WO2005021511A1 - A novel process for amorphous rosuvastatin calcium - Google Patents

A novel process for amorphous rosuvastatin calcium Download PDF

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Publication number
WO2005021511A1
WO2005021511A1 PCT/IN2003/000288 IN0300288W WO2005021511A1 WO 2005021511 A1 WO2005021511 A1 WO 2005021511A1 IN 0300288 W IN0300288 W IN 0300288W WO 2005021511 A1 WO2005021511 A1 WO 2005021511A1
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WO
WIPO (PCT)
Prior art keywords
rosuvastatin calcium
solvent
amorphous
ketone
amorphous rosuvastatin
Prior art date
Application number
PCT/IN2003/000288
Other languages
French (fr)
Inventor
Bandi Parthasaradhi Reddy
Kura Rathnakar Reddy
Rapolu Raji Reddy
Dasari Muralidhara Reddy
Original Assignee
Hetero Drugs 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 Hetero Drugs Limited filed Critical Hetero Drugs Limited
Priority to AU2003269478A priority Critical patent/AU2003269478A1/en
Priority to PCT/IN2003/000288 priority patent/WO2005021511A1/en
Publication of WO2005021511A1 publication Critical patent/WO2005021511A1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
    • C07D239/32—One oxygen, sulfur or nitrogen atom
    • C07D239/42—One nitrogen atom
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim

Definitions

  • the present invention provides a novel process for the preparation of amorphous rosuvastatin calcium.
  • (+)-7-[4-(4-f!uorophenyl)-6-isopropyl-2-(N-methyl-N-methyl sulfonyl amino)pyrimidin-5-yl]-(3R,5S)-dihydroxy-(E)-6-heptenoic acid and its salts are 3- hydroxy-3-methyl-glutaryl coenzyme A (HMG-CoA) reductase inhibitors and useful in the treatment of hypercholesterolemia, hyperlipoproteinemia and atherosclerosis.
  • HMG-CoA 3- hydroxy-3-methyl-glutaryl coenzyme A reductase inhibitors and useful in the treatment of hypercholesterolemia, hyperlipoproteinemia and atherosclerosis.
  • HMG-CoA 3- hydroxy-3-methyl-glutaryl coenzyme A
  • WO 00/42024 disclosed a crystalline form (form A) of rosuvastatin calcium.
  • Various crystalline salts of rosuvastatin were disclosed in WO 01/60804.
  • the amorphous form produced by the novel process has better dissolution characteristics than the crystalline form known in the art.
  • the object of the present invention is to provide a novel process for the preparation of amorphous rosuvastatin calcium and a pharmaceutical composition containing it.
  • amorphous rosuvastatin calcium is characterized by having broad x-ray diffraction spectrum as in figure 1.
  • a process is provided for preparation of amorphous rosuvastatin calcium.
  • Amorphous rosuvastatin calcium is prepared by dissolving rosuvastatin calcium in an alcohol, a ketone or an ester solvent and removing the solvent.
  • the alcohol solvent is selected from the group consisting of methanol, ethanol, isopropyl alcohol, tert-butyl alcohol and n-butyl alcohol.
  • the ketone solvent is selected from the group consisting of acetone, diethyl ketone, methylethyl ketone, methylisobutyl ketone and methylpropyl ketone.
  • the ester solvent is selected from ethylacetate and methylacetate. A mixture of two or more of these solvents may also be used.
  • the preferable alcohols are ethanol and methanol.
  • the solvent may be removed from the solution by vacuum drying, freeze- drying, lyophilization or spray drying. Rosuvastatin calcium obtained by a known process may be used in the process.
  • a pharmaceutical composition comprising amorphous rosuvastatin calcium and a pharmaceutically acceptable carrier or diluent.
  • Figure 1 is ' a x-ray powder diffraction spectrum of amorphous rosuvastatin calcium. x-Ray powder diffraction spectrum was measured on a Bruker axs D8 advance x-ray powder diffractometer having a copper-Kr radiation.
  • Example 1 Rosuvastatin calcium (25 gm) is dissolved in ethanol (250 ml). The solution is subjected to vacuum drying at about 55°C for 10 hours to give 23 gm of amorphous rosuvastatin calcium.
  • Example 2 Rosuvastatin calcium (25 gm) is dissolved in methanol (200 ml). The solution is subjected to spray drying at about 50°C for 8 hours to give 22.5 gm of amorphous rosuvastatin calcium.
  • Example 3 Rosuvastatin calcium (20 gm) is dissolved in water (200 ml). The solution is subjected to lyophilization to give 18 gm of amorphous rosuvastatin calcium.

Abstract

The present invention provides a novel process for the preparation of amorphous rosuvastatin calcium.

Description

A NOVEL PROCESS FOR AMORPHOUS ROSUVASTATIN CALCIUM
FILELD OF THE INVENTION
The present invention provides a novel process for the preparation of amorphous rosuvastatin calcium. BACKGROUND OF THE INVENTION
Rosuvastatin of formula (1 ):
Figure imgf000002_0001
or (+)-7-[4-(4-f!uorophenyl)-6-isopropyl-2-(N-methyl-N-methyl sulfonyl amino)pyrimidin-5-yl]-(3R,5S)-dihydroxy-(E)-6-heptenoic acid and its salts are 3- hydroxy-3-methyl-glutaryl coenzyme A (HMG-CoA) reductase inhibitors and useful in the treatment of hypercholesterolemia, hyperlipoproteinemia and atherosclerosis. The therapeutic uses of rosuvastatin calcium and its related compounds were disclosed in US 5,260,440. Process for the preparation of amorphous(powder) rosuvastatin calcium was described in US 5,260,440. WO 00/42024 disclosed a crystalline form (form A) of rosuvastatin calcium. Various crystalline salts of rosuvastatin were disclosed in WO 01/60804. We have discovered a simple novel process for the preparation of sufficiently stable amorphous rosuvastatin calcium. The amorphous form produced by the novel process has better dissolution characteristics than the crystalline form known in the art. The object of the present invention is to provide a novel process for the preparation of amorphous rosuvastatin calcium and a pharmaceutical composition containing it.
DETAILED DESCRIPTION OF THE INVENTION In accordance with the present invention, there is provided a novel process for the preparation of amorphous rosuvastatin calcium. The amorphous rosuvastatin calcium is characterized by having broad x-ray diffraction spectrum as in figure 1. In accordance with the present invention, a process is provided for preparation of amorphous rosuvastatin calcium. Amorphous rosuvastatin calcium is prepared by dissolving rosuvastatin calcium in an alcohol, a ketone or an ester solvent and removing the solvent. The alcohol solvent is selected from the group consisting of methanol, ethanol, isopropyl alcohol, tert-butyl alcohol and n-butyl alcohol. The ketone solvent is selected from the group consisting of acetone, diethyl ketone, methylethyl ketone, methylisobutyl ketone and methylpropyl ketone. The ester solvent is selected from ethylacetate and methylacetate. A mixture of two or more of these solvents may also be used. The preferable alcohols are ethanol and methanol. The solvent may be removed from the solution by vacuum drying, freeze- drying, lyophilization or spray drying. Rosuvastatin calcium obtained by a known process may be used in the process. In accordance with the present invention, there is provided a pharmaceutical composition comprising amorphous rosuvastatin calcium and a pharmaceutically acceptable carrier or diluent.
BRIEF DESCRIPTION OF THE DRAWINGS Figure 1 is ' a x-ray powder diffraction spectrum of amorphous rosuvastatin calcium. x-Ray powder diffraction spectrum was measured on a Bruker axs D8 advance x-ray powder diffractometer having a copper-Kr radiation.
The invention will now be further described by the following non-limiting examples. Example 1 Rosuvastatin calcium (25 gm) is dissolved in ethanol (250 ml). The solution is subjected to vacuum drying at about 55°C for 10 hours to give 23 gm of amorphous rosuvastatin calcium. Example 2 Rosuvastatin calcium (25 gm) is dissolved in methanol (200 ml). The solution is subjected to spray drying at about 50°C for 8 hours to give 22.5 gm of amorphous rosuvastatin calcium. Example 3 Rosuvastatin calcium (20 gm) is dissolved in water (200 ml). The solution is subjected to lyophilization to give 18 gm of amorphous rosuvastatin calcium.

Claims

We claim:
1. A process for preparation of amorphous rosuvastatin calcium, which comprises the steps of: a) dissolving rosuvastatin calcium in a solvent; and b) removing the solvent from the solution formed in step (a) by vacuum drying, freeze drying, lyophilization or spray drying; wherein the solvent is selcted from methanol, ethanol, isopropyl alcohol, tert- butyl alcohol, n-butyl alcohol, acetone, diethyl ketone, methylethyl ketone, methylisobutyl ketone, methylpropyl ketone, ethylacetate, methylacetate and a mixture thereof.
2. A process according to claim 1 , wherein the solvent is ethanol.
3. A process according to claim 1 , wherein the solvent is methanol.
4. A process according to claim 1, wherein the solvent is removed by vacuum drying.
5. A process according to claim 1, wherein the solvent is removed by spray drying.
6. A pharmaceutical composition comprising amorphous rosuvastatin calcium and a pharmaceutically acceptable carrier or diluent.
PCT/IN2003/000288 2003-08-27 2003-08-27 A novel process for amorphous rosuvastatin calcium WO2005021511A1 (en)

Priority Applications (2)

Application Number Priority Date Filing Date Title
AU2003269478A AU2003269478A1 (en) 2003-08-27 2003-08-27 A novel process for amorphous rosuvastatin calcium
PCT/IN2003/000288 WO2005021511A1 (en) 2003-08-27 2003-08-27 A novel process for amorphous rosuvastatin calcium

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
PCT/IN2003/000288 WO2005021511A1 (en) 2003-08-27 2003-08-27 A novel process for amorphous rosuvastatin calcium

Publications (1)

Publication Number Publication Date
WO2005021511A1 true WO2005021511A1 (en) 2005-03-10

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Country Status (2)

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WO (1) WO2005021511A1 (en)

Cited By (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2005077917A1 (en) * 2004-01-19 2005-08-25 Ranbaxy Laboratories Limited Amorphous salts of rosuvastatin
US7244844B2 (en) 2003-12-02 2007-07-17 Teva Pharmaceutical Industries Ltd. Reference standard for characterization of rosuvastatin
US7396927B2 (en) 2003-08-28 2008-07-08 Teva Pharmaceutical Industries Ltd. Process for preparation of rosuvastatin calcium
US7612203B2 (en) 2005-02-22 2009-11-03 Teva Pharmaceutical Industries Ltd. Rosuvastatin and salts thereof free of rosuvastatin alkylether and a process for the preparation thereof
JP2010503723A (en) * 2006-09-18 2010-02-04 リチュテル・ゲデオン・ヴェジェーセティ・ジャール・ニュイルヴァーノシャン・ミューコェデー・レースヴェーニュタールシャシャーグ Rosuvastatin calcium-containing pharmaceutical composition
US7777034B2 (en) 2003-11-24 2010-08-17 Teva Pharmaceutical Industries Ltd. Crystalline ammonium salts of rosuvastatin
US7868169B2 (en) 2005-08-16 2011-01-11 Teva Pharmaceutical Industries, Ltd. Crystalline rosuvastatin intermediate
US7994178B2 (en) 2006-09-18 2011-08-09 Teva Pharmaceutical Industries, Ltd. Crystalline rosuvastatin calcium and compositions thereof for treatment of hyperlipidaemia

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5260440A (en) * 1991-07-01 1993-11-09 Shionogi Seiyaku Kabushiki Kaisha Pyrimidine derivatives
WO2001060804A1 (en) * 2000-02-15 2001-08-23 Astrazeneca Ab Crystalline salts of 7-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)amino]pyrimidin-5-yl]-(3r,5s)-3,5-dihydroxyhept-6-enoic acid
WO2003097614A2 (en) * 2002-05-21 2003-11-27 Ranbaxy Laboratories Limited Process for the preparation of rosuvastatin

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5260440A (en) * 1991-07-01 1993-11-09 Shionogi Seiyaku Kabushiki Kaisha Pyrimidine derivatives
WO2001060804A1 (en) * 2000-02-15 2001-08-23 Astrazeneca Ab Crystalline salts of 7-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)amino]pyrimidin-5-yl]-(3r,5s)-3,5-dihydroxyhept-6-enoic acid
WO2003097614A2 (en) * 2002-05-21 2003-11-27 Ranbaxy Laboratories Limited Process for the preparation of rosuvastatin

Cited By (14)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7396927B2 (en) 2003-08-28 2008-07-08 Teva Pharmaceutical Industries Ltd. Process for preparation of rosuvastatin calcium
US7777034B2 (en) 2003-11-24 2010-08-17 Teva Pharmaceutical Industries Ltd. Crystalline ammonium salts of rosuvastatin
US7692008B2 (en) 2003-12-02 2010-04-06 Teva Pharmaceutical Industries Ltd. Reference standard for characterization of rosuvastatin
US7692009B2 (en) 2003-12-02 2010-04-06 Teva Pharmaceutical Industries Ltd. Reference standard for characterization of rosuvastatin
US7692010B2 (en) 2003-12-02 2010-04-06 Teva Pharmaceutical Industries Ltd. Reference standard for characterization of rosuvastatin
US7741482B2 (en) 2003-12-02 2010-06-22 Teva Pharmaceutical Industries Ltd. Reference standard for characterization of rosuvastatin
US7244844B2 (en) 2003-12-02 2007-07-17 Teva Pharmaceutical Industries Ltd. Reference standard for characterization of rosuvastatin
US8487097B2 (en) 2003-12-02 2013-07-16 Teva Pharmacedutical Industries Ltd. Reference standard for characterization of rosuvastatin
WO2005077917A1 (en) * 2004-01-19 2005-08-25 Ranbaxy Laboratories Limited Amorphous salts of rosuvastatin
US7612203B2 (en) 2005-02-22 2009-11-03 Teva Pharmaceutical Industries Ltd. Rosuvastatin and salts thereof free of rosuvastatin alkylether and a process for the preparation thereof
US8063211B2 (en) 2005-02-22 2011-11-22 Teva Pharmaceutical Industries, Ltd. Rosuvastatin and salts thereof free of rosuvastatin alkylether and a process for the preparation thereof
US7868169B2 (en) 2005-08-16 2011-01-11 Teva Pharmaceutical Industries, Ltd. Crystalline rosuvastatin intermediate
JP2010503723A (en) * 2006-09-18 2010-02-04 リチュテル・ゲデオン・ヴェジェーセティ・ジャール・ニュイルヴァーノシャン・ミューコェデー・レースヴェーニュタールシャシャーグ Rosuvastatin calcium-containing pharmaceutical composition
US7994178B2 (en) 2006-09-18 2011-08-09 Teva Pharmaceutical Industries, Ltd. Crystalline rosuvastatin calcium and compositions thereof for treatment of hyperlipidaemia

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