WO2004096765A2 - Nouvelle forme polymorphe cristalline du sodium de fluvastatine et procede de preparation associe - Google Patents

Nouvelle forme polymorphe cristalline du sodium de fluvastatine et procede de preparation associe Download PDF

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Publication number
WO2004096765A2
WO2004096765A2 PCT/IN2004/000121 IN2004000121W WO2004096765A2 WO 2004096765 A2 WO2004096765 A2 WO 2004096765A2 IN 2004000121 W IN2004000121 W IN 2004000121W WO 2004096765 A2 WO2004096765 A2 WO 2004096765A2
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WIPO (PCT)
Prior art keywords
fluvastatin sodium
aliphatic
organic solvent
crystalline form
sodium
Prior art date
Application number
PCT/IN2004/000121
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English (en)
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WO2004096765A3 (fr
Inventor
Sanjay Suri
Gurdeep Singh Sarin
Original Assignee
Morepen Laboratories Ltd.
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Publication date
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Publication of WO2004096765A2 publication Critical patent/WO2004096765A2/fr
Publication of WO2004096765A3 publication Critical patent/WO2004096765A3/fr

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    • 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
    • C07D209/12—Radicals substituted by oxygen atoms

Definitions

  • This invention relates to "A Novel Crystalline Polymorph of Fluvastatin Sodium and a Process for Preparing it". Particularly the invention relates to a novel crystalline polymorph of Fluvastatin Sodium having higher purity, stability, and solubility.
  • the polymorph of the present invention contains up to 8% water content.
  • the invention also provides a process, for the preparation of a novel polymorph, that is simple cost effective, reproducible, environment friendly easy to scale up for industrial manufacture without compromising the quality of the title product.
  • Fluvastatin is a member of the class of drug called statins. It is an inhibitor of 3- hydro ⁇ y-3 -methyl glutaryl Coenzyme A (HMG - CO A) and is used for the treatment of hyperlipidemia and hypocholesterolemia. -
  • Fluvastatin Sodium is known by its chemical name as R*, S*-(E)-( ⁇ )-7-[3-(4- fluorophenyl)-l-(l -methyl ethyl)-lH-indol-2-yl]-3,5-dihydroxy-6-heptanoic acid mono sodium salt.
  • Fluvastatin Sodium is a racemic mixture of the 3R, 5S- and 3S, 5R- dihydroxy enantiomers.
  • the empirical formula of Fluvastatin Sodium is C 2 H 25 FNNaO 4j molecular weight is 433.5 and it displays the following structural formula (1)
  • Fluvastatin Sodium is a white to pale yellow amorphous or crystalline powder that is i soluble in water & alcohol and pH of 1% solution in DM- Water is 8-10.
  • Fluvastatin as racemate well as its sodium salts are first disclosed in US Patent No. 4,739,073 and its EP equivalent EP patent no. 114027. Fluvastatin sodium is obtained in this patent by lyophilization and discloses the amorphous form, which has unsuitable characteristics for large-scale production and has an unsuitable stability,
  • WO-A-97/49681 and its US equivalent US 6,124,340 describes that freeze drying of Fluvastatin Sodium yields a mixture of a crystalline form and amorphous material.
  • the crystalline form comprised in this mixture is referred to as Fluvastatin Sodium form A.
  • the estimated amount of Form A obtained by lyophilization as described in these patents is about 50%.
  • This patent describes a new crystalline form B preferably containing no more that 5% of any other crystalline form of Fluvastatin Sodium.
  • the crystalline form B is precipitated from a mixture of one or more organic solvents preferably polar organic solvents such as methanol or ethanol and water and isolated there from using polar organic solvent such as aliphatic alkanols, ketones and esters their of as precipitating solvent.
  • polar organic solvent such as aliphatic alkanols, ketones and esters their of as precipitating solvent.
  • This patent describes the process in which any non-B form of Fluvastatin sodium amorphous material or fluvastatin sodium form A can initially be partly dissolved in the organic solvent and water mixture and stirred until the desired form B is formed. The process comprises a transformation in the slurry without a complete dissolution of the starting material.
  • the patent discloses the crystallisation in an organic solvent and water, with a suitable sodium compound preferably an aqueous solution of sodium hydroxide or sodium carbonate.
  • a suitable sodium compound preferably an aqueous solution of sodium hydroxide or sodium carbonate.
  • the starting material is eg. the corresponding free acid or the ester or a salt of fluvastatin.
  • the patent discloses the crystallisation from a solution of fluvastatin sodium in a mixture of organic solvent and water.
  • the starting solution of fluvastatin sodium can be formed either by dissolution of already isolated fluvastatin sodium or it can be formed in a previous process step where fluvastatin sodium is formed by chemical reaction.
  • form B is less hygroscopic than fluvastatin sodium form A and amorphous fluvastatin sodium, improved stability against light exposure.
  • WO 02/36563 describes the crystalline forms of the (3R, 5S) - and the (3S, 5R) - enantiomers of fluvastatin sodium.
  • the patent designated these forms as form A, Form Bl, Form B2, Form C, Form D and Form E. These crystalline forms are hydrates and have water contents from 0 upto 8 molecules of water per molecules of fluvastatin sodium.
  • form E can be prepared by treating an aqueous solution of the (3R, 5S) - or (3S, 5R) ⁇ enantiomers of fluvastatin sodium to precipitation either by concentrating or cooling followed by freeze drying of the suspension or of the precipitated compound.
  • Form A, B, B 2 , C and D are prepared by using form E as the starting compound and by exposing from E to an atmospheric having a defined relative humidity depending on the relative humidity used, the different forms can be obtained, WO 03/013512 and its US equivalent US 2003032606 describes crystalline hydrates designated as form C, D, E and F with water content ranging from 3 to 32%.
  • the patent also describes a new process for the preparation pf highly crystalline Fluvastatin Sodium form A.
  • the patent describes the process wherein Fluvastatin Sodium is exposed to an atmosphere having defined relative humidity to get form C, D, E and F,
  • These forms are less susceptible toward air humidity and show high stability and are easier to handle at normal environment humidity levels.
  • the present invention provides a new crystalline form BA of Fluvastatin Sodium.
  • This new crystalline form of Fluvastatin sodium is generally monohydrate with water content of 3 to 6% but also exhibits water content up to 8%.
  • Fig I depicts infrared spectra of new crystalline form BA of Fluvastatin sodium.
  • Fig II relates to powder x-ray diffraction (PXRD) pattern of new crystalline form
  • the main object of the present invention is to provide to a novel crystalline polymorph of Fluvastatin sodium.
  • ⁇ nother object is to provide a polymorph having higher purity, stability, and solubility.
  • Yet another object is to provide a polymorph having reduced residual solvent.
  • Still yet another object is to provide a polymorph that contains up to 8% preferably 3-
  • One of the objects of the invention is also to provide a process, for the preparation of a novel polymorph.
  • the process is simple cost effective, involving less number of steps, high yielding, precise, reproducible, environment friendly easy to scale up for industrial manufacture without compromising the quality of the title product.
  • the process has merits of easy and rapid isolation and crystallization of stable
  • Fluvastatin sodium can be prepared as a novel crystalline hydrates which have improved stability, less hygroscopicity, without the risk of residual solvent, photostability by using ethers as precipitating solvent.
  • the new crystalline form BA of Fluvastatin sodium is characterised by its infrared and powder x-ray diffraction pattern.
  • Fourier transform infrared (FT - IR) spectra of Fluvastatin sodium were obtained from 4 mg of new crystalline form in 250 mg KBr, mortared and pressed into tablets.
  • the powder x-ray diffractogram was performed on a Shimadzu XRD - 6000 with
  • the new crystalline form BA of Fluvastatin sodium is generally monohydrate with water contents in the range of 3 to 6 %. However, the hydrated form may exhibit water content up to 8.0%.
  • the present invention provides a process for the preparation of new crystalline form BA of Fluvastatin sodium in hydrated state.
  • R*, S*-(E) ( ⁇ ) 7- [3-(4-Fluorophenyl)-l-(l-methylethyl)-lH-indol-2-yl]-3,5-dihydroxy-6- heptanoicacid mono sodium salt having formula 1 is prepared using the following method.
  • the present invention provides a process for the preparation of a novel crystalline polymorph BA of Fluvastatin sodium comprising of the following steps: (a) optionally converting methyl ester of Fluvastatin sodium having formula 2 to
  • Fluvastatin sodium in an organic solvent using any known methods till reaction completion, (b) providing clear solution of the said Fluvastatin sodium using water immiscible organic solvent exemplified without restriction, aliphatic alkanols,
  • the Fluvastatin sodium used may be amorphous or its any known form reported in prior art or mixture thereof in case step (a) involving conversion of methyl ester is not adopted.
  • Fluvastatin sodium when used as a starting material may be in anhydrous or hydrated state.
  • an organic solvent used for converting methyl ester of Fluvastatin sodium may be selected from water immiscible organic solvent exemplified without restriction, aliphatic alkanols, aliphatic ketones or lower ethers.
  • the aliphatic alkanols used may be such as aliphatic branched or straight chain alkanols having 1 to 5 carbon atoms preferably methanol, ethanol, 1-propanol, 2-propanol, 1-buianol, 2-butanol more preferably methanol.
  • the aliphatic ketones used may be the one having carbon atom up to 6 and may preferably be acetone.
  • the ether when employed may be tetrahydrofuran (THF), dimefhoxy ethane or dimethoxy propane.
  • the organic solvent used for converting methyl ester of Fluvastatin sodium may be 100 times preferably 10 times, more preferably 3.5 times of methyl ester of Fluvastatin sodium.
  • the orgamc solvent is completely recovered in case other than aliphatic alkanol is used for converting Fluvastatin methyl ester, and the residue thus produced is redissolved in alkanol to provide clear solution.
  • the methyl ester is converted to Fluvastatin sodium using aqueous solution of alkali metal hydroxide preferably sodium hydroxide.
  • aqueous solution of alkali metal hydroxide used may be 100 times preferably 1.0 times more preferably 0.25 times.
  • DM-water may be used during step (a) and may be 100 times preferably 1.0 times more preferably 0.25 times of the starting compound.
  • an organic solvent used for providing clear solution of Fluvastatin sodium may be selected from water immiscible organic solvent exemplified without restriction, aliphatic alkanols branched or straight chain, having 1 to 5 carbon atoms.
  • the alkanols used may preferably be methanol, ethanol, 1- propanol,2-propanol, 1-butanol or 2-butanol, more preferably methanol.
  • the organic solvent used for providing clear solution in step (b) may be 100 times preferably 15 times, more preferably 10 times of the Fluvastatin sodium or any form of Fluvastatin sodium used.
  • the organic solvent used for providing clear solution may be recovered by concentrating under vacuum to preferably 4.5 times of the source of Fluvastatin sodium
  • the clear solution may be obtained by heating to the reflux temperature of the solvent used preferably above 20°C & more preferably 30 to
  • the anti solvent used for facilitating precipitation of new crystalline from of Fluvastatin sodium maybe selected from aliphatic ethers.
  • the aliphatic ethers used may be diethyl ether, di-isopropyl ether, methyl-t-butyl ether preferably di-isopropyl ether.
  • the aliphatic ether used may be 100 times preferably 70 times more preferably 50 times of the starting compound.
  • the addition of aliphatic ether may be carried out at temperature between -10 to 80° C preferably 40-70° C more preferably 60-65°C.
  • the seeding may be done in step (c) to accelerate precipitation.
  • the seed may be used from the previous batch and added in the range of 1 to 10% w/w of the starting material.
  • the precipitation may be effected at 5°C to room temperature (about 25°C) when
  • Fluvastatin Sodium may be carried out up to 48 hrs. preferably for 24 hrs, more preferably 13-16 hrs.
  • the isolation may be effected by any conventional methods such as filtration either with pressure or vacuum, decantation, centrifugation.
  • the drying may be effected, after step (d), by known means like vacuum tray drier, Rotacon vacuum drier and at a temperature above 50 and below 80°C preferably at 50-60°C for 12 to 48 hours to regulate the water of molecules.
  • the IR spectra is well distinguished from that of IR spectra of known forms in the prior art.
  • IR shows absorption bands at 3409, 2976, 2937, 1587, 1535, 1499, 1458, 1420, 1347, 1216, 1156, 1105, 1041, 1013, 967, 841, 740 , 564 cm "1
  • the powder x-ray diffractogram of new polymorphic crystalline form (Fig.2) displays peaks at 03.97 ⁇ 0.2, 11.08 ⁇ 0.2, 12.06 ⁇ 0.2, 12.92+ 0.2, 14.92+ 0.2, 15.79 ⁇ 0.2, 16.54 ⁇ 0.2, 17.78+ 0.2, 18.32+.
  • This x-ray pattern is well distinguished from that of known crystalline forms in prior art, which is characterised by sharp and strong peaks at 12.06, 12.92 degree 2 ⁇ , medium intensity sharp peaks at 18.32, 18.84, 19.64, 20.42, and medium intensity broad peaks at 21.58 and 25.56 ⁇ 0.2 degree 2 ⁇ .
  • the new polymorphic form BA exists in hydrated form, generally monohydrate form. It contains up to 8.0% of water content.
  • Fluvastatin sodium (25.0 g) was added to a mixture of methanol (250) and DM water (7.0 ml) at room temperature and the mixture was heated for 30-45 minutes at 30 to 40°C to get clear solution. The clear solution was fine filtered to remove suspended particles and concentrated under vacuum at 35-40°C till 125 ml of the reaction volume was left. The reaction mass was heated to 60-65°C and di- isopropyl ether (1.25 It) was added slowly at 60-65°C. The reaction mass was stirred for 15 hrs. at 60-65°C during which time new crystalline form BA of Fluvastatin sodium precipitated out. The product was filtered and then dried in vacuum tray drier at 50-60°C for34- 36 hrs.
  • the process has merits of easy and rapid isolation and crystallization of stable polymorph.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Indole Compounds (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention concerne une nouvelle forme BA polymorphe cristalline du sodium de fluvastatine et ses hydrates, ainsi que son analyse IR et PXRD. La présente invention porte également sur un procédé pour préparer ce nouvel élément polymorphe, selon lequel des éthers aliphatiques sont utilisés comme anti-solvants pour faciliter la précipitation, un anti-solvant étant de préférence additionné à une température supérieure à 40 °C sans ensemencement.
PCT/IN2004/000121 2003-05-01 2004-04-30 Nouvelle forme polymorphe cristalline du sodium de fluvastatine et procede de preparation associe WO2004096765A2 (fr)

Applications Claiming Priority (2)

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IN656/DEL/2003 2003-05-01
IN656DE2003 2003-05-01

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WO2004096765A2 true WO2004096765A2 (fr) 2004-11-11
WO2004096765A3 WO2004096765A3 (fr) 2005-01-27

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Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2005037787A1 (fr) * 2003-10-16 2005-04-28 Ciba Specialty Chemicals Holding Inc. Forme cristalline du sel de sodium de fluvastatine
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
WO2006109147A1 (fr) * 2005-04-12 2006-10-19 Glenmark Pharmaceuticals Limited Fluvastatine amorphe pratiquement pure, procede de preparation et compositions pharmaceutiques qui la contiennent
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
US8115013B2 (en) * 2004-10-05 2012-02-14 Biocon Limited Process for the preparation of amorphous fluvastatin sodium

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1997049681A1 (fr) * 1996-06-24 1997-12-31 Astra Aktiebolag (Publ) Composes polymorphes
WO2002036563A1 (fr) * 2000-10-31 2002-05-10 Ciba Specialty Chemicals Holding Inc. Formes cristallines de sodium de fluvastatine
WO2003013512A2 (fr) * 2001-08-03 2003-02-20 Ciba Specialty Chemicals Holding Inc. Formes cristallines

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1997049681A1 (fr) * 1996-06-24 1997-12-31 Astra Aktiebolag (Publ) Composes polymorphes
WO2002036563A1 (fr) * 2000-10-31 2002-05-10 Ciba Specialty Chemicals Holding Inc. Formes cristallines de sodium de fluvastatine
WO2003013512A2 (fr) * 2001-08-03 2003-02-20 Ciba Specialty Chemicals Holding Inc. Formes cristallines

Cited By (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2005037787A1 (fr) * 2003-10-16 2005-04-28 Ciba Specialty Chemicals Holding Inc. Forme cristalline du sel de sodium de fluvastatine
US7432380B2 (en) 2003-10-16 2008-10-07 Ciba Specialty Chemicals Corp. Crystalline form of Fluvastatin sodium
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
US8115013B2 (en) * 2004-10-05 2012-02-14 Biocon Limited Process for the preparation of amorphous fluvastatin sodium
US7795451B2 (en) 2005-02-11 2010-09-14 Jubilant Organosys Limited Polymorphic forms of fluvastatin sodium and process for preparing the same
WO2006109147A1 (fr) * 2005-04-12 2006-10-19 Glenmark Pharmaceuticals Limited Fluvastatine amorphe pratiquement pure, procede de preparation et compositions pharmaceutiques qui la contiennent
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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