WO2007099552A2

WO2007099552A2 - Novel crystalline form of atovastatin hemi-magnesium

Info

Publication number: WO2007099552A2
Application number: PCT/IN2007/000063
Authority: WO
Inventors: Gogulapati Venkata Panakala Rao; Chavakula Ramdas; Bandari Mohan; Gorantla Seeta Ramanjaneyulu
Original assignee: Matrix Labaratories Ltd
Priority date: 2006-03-02
Filing date: 2007-02-20
Publication date: 2007-09-07
Also published as: WO2007099552A3

Abstract

The present invention relates to a novel crystalline form of Atorvastatin hemi-magnesium and it further relates to a process for preparation of the same through the formation of Atorvastatin hemi-magnesium isopropanol solvate.

Description

"Novel crystalline form of Atorvastatin hemi-magnesium"

Field of the Invention: The present invention relates to a novel crystalline form, solvate and the process for preparation of Atorvastatin hemi-magnesium.

Background of the Invention: Atorvastatin hemi-magnesium is known by the chemical name { [R-(R* ,R*)]-2-(4- Fluorophenyl)-β ,δ-dihydroxy-5 -( 1 -methyl ethyl)-3 -phenyl-4- [(phenylamino)carbonyl] - 1 H- pyrrole-1-heptanoicacid} magnesium salt (2:1). Atorvastatin has the following formula.

Atorvastatin

Atorvastatin as its hemi-calcium trihydrate, {[R-(R*,R*)]-2-(4-Fluorophenyl)-β,δ- dihydroxy-5-(l-methylethyl)-3-phenyl-4-[(phenylamino)carbonyl]-lH-pyrrole-l-heptanoic acid} calcium salt trihydrate has been marketed as Lipitor, used for the inhibition of biosynthesis of cholesterol.

U.S. Pat No. 4,681,893 first disclosed and claimed Atorvastatin. U.S. Pat. No. 5,273,995 disclosed Atorvastatin hemi calcium salt and it also disclosed the process for preparation of Atorvastatin hemi calcium salt by hydrolysis of lactone with sodium hydroxide in aq.methanol and treatment with aqueous calcium chloride. U.S. Pat. No. 4,681,893 further discloses the pharmaceutically acceptable metal or amine salts of ring-opened hydroxy acids, process for preparation and their pharmaceutical compositions, method of inhibiting the biosynthesis of cholesterol employing such pharmaceutical compositions. The disclosed pharmaceutically acceptable metal salts contemplate the salts formed with sodium, potassium, calcium, magnesium, aluminum, iron and zinc ions.

U.S. Pat. No 5,273,995 discloses pharmaceutically acceptable salts of [R-(R*, R*)] -2-(4- fluoroρhenyl)-β,δ-dihydroxy-5-((l-methylethyl)-3-ρhenyl-4-[(ρhenylamino)carbonyl]-lH- pyrrole- 1 -heptanoic acid, (2R-trans)-5-(4-fluorophenyl)-2-( 1 -methylethyl)-N,4-diphenyl- 1 - [2-(tetrahydro-4-hydroxy-6-oxo-2H-pyran-2-yl)ethy 1] - 1 H-pyrrole-3 -carboxamide (the lactone form of the heptanoic acid), pharmaceutical composition and the process for preparation thereof.

The disclosed pharmaceutically acceptable salts are derived by dissolving free acid or the lactone; preferably the lactone in aqueous or aqueous alcohol solvent or other suitable solvents with an appriopriate base such as lithium hydroxide, sodium hydroxide, potassium hydroxide, calcium hydroxide, l-deoxy-2(methylamino)-D-glucitol, magnesium hydroxide, zinc hydroxide, aluminum hydroxide or organic amines such as N-methylglucamine, choline, arginine and the like.

U.S. Pat. No. 5,273,995 discloses the process for preparation of calcium salt, N- methylglucamine salts of free acid. '995 patent also discloses that salts like potassium salt, hemi-magnesium salt, hemi-zinc salt or the l-deoxy-2(methylamino)-D-glucitol complex can be prepared analogously. The disclosed process for preparation of hemi-calcium salt involves the hydrolysis of lactone with sodium hydroxide in aqueous methanol and the resulted free acid is converted to its hemi-calcium salt by the slow addition of aqueous calcium chloride. However the crystallinity of the salts prepared has not been disclosed. The prior art disclosed the process starting from the lactone. Thus there is a need of the industry for a process to prepare Atorvastatin hemi-magnesium salt without the isolation of lactone and carboxylic acid.

Summary of the invention:

In one general aspect there is provided a process for the preparation of Atorvastain hemi- magnesium salt and the process steps include

a) hydrolysis of (4R-Cis)-6-[2-(3-phenyl-4-(phenyl-carbomoyl)-(4-fluoro-phenyl)-5-

( 1 -methylethyl)-pyrrol- 1 -yl)-ethyl]-2,2-dimethyl] [ 1 ,3]dioxane-4-yl)-acetic acid tertbutyl ester of formula I

Formula I b) treating with magnesium acetate gives the amorphous Atorvastatin hemi-magnesium salt

In another aspect of there is provided a crystalline polymorphic form of Atorvastatin hemi- magnesium salt (hereinafter designated as Form A)

Atorvastatin hemi-magnesium form A exhibits the X-ray powder diffraction pattern as depicted in Figure I, and the differential scanning calorimetry profile as depicted in Figure II. In another aspect of there is provided a process for the preparation of Atorvastatin hemi- magnesium form A via the formation of Atorvastatin hemi-magnesium isopropanol solvate

Brief description of the drawings:

Fig I is the XRD pattern of Atorvastatin hemi-magnesium Form A

Fig II is the DSC thermogram of Atorvastatin hemi-magnesium Form A

Fig III is the XRD pattern of Atorvastatin hemi-magnesium isopropanol solvate

Fig IV is the DSC thermogram of Atorvastatin hemi-magnesium isopropanol solvate

Detailed description of the invention:

Thus in accordance with the present invention Atorvastatin hemi-magnesium is prepared by treating (4R-Cis)-6-[2-(3-phenyl-4-(ρhenyl-carbomoyl)-(4-fluoro-phenyl)-5-(l -methyl ethyl)-pyrrol-l-yl)-ethyl]-2,2-dimethyl][l,3]dioxane-4-yl)-acetic acid tert.butyl ester in methanol with Hydrochloric acid preferably IN hydrochloric acid at temperature of 20 - 25⁰C for about 2 to 4 hrs. To the reaction mixture sodium hydroxide solution is added and maintained at temperature of 20-25⁰C for about 2 to 6 hrs. Reaction mass pH is adjusted to slightly basic to neutral with hydrochloric acid. Reaction mass is concentrated by distillation of methanol and water preferably under vacuum at temperature below 45⁰C to about half to one-third of its original volume. Optionally the resulted mass is seeded with Atorvastatin hemi-magnesium at temperature of about 10 to 55⁰C, preferably at about 25 to 45⁰C and magnesium acetate preferably as aqueous solution is added at a temperature of about 10 to 55⁰C, preferably at about 25 to 45⁰C. To the reaction mixture water is added and maintained for about 2 to 8 hrs at temperature of 10 to 55⁰C preferably at 15 to 35⁰C. The precipitated product is isolated and washed the wet cake with water and dried to get the amorphous form of Atorvastatin hemi-magnesium. The above obtained amorphous Atorvastatin hemi-magnesium is dissolved in 3 to 12 volumes of methanol with reference to Atorvastatin hemi-magnesium at a temperature of 20 to 65⁰C preferably at a temperature of about 20 to 40⁰C. The obtained solution is filtered to remove the insolubles. To the clear filtrate water about 1 volume to 4 volumes is added at temperature of about 2O⁰C to 40⁰C and maintained at about 2O⁰C to 4O⁰C for about 1 to 4 hrs. The reaction mass is concentrated to remove methanol under vacuum at temperature preferably below 45⁰C. The concentrated mass is cooled and isopropanol about 3 to 8 volumes is added and maintained for about 1 to 8 hrs preferably for about 4 hrs. The reaction mass is optionally further diluted with about 1 to 4 volumes of isopropanol and the product is isolated. The wet cake is washed with isopropanol to get the Atorvastatin hemi-magnesium isopropanol solvate.

The above obtained Atorvastatin hemi-magnesium isopropanol solvate has the characteristic peaks at 2 theta values of 8.6, 11.5, 18.3, 18.9, 23.1, 28.1 ± 0.2 in PXRD, contains about 15,000 to about 45,000 ppm of isopropanol. The crystalline Atorvastatin hemi-magnesium, isopropanol solvate is in the form of anhydrous or hydrate form containing water about 1.5 to about 6% w/w.

Atorvastatin hemi-magnesium isopropanol solvate is converted to Atorvastatin hemi- magnesium form A by

• Suspending Atorvastatin hemi-magnesium isopropanol solvate in water

• Maintaining the suspension at room temperature

• Filtering the wet material and washing with water

• Drying the product below 55⁰C to get Atorvastatin hemi-magnesium form A

Atorvastatin hemi-magnesium form A obtained above exhibits the characteristic 2 theta values at 9.0, 10.0, 11.6, 18.3, 21.5, 27.9 ± 0.2 deg in powdered XRD pattern.

Crystalline Atorvastatin hemi-magnesium form A can also be prepared by - Dissolving Atorvastatin hemi-magnesium in a mixture of water and water miscible solvent selected from the group methanol, ethanol, isopropanol, n-propanol and acetone at about 3O⁰C to reflux temperature of solvent

- Treating the above solution with activated carbon - Cooling the mass to 10⁰C - 30⁰C

Adding water to the above obtained solution till turbidity appears

- Cooling the mass to about 10⁰C to 2O⁰C and maintaining at the same temperature isolating the product and drying at temperature of 40 to 55⁰C to get Atorvastatin hemi-magnesium form A

The crystalline polymorphic form of Atorvastatin hemi-magnesium has the characteristic 2 theta values at 9.0, 10.0, 11.6, 18.3, 21.5 (br), 27.9 (br) ± 0.2 deg in powdered X-ray diffraction pattern.

The required 4(4R-CIS)-6-[2-(3-phenyl-4-(phenyl-carbomoyl)-(4-fluoro-phenyl)-5-(l- methylethyl)-pyrrol-l-yl)-ethyl]-2,2-dimethyl][l,3]dioxane-4-yl)-acetic acid tert.butyl ester can be obtained commercially or can be prepared by reported prior art methods.

The invention is further illustrated with a few non-limiting examples

Example 1: Preparation of Crystalline Atorvastatin hemi-magnesium

Step-I: Preparation of amorphous Atorvastatin hemi-magnesium (4R-Cis)-6-[2-(3-phenyl-4-(phenyl-carbomoyl)-(4-fluoro-phenyl)-5-(l-methylethyl)- pyrrol-l-yl)-ethyl]-2,2-dimethyl][l,3]dioxane-4-yl)-acetic acid tert.butyl ester (120 gm) is suspended in methanol (2520 ml) and stirred for 10 min. at about 35⁰C. The reaction mass is cooled to 20 - 25⁰C and IN Hydrochloric acid (240 ml) is added over 45 min. The reaction mass is maintained for 3 hrs at 20 - 25⁰C and 10% sodium hydroxide solution ( 252 ml) is added and maintained for 3 hrs at 20 - 25⁰C. pH of the reaction mass is adjusted to 7.6 with 6N hydrochloric acid (20 ml). Reaction mass is treated with activated carbon (3.7 gm) and filtered. The clear filtrate is concentrated to about l/3rd of its original volume below 45⁰C under vacuum and aqueous magnesium acetate solution (21.6 gm in 95 ml water) is added at temperature of 25 - 3O⁰C over 20 min. To the reaction mass water (950 ml) is added over 10 min and maintained for 4 hrs at 25 - 3O⁰C. The precipitated product is filtered; wet cake is washed with water (100 ml) and dried at 40 - 45⁰C under vacuum to get amorphous Atorvastatin hemi-magnesium. Yield: 83 gm. Water content: 5.86% w/w

Step-2: Preparation of Atorvastatin hemi magnesium isopropanol solvate

Water (115 ml) is added to a solution of Atorvastatin hemi-magnesium (82 gm) in methanol (328 ml) at temperature of 25 - 3O⁰C and maintained for 2 hrs. Solvent is distilled off under vacuum below 45⁰C. Reaction mass is cooled, isopropanol (410 ml) is added and maintained at temperature of 25 - 3O⁰C for 4 hrs. To the reaction mass 2^nd lot of isopropanol (164 ml) is added and maintained for 15 min. The precipitated product is filtered; wet cake is washed with isopropanol (120 ml) and dried at 50 - 55⁰C under vacuum to get Atorvastatin hemi magnesium isopropanol solvate. Yield: 60 gm

Isopropanol content is 41,000 ppm, water content is 3.10% w/w

Step-3: Preparation of Crystalline Atorvastatin hemi-magnesium (from Isopropanol solvate)

Atorvastatin hemi-magnesium isopropanol solvate (60 gm) is suspended in water (480 ml).the resultant suspension is maintained for 30 min at 25 - 3O⁰C and filtered. The filtered product is washed with water (100 ml)) and dried at 50 - 55⁰C under vacuum to get crystalline Atorvastatin hemi-magnesium form A. Yield: 54.0 gm

Water content is 4.48% w/w Example 2: Preparation of Crystalline Atorvastatin hemi-magnesium

Atorvastatin hemi-magnesium (20 gm) is suspended in a mixture of ethanol (100 ml), water (100 ml); temperature of reaction mass is raised and maintained at 50 - 55⁰C for 30 min. The reaction mass is filtered and to the clear filtrate water (40 ml) is added and cooled the solution slowly to 20 - 25⁰C over a period of 1 hr. Reaction mass is maintained for lhr, further cooled and maintained at temperature of 0 - 5⁰C for 2 hrs. Product is filtered; wet cake is washed with mixture of ethanol and water (4:6, 50 ml) and dried at temperature of 50 - 55⁰C under vacuum to get crystalline Atorvastatin hemi-magnesium form A. Yield: 17 gm

Water content is 4.37% w/w

Claims

We claim:

1. Crystalline form A of Atorvastatin hemi-magnesium

2. Crystalline form A of Atorvastatin hemi-magnesium of claim 1, further characterized by an X-ray powder diffraction pattern having peaks at about 9.0, 10.0, 11.6, 18.3, 21.5, 27.9 ± 0.2 degrees two-theta

3. Crystalline form A of Atorvastatin hemi-magnesium of claim 1, which exhibits characteristic X-ray powder diffraction pattern as depicted in Fig. 1

4. Crystalline form A of Atorvastatin hemi-magnesium of claim 1 , which exhibits DSC thermogram as depicted in Fig. 2

5. A process for the preparation of crystalline Atorvastatin hemi-magnesium comprises

- Treating (4R-Cis)-6-[2-(3-phenyl-4-(phenyl-carbomoyl)-(4-fluoro-phenyl)-5- ( 1 -methyl ethyl)-pyrrol- 1 -yl)-ethyl] -2,2-dimethyl] [1,3] dioxane-4-yl)-acetic acid tert.butyl ester with HCl followed by sodium hydroxide solution - Concentrating the reaction mass under vacuum at slightly basic or under neutral condition

Adding magnesium acetate at temperature of about 10 to 55⁰C, Optionally adding water and maintaining the reaction mass for about 2 to 8 hrs at temperature of 10 to 55⁰C preferably at 15 to 35⁰C. - Isolating the precipitated Atorvastatin hemi-magnesium.

- Dissolving Atorvastatin hemi-magnesium in methanol at a temperature of about 20 to 65⁰C.

- Filtering the mass and adding water at about 2O⁰C to 4O⁰C

- Concentrating the reaction mass. - Adding isopropanol and isolating the Atorvastatin hemi-magnesium isopropanol solvate - Treating the Atorvastatin hemi-magnesium isopropanol solvate with water

- Isolating and drying the product to get Atorvastatin hemi-magnesium form A

6. A process for the preparation of crystalline Atorvastatin hemi-magnesium form A comprises

- Dissolving Atorvastatin hemi-magnesium in a mixture of water and water miscible solvent selected from the group methanol, ethanol, isopropanol, n-propanol and acetone

- Diluting the mass with water - Isolating the product and drying to get Atorvastatin hemi-magnesium form A

7. Atorvastatin hemi-magnesium isopropanol solvate

8. Atorvastatin hemi-magnesium isopropanol solvate of claim 7, further characterized by an X-ray powder diffraction pattern having peaks at about 8.6, 11.5, 18.3, 18.9,

23.1, 28.1 ± 0.2 degrees two-theta

9. Atorvastatin hemi-magnesium isopropanol solvate of claim 7, which exhibits characteristic X-ray powder diffraction pattern as depicted in Fig. 3

10. Atorvastatin hemi-magnesium isopropanol solvate of claim 7, which exhibits DSC thermogram as depicted in Fig. 4