sodium from pure water comprising : (a) dissolving any form of Fluvastatin sodium in pure water; (b) distilling a part of water under reduced pressure; (c) cooling at 5°C to 50°C; (d) maintaining the temperature between 5°C to 50°C; (e) filtering or centrifuging the precipitated material; (f) drying the wet cake at moderate temperature under vacuum; (g) homogenizing the dried material to uniform free flowing Fluvastatin sodium by multimilling or jetmilling;
  • said known form of Fluvastatin sodium is dissolved in 1-10 volumes, preferably 2-5 volumes of pure water as that of Fluvastatin sodium taken for dissolution.
  • the dissolution temperature of Fluvastatin sodium in pure water is
  • the volume of pure water taken for dissolution is more than five as that of Fluvastatin sodium taken and is reduced to half below 80°C, preferably below 50°C under vacuum.
  • clear solution of Fluvastatin sodium in pure water is cooled to 0° -
  • the precipitated material is maintained at 0° - 50°C, preferably to 5° - 30°C for 15 min to 240min, preferably 60 min for complete crystallization of Fluvastatin sodium.
  • the crystallized material is isolated from its mother liquor by filtration under vacuum or by centrifuging at 600 to 2000 rpm, preferably at 800 rpm.
  • the wet cake is dried at 40° - 80°C, preferably 55° - 60°C under vacuum for 6 to 48 hr, preferably 24 hr.
  • the water content in final Fluvastatin sodium is 1 - 8 %, preferably 2 - 5 %.
  • Fig 1 is a X-ray powder diffractogram of Fluvastatin sodium monohydrate
  • Fig 2 to 8 depict is X-ray powder diffractograms of the material obtained in accordance with the present invention
  • X-ray powder diffractograms of Fig. 2 to 8 shows very new pattern of peaks at 2° theta 7.0 ⁇ 0.2°, 10.5 ⁇ 0.2°.
  • Fig 9 shows infrared spectroscopy of novel form of Fluvastatin sodium shows characteristic peaks at 1572, 1569, 1560, and 1400 cm '1 It has been found that crystalline forms are less readily soluble than amorphous form, which may cause problems in the bioavailibility of Fluvastatin sodium in the body. It therefore remains a need for a form of Fluvastatin sodium having limited crystallinity with improved process and formulation characteristics. It is the principal object of the present invention to provide an efficient process as well as to obtain a novel form of Fluvastatin sodium that eliminates the problems of prior arts and is convenient to operate on commercial scale that also meets economic demands.
  • a preferred embodiment of the invention is the crystallization of Fluvastatin sodium from aqueous solution to obtain a novel form.
  • the objective of present invention is also to determine the solubility of Fluvastatin sodium in water at various temperatures for optimum recovery of novel form of Fluvastatin Sodium. While warming the suspension of Fluvastatin sodium in pure water, it was found that solubility of Fluvastatin sodium increases. Hence, it was thought to optimize the solubility of the Fluvastatin sodium in pure water. To emphasize the process of crystallization, more amount of Fluvastatin sodium in pure water is stirred and is heated to get a clear solution at the temperature range 50-80°C. The clear solution so obtained is allowed to approach at cool to ambient temperature affording novel form of Fluvastatin sodium.
  • Fluvastatin sodium (form-B) varying the volume of water (2 to 5 volumes as that of Fluvastatin sodium monohydrate form-B) to dissolve Fluvastatin sodium monohydrate form-B at various temperature (45 - 80°C). It was observed that with more volumes of water taken for dissolution, the temperature for dissolution is lesser and the recovery of product is also less. Fluvastatin sodium monohydrate form-B is dissolved completely in two volumes of water as that of form-B at 78°C, cooled to 25 - 30°C, filtered at 25 - 30°C, dried at 55 - 60°C under vacuum for 24 hours to provide a free flowing material with 80% recovery.
  • the precipitated material is filtered and is sucked dry. Finally the wet cake is dried at
  • the precipitated material is filtered and is sucked dry. Finally the wet cake is dried at
  • X-ray powder diffractogram ( Figure - 4) of the material thus obtained is completely different with that of Fluvastatin sodium monohydrate ( Figure - 1) demonstrating the change in crystalline structure.

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Veterinary Medicine (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Epidemiology (AREA)
  • Child & Adolescent Psychology (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Diabetes (AREA)
  • Hematology (AREA)
  • Obesity (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Indole Compounds (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

La présente invention se rapporte à une nouvelle forme de fluvastatine sodique possédant des pics caractéristiques sur un diffractogramme de poudre soumise à des rayons X à 2υ 7,0 ?0,2°, 10,5 ? 0,2°, 12,7°, 13,6 ? 0,2°, 20,5 ? 0,2°, 22,2 ? 0,2°. Cette nouvelle forme de fluvastatine sodique possède des pics caractéristiques pour des études spectroscopiques en infrarouge à 1572, 1569, 1560 et 1400 cm-1.
PCT/IN2005/000018 2004-01-14 2005-01-14 Nouvelle formule de fluvastatine sodique WO2005080332A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
IN40/MUM/2004 2004-01-14
IN40MU2004 2004-01-14

Publications (1)

Publication Number Publication Date
WO2005080332A1 true WO2005080332A1 (fr) 2005-09-01

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ID=34878797

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/IN2005/000018 WO2005080332A1 (fr) 2004-01-14 2005-01-14 Nouvelle formule de fluvastatine sodique

Country Status (1)

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WO (1) WO2005080332A1 (fr)

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2006030304A2 (fr) * 2004-09-17 2006-03-23 Ranbaxy Laboratories Limited Nouvelles formes de sodium de la fluvastatine, leurs procedes de preparation et compositions pharmaceutiques
WO2007100894A2 (fr) * 2006-02-27 2007-09-07 Teva Pharmaceutical Industries Ltd. Nouvelles formes de fluvastatine sodique et leur préparation
US7795451B2 (en) 2005-02-11 2010-09-14 Jubilant Organosys Limited Polymorphic forms of fluvastatin sodium and process for preparing the same

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20030032666A1 (en) * 2001-08-03 2003-02-13 Van Der Schaaf Paul Adriaan Crystalline forms
WO2004113292A2 (fr) * 2003-06-18 2004-12-29 Teva Pharmaceutical Industries Ltd. Formes cristallines de sodium de fluvastatine, leurs procedes de preparation, compositions les contenant et procedes d'utilisation correspondants

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20030032666A1 (en) * 2001-08-03 2003-02-13 Van Der Schaaf Paul Adriaan Crystalline forms
WO2004113292A2 (fr) * 2003-06-18 2004-12-29 Teva Pharmaceutical Industries Ltd. Formes cristallines de sodium de fluvastatine, leurs procedes de preparation, compositions les contenant et procedes d'utilisation correspondants

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2006030304A2 (fr) * 2004-09-17 2006-03-23 Ranbaxy Laboratories Limited Nouvelles formes de sodium de la fluvastatine, leurs procedes de preparation et compositions pharmaceutiques
WO2006030304A3 (fr) * 2004-09-17 2006-12-07 Ranbaxy Lab Ltd Nouvelles formes de sodium de la fluvastatine, leurs procedes de preparation et compositions pharmaceutiques
US7795451B2 (en) 2005-02-11 2010-09-14 Jubilant Organosys Limited Polymorphic forms of fluvastatin sodium and process for preparing the same
WO2007100894A2 (fr) * 2006-02-27 2007-09-07 Teva Pharmaceutical Industries Ltd. Nouvelles formes de fluvastatine sodique et leur préparation
WO2007100894A3 (fr) * 2006-02-27 2008-01-24 Teva Pharma Nouvelles formes de fluvastatine sodique et leur préparation

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