WO2011074016A1 - Nouvelles formes polymorphes de rosuvastatine calcique et procédé de préparation de ces dernières - Google Patents

Nouvelles formes polymorphes de rosuvastatine calcique et procédé de préparation de ces dernières Download PDF

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Publication number
WO2011074016A1
WO2011074016A1 PCT/IN2010/000827 IN2010000827W WO2011074016A1 WO 2011074016 A1 WO2011074016 A1 WO 2011074016A1 IN 2010000827 W IN2010000827 W IN 2010000827W WO 2011074016 A1 WO2011074016 A1 WO 2011074016A1
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WIPO (PCT)
Prior art keywords
rosuvastatin calcium
crystalline
calcium
rosuvastatin
present
Prior art date
Application number
PCT/IN2010/000827
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English (en)
Inventor
Madhuresh Kumar Sethi
Vijendrasingh Rawat
Rajakrishna Yerramalla
Jagan Mohana Rao Bontalakoti
Lakshminarayana Vemula
Kartikeyan Ayyaran
Sanjay Mahajan
Bhairaiah Mara
Debashish Datta
Original Assignee
Matrix Laboratories Ltd
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Publication date
Application filed by Matrix Laboratories Ltd filed Critical Matrix Laboratories Ltd
Publication of WO2011074016A1 publication Critical patent/WO2011074016A1/fr

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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

Definitions

  • This invention relates to novel polymorphic Forms of Bis [(E)-7-[4-(4-Fluorophenyl)-6- isopropyl-2-[methyl (methylsulfonyl) amino] pyrimidin-5-yl] (3R, 5S)-3, 5-dihydroxyhept-6- enoic acid] Calcium Salt (Rosuvastatin Calcium) and process for preparation of the same.
  • Rosuvastatin calcium is marketed under the proprietary name CRESTOR for treatment of mammals such as human and administrated as daily dosage form of 5 mg, 10 mg, 20 mg and 40 mg.
  • European patent publication EP 0521471 discloses Rosuvastatin and its pharmaceutically acceptable salts including calcium salt of Rosuvastatin. This patent discloses Rosuvastatin calcium, which is prepared by dissolving the corresponding sodium salt in water, adding calcium chloride and collecting the resultant precipitate by filtration.
  • US Pat No. US 6,589,959 further confirms that Rosuvastatin Calcium obtained according to this process is amorphous Form.
  • the present invention provides stable and industrially scalable polymorphic Forms of Rosuvastatin calcium.
  • Another main object of the present invention is to provide a process for producing the novel polymorphic Forms of Rosuvastatin calcium.
  • crystalline Form R of Rosuvastatin calcium characterized by PXRD, DSC and TGA
  • novel polymorphic Form S of Rosuvastatin calcium characterized by PXRD and DSC
  • a process for producing crystalline Form R of Rosuvastatin calcium comprising, adding Rosuvastatin calcium to a mixture of organic solvent and water, heating the resultant mixture, cooling and isolating the crystalline Form R.
  • a process for producing novel polymorphic Form S of Rosuvastatin calcium comprising, adding (S)-(-)-a-methyl benzyl amine salt of Rosuvastatin to a mixture of ester solvent and water, adjusting the pH to acidic, concentrating the organic layer, adding obtained residue to a mixture of organic solvent and water; adjusting the pH to basic and separating the layers, reducing the aqueous layer by distillation, seeding with amorphous Rosuvastatin calcium followed by the addition of calcium source and isolating the polymorphic Form S of Rosuvastatin calcium.
  • Figure 1 illustrates the characteristic X-ray powder diffraction (PXRD) of crystalline Rosuvastatin calcium Form R.
  • Figure 2 illustrates the characteristic differential scanning calorimetric (DSC) thermogram of crystalline Rosuvastatin calcium Form R.
  • FIG. 3 illustrates the characteristic thermogravimetric analysis (TGA) spectrum of crystalline Rosuvastatin calcium Form R.
  • Figure 4 illustrates the characteristic X-ray powder diffraction (PXRD) of polymorphic Rosuvastatin calcium Form S.
  • Figure 5 illustrates the characteristic differential scanning calorimetric (DSC) thermogram of polymorphic Rosuvastatin calcium Form S.
  • the present invention relates to novel polymorphic forms of bis [(E)-7-[4-(4-Fluorophenyl)-6- isopropyl-2-[methyl (methylsulfonyl) amino] pyrimidin-5-yl] (3R, 5S)-3, 5-dihydroxyhept-6- enoic acid] Calcium salt herein designated as Form R and Form S
  • the present invention also relates to novel process, for the preparation of polymorphic Forms R and S of Rosuvastatin calcium.
  • the polymorphs of the present invention are characterized by their X-ray powder diffraction pattern.
  • the X-ray diffraction patterns of the polymorphs of the invention were measured on PANalytical, X'Pert PRO powder diffractometer equipped with goniometer of ⁇ / ⁇ configuration and X'Celerator detector.
  • the Cu-anode X-ray tube was operated at 40kV and 30mA. The experiments were conducted over the 2-theta range of 2.0°-50.0°, 0.030° step size and 50 seconds step time.
  • DSC Differential scanning calorimetric
  • the DSC measurements were carried out on Mettler Toledo 822 star 6 and TA Q1000 of TA instruments. The experiments were performed at a heating rate of 10.0 °C/min over a temperature range of 30°C-300°C purging with nitrogen at a flow rate of 50ml/min. Standard aluminum crucibles covered by lids with three pin holes were used.
  • TGA was recorded on out using the instrument Mettler Toledo TGA/SDTA 85 l e and TGA Q5000 of TA instruments. The experiments were performed at a heating rate of 10.0 °C/min over a temperature range of 30°C-300°C purging with nitrogen at a flow rate of 25ml/min.
  • the novel crystalline Form R of Rosuvastatin calcium is characterized by an X-ray powder diffraction pattern having peaks at about 4.08, 4.55, 5.8, 6.3, 8.93, 9.6 and 18.01° ( ⁇ ) 0.2° 2-theta.
  • the crystalline Form R of Rosuvastatin calcium may also be substantially identified by the PXRD pattern depicted in Figure 1.
  • the crystalline Form R of Rosuvastatin calcium may be further characterized by a DSC thermogram as depicted in Figure 2.
  • the crystalline Form R of Rosuvastatin calcium may be further characterized by a TGA spectrum as depicted in Figure 3, which is showing ⁇ 5.6 % loss of moisture content.
  • the crystalline Form R is stable. Stability of the Form R is confirmed by taking PXRD of the sample after one year, which is essentially similar to the initial PXRD pattern.
  • the present invention there is provided a process for the preparation of crystalline Form R of Rosuvastatin calcium adding Rosuvastatin calcium to a mixture of organic solvent and water, heating the resultant mixture, cooling and isolating the crystalline Form R.
  • the organic solvent is preferably methyl t-butyl ether (MTBE).
  • Rosuvastatin calcium is added to a mixture of organic solvent and water preferably the organic solvent is methyl t-butyl ether (MTBE).
  • MTBE methyl t-butyl ether
  • the resultant mixture is heated, and cooled to 0-10 °C.
  • novel crystalline Form R of Rosuvastatin calcium is isolated.
  • the polymorphic Form S of Rosuvastatin calcium is characterized by an X-ray powder diffraction pattern having peaks at about 3.5, 4.2 and 6.8° ( ⁇ ) 0.2° 2-theta.
  • the polymorphic Form S of Rosuvastatin calcium may also be substantially identified by the PXRD pattern depicted in Figure 4.
  • the polymorphic Form S of Rosuvastatin calcium may be further characterized by a DSC thermogram as depicted in Figure 5.
  • a process for producing novel polymorphic Form S of Rosuvastatin calcium comprising, adding (S)-(-)-a-methyl benzyl amine salt of Rosuvastatin to a mixture of ester solvent and water, adjusting the pH to acidic, concentrating the organic layer, adding obtained residue to a mixture of organic solvent and water, adjusting the pH to basic and separating the layers, reducing the aqueous layer by distillation, seeding with amorphous Rosuvastatin calcium followed by the addition of calcium source and isolating the polymorphic Form S of Rosuvastatin calcium.
  • the ester solvent is preferably ethyl acetate.
  • pH is adjusted to acidic by using mineral acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, preferably hydrochloric acid.
  • the organic solvent is preferably methyl t-butyl ether (MTBE).
  • pH is adjusted to basic by using a base selected from alkali metal hydroxides such as sodium hydroxide.
  • calcium source is calcium acetate.
  • process for the preparation of crystalline Rosuvastatin calcium Form S comprising the steps of: providing Rosuvastatin sodium salt in aqueous medium, seeding with Rosuvastatin calcium, adding a source of calcium, and isolating the polymorphic Form S of Rosuvastatin calcium.
  • (S)-(-)-a-methyl benzyl amine salt of Rosuvastatin is added to a mixture of ester solvent preferably ethyl acetate, and water.
  • the pH of the reaction mixture is adjusted 3-4 by the addition of acid preferably hydrochloric acid.
  • Ethyl acetate layer is separated and concentrated.
  • the obtained residue is added to a mixture of organic solvent and water preferably the organic solvent is methyl t-butyl ether (MTBE).
  • the pH of the reaction mixture is adjusted to 10-12 by using a base preferably sodium hydroxide and aqueous layer is washed with methyl t-butyl ether.
  • aqueous layer is distilled, preferably to l/3 rd of aqueous layer is distilled off, and seeded with amorphous Rosuvastatin Calcium followed addition of calcium acetate solution in water. And novel polymorphic Form S of Rosuvastatin calcium is isolated.
  • the Rosuvastatin calcium used herein is selected from the group consisting of but not limited to crystalline or amorphous form or any solvate.
  • Rosuvastatin calcium (10 gm) was added to the mixture of methyl t-butyl ether (600 ml) and water (10 ml) and heated to 45-60 °C for 15 minutes. The reaction mass was cooled to room temperature and further cooled to 0-5 °C and stirred for 1-2 days. The reaction mass was filtered and dried under vacuum to yield crystalline Rosuvastatin calcium Form R.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

La présente invention concerne de nouvelles formes polymorphes R et S de sel calcique (Rovastatine calcique) d'acide bis [(E)-7-[4-(4- Fluorophényl)-6-isopropyl-2-[méthyl (méthylsulfonyl) amino] pyrimidin-5-yl] (3R, 5S)-3, 5-dihydroxyhept-6-énoïque]. Cette invention porte également sur un procédé de préparation de nouvelles formes polymorphes R et S.
PCT/IN2010/000827 2009-12-17 2010-12-20 Nouvelles formes polymorphes de rosuvastatine calcique et procédé de préparation de ces dernières WO2011074016A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
IN3124/CHE/2009 2009-12-17
IN3124CH2009 2009-12-17

Publications (1)

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WO2011074016A1 true WO2011074016A1 (fr) 2011-06-23

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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN104030989A (zh) * 2014-05-16 2014-09-10 南通常佑药业科技有限公司 一种瑞舒伐他汀钙的制备方法
CN105837516A (zh) * 2016-05-16 2016-08-10 山东新时代药业有限公司 一种瑞舒伐他汀钙晶型及其制备方法
EP3445751A4 (fr) * 2016-04-18 2020-01-22 Morepen Laboratories Limited Nouvelle forme polymorphe de rosuvastatine calcique cristalline et nouveaux procédés pour la rosuvastatine calcique cristalline et amorphe

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0521471A1 (fr) 1991-07-01 1993-01-07 Shionogi Seiyaku Kabushiki Kaisha Dérivés de pyrimidine comme inhibiteurs de la HMG-CoA reductase
US6589959B1 (en) 1999-01-09 2003-07-08 Astrazeneca Ab Crystalline bis[(e)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)amino]pyrimidin-5-yl](3R,5S)-3,5-dihydroxyhept-6-enoic acid]calcium salt
WO2005023779A1 (fr) 2003-09-10 2005-03-17 Astrazeneca Uk Limited Forme cristalline du sel de calcium de bis [acide (e)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)amino]pyrimidin-5-yl](3r,5s)-3,5-dihydroxyhept-6-enoique]
WO2006079611A1 (fr) * 2005-01-31 2006-08-03 Ciba Specialty Chemicals Holding Inc. Formes cristallines de sel de rosuvastatine calcique
US20080176878A1 (en) 2006-09-18 2008-07-24 Shlomit Wizel Crystalline rosuvastatin calcium

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0521471A1 (fr) 1991-07-01 1993-01-07 Shionogi Seiyaku Kabushiki Kaisha Dérivés de pyrimidine comme inhibiteurs de la HMG-CoA reductase
US6589959B1 (en) 1999-01-09 2003-07-08 Astrazeneca Ab Crystalline bis[(e)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)amino]pyrimidin-5-yl](3R,5S)-3,5-dihydroxyhept-6-enoic acid]calcium salt
WO2005023779A1 (fr) 2003-09-10 2005-03-17 Astrazeneca Uk Limited Forme cristalline du sel de calcium de bis [acide (e)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)amino]pyrimidin-5-yl](3r,5s)-3,5-dihydroxyhept-6-enoique]
WO2006079611A1 (fr) * 2005-01-31 2006-08-03 Ciba Specialty Chemicals Holding Inc. Formes cristallines de sel de rosuvastatine calcique
US20080176878A1 (en) 2006-09-18 2008-07-24 Shlomit Wizel Crystalline rosuvastatin calcium

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN104030989A (zh) * 2014-05-16 2014-09-10 南通常佑药业科技有限公司 一种瑞舒伐他汀钙的制备方法
EP3445751A4 (fr) * 2016-04-18 2020-01-22 Morepen Laboratories Limited Nouvelle forme polymorphe de rosuvastatine calcique cristalline et nouveaux procédés pour la rosuvastatine calcique cristalline et amorphe
CN105837516A (zh) * 2016-05-16 2016-08-10 山东新时代药业有限公司 一种瑞舒伐他汀钙晶型及其制备方法
CN105837516B (zh) * 2016-05-16 2018-07-10 山东新时代药业有限公司 一种瑞舒伐他汀钙晶型及其制备方法

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