WO2007039784A2 - A novel crystalline polymorph of fluvastatin sodium and process for preparing it - Google Patents

A novel crystalline polymorph of fluvastatin sodium and process for preparing it Download PDF

Info

Publication number
WO2007039784A2
WO2007039784A2 PCT/IB2005/002962 IB2005002962W WO2007039784A2 WO 2007039784 A2 WO2007039784 A2 WO 2007039784A2 IB 2005002962 W IB2005002962 W IB 2005002962W WO 2007039784 A2 WO2007039784 A2 WO 2007039784A2
Authority
WO
WIPO (PCT)
Prior art keywords
sodium
fluvastatin sodium
heptenoate
indol
methylethyl
Prior art date
Application number
PCT/IB2005/002962
Other languages
French (fr)
Other versions
WO2007039784A3 (en
Inventor
Bhatraju Sreenivasa Rao
Aravind Yekanathsa Merwade
Siddiqui Mohammed Jaweed Mukarram
Yatendra Kumar
Original Assignee
Wockhardt 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 Wockhardt Limited filed Critical Wockhardt Limited
Priority to PCT/IB2005/002962 priority Critical patent/WO2007039784A2/en
Publication of WO2007039784A2 publication Critical patent/WO2007039784A2/en
Publication of WO2007039784A3 publication Critical patent/WO2007039784A3/en

Links

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

Definitions

  • Fluvastatin sodium A novel, stable and highly crystalline polymorphic form of HMG CoA reductase inhibitor Fluvastatin sodium, referred as Fluvastatin sodium form 'W' i s described.
  • the present invention also provides processes for preparing it.
  • 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 racemic mixture of the 3R, 5S and 3S,5R-dihyroxy enantiomers and has the following formula:
  • 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- hyper chlesterolemic, hyperlipoproteinemic agent. Fluvastatin sodium salt was first disclosed in U.S. Patent No. 4,739,073. Fluvastatin sodium is obtained in this patent by lyophilization and discloses amorphous form, which is unstable and unsuitable for the large scale production. U.S. Patent No. 6,124,340 describes that lyophilization of Fluvastatin sodium yields a mixture of crystalline form designated as form A and amorphous material and also discloses new crystalline form designated as Form B.
  • HMG-CoA 3-hydroxy-3-methylglutaryl coenzyme A reductase
  • U.S. Patent No. 6,696,479 discloses 4 new crystalline hydrate forms designated as Form C, D, E and F. The stability of these crystalline forms depends on the relative humidities of the atmosphere.
  • PCT application WO 05/037787 discloses another crystalline form G, it is a liquid crystalline material having moisture content 32%, by a small change in its moisture content it loses its crystallinity.
  • Crystalline hydrate form BA of Fluvastatin that is precipitated by ether as anti solvent is discussed in patent application WO 04/096765.
  • Form W of Sodium [R*,S*-(E )]-( ⁇ )-7-[3-(4- fluorophenyl)-l-(l-methylethyl)-lH -indol-2-yl]-3 ,5-dihydroxy-6-heptenoate is discussed.
  • the W form of the Fluvatatin sodium is prepared by dissolving between about 55 to 60°C in tetahydrofuran, filtering and concentrating followed by addition of anti-solvent, e.g., methyl ethyl ketone or 1-butanol. Volume ratio of anti-solvent varies from 10 to 30 times of the concentrated volume of Fluvastatin sodium.
  • Fluvastatin sodium is dissolved in methanol and crystallized by adding aromatic hydrocarbon, e.g., toluene, xylene etc., preferably toluene or by a ketone, e.g., acetone, methyl ethyl ketone etc. preferably methyl ethyl ketone at low temperature.
  • aromatic hydrocarbon e.g., toluene, xylene etc.
  • a ketone e.g., acetone, methyl ethyl ketone etc. preferably methyl ethyl ketone at low temperature.
  • the crystals of Fluvastatin sodium obtained in the present invention are characterized as Form W based on different X-Ray Diffraction and IR peaks.
  • Figure 1 is an X-Ray Diffraction Pattern (XRD) of Fluvastatin sodium crystallized in a mixture of tetrahydrofuran and methyl ethyl ketone.
  • XRD X-Ray Diffraction Pattern
  • Figure 2 is an X-Ray Diffraction Pattern (XRD) of Fluvastatin sodium crystallized in a mixture of tetrahydrofuran and 1-butanol.
  • XRD X-Ray Diffraction Pattern
  • Figure 3 is an X-Ray Diffraction Pattern (XRD) of Fluvastatin sodium crystallized in a mixture of methanol and methyl ethyl ketone.
  • XRD X-Ray Diffraction Pattern
  • Figure 4 is an X-Ray Diffraction Pattern (XRD) of Fluvastatin sodium crystallized in a mixture of methanol and toluene.
  • XRD X-Ray Diffraction Pattern
  • Figure 5 is an IR Spectrum of Fluvastatin sodium crystallized in a mixture of tetrahydrofuran and methyl ethyl ketone.
  • Figure 6 is an IR Spectrum of Fluvastatin sodium crystallized in a mixture of in a mixture of tetrahydrofuran and 1-butanol.
  • Figure 7 is an IR Spectrum of Fluvastatin sodium crystallized in a mixture of in a mixture of methanol and methyl ethyl ketone.
  • Figure 8 is an IR Spectrum of Fluvastatin sodium crystallized in a mixture of methanol and toluene.
  • 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 its highly crystalline and stable polymorphic form is under taken.
  • the present invention is directed towards different solvent combinations for the preparation of Sodium [R*,S*-(E )]-( ⁇ )-7-[3-(4-fluorophenyl)-l-(l-methylethyl)-lH -indol-2-yl]- 3,5-dihydroxy-6-heptenoate (Fluvastatin sodium).
  • the present invention provides a novel crystalline form of Fluvastatin sodium preferably highly crystalline and stable Fluvastatin sodium Form W.
  • Polymorphic form W of Fluvastatin sodium is characterized by FT-IR and X-Ray Diffraction pattern.
  • Fluvastatin sodium Form W is prepared by using a mixture of organic solvents. According to one embodiment, following methods were employed for the preparation of Fluvastatin sodium Form W:
  • Fluvastatin sodium is suspended in an organic solvent between about 5 to 15 fold volume.
  • Suitable solvent for preparing Fluvastatin sodium Form W include, but are not limited to, ether, e.g., tetrahydrofuran etc. and alcohols, e.g., methanol, ethanol, propanol, isopropanol and butanol etc., preferably methanol.
  • Fluvastatin sodium taken in organic solvent is heated between about 30 to about 7O 0 C, more preferably between 50 to 6O 0 C. The hot solution is filtered and concentrated to a volume of about 1/6* of its original volume.
  • aromatic hydrocarbon or a ketone is added to the methanol containing Fluvastating sodium after concentration.
  • Suitable ketone for this process includes, but not limited to, methyl ethyl ketone and aromatic hydrocarbon tolune or xylene etc. preferably toluene.
  • a ketone or alcohol used for adding to concentrated Fluvastatin sodium solution include, but not limited to, ketone, e.g., acetone, methyl ethyl ketone, etc. , preferably methyl ethyl ketone and suitable alcohol includes, methanol, ethanol, propanol, isopropanol and 1-butanol etc. preferably 1- butanol.
  • the present invention provides, Sodium [R*,S*-(E )]-(+)-7-[3-(4-fluorophenyl)- l-(l-methylethyl)-lH -indol-2-yl]-3,5-dihydroxy-6-heptenoate Form W that is characterized by X-ray diffraction (XRD) having the following peaks at about 3.34, 4.00, 10.98, 12.1, 12.88, 14.84, 15.18, 15.68, 16.24, 17.28, 17.66, 18.22, 18.78, 19.3, 19.58, 20.28, 21.26, 21.7, 22.1, 22.46, 23.74, 24.18, 24.76, 25.28, 25.56, 25.8, 26.28, 26.9, 28.62, 28.72, 28.98, 29.64, 29.8, 29.84, 30.62, 30.8, 32.12, 32.9, 34.66, 35.08, 36.0, 36.12 and 37.0 ⁇
  • FT-IR Spectrum of crystalline form of Fluvastatin sodium Form W is expressed in cm "1 and the peaks are at about 3347, 2994, 2938, 1647,1587,1538,1499, 1455, 1413, 1385, 1345, 1215,1157, 1104,1041,1013,841,740,690 and 566.
  • Fluvastatin sodium (3.0 g) was suspended in THF (30 niL) and heated to 50-55°C for dissolving. The solution was filtered to remove particulate material. The clear solution was added slowly to MEK (60 mL) at ambient temperature and stirred the contents for 1 hour at same temperature then cooled to 0-5 0 C and stirred for 4 hrs. During the cooling, material started crystallizing. The product was filtered and dried in oven at 45- 5O 0 C for 4 hrs which gave 2.0 g of pale yellow crystalline powder of the desired product. XRD showed a novel crystalline Form W of Fluvastatin sodium. Method 2
  • Fluvastatin sodium (2.0 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 minimum (6 mL) and added slowly to MEK (30 mL) at ambient temperature and stirred the contents for 2 hrs at same temperature then cooled to 0-5 0 C and stirred for 48 hrs. The product was filtered and dried in oven at 45-5O 0 C for 4 hrs which gave 1.0 g of pale yellow crystalline powder. XRD showed a novel crystalline Form W of Fluvastatin sodium.
  • Fluvastatin sodium (2.0 g) was suspended in THF (20 mL) and heated to 50 -55 0 C for dissolving. The solution was filtered to remove particulate material. The clear solution was concentrated to minimum (6 mL) and added slowly to 1-butanol (30 mL) at ambient temperature and stirred the contents for 6 hrs at same temperature. The product was filtered and dried in oven at 45-50 0 C for 4 hrs, which gave 1.0 g of off white crystalline powder. XRD showed a novel crystalline form W of Fluvastatin sodium.
  • Fluvastatin sodium (2.0 g) was suspended in methanol (20 mL) and heated to 50-55 0 C for dissolving. The solution was filtered to remove particulate material. The clear solution was concentrated to minimum (6 mL) and added slowly to toluene (30 mL) at ambient temperature and stirred the contents for 3 hrs at same temperature. The contents were cooled to 0-5 0 C and stirred for 4 hrs. The precipitated material was filtered and dried in oven at 45-50 0 C for 4 hrs, which gave 1.0 g of off white crystalline solid. XRD showed a novel crystalline form W.

Abstract

Present invention describes, Sodium [R*,S*-(E )] -(±)-7-[3-(4-fluorophenyl)-1­(1-methylethyl)-1H -indol-2-yl]-3,5-dihydroxy-6-heptenoate Form W and process for preparing it.

Description

A NOVEL CRYSTALLINE POLYMORPH OF FLUVASTATIN SODIUM AND PROCESS FOR PREPARING IT
FIELD OF THE INVENTION
A novel, stable and highly crystalline polymorphic form of HMG CoA reductase inhibitor Fluvastatin sodium, referred as Fluvastatin sodium form 'W' i s described. The present invention also provides processes for preparing it.
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 racemic mixture of the 3R, 5S and 3S,5R-dihyroxy enantiomers and has the following formula:
Figure imgf000002_0001
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- hyper chlesterolemic, hyperlipoproteinemic agent. Fluvastatin sodium salt was first disclosed in U.S. Patent No. 4,739,073. Fluvastatin sodium is obtained in this patent by lyophilization and discloses amorphous form, which is unstable and unsuitable for the large scale production. U.S. Patent No. 6,124,340 describes that lyophilization of Fluvastatin sodium yields a mixture of crystalline form designated as form A and amorphous material and also discloses new crystalline form designated as Form B.
Another U.S. Patent No. 6,696,479 discloses 4 new crystalline hydrate forms designated as Form C, D, E and F. The stability of these crystalline forms depends on the relative humidities of the atmosphere. PCT application WO 05/037787 discloses another crystalline form G, it is a liquid crystalline material having moisture content 32%, by a small change in its moisture content it loses its crystallinity. Crystalline hydrate form BA of Fluvastatin that is precipitated by ether as anti solvent is discussed in patent application WO 04/096765.
U.S. Patent publication 2005/0038114 Al discloses and claims polymorphic forms XVI and LXXX, their characteristics and hydrates of Fluvastatin sodium. AU these patents and patent applications discuss advantages over other patents. However, there is still need of crystalline form which has more stable and easy to handle for formulation under normal environmental conditions. It has been found that Fluvastatin sodium can surprisingly be prepared as novel highly crystalline powder, which is stable and less hygroscopic nature.
SUMMARY OF THE INVENTION
According to present different, Form W of Sodium [R*,S*-(E )]-(±)-7-[3-(4- fluorophenyl)-l-(l-methylethyl)-lH -indol-2-yl]-3 ,5-dihydroxy-6-heptenoate is discussed. The W form of the Fluvatatin sodium is prepared by dissolving between about 55 to 60°C in tetahydrofuran, filtering and concentrating followed by addition of anti-solvent, e.g., methyl ethyl ketone or 1-butanol. Volume ratio of anti-solvent varies from 10 to 30 times of the concentrated volume of Fluvastatin sodium. In another aspect of the this invention, Fluvastatin sodium is dissolved in methanol and crystallized by adding aromatic hydrocarbon, e.g., toluene, xylene etc., preferably toluene or by a ketone, e.g., acetone, methyl ethyl ketone etc. preferably methyl ethyl ketone at low temperature.
The crystals of Fluvastatin sodium obtained in the present invention are characterized as Form W based on different X-Ray Diffraction and IR peaks.
BRIEF DESCRIPTION OF THE DRAWINGS
Figure 1 is an X-Ray Diffraction Pattern (XRD) of Fluvastatin sodium crystallized in a mixture of tetrahydrofuran and methyl ethyl ketone.
Figure 2 is an X-Ray Diffraction Pattern (XRD) of Fluvastatin sodium crystallized in a mixture of tetrahydrofuran and 1-butanol.
Figure 3 is an X-Ray Diffraction Pattern (XRD) of Fluvastatin sodium crystallized in a mixture of methanol and methyl ethyl ketone.
Figure 4 is an X-Ray Diffraction Pattern (XRD) of Fluvastatin sodium crystallized in a mixture of methanol and toluene.
Figure 5 is an IR Spectrum of Fluvastatin sodium crystallized in a mixture of tetrahydrofuran and methyl ethyl ketone.
Figure 6 is an IR Spectrum of Fluvastatin sodium crystallized in a mixture of in a mixture of tetrahydrofuran and 1-butanol.
Figure 7 is an IR Spectrum of Fluvastatin sodium crystallized in a mixture of in a mixture of methanol and methyl ethyl ketone.
Figure 8 is an IR Spectrum of Fluvastatin sodium crystallized in a mixture of methanol and toluene. 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 its highly crystalline and stable polymorphic form is under taken. The present invention is directed towards different solvent combinations for the preparation of Sodium [R*,S*-(E )]-(±)-7-[3-(4-fluorophenyl)-l-(l-methylethyl)-lH -indol-2-yl]- 3,5-dihydroxy-6-heptenoate (Fluvastatin sodium).
In a first embodiment, the present invention provides a novel crystalline form of Fluvastatin sodium preferably highly crystalline and stable Fluvastatin sodium Form W. Polymorphic form W of Fluvastatin sodium is characterized by FT-IR and X-Ray Diffraction pattern.
In the present invention Fluvastatin sodium Form W is prepared by using a mixture of organic solvents. According to one embodiment, following methods were employed for the preparation of Fluvastatin sodium Form W:
Fluvastatin sodium is suspended in an organic solvent between about 5 to 15 fold volume. Suitable solvent for preparing Fluvastatin sodium Form W include, but are not limited to, ether, e.g., tetrahydrofuran etc. and alcohols, e.g., methanol, ethanol, propanol, isopropanol and butanol etc., preferably methanol. Fluvastatin sodium taken in organic solvent is heated between about 30 to about 7O0C, more preferably between 50 to 6O0C. The hot solution is filtered and concentrated to a volume of about 1/6* of its original volume. To the methanol containing Fluvastating sodium after concentration, is added aromatic hydrocarbon or a ketone. Suitable ketone for this process includes, but not limited to, methyl ethyl ketone and aromatic hydrocarbon tolune or xylene etc. preferably toluene. In next embodiment, to the Fluvastatin sodium that is heated in tetrahydrofuran and concentrated, is added a ketone or alcohol. Suitable ketone used for adding to concentrated Fluvastatin sodium solution include, but not limited to, ketone, e.g., acetone, methyl ethyl ketone, etc. , preferably methyl ethyl ketone and suitable alcohol includes, methanol, ethanol, propanol, isopropanol and 1-butanol etc. preferably 1- butanol. After addition of alcohol or toluene to the concentrated solution of Fluvastatin sodium is stirred for few hours between about 0 to about 10°C. Fluvastatin sodium obtained by any of the above process is dried between 45 to 50°C.
The present invention provides, Sodium [R*,S*-(E )]-(+)-7-[3-(4-fluorophenyl)- l-(l-methylethyl)-lH -indol-2-yl]-3,5-dihydroxy-6-heptenoate Form W that is characterized by X-ray diffraction (XRD) having the following peaks at about 3.34, 4.00, 10.98, 12.1, 12.88, 14.84, 15.18, 15.68, 16.24, 17.28, 17.66, 18.22, 18.78, 19.3, 19.58, 20.28, 21.26, 21.7, 22.1, 22.46, 23.74, 24.18, 24.76, 25.28, 25.56, 25.8, 26.28, 26.9, 28.62, 28.72, 28.98, 29.64, 29.8, 29.84, 30.62, 30.8, 32.12, 32.9, 34.66, 35.08, 36.0, 36.12 and 37.0 ± 0.2 degree 2 theta.
The X-Ray diffractogram pattern expressed in terms of angles (2 , degrees), d- values, and relative intensities of Fluvastatin Form W are shown in the table below:
Figure imgf000006_0001
Figure imgf000007_0001
Figure imgf000008_0001
FT-IR Spectrum of crystalline form of Fluvastatin sodium Form W is expressed in cm"1 and the peaks are at about 3347, 2994, 2938, 1647,1587,1538,1499, 1455, 1413, 1385, 1345, 1215,1157, 1104,1041,1013,841,740,690 and 566.
The following examples illustrate the invention, but is not limiting thereof.
EXAMPLE 1
Sodium (±)-7-[3-(4-fluorophenyl)-l-(l-methylethyl)-lH -indol-2-yl]-3, 5-dihydroxy-6- heptenoate (Fluvastatin sodium)
Following methods describe the preparation of Fluvastatin sodium Form W:
Method 1
Fluvastatin sodium (3.0 g) was suspended in THF (30 niL) and heated to 50-55°C for dissolving. The solution was filtered to remove particulate material. The clear solution was added slowly to MEK (60 mL) at ambient temperature and stirred the contents for 1 hour at same temperature then cooled to 0-50C and stirred for 4 hrs. During the cooling, material started crystallizing. The product was filtered and dried in oven at 45- 5O0C for 4 hrs which gave 2.0 g of pale yellow crystalline powder of the desired product. XRD showed a novel crystalline Form W of Fluvastatin sodium. Method 2
Fluvastatin sodium (2.0 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 minimum (6 mL) and added slowly to MEK (30 mL) at ambient temperature and stirred the contents for 2 hrs at same temperature then cooled to 0-50C and stirred for 48 hrs. The product was filtered and dried in oven at 45-5O0C for 4 hrs which gave 1.0 g of pale yellow crystalline powder. XRD showed a novel crystalline Form W of Fluvastatin sodium.
Method 3
Fluvastatin sodium (2.0 g) was suspended in THF (20 mL) and heated to 50 -550C for dissolving. The solution was filtered to remove particulate material. The clear solution was concentrated to minimum (6 mL) and added slowly to 1-butanol (30 mL) at ambient temperature and stirred the contents for 6 hrs at same temperature. The product was filtered and dried in oven at 45-500C for 4 hrs, which gave 1.0 g of off white crystalline powder. XRD showed a novel crystalline form W of Fluvastatin sodium.
Method 4
Fluvastatin sodium (2.0 g) was suspended in methanol (20 mL) and heated to 50-550C for dissolving. The solution was filtered to remove particulate material. The clear solution was concentrated to minimum (6 mL) and added slowly to toluene (30 mL) at ambient temperature and stirred the contents for 3 hrs at same temperature. The contents were cooled to 0-50C and stirred for 4 hrs. The precipitated material was filtered and dried in oven at 45-500C for 4 hrs, which gave 1.0 g of off white crystalline solid. XRD showed a novel crystalline form W.

Claims

We claim:
1 A compound of Formula I
Figure imgf000010_0001
Fluvastatin sodium Form W
2 A pharmaceutical composition comprising compound of Formula I.
3 A crystalline, Sodium (+)-7-[3-(4-fluorophenyl)-l-(l-methylethyl)-lH -indol-2- yl]-3,5-dihydroxy-6-heptenoate Form W, as claimed in claim 1 and characterized by an X-Ray Diffraction (XRD) having the following peaks at about 3.34, 4.00, 10.98, 12.1, 12.88, 14.84, 15.18, 15.68, 16.24, 17.28, 17.66, 18.22, 18.78, 19.3, 19.58, 20.28, 21.26, 21.7, 22.1, 22.46, 23.74, 24.18, 24.76, 25.28, 25.56, 25.8, 26.28, 26.9, 28.62, 28.72, 28.98, 29.64, 29.8, 29.84, 30.62, 30.8, 32.12, 32.9, 34.66, 35.08, 36.0, 36.12 and 37.0 ± 0.2 degree 2 theta.
4 A crystalline, Sodium (+)-7-[3-(4-fluorophenyl)-l-(l-methylethyl)-lH -indol-2- yl]-3,5-dihydroxy-6-heptenoate Form W, as claimed in claim 1 and characterized by an Infra Red Spectrum having the following peaks at about 3347, 2994, 2938, 1647,1587,1538,1499, 1455,1413,1385, 1345, 1215,1157, 1104,1041,1013,841,740,690 and 566 cm"1.
5 A process for the manufacturing Fluvastatin sodium Form W having the Formula I '
Figure imgf000011_0001
Fluvastatin sodium Form W the said method comprising:
(a) contacting Sodium (+)-7-[3-(4-fluorophenyl)-l-(l-methylethyl)-lH -indol-2-yl]- 3,5-dihydroxy-6-heptenoate acid in an organic solvent.
(b) isolating Sodium (±)-7-[3-(4-fluorophenyl)-l-(l-methylethyl)-lH -indol-2-yl]- 3,5-dih.ydroxy-6-heptenoate Form W.
6 The process of claim 5, wherein step (a) is carried out in an organic solvent.
7 The process of claim 6, wherein said organic solvent is ether and alcohol.
8 The process of claim 7, wherein preferably ether is tetrahydrofuran.
9 The process of claim 7, wherein said alcohol is methanol, ethanol, propanol and isopropanol.
10 The process of claim 9, wherein preferably alcohol is methanol.
11 The process of claim 5, wherein Sodium (±)-7-[3-(4-fluorophenyl)-l-(l- methylethyl)-lH -indol-2-yl]-3,5-dihydroxy-6-heptenoate is heated with methanol and is added a ketone or aromatic hydrocarbon to it.
12 The process of claim 11, wherein ketone is methyl ethyl ketone.
13 The process of claim 11, wherein aromatic hydrocarbon is toluene.
14 The process of claim 5, wherein Sodium (±)-7-[3-(4-fluorophenyl)-l-(l- methylethyl)-lH -indol-2-yl]-3,5-dihydroxy-6-heptenoate is heated with tetrahydrofuran followed by addition of a ketone or aromatic hydrocarbon.
15 The process of claim 14, wherein methyl ethyl ketone is added and stirred at low temperature. The process of claim 14, wherein toluene is added and stirred at low temperature. The process of claim 5, wherein Sodium (±)-7-[3-(4-fluorophenyl)-l-(l- methylethyl)-lH -indol-2-yl]-3,5-dihydroxy-6-heptenoate is heated from about 30 to about 7O0C. The process of claim 10, wherein more particularly heating temperature is between about 50 to about 600C.
PCT/IB2005/002962 2005-10-06 2005-10-06 A novel crystalline polymorph of fluvastatin sodium and process for preparing it WO2007039784A2 (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
PCT/IB2005/002962 WO2007039784A2 (en) 2005-10-06 2005-10-06 A novel crystalline polymorph of fluvastatin sodium and process for preparing it

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
PCT/IB2005/002962 WO2007039784A2 (en) 2005-10-06 2005-10-06 A novel crystalline polymorph of fluvastatin sodium and process for preparing it

Publications (2)

Publication Number Publication Date
WO2007039784A2 true WO2007039784A2 (en) 2007-04-12
WO2007039784A3 WO2007039784A3 (en) 2007-11-29

Family

ID=37906537

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/IB2005/002962 WO2007039784A2 (en) 2005-10-06 2005-10-06 A novel crystalline polymorph of fluvastatin sodium and process for preparing it

Country Status (1)

Country Link
WO (1) WO2007039784A2 (en)

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6696479B2 (en) * 2001-08-03 2004-02-24 Ciba Specialty Chemicals Corporation Crystalline forms

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6696479B2 (en) * 2001-08-03 2004-02-24 Ciba Specialty Chemicals Corporation Crystalline forms

Also Published As

Publication number Publication date
WO2007039784A3 (en) 2007-11-29

Similar Documents

Publication Publication Date Title
US20080234302A1 (en) Novel Processes for Preparing Amorphous Rosuvastatin Calcium and a Novel Polymorphic Form of Rosuvastatin Sodium
JP2004516311A (en) Atorvastatin crystal
US8722722B2 (en) Raltegravir salts and crystalline forms thereof
US6858643B2 (en) Crystalline forms of Fluvastatin sodium
AU2002223639A1 (en) Crystalline forms of fluvastatin sodium
WO2013171756A1 (en) Amorphous form of linagliptin and process for preparation thereof
EA010166B1 (en) Polymorphs of atorvastatin tert.-butylester and use as intermediates for the preparation of atorvastatin
US20070155765A1 (en) Method of preparation of the hemi-calcium salt of (e)-7-[4-(4fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonvl)aminolpyrimidin-5-yl](3r,5s)-3,5-, dihvdroxy-6-heptenoic acid
US20090099371A1 (en) Process for the preparation of amorphous atorvastatin calcium salt
WO2006092809A1 (en) PROCESS FOR PRODUCING POLYMORPH FORM (I) OF l-BENZYL-4- [(5, 6-DIMETHOXY-l-INDANONE) -2YL] METHYL PIPERIDINE HYDROCHLORIDE (DONEPEZIL HYDROCHLORIDE)
WO2007039784A2 (en) A novel crystalline polymorph of fluvastatin sodium and process for preparing it
US20100125149A1 (en) Ibandronate sodium polymorphs
WO2004096765A2 (en) A novel crystalline polymorph of fluvastatin sodium and a process for preparing it
NZ531993A (en) New anhydrous crystalline forms of gabapentin
US20110046396A1 (en) Polymorphic forms of fluvastatin sodium and process for preparing the same
WO2012025939A1 (en) Pitavastatin calcium and process for its preparation
EP3166929A1 (en) Polymorphic forms of pitavastatin sodium
EP2888231A2 (en) Process for preparation of crystalline etoricoxib
US8115013B2 (en) Process for the preparation of amorphous fluvastatin sodium
WO2005080332A1 (en) Novel form of fluvastatin sodium
AU2013204129B2 (en) Crystal Form of Quinoline Compound and Process for its Production
US20080171884A1 (en) Novel Polymorph Form G of Fluvastatin Sodium and Process For the Preparation Thereof
WO2006048888A1 (en) Novel process for the preparation of amorphous atorvastatin calcium salt
WO2006021967A1 (en) Process for the preparation of fluvastatin sodium form a.
WO2003104212A1 (en) A novel amorphous form of [2-[4-[(4-chlorophenyl)-phenyl methyl]-1- piperazinyl] ethoxy] acetic acid dihydrochloride (cetirizine dihydrochloride)

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application
NENP Non-entry into the national phase in:

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 05817087

Country of ref document: EP

Kind code of ref document: A2