WO2012011129A2 - Nouveau polymorphe de sel de calcium d'acide bis[(e)-7-[4-(4-fluorophényl)-6-iso-propyl-2-[méthyl (méthylsulfonyl)amino]pyrimidin-5-yl](3r,5s)-3,5-dihydroxyhept-6-énoïque] - Google Patents

Nouveau polymorphe de sel de calcium d'acide bis[(e)-7-[4-(4-fluorophényl)-6-iso-propyl-2-[méthyl (méthylsulfonyl)amino]pyrimidin-5-yl](3r,5s)-3,5-dihydroxyhept-6-énoïque] Download PDF

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Publication number
WO2012011129A2
WO2012011129A2 PCT/IN2011/000485 IN2011000485W WO2012011129A2 WO 2012011129 A2 WO2012011129 A2 WO 2012011129A2 IN 2011000485 W IN2011000485 W IN 2011000485W WO 2012011129 A2 WO2012011129 A2 WO 2012011129A2
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WO
WIPO (PCT)
Prior art keywords
reaction mixture
calcium
crystalline form
water
rosuvastatin calcium
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Ceased
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PCT/IN2011/000485
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English (en)
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WO2012011129A3 (fr
Inventor
Manne Satyanarayana Reddy
Srinivasan Thirumalai Rajan
Maramreddy Sahadeva Reddy
Ningam Srinivasa Reddy
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MSN Laboratories Pvt Ltd
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MSN Laboratories Pvt Ltd
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Publication of WO2012011129A2 publication Critical patent/WO2012011129A2/fr
Publication of WO2012011129A3 publication Critical patent/WO2012011129A3/fr
Anticipated expiration legal-status Critical
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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
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/06—Antihyperlipidemics

Definitions

  • the present invention relates to novel polymorphic forms of bis[(E)-7-[4-(4- fluorophenyl)-6-iso-propyl-2-[methyl (methyl sulfonyl)amino]pyrimidin-5-yl](3R,5S)- 3,5-dihydroxyhept-6-enoic acid] calcium and its use in the preparation of pharmaceutical composition.
  • Rosuvastatin calcium is commercially available under the brand name of Crestor® for the treatment of high cholesterol and related conditions, and to prevent cardiovascular disease, marketed by AstraZeneca.
  • Rosuvastatin its pharmaceutically acceptable salts, especially calcium salt and process for its preparation have been disclosed in US 5260440.
  • the disclosed process involves the dissolution of rosuvastatin sodium salt in water, adding calcium chloride and isolating the resultant precipitate by filtration then drying it to get calcium salt of rosuvastatin.
  • Rosuvastatin calcium obtained as per this process is an amorphous powder.
  • International publication WO 00/42024 disclosed a crystalline form A of rosuvastatin calcium, which is prepared by dissolving the amorphous rosuvastatin calcium in a mixture of water and an organic solvent such as acetonitrile under heating then cooling the obtained reaction mixture to get the crystalline form A of rosuvastatin calcium.
  • International publication WO 05/023779 disclosed hydrated crystalline form-B and anhydrous crystalline form-B 1 of rosuvastatin calcium.
  • Form B is prepared by dissolving the amorphous form in water and where as form-B 1 is prepared by removing water from the crystal lattice of form-B.
  • International publication WO 06/079611 disclosed crystalline form-B and form-C rosuvastatin calcium.
  • the said crystalline forms are prepared by dissolving the amorphous rosuvastatin in a mixture of water and an anionic surfactant such as alkyl sulphates or dissolving the amorphous form in a mixture of water and organic solvent under heating and then cooling the obtained solution to precipitate crystalline form B or form C.
  • an anionic surfactant such as alkyl sulphates
  • Crystalline forms often show different physical and/or biological characteristics which may assist in the manufacture or formulation of the active compound, with the purity levels and uniformity required for regulatory approval. Crystalline forms of such active compounds may also possess improved pharmacological characteristics, for example, improved bioavailability, and therefore, novel crystalline forms offer enhanced possibilities to modulate and design improved drug products. Therefore there exists a need for crystal forms other than those prior reported forms of rosuvastatin calcium which have the desired and the required biological qualities which would be helpful in optimizing, manufacturing and formulating an effective pharmaceutical composition.
  • the first aspect of the present invention provides a novel crystalline form-M of rosuvastatin calcium and hydrates thereof.
  • the second aspect of the present invention is to provide a process for the preparation of novel crystalline form-M of rosuvastatin calcium and hydrates thereof.
  • the third aspect of the present invention is to provide a process for the preparation of novel crystalline form-M of rosuvastatin calcium and hydrates thereof.
  • the fourth aspect of the present invention is to provide a process for the preparation of novel crystalline form-M of rosuvastatin calcium.
  • Figure-1 Illustrates PXRD of crystalline form-M of bis[(E)-7-[4-(4-fluorpphenyl)-6-iso- propyl-2- [methyl (methyl sulfonyl)amino]pyrimidin-5-yl](3R,5S)-3,5-dihydroxyhept-6- enoic acid] calcium salt.
  • Figure-II Illustrates DSC of crystalline form-M of bis[(E)-7-[4-(4-fluorophenyl)-6-iso- propyl-2-[methyI (methyl suIfonyI)amino]pyrimidin-5-yI](3R,5S)-3,5-dihydroxyhept-6- enoic acid] calcium salt.
  • suitable solvent refers to the solvent selected from “polar solvents” such as water;- "polar aprotic solvents” such as dimethylsulfoxide, dimethylacetamide, dimethyl formamide and the like; “nitrile solvents” such as acetonitrile, propionitrile, butyronitrile and isobutyronitrile and the like; “ether solvents” such as di-tert-butylether, diethylether, diisopropyl ether, 1 ,4-dioxane, methyltert-butylether, ethyl tert-butyl ether, tetrahydrofuran and dimethoxyethane; “alcohol solvents” such as methanol, ethanol, n-propanol, isopropanol and n-butanol and the like; “chloro solvents” such as methylene chloride, ethylene dichloride, carbon te
  • suitable base refers to the bases selected from “alkali metal hydroxides” such as sodium hydroxide, .potassium hydroxide and the like; “alkali metal carbonates” such as sodium carbonate, potassium carbonate, cesium carbonate and the like; “alkali metal bicarbonates” such as sodium bicarbonate, potassium bicarbonate and the like; “alkali metal alkoxide” such as sodium methoxide, potassium methoxide, sodium tertiary butoxide and potassium tertiary butoxide and the like;
  • the amorphous rosuvastatin calcium and rosuvastatin tertiary butyl amine salts used in the present invention are obtained according to the processes reported in the patent publications WO2007125547 or WO2008044243.
  • the first aspect of the present invention provides a novel crystalline form of rosuvastatin calcium, which is characterized by its powder X-ray diffraction pattern showing characteristic peaks at 3.33, 5.30, 7.52 and 22.46 ⁇ 0.2 degrees 2 ⁇ .
  • This crystalline form of rosuvastatin calcium is hereinafter designated as crystalline form-M.
  • the crystalline form-M of the present invention further characterized by its PXRD showing peaks at 10.37 and 20.45 ⁇ 0.2 degrees 20.
  • the PXRD of crystalline form-M is substantially similar to the PXRD pattern depicted in figure- 1.
  • the crystalline form-M of the rosuvastatin calcium is characterized by its DSC thermo gram.
  • the DSC having an endotherm at about 103.3°C and another endotherm at about 175.7°C.
  • the DSC of crystalline form-M of rosuvastatin calcium is depicted in Figure-II.
  • the second aspect of the present invention provides a process for the preparation of crystalline form-M of rosuvastatin calcium, which comprises of
  • the ketone solvent used is selected from acetone or methyl isobutyl ketone; the ratio of water is in amount of about 2 volumes to about 15 volumes preferably 10 volumes' to the weight of the compound.
  • the amount of ketone solvent taken is about 2 volumes to about 15 volumes, preferably 10 volumes to the weight of the compound taken.
  • the temperature to which the mixture is heated is in the range of 25°C to 50°C, preferably 41°C and in step c) ambient temperature refers to the temperature in the range of 25°C to 28°C.
  • the third aspect of the present invention provides a process for the preparation of crystalline form-M of rosuvastatin calcium, which comprises of,
  • the suitable solvent is selected from polar solvents like water, ketone solvents and alcohol solvents, preferably water;
  • step b) the suitable temperature is 35°C to reflux temperature of the solvent used in the reaction;
  • ambient temperature refers to the temperature in the range of 25°C to 28°C.
  • the preferred embodiment of the present invention provides a process for the preparation of crystalline form-M of rosuvastatin calcium, which comprises of, a) Taking the amorphous rosuvastatin calcium in water,
  • the fourth aspect of the present invention provides a novel process for the preparation of crystalline form-M of rosuvastatin calcium, which comprises of, a) Taking the rosuvastatin tertiary butyl amine salt in a suitable solvent,
  • the suitable solvent is selected from polar solvents, ketone solvents and alcohol solvents, preferably water;
  • the suitable base is selected from alkali metal hydroxides* preferably sodium hydroxide;
  • the suitable solvent is selected from polar solvents, ketone solvents and alcohol solvents, preferably water;
  • the suitable acid is selected from inorganic acids such as hydrochloric acid, hydro bromic acid and hydro iodic acid; preferably hydrochloric acid;
  • the suitable calcium source is selected from calcium chloride, calcium hydroxide and calcium acetate; preferably calcium acetate; in ste i) the suitable temperature is 35°C to reflux temperature of the solvent used in the reaction;
  • ambient temperature refers to the temperature in the range of 25°C to 28°C.
  • the suitable solvent is selected from polar solvents, ketone solvents and alcohol solvents, preferably water;
  • the preferred embodiment of the present invention provides a novel process for the preparation of crystalline form-M of rosuvastatin calcium, which comprises of, a) Taking the rosuvastatin tertiary butyl amine salt in water,
  • crystalline rosuvastatin calcium is stable even at higher temperatures like 90-95 °C in water in terms of purity by HPLC and in terms of polymorph, there is no change in polymorph even after slurring the crystalline rosuvastatin calcium in water at higher temperatures.
  • the crystalline form-M is free flow solid and easy to handle during formulation.
  • a pharmaceutical composition comprising a polymorphic form of rosuvastatin calcium and pharmaceutically acceptable carrier or diluent.
  • the polymorphic form includes form M of rosuvastatin calcium.
  • PXRD analysis of rosuvastatin calcium were carried out using BRUKER AXS X- Ray diffractometer using Cu, Ka radiation of wavelength 1.54 A° and continuous scan speed of 0.045°/min.
  • the thermal analysis of rosuvastatin calcium was carried out on Waters DSC Q-10 model differential scanning calorimeter.
  • Rosuvastatin calcium was analyzed by HPLC using the following conditions: A liquid chromatograph is equipped with variable wavelength UV detector or PDA detector; Column: Phenomenex, CI 8, 250 x 4.6 mm, 5.0 ⁇ or equivalent; wavelength: 248 nm; Temperature: 25°C; Load: 20 ⁇ ; Run time: 70 min; and using a mixture of acetonitrile and water in the ration of 1 :1 as a diluent and mixture of water: acetonitirle: methanol: triethylamine as a mobile phase.
  • Example-1 Preparation of crystalline Form-M of bis[(E)-7-[4-(4-fluorophenyl)-6- iso-propyI-2-[methyI(methyIsuIfonyI)aminoIpyrimidin-5-yI](3R,5S)-3,5-dihydroxy hept-6-enoic acid] calcium:
  • Example-2 Preparation of crystalline Form-M of bis[(E)-7-[4-(4-fluorophenyl)-6- iso-propyl-2-[methyl(methylsulfonyl)amino]pyrimidin-5-yl](3R,5S)-3,5-dihydroxy hept-6-enoic acid] calcium:
  • amorphous rosuvastatin calcium salt To 50 grams of amorphous rosuvastatin calcium salt added a mixture of water (500 ml) and methylisobutylketone (500 ml) at 27°C. The reaction mixture was heated to 40°C and then slowly cooled to 27°C. Stirred the reaction mixture for 20 hrs at the same temperature. Filtered the precipitated product and dried under aerial conditions to get the crystalline form-M of bis[(E)-7-(4-(4-fluorophenyl)-6-iso-propyl-2-[methyl(methyl sulfonyl)amino]pyrimidin-5-yl](3R,5S)-3,5-dihydroxyhept-6-enoic acid] calcium.
  • Example-3 Preparation of crystalline Form-M of bis[(E)-7-[4-(4-fliiorophenyl)-6- iso-propyl-2- [methyl(methylsulfonyl)amino] pyrimidin-5-yl] (3R,5S)-3,5-dihy droxy hept-6-enoic acid] calcium: To 10 grams of amorphous rosuvastatin calcium salt added water (100 ml) at 25- 30°C. The reaction mixture was heated to 94°C ' and stirred for 10 hrs at same temperature. Cooled the reaction mixture to 25-30°C. Filtered the precipitated product and washed with water.
  • Example-4 Preparation of crystalline Form-M of bis[(E)-7-[4-(4-fluorophenyl)-6- iso-propyl-2-[methyl(methylsulfonyl)amino]pyrimidin-5-yI](3R,5S)-3,5-dihydroxy hept-6-enoic acid] calcium:

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Diabetes (AREA)
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Abstract

L'invention concerne un nouveau polymorphe de sel de calcium d'acide bis[(e)-7-[4-(4-fluorophényl)-6-iso-propyl-2-[méthyl(méthylsulfonyl)amino] pyrimidin-5-yl](3r,5s)-3,5-dihydroxyhept-6-énoïque].
PCT/IN2011/000485 2010-07-22 2011-07-21 Nouveau polymorphe de sel de calcium d'acide bis[(e)-7-[4-(4-fluorophényl)-6-iso-propyl-2-[méthyl (méthylsulfonyl)amino]pyrimidin-5-yl](3r,5s)-3,5-dihydroxyhept-6-énoïque] Ceased WO2012011129A2 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
IN2088/CHE/2010 2010-07-22
IN2088CH2010 2010-07-22

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WO2012011129A2 true WO2012011129A2 (fr) 2012-01-26
WO2012011129A3 WO2012011129A3 (fr) 2012-03-15

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PCT/IN2011/000485 Ceased WO2012011129A2 (fr) 2010-07-22 2011-07-21 Nouveau polymorphe de sel de calcium d'acide bis[(e)-7-[4-(4-fluorophényl)-6-iso-propyl-2-[méthyl (méthylsulfonyl)amino]pyrimidin-5-yl](3r,5s)-3,5-dihydroxyhept-6-énoïque]

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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2014050874A1 (fr) * 2012-09-27 2014-04-03 東和薬品株式会社 Nouvelle forme cristalline de rosuvastatine de calcium et son procédé de fabrication
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
WO2017183040A1 (fr) * 2016-04-18 2017-10-26 Morepen Laboratories Limited Nouvelle forme polymorphe de rosuvastatine calcique cristalline et nouveaux procédés pour la rosuvastatine calcique cristalline et amorphe

Family Cites Families (14)

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Publication number Priority date Publication date Assignee Title
GB9903472D0 (en) * 1999-02-17 1999-04-07 Zeneca Ltd Chemical process
EA200401533A1 (ru) * 2002-05-21 2005-06-30 Ранбакси Лабораторис Лимитед Способ получения росувастатина
DK1578733T3 (da) * 2002-12-10 2011-06-14 Ranbaxy Lab Ltd Fremgangsmåde til fremstilling af rosuvastatin
GB0312896D0 (en) * 2003-06-05 2003-07-09 Astrazeneca Ab Chemical process
CA2546701C (fr) * 2003-11-24 2010-07-27 Teva Pharmaceutical Industries Ltd. Sels d'ammonium cristallins de la rosuvastatine
CN1763015B (zh) * 2004-10-22 2011-06-22 四川抗菌素工业研究所有限公司 一种罗舒伐他汀及其药用盐的制备方法及中间体
CN100351240C (zh) * 2005-01-19 2007-11-28 安徽省庆云医药化工有限公司 瑞舒伐他汀钙的合成方法
WO2006100689A1 (fr) * 2005-03-22 2006-09-28 Unichem Laboratories Limited Procede de preparation de la rosuvastatine
US8354530B2 (en) * 2005-07-28 2013-01-15 Lek Pharmaceuticals d. d Process for the synthesis of rosuvastatin calcium
CN100436428C (zh) * 2005-08-22 2008-11-26 鲁南制药集团股份有限公司 瑞舒伐他汀及其盐的制备方法
US8404841B2 (en) * 2006-10-09 2013-03-26 Msn Laboratories Limited Process for the preparation of statins and their pharmaceutically acceptable salts thereof
TW200831469A (en) * 2006-12-01 2008-08-01 Astrazeneca Uk Ltd Chemical process
CN101376647B (zh) * 2007-08-31 2010-12-08 中山奕安泰医药科技有限公司 一种用于合成瑞舒伐他汀中间体及瑞舒伐他汀的合成方法
EP2298745B1 (fr) * 2008-05-27 2014-09-03 Changzhou Pharmaceutical Factory Procédé de préparation de la rosuvastatine calcique et de ses intermédiaires

Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2014050874A1 (fr) * 2012-09-27 2014-04-03 東和薬品株式会社 Nouvelle forme cristalline de rosuvastatine de calcium et son procédé de fabrication
WO2017183040A1 (fr) * 2016-04-18 2017-10-26 Morepen Laboratories Limited Nouvelle forme polymorphe de rosuvastatine calcique cristalline et nouveaux procédés pour la rosuvastatine calcique cristalline et amorphe
US20190127334A1 (en) * 2016-04-18 2019-05-02 Morepen Laboratories Limited New polymorphic form of crystalline rosuvastatin calcium & novel processes for crystalline as well as amorphous rosuvastatin calcium
US10626093B2 (en) 2016-04-18 2020-04-21 Morepen Loboratories Limited Polymorphic form of crystalline rosuvastatin calcium and novel processes for crystalline as well as amorphous rosuvastatin calcium
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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