WO2006021967A1 - Process for the preparation of fluvastatin sodium form a. - Google Patents
Process for the preparation of fluvastatin sodium form a. Download PDFInfo
- Publication number
- WO2006021967A1 WO2006021967A1 PCT/IN2004/000263 IN2004000263W WO2006021967A1 WO 2006021967 A1 WO2006021967 A1 WO 2006021967A1 IN 2004000263 W IN2004000263 W IN 2004000263W WO 2006021967 A1 WO2006021967 A1 WO 2006021967A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- fluvastatin sodium
- preparation
- fluvastatin
- sodium form
- amorphous
- Prior art date
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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
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
Definitions
- the instant invention relates to a novel process for the preparation of the HMG-CoA reductase inhibitor, fluvastatin, more specifically to a process for the preparation of crystalline form A of fluvastatin sodium.
- Fluvastatin of which the full chemical name is R*, S*-(E)-(. +-.)-7-[3- (4-fluorophenyl)-l-(l-methyl-ethyl)-lH-indol-2-yl]-3,5- dihydroxy-6-heptenoic acid, as well as its sodium salt, are disclosed in EP-A-O 114 027.
- Fluvastatin is an inhibitor of 3-hydroxy-3-methyl-glutaryl coenzyme A (HMG-CoA) reductase, which is a key enzyme in the regulation of cholesterol biosynthesis.
- Fluvastatin can be used pharmaceutically particularly as a hypercholesterolemic, hyperlipoproteinemic and antiatherosclerotic agent.
- the present invention relates to a novel process for the preparation fluvastatin form A.
- Polymorphism is the existence of more than one crystal structure for a compound. Since properties can and do vary with crystal structure, polymorphism can influence many important properties of pharamceuticals: bioavailability, dissolution rate, compressibility, solubility, stability, filtering and drying characteristics etc. Different combination of experimental techniques (microscopy, variable temperature X-ray structure determination, spectroscopic and calorimetric methods) are used to discover, prepare, characterize, and study polymorphs of compounds of pharamceutical importance.
- polymorphism during heating and this refers to the generation of thermodynamically unstable melting forms. These polymorphic forms can be produced due to the given thermal history of the material. Different polymorphic forms can have differing solubilities and this can have a potentially major effect on the bioavailability of the drug when ingested. One polymorphic form may dissolve rapidly while another is very slow to dissolve. It is essential to screen pharmaceuticals for polymorphism for process optimization and for quality assurance purposes.
- Fluvastatin sodium is specifically claimed as a substance in patent US 5,354,772.
- Fluvastatin sodium Polymorphic forms of Fluvastatin sodium are claimed in various patent applications viz. WO 97/49681, WO 02/36563 and WO 03/013512.
- WO 97/49681 (equivalent patents US 6,124,340 and EP 0 907 639) claims fluvastatin sodium crystalline form B.
- the PCT publication has compared properties of form B with form A.
- the form A could be obtained by lyophilization process disclosed in U.S. Pat. No. 4,739,073.
- Several of these prior art process often result in a mixture of amorphous form and different crystalline form.
- the present invention provides a robust process for the preparation of fluvastatin sodium form A without any formation amorphous fluvastatin sodium.
- the form A of fluvastatin sodium thus prepared is chemically stable which overcomes all problems shown in prior art.
- the invention relates to a novel process for the preparation of fluvastatin sodium form A comprising: a) Treating amorphous or any form of fluvastatin sodium with a mixture of water and acetonitrile b) Isolating the product as fluvastatin sodium form A.
- FIG. 1 X-ray powder diffractogram of fluvastatin sodium form A. DETAILED DESCRIPTION OF THE INVENTION
- the present invention relates to a novel process for the preparation of the HMG-CoA reductase inhibitor, fluvastatin, more specifically to a process for the preparation of crystalline form A of fluvastatin sodium.
- the process for the preparation of fluvastatin sodium form A comprising of: (a) treating fluvastatin sodium with a mixture of water and a water miscible solvent, and
- step (a) The process of for the preparation of fluvastatin sodium form A where fluvastatin used in step (a) is selected from amorphous or any other crystalline forms.
- Fluvastatin sodium form A thus prepared by the instant process is chemically stable and stable against exposure to light.
- the fluvastatin sodium form A can be prepared from amorphous or any other crystalline polymorphic form of fluvastatin sodium.
- amorphous or any other crystalline of fluvastatin sodium can be dissolved or suspended in a mixture of water and acetonitrile.
- Fluvastatin sodium form A can be isolated by filtration.
- the process is environmentally friendly.
- Fluvastatin sodium form B (500 g) was suspended in a mixture of water
- Amorphous Fluvastatin sodium 500 g was suspended in a mixture of water (100 ml) and acetonitrile (6 L) and stirred at room temperature for 8 h. The product was filtered and dried. The XRD pattern showed that the product corresponds to polymorphic Form A, as disclosed in WO 97/49681. Yield: 450 g
Abstract
The present invention relates to a novel process for the preparation of the HMG-CoA reductase inhibitor, fluvastatin, more specifically to a process for the preparation of crystalline form A of fluvastatin sodium.
Description
TITLE OF THE INVENTION
A process for the preparation of fluvastatin sodium form A.
FIELD OF THE INVENTION
The instant invention relates to a novel process for the preparation of the HMG-CoA reductase inhibitor, fluvastatin, more specifically to a process for the preparation of crystalline form A of fluvastatin sodium. BACKGROUND OF THE INVENTION
Fluvastatin, of which the full chemical name is R*, S*-(E)-(. +-.)-7-[3- (4-fluorophenyl)-l-(l-methyl-ethyl)-lH-indol-2-yl]-3,5- dihydroxy-6-heptenoic acid, as well as its sodium salt, are disclosed in EP-A-O 114 027. Fluvastatin is an inhibitor of 3-hydroxy-3-methyl-glutaryl coenzyme A (HMG-CoA) reductase, which is a key enzyme in the regulation of cholesterol biosynthesis. Fluvastatin can be used pharmaceutically particularly as a hypercholesterolemic, hyperlipoproteinemic and antiatherosclerotic agent.
The present invention relates to a novel process for the preparation fluvastatin form A. Polymorphism is the existence of more than one crystal structure for a compound. Since properties can and do vary with crystal structure, polymorphism can influence many important properties of pharamceuticals: bioavailability, dissolution rate, compressibility, solubility, stability, filtering and drying characteristics etc. Different combination of experimental techniques (microscopy, variable temperature X-ray structure determination, spectroscopic and calorimetric methods) are used to discover, prepare, characterize, and study polymorphs of compounds of pharamceutical importance.
Many pharmaceutical materials exhibit polymorphism during heating and this refers to the generation of thermodynamically unstable melting forms. These polymorphic forms can be produced due to the given thermal history of the material. Different polymorphic forms can have differing solubilities and this can have a potentially major effect on the bioavailability of the drug when ingested. One polymorphic form may dissolve rapidly while another is very
slow to dissolve. It is essential to screen pharmaceuticals for polymorphism for process optimization and for quality assurance purposes.
Fluvastatin sodium is specifically claimed as a substance in patent US 5,354,772.
Polymorphic forms of Fluvastatin sodium are claimed in various patent applications viz. WO 97/49681, WO 02/36563 and WO 03/013512.
WO 97/49681 (equivalent patents US 6,124,340 and EP 0 907 639) claims fluvastatin sodium crystalline form B. The PCT publication has compared properties of form B with form A. In accordance to WO 97/49681, the form A could be obtained by lyophilization process disclosed in U.S. Pat. No. 4,739,073. Several of these prior art process often result in a mixture of amorphous form and different crystalline form.
The present invention provides a robust process for the preparation of fluvastatin sodium form A without any formation amorphous fluvastatin sodium. The form A of fluvastatin sodium thus prepared is chemically stable which overcomes all problems shown in prior art. SUMMARY OF THE INVENTION
The invention relates to a novel process for the preparation of fluvastatin sodium form A comprising: a) Treating amorphous or any form of fluvastatin sodium with a mixture of water and acetonitrile b) Isolating the product as fluvastatin sodium form A. BRIEF DESCRIPTION OF THE DRAWINGS
FIG. 1: X-ray powder diffractogram of fluvastatin sodium form A. DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a novel process for the preparation of the HMG-CoA reductase inhibitor, fluvastatin, more specifically to a process for the preparation of crystalline form A of fluvastatin sodium.
The process for the preparation of fluvastatin sodium form A comprising of:
(a) treating fluvastatin sodium with a mixture of water and a water miscible solvent, and
(b)isolating the fluvastatin sodium form A. The process further comprising
(c)subjecting the isolated fluvastatin sodium form A to drying. The process for the preparation of fluvastatin sodium form A has an
XRD pattern as shown in FIG. 1.
The process of for the preparation of fluvastatin sodium form A where fluvastatin used in step (a) is selected from amorphous or any other crystalline forms. The process where the water miscible solvent in step (a) is acetonitrile.
The process for the preparation of fluvastatin sodium form A where the fluvastatin form A in step (b) is isolated by filtration.
The process for the preparation of fluvastatin sodium form A, where the fluvastatin form A is vacuum dried. Fluvastatin sodium form A thus prepared by the instant process is chemically stable and stable against exposure to light.
The fluvastatin sodium form A can be prepared from amorphous or any other crystalline polymorphic form of fluvastatin sodium.
Thus, amorphous or any other crystalline of fluvastatin sodium can be dissolved or suspended in a mixture of water and acetonitrile. Fluvastatin sodium form A can be isolated by filtration.
The instant invention has following advantages over prior art:
1. The process is robust resulting in form A only.
2. The product prepared by the process is chemically stable. 3. The process is simple and economic
4. The process does not require costly instruments like lyophilizer.
5. The process is environmentally friendly.
The present invention is further illustrated by the following non-limiting examples.
EXAMPLES EXAMPLE 1
Fluvastatin sodium form B (500 g) was suspended in a mixture of water
(120 ml) and acetonitrile (8 L) and stirred at room temperature for 15 h. The product was filtered and dried. The XRD pattern showed that the product corresponds to polymorphic Form A, as disclosed in WO 97/49681. Yield 460
9- EXAMPLE 2
Amorphous Fluvastatin sodium (500 g) was suspended in a mixture of water (100 ml) and acetonitrile (6 L) and stirred at room temperature for 8 h. The product was filtered and dried. The XRD pattern showed that the product corresponds to polymorphic Form A, as disclosed in WO 97/49681. Yield: 450 g
Claims
1. A process for the preparation of fluvastatin sodium form A comprising of:
(a) treating fluvastatin sodium with a mixture of water and a water miscible solvent, and (b)isolating the fluvastatin sodium form A.
2. A process of claim 1, further comprising
(c)subjecting the isolated fluvastatin sodium form A to drying.
3. A process of claim 1, wherein the fluvastatin sodium form A has an XRD pattern as shown in FIG. 1.
4. A process of claim 1, wherein fluvastatin sodium used in step (a) is selected from amorphous or any other crystalline forms.
5. A process of claim 1, wherein the water miscible solvent in step (a) is acetonitrile.
6. A process of claim 1, wherein the fluvastatin sodium form A in step (b) is isolated by filtration.
7. A process of claim 2, wherein the fluvastatin sodium form A is vacuum dried.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| PCT/IN2004/000263 WO2006021967A1 (en) | 2004-08-26 | 2004-08-26 | Process for the preparation of fluvastatin sodium form a. |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| PCT/IN2004/000263 WO2006021967A1 (en) | 2004-08-26 | 2004-08-26 | Process for the preparation of fluvastatin sodium form a. |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| WO2006021967A1 true WO2006021967A1 (en) | 2006-03-02 |
Family
ID=35967197
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| PCT/IN2004/000263 WO2006021967A1 (en) | 2004-08-26 | 2004-08-26 | Process for the preparation of fluvastatin sodium form a. |
Country Status (1)
| Country | Link |
|---|---|
| WO (1) | WO2006021967A1 (en) |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1997049681A1 (en) * | 1996-06-24 | 1997-12-31 | Astra Aktiebolag (Publ) | Polymorphic compounds |
| WO2002036563A1 (en) * | 2000-10-31 | 2002-05-10 | Ciba Specialty Chemicals Holding Inc. | Crystalline forms of fluvastatin sodium |
| US6696479B2 (en) * | 2001-08-03 | 2004-02-24 | Ciba Specialty Chemicals Corporation | Crystalline forms |
-
2004
- 2004-08-26 WO PCT/IN2004/000263 patent/WO2006021967A1/en active Application Filing
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1997049681A1 (en) * | 1996-06-24 | 1997-12-31 | Astra Aktiebolag (Publ) | Polymorphic compounds |
| WO2002036563A1 (en) * | 2000-10-31 | 2002-05-10 | Ciba Specialty Chemicals Holding Inc. | Crystalline forms of fluvastatin sodium |
| US6696479B2 (en) * | 2001-08-03 | 2004-02-24 | Ciba Specialty Chemicals Corporation | Crystalline forms |
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