Title of Invention

NOVEL PROCESSES FOR PREPARING FLUVASTATIN SODIUM AMORPHOUS FORM

Abstract Present invention describes,amorphous Sodium[R*,S*-(E)]-(±)-7-[3-(4-fluorophenyl)-1-(1-methylethyl)-1H-indol-2-yl]-3,5-dihydroxy-6-heptenoate and a novel process for preparing it.
Full Text FORM 2
THE PATENT ACT 1970
(39 of 1970)
&
The Patents Rules, 2003
COMPLETE SPECIFICATION
(See section 10 and rule !3)
1. TITLE OF THE INVENTION:
NOVEL PROCESSES FOR PREPARING FLUVASTATIN SODIUM
AMORPHOUS FORM
2. APPLICANT (S)
(a) NAME: Wockhardt Limited
(b) NATIONALITY: Indian
(c) ADDRESS:
Wockhardt Towers,
Bandra-Kurla Complex,
Bandra (East),
Mumbai-400051,
India
3. PREAMBLE TO THE DESCRIPTION
The present invention relates to some novel processes for the preparation of amorphous Fluvastatin sodium. The amorphous form of Fluvatatin sodium is prepared by dissolving Fluvatatin sodium in methanol, followed by evaporation of complete solvent and addition of cyclohexane or methyl t-butyl ether at ambient temperature and filtration of the precipitated material. In another aspect of this invention, Fluvatatin sodium is dissolved in tetrahydrofuran followed by evaporation, addition of methyl t-butyl ether (MTEB) and filtration to get desired amorphous product.

FIELD OF THE INVENTION
The present invention relates to novel processes for preparation of amorphous form of HMG CoA inhibitor Fluvastatin sodium using different organic solvents and mixtures thereof.
BACKGROUND OF THE INVENTION
Fluvastatin sodium is known by its chemical name, Sodium [R*,S*-(E )]-(±)-7-[3-(4-fluorophenyl)-l-(l-methylethyl)-lH -indol-2-yl]-3,5-dihydroxy-6-heptenoate. It is a racemic mixture of the 3R, 5S and 3S, 5R-dihyroxy enantiomers and has the following structural formula:

H3 ,C CH,
Fluvastatin sodium
Fluvastatin sodium is an inhibitor of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase, which is a key enzyme in the regulation of cholesterol biosynthesis. Fluvastatin can be used pharmaceutically particularly as an anti-hyperchlesterolemic, hyperlipoproteinemic agent.
Fluvastatin sodium salt was first disclosed in U.S. Patent No. 4,739,073. It is obtained in this patent by lyophilization and discloses amorphous form with contamination of crystalline form of the product. U.S. Patent No. 6,124,340 describes lyophilization of Fluvastatin sodium that yields a mixture of crystalline form

designated as form A and amorphous material. Amorphous Fluvastatin sodium dissolves rapidly in the gastric juice and has enhanced advantages.
SUMMARY OF THE INVENTION
The present invention relates to some novel processes for the preparation of amorphous Fluvastatin sodium. The amorphous form of Fluvatatin sodium is prepared by dissolving Fluvatatin sodium in methanol, followed by evaporation of complete solvent and addition of cyclohexane or methyl t-butyl ether at ambient temperature and filtration of the precipitated material. In another aspect of this invention, Fluvatatin sodium is dissolved in tetrahydrofuran followed by evaporation, addition of methyl t-butyl ether (MTEB) and filtration to get desired amorphous product.
The amorphous Fluvastatin sodium obtained in the present invention is characterized from X-Ray Diffraction Pattern (XRD).
BRIEF DESCRIPTION OF THE DRAWINGS
Figure 1 is an X-Ray Diffraction Pattern (XRD) of Fluvastatin sodium prepared by Method 1.
Figure 2 is an X-Ray Diffraction Pattern (XRD) of Fluvastatin sodium prepared by Method 2.
Figure 3 is an X-Ray Diffraction Pattern (XRD) of Fluvastatin sodium prepared by Method 3.
DETAILED DESCRIPTION OF THE INVENTION
Fluvastatin being cholesterol lowering agent that acts through the inhibition of 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase, systematic study and development of amorphous form is under taken. The present invention is directed

towards different solvent combinations for the preparation of Amorphous Sodium [R*,S*-(E)]-(±)-7-[3-(4-fluorophenyl)-l-(l-methylethyl)-lH-indol-2-yl]-3,5-dihydroxy-6-heptenoate (Fluvastatin sodium).
In the present invention, amorphous Fluvastatin sodium is prepared by first dissolving Fluvastatin sodium in an aliphatic alcohol or ether followed by evaporation of organic solvents. The residue obtained after evaporating alcohol is heated with cyclohexane or methyl tertiary butyl ether. Cyclohexane containing product is stirred for about 15 minutes to 10 hours and the precipitate thus obtained is filtered and dried to get amorphous product. In another embodiment, Fluvastatin sodium after evaporation with methanol is co-distilled with MTEB followed by re-addition of MTEB and stirring for about 15 minutes to about 10 hours preferably between about 1 hour to 4 hours. Fluvastatin sodium taken in MTBE is stirred for about for 2 hours and filtered to get amorphous product. In last embodiment of the invention Fluvastatin sodium is suspended in THF and heated to about 55 to 55 °C. The solution is filtered to remove particulate material from the solution. THF is concentrated to dryness under vacuum and is co-distilled with MTBE. After evaporation of organic solvents, MTBE is re-added and it is stirred for about 2 hours at ambient temperature. The precipitated material thus obtained is filtered and dried under vacuum to get amorphous Fluvastatin sodium.
Fluvastatin sodium is suspended in an organic solvent between about 5 to 15 fold volume. Suitable solvents for dissolving Fluvastatin sodium include, but are not limited to, alcohols or ethers. Suitable alcohols include, methanol, ethanol, propanol, isopropanol and butanol, preferably methanol. Suitable ethers for the process includes, tetrahydrofuran, ethyl methyl ether, diethyl ether, preferably tetrahydrofuran. Fluvastatin sodium is heated between about 30 to about 70°C to get clear solution. The clear solution thus obtained is evaporated to dryness under vacuum. To the methanol containing Fluvastatin sodium, an aliphatic cyclic hydrocarbon or an aliphatic ether is

added to get the amorphous product. Suitable hydrocarbon and ether for this process include, but not limited to, cyclohaxane and methyl t-butyl ether, respectively.
In another embodiment, Fluvastatin sodium is heated with ether, e.g., tetrahydrofuran and evaporated to dryness under vacuum. Suitable solvent for making it amorphous includes, but not limited to, methyl t-butyl ether, ethyl methyl ether, diethyl ether, etc., preferably methyl t-butyl ether.
The present invention provides, amorphous Sodium [R*,S*-(E )]-(±)-7-[3-(4-fluorophenyl)-l-(l-methylethyl)-lH -indol-2-yl]-3,5-dihydroxy-6-heptenoate that is characterized by X-ray diffraction (XRD) and IR Spectrum.
The infrared spectrum of amorphous form of Fluvastatin Sodium is expressed in cm"1 and the peaks are at about 3425, 2977, 2361, 1650, 1561, 1500, 1456, 1346, 1215, 1157,1107, 969, 840, 814, 741, 652, 565.
The following examples illustrate the invention, but is not limiting thereof.
EXAMPLE 1
Amorphous, Sodium (±)-7-[3-(4-fluorophenyl)-l-(l-methylethyl)-lH -indol-2-yl]-3,5-dihydroxy-6-heptenoate (Amorphous Fluvastatin sodium)
Following methods describe the preparation of Amorphous Fluvastatin sodium.
Method 1
Fluvastatin sodium (10 g) was suspended in methanol (100 ml) and heated to 50-55°C for dissolving. The solution was filtered to remove particulate material. The clear solution was concentrated to dryness completely under vacuum. Then cyclohexane (200 ml) was added and distilled it out again to dryness. Again cyclohexane (200 ml) was added and stirred at ambient temperature for 2 hrs. The material was filtered under nitrogen and

dried for 6 hrs at 45-50°C under vacuum to give 9.0 g of pale yellow powder. The PXRD demonstrates the amorphous nature of the product.
Method 2
Fluvastatin sodium (2 g) was suspended in methanol (20 ml) and heated to 50-55°C for dissolving. The solution was filtered to remove particulate material. The clear solution was concentrated to dryness completely under vacuum. The residue was codistilled with MTBE (20 mL), then MTBE (40 mL) was added and stirred at ambient temperature for 2 hrs. The material was filtered under nitrogen and dried for 4 hrs at 45-50°C under vacuum to give 1.4 g of pale yellow powder. The PXRD demonstrates the amorphous nature of the product.
Method 3
Fluvastatin sodium (2 g) was suspended in THF (20 mL) and heated to 50-55°C for dissolving. The solution was filtered to remove particulate material. The clear solution was concentrated to dryness completely under vacuum. The residue was codistilled with MTBE (20 mL), then MTBE (40 mL) was added and stirred at ambient temperature for 2 hrs. The material was filtered under nitrogen and dried for 4 hrs at 45-50°C under vacuum to give 1.5 g of pale yellow powder. The PXRD demonstrates the amorphous nature of the product.

We claim:
1 A process for the preparation of an amorphous form of a compound of Formula 1




Fluvastatin sodium
which comprises:
a) dissolving compound of Formula I in a suitable solvent
b) filtering and removing the solvent
c) adding organic solvent after removing the solvent of step b.
d) stirring the solution for few hours
e) filtering and removing the amorphous Fluvastatin sodium.

2 The process of claim 1, wherein step a) is carried out in an organic solvent.
3 The process of claim 2, wherein said organic solvent is an alcohol.
4 The process of claim 3, wherein said alcohol is methanol, ethanol, propanol and isopropanol.
5 The process of claim 1 step c), wherein said organic solvent is aliphatic hydrocarbon and aliphatic ether.
6 The process of claim 6, wherein aliphatic hydrocarbon is cyclohexane.
7 The process of claim 5, wherein said ether is methyl t-butyl ether, ethyl methyl ether and diethyl ether.
8 The process of claim 7, wherein more preferable ether is methyl t-butyl ether.
9 A process for the preparation of an amorphous form of a compound of Formula 1


H3C CH3
Fluvastatin sodium
which comprises:
a) dissolving compound of Formula I in a suitable solvent
b) filtering and removing the solvent
c) adding organic solvent after removing the solvent of step b.
d) stirring the solution for few hours
e) filtering and removing the amorphous Fluvastatin sodium.

10 The process of claim 9, wherein step a) is carried out in an organic solvent.
11 The process of claim 10, wherein said organic solvent is ether.
12 The process of claim 11, wherein said ether is tetrahydrofuran.
13 The process of claim 9 step c), wherein said organic solvent is aliphatic ether.
14 The process of claim 13, wherein said aliphatic ether is methyl t-butyl ether, ethyl methyl ether and diethyl ether.
15 The process of claim 14, wherein more preferable ether is methyl t-butyl ether.
16 An amorphous, Sodium (±)-7-[3-(4-fluorophenyl)-l-(l-methylethyl)-lH-indol-2-yl]-3,5-dihydroxy-6-heptenoate, characterized by an Infra Red Spectrum having the following peaks at about 3425, 2977, 2361, 1650, 1561, 1500, 1456, 1346, 1215, 1157, 1107, 969, 840, 814, 741, 652, 565 cm1.
17 An amorphous, Sodium (±)-7-[3-(4-fluorophenyl)-l-(l-methylethyl)-lH-indol-2-yl]-3,5-dihydroxy-6-heptenoate characterized by the X-Ray Diffraction (XRD) as shown in Figures 1-3.

ABSTRACT
Present invention describes, amorphous Sodium [R*,S*-(E )]-(±)-7-[3-(4-fluorophenyl)-l-(l-methylethyl)-lH -indol-2-yl]-3,5-dihydroxy-6-heptenoate and a novel process for preparing it.

Documents:

1349-MUM-2005-ABSTRACT(2-8-2010).pdf

1349-MUM-2005-ABSTRACT(22-9-2008).pdf

1349-mum-2005-abstract(27-10-2005).pdf

1349-mum-2005-abstract(granted)-(14-9-2010).pdf

1349-mum-2005-abstract.doc

1349-mum-2005-abstract.pdf

1349-mum-2005-cancelled pages(2-8-2010).pdf

1349-MUM-2005-CLAIMS(22-9-2008).pdf

1349-mum-2005-claims(27-10-2005).pdf

1349-mum-2005-claims(amended)-(1)-(2-8-2010).pdf

1349-MUM-2005-CLAIMS(AMENDED)-(18-9-2008).pdf

1349-MUM-2005-CLAIMS(AMENDED)-(2-8-2010).pdf

1349-mum-2005-claims(amended)-(22-9-2008).pdf

1349-MUM-2005-CLAIMS(AMENDED)-(27-10-2005).pdf

1349-MUM-2005-CLAIMS(CANCELLED PAGES)-(22-9-2008).pdf

1349-mum-2005-claims(granted)-(14-9-2010).pdf

1349-mum-2005-claims.doc

1349-mum-2005-claims.pdf

1349-MUM-2005-CORRESPONDENCE(2-8-2010).pdf

1349-MUM-2005-CORRESPONDENCE(22-9-2008).pdf

1349-mum-2005-correspondence(ipo)-(15-9-2010).pdf

1349-mum-2005-correspondence(ipo)-(28-9-2007).pdf

1349-mum-2005-description (complete).pdf

1349-MUM-2005-DESCRIPTION(COMPLETE)-(22-9-2008).pdf

1349-mum-2005-description(complete)-(27-10-2005).pdf

1349-mum-2005-description(granted)-(14-9-2010).pdf

1349-MUM-2005-DRAWING(22-9-2008).pdf

1349-mum-2005-drawing(27-10-2005).pdf

1349-mum-2005-drawing(granted)-(14-9-2010).pdf

1349-mum-2005-drawings.pdf

1349-mum-2005-form 13(2-8-2010).pdf

1349-mum-2005-form 18(13-9-2006).pdf

1349-mum-2005-form 2(22-9-2008).pdf

1349-mum-2005-form 2(27-10-2005).pdf

1349-mum-2005-form 2(granted)-(14-9-2010).pdf

1349-MUM-2005-FORM 2(TITLE PAGE)-(2-8-2010).pdf

1349-MUM-2005-FORM 2(TITLE PAGE)-(22-9-2008).pdf

1349-mum-2005-form 2(title page)-(27-10-2005).pdf

1349-mum-2005-form 2(title page)-(granted)-(14-9-2010).pdf

1349-MUM-2005-FORM 3(22-9-2008).pdf

1349-MUM-2005-FORM 5(22-9-2008).pdf

1349-mum-2005-form-1.pdf

1349-mum-2005-form-2.doc

1349-mum-2005-form-2.pdf

1349-mum-2005-form-5.pdf

1349-MUM-2005-GENERAL POWER OF ATTORNEY(2-8-2010).pdf

1349-MUM-2005-PETITION UNDER RULE 137(2-8-2010).pdf

1349-MUM-2005-SPECIFICATION(AMENDED)-(2-8-2010).pdf

abstract1.jpg


Patent Number 242826
Indian Patent Application Number 1349/MUM/2005
PG Journal Number 38/2010
Publication Date 17-Sep-2010
Grant Date 14-Sep-2010
Date of Filing 27-Oct-2005
Name of Patentee WOCKHARDT LIMITED
Applicant Address Wockhardt Towers, Bandra-Kurla Complex, Bandra (East), Mumbai-400051,
Inventors:
# Inventor's Name Inventor's Address
1 RAO,BHATRAJU SREENIVASA Plot NO.24/F1/CIDCO, Aurangabad-431003,
2 MERWADE,ARAVIND YEKANATHSA F-54,Srinagar Colony, CIDCO,N-5,Aurangabad-431003,
3 JAWEED MUKARRAM,SIDDIQUI MOHAMMED House no.4-8-65, Nawabpura,Near Nagina Masjid, Aurangabad-431001,
4 KUMAR YATENDRA Plot No.79,N-4,CIDCO, Aurangabad-431003,
PCT International Classification Number A61K37/407 C07D209/118 C07D209/24
PCT International Application Number N/A
PCT International Filing date
PCT Conventions:
# PCT Application Number Date of Convention Priority Country
1 NA