WO2006048894A1 - Nouvelles formes cristallines de calcium d'atorvastatine et procedes de fabrication - Google Patents

Nouvelles formes cristallines de calcium d'atorvastatine et procedes de fabrication Download PDF

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Publication number
WO2006048894A1
WO2006048894A1 PCT/IN2005/000360 IN2005000360W WO2006048894A1 WO 2006048894 A1 WO2006048894 A1 WO 2006048894A1 IN 2005000360 W IN2005000360 W IN 2005000360W WO 2006048894 A1 WO2006048894 A1 WO 2006048894A1
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WIPO (PCT)
Prior art keywords
atorvastatin calcium
ketone
calcium
hrs
values
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Application number
PCT/IN2005/000360
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English (en)
Inventor
Sanjay Suri
Gurdeep Singh Sarin
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Morepen Laboratories Limited
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Publication date
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Publication of WO2006048894A1 publication Critical patent/WO2006048894A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/30—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members
    • C07D207/34—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two 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, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • 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

  • This invention relates to "Novel Crystalline Forms Of Atorvastatin Calcium And Processes For Preparing Them".
  • This invention particularly relates to novel crystalline polymorphs of Atorvastatin Calcium, which have been designated by us sas M-2, M-3 and M-4.
  • the new crystalline polymorphs of the present invention may be anhydrous or trihydrate and could contain up to 4.5 to 8 % water.
  • the invention also provides processes for the preparation of these novel polymorphs, which are simple, cost effective, reproducible, environment friendly and easy to scale up for industrial manufacture while maintaining the quality of the title product. The process more particularly results in the title compound with superior filtration characteristics.
  • Atorvastatin Calcium is a member of the class of drug called statins, which are considered to be the therapeutically most effective drugs available for the treatment of hyperlipidemia and hypocholesterolemia.
  • Atorvastatin calcium is an orally active hypocholesterolaemic, a liver-selective HMG-CoA reductase inhibitor.
  • the empirical formula of Atorvastatin Calcium is CeOH 6 SCaF 2 N 4 O io.
  • Atorvastatin Calcium is a white to off white amorphous or crystalline powder that is soluble in water and alcohols like methanol, ethanol, aliphatic ketones like acetone, tetrahydrofuran, dimethylformamide, dimethylacetamide and dimethylsulfoxide etc.
  • Atorvastatin calcium (I) is displays the following Chemical Structure as shown in Fig.. I
  • the present invention is directed to new crystalline forms of Atorvastatin Calcium and processes for the preparation thereof. It has been reported in a number of publications and patents that both the crystalline and amorphous forms of several drugs exhibit distinct dissolution characteristics and bioavailability patterns. Depending upon the nature of the structure, the dissolution rate may favour one formulation over the other as a result of which, for some therapeutic indications, one specific formulation may be favored over another. (See, T. Konno, Chem. Pharm. Bull, 38, 2003-2007, 1990). Similarly, one formulation may be more suitable for treating certain patient populations. Therefore it is desirable to develop methodologies for converting crystalline and amorphous forms of active pharmaceutical ingredients into one another. In addition it is desirable to prepare fast melt tablet formulations for quick action and relief to the patients.
  • the formation of different polymorphic forms can be achieved by crystallising the compound from different solvents under varying conditions. Polymorph formation is influenced by temperature of the solution, rate of stirring, rate of precipitation, mode of mixing and rate of addition of the mixing of solvents and time of stirring. Very often the different polymorphs can be isolated from the same solvent system by simply stirring the mixture for different period of times and one form can be converted into another. In view of the very tight limits of residual solvent specification norms as per ICH guidelines for the Active Pharmaceutical Ingredient (API) 5 only a limited number of solvents, preferably C class solvents are being used for generating the new polymorphs. Thus choice is narrowed down to very few solvent systems.
  • API Active Pharmaceutical Ingredient
  • mixtures of polar organic solvents such as methanol, ethanol, isopropanol, butanol or aliphatic ketones like acetone and methyl isobutyl ketone and ethers like methyl tertiary butyl ether (MTBE) , diisopropyl ether or tetrahydrofuran ( THF) or acetonitrile in pure form or in combination, preferably with water have been used for generating the different crystalline forms.
  • polar organic solvents such as methanol, ethanol, isopropanol, butanol or aliphatic ketones like acetone and methyl isobutyl ketone and ethers like methyl tertiary butyl ether (MTBE) , diisopropyl ether or tetrahydrofuran ( THF) or acetonitrile in pure form or in combination, preferably with water
  • Atorvastatin calcium in a reproducible, pure and crystalline form to enable formulations to meet exacting pharmaceutical requirements and specifications. Furthermore, it is economically desirable that the product is stable for extended periods of time without the need for specialised storage conditions and can be produced by the processes that can be easily scale up for industrial manufacture. Moreover, the product thus produced can be isolated easily minimising losses as it has better f ⁇ lterability. This leads to higher yields.
  • FIG I displays chemical structure of Atorvastatin calcium
  • FIG II displays XRD pattern of crystalline Form M-I of Atorvastatin Calcium
  • FIG III displays XRD pattern of crystalline Form M-2 of Atorvastatin Calcium
  • FIG IV displays XRD pattern of crystalline Form M-3 of Atorvastatin Calcium
  • FIG V displays XRD pattern of crystalline Form M-4 of Atorvastatin Calcium.
  • the present invention provides new crystalline forms of Atorvastatin Calcium designated by us as M-2, M-3 and M-4 and methods for preparing them in anhydrous as well as hydrated forms.
  • the new crystalline forms of Atorvastatin Calcium are generally trihydrate with water content around 4.0 to 6.0%, but may also exhibit water content up to 8.0 % w/w. or more.
  • the main object of the present invention is to provide novel crystalline polymorphs of Atorvastatin Calcium and processes for preparing the said polymorphs.
  • Another object is to provide new polymorphic forms of Atorvastatin Calcium having higher purity and stability.
  • Yet another object is to provide new crystalline polymorphic form of Atorvastatin Calcium that is easy to filter, has superior texture, and displays reduced residual solvent.
  • Still another object of the invention is also to provide a process for the preparation of a new crystalline which are simple, cost effective, involving less number of steps, high yielding, precise, reproducible, environment friendly and easy to scale up for industrial manufacture while maintaining the quality of the title product.
  • the processes for the new crystalline forms of Atorvastatin Calcium have merits of residual solvent limits, which are well below ICH guidelines.
  • the present invention is directed to new crystalline polymorphs designated as M-2, M-3 and M-4.
  • Atorvastatin designated as M-2 exhibits a characteristic X-ray powder diffraction pattern obtained using conventional CuK ⁇ radiation with characteristic sharp peaks expressed in 20 values at 8.64, 10.16, 19.38 and specific peak at 29.34. It further exhibits Powder X ray diffraction (PXRD) pattern as shown in FIG III with additional characteristic peaks at 2 ⁇ ( ⁇ 0.2) values of 8.24, 16.94, 17.66, 18.14, 18.42, 20.10, 20.36, 20.82, 27.10 and 32.80.
  • PXRD Powder X ray diffraction
  • the new polymorph M-3 displays a broad peak at 8.0, sharp peaks at 18.22 surrounded by broad peaks in the region of 19 to 22 and a very strong peak at 29.26. Its powder XRD spectrum is reproduced in FIG IV displays additional characteristic 29 ( ⁇ 0.2) values of 8.30, 8.58, 18.76, 19.46, 20.16 and 36.00.
  • Crystalline Form M-4 is shows sharp peaks at 5.52, 8.20 (100%), 18.30, 19.00 and a very strong unique peak at 31.68. Additionally, it displays characteristic 20 ( ⁇ 0.2) values of 2.72, 10.90, and 20.04 which are shown in the powder XRD spectrum in FIG V.
  • the process comprises crystallizing from a mixture of aliphatic ketone and water at 0 to 55 0 C under stirring, while allowing the ketone to evaporate till thick precipitate is obtained if so desired, followed by drying.
  • the ketone used is acetone, diethyl ketone or ethyl methyl ketone using quantities varying between 10 times and 150 times, preferably 70 to 100 times w. r. t.
  • the Atorvastatin calcium used the ratio of acetone and water used ranging from 0.25:1.0 to 1.0 to 0.25, preferably 0.75:1.0 to 1.0 to 0.75, the crystallization being carried out preferably at 20 to 4O 0 C, with stirring over a period of 50 to 250 hrs, preferably over 75 to 125 hrs and the sample being dried at 20 to 7O 0 C, preferably at 50 to 6O 0 C to desired level of moisture.
  • a process comprising slow crystallization of Atorvastatin calcium in dichloromethane that is dissolved at reflux temperature followed by isolation and drying to get polymorph M-4.
  • the quantity of dichloromethane used varies between 3 to 100 times, preferably 10 to 20 times v/w w. r. t. the starting material and refluxing is effected over a period of 3 to 96 hrs, preferably 18 to 30 hrs at 40 to 45 0 C under stirring.
  • Atorvastatin Calcium can be isolated as novel crystalline in anhydrous and hydrated forms at different temperatures by varying the rate of addition, ratio of ingredients, and time of stirring of the reaction mixture.
  • Atorvastatin calcium either in form of solution or solid, is mixed with anti- solvent optionally in presence of water.
  • the solvent used for preparing solution of Atorvastatin calcium may be such as aliphatic ketones preferably acetone, diethyl ketone and ethyl methyl ketone and the like. This solution was added to anti-solvent i.e. water. Alternately Atorvastatin calcium may be added to a mixture of the ketone and water.
  • Atorvastatin Calcium in acetone and water mixture for over 100 or more hrs and allowing the acetone to evaporate over a period of time leads to the crystallization of thick precipitate which after filtration and drying affords Form M-3.
  • the amount of acetone and water used may vary between 10 times to 150 times, preferably 70 to 100 times w. r. t. the Atorvastatin calcium used.
  • the ratio of acetone and water used may be between 0.25:1.0 to 1.0 to 0.25, preferably between 0.75:1.0 to 1.0 to 0.75 and the crystallization is carried out at 0 to 55 0 C, preferably at 20 to 40 0 C, the stirring is performed over a period of 48 to 250 hrs, preferably over 125 to 200 hrs and the sample is dried at 20 to 70 0 C, preferably at 50 to 6O 0 C.
  • the quantity of dichloromethane in which Atorvastatin calcium is dissolved may be between 3 to 100 times, preferably 10 to 20 times v/w w. r. t. the starting material and the solvent is slowly allowed to evaporate from the reaction flask over a period of 3 to 96 hrs, preferably 24 to 30 hrs at +5 to 35 0 C under slow stirring.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Obesity (AREA)
  • Diabetes (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Engineering & Computer Science (AREA)
  • Hematology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pyrrole Compounds (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

La présente invention concerne de nouveaux polymorphes d'atorvastatine appelés M-2, M-3 et M-4, présentant des diffractions X différentes de celles des formes connues, ainsi que des procédés de fabrication desdits composés. Le procédé selon l'invention consiste à cristalliser la forme souhaitée au moyen d'atorvastatine sous forme solide ou liquide, de solvants écologiques tels que des cétones aliphatiques, par exemple acétone, diéthyle cétone, et éthylméthyle cétone, et d'antisolvants tels que l'eau, par variation du rapport des réactifs et de paramètres de processus.
PCT/IN2005/000360 2004-11-05 2005-11-03 Nouvelles formes cristallines de calcium d'atorvastatine et procedes de fabrication WO2006048894A1 (fr)

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IN2207DE2004 2004-11-05
IN2207/DEL/2004 2004-11-05

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Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2007070667A2 (fr) * 2005-12-13 2007-06-21 Teva Pharmaceutical Industries Ltd. Forme cristalline d’hemi-calcium d’atorvastatine et procedes de fabrication de celle-ci
JP2010520273A (ja) * 2007-03-02 2010-06-10 ドン・ア・ファーム・カンパニー・リミテッド ピロリルヘプタン酸誘導体の新規な結晶形態
JP2011219437A (ja) * 2010-04-14 2011-11-04 Towa Yakuhin Kk 結晶性形態ｔｗ−１のアトルバスタチンヘミカルシウム水和物とその製造方法
JP2012031130A (ja) * 2010-07-28 2012-02-16 Kyongbo Pharm Co Ltd アトルバスタチンヘミカルシウム塩の新規な結晶形、その水和物、及びその製造方法

Citations (13)

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Publication number Priority date Publication date Assignee Title
WO1997003959A1 (fr) * 1995-07-17 1997-02-06 Warner-Lambert Company Formes cristallines d'hemi-sel de calcium d'acide [r-(r*,r*)]-2-(4-fluorophenyl)-beta,delta-dihydroxy-5-(1-methylethyl)-3-phenyl-4-[(phenylamino)carbonyl]-1h-pyrrole-1-heptanoique (atorvastatine)
WO1997003958A1 (fr) * 1995-07-17 1997-02-06 Warner-Lambert Company Forme cristalline iii d'hemi-sel de calcium d'acide [r-(r*,r*)]-2(4-fluorophenyl)-beta-delta-dihydroxy-5-(1-methylethyl)-3-phenyl-4-[(phenylamino)carbonyl]-1h-pyrrole-1-heptanoique (atorvastatine)
WO2001036384A1 (fr) * 1999-11-17 2001-05-25 Teva Pharmaceutical Industries Ltd. Forme polymorphe de calcium d'atorvastatine
WO2002041834A2 (fr) * 2000-11-03 2002-05-30 Teva Pharmaceutical Industries, Ltd. Atorvastatine hemicalcique forme vii
WO2002043732A1 (fr) * 2000-11-30 2002-06-06 Teva Pharmaceutical Industries Ltd. Nouvelles formes cristallines d'hemi-calcium d'atorvastatine et leurs procedes de preparation, et nouveaux procedes de preparation d'autres formes
WO2002051804A1 (fr) * 2000-12-27 2002-07-04 Ciba Specialty Chemicals Holding Inc. Formes cristallines d'atorvastatine
WO2003004470A1 (fr) * 2001-06-29 2003-01-16 Warner-Lambert Company Llc Formes cristallines de sel hemicalcique d'acide [r-(r*,r*)]-2-(4-fluorophenyl)-beta,delta-dihydroxy-5-(1-methylethyl)-3-phenyl-4-[(phenylamino)carbonyl]-1h-pyrrole-1-heptanoique (atorvastatine)
WO2003011826A1 (fr) * 2001-07-30 2003-02-13 Dr. Reddy's Laboratories Ltd. Formes cristallines vi et vii de calcium d'atorvastatine
WO2003050085A1 (fr) * 2001-12-12 2003-06-19 Ivax Corporation Sel de calcium cristallin (2:1)de l'acide [r-(r*,r*)]-2-(4-fluorophenyl)-$g(b),$g(d)-dihydroxy-5-(1-methylethyl)-3-phenyl-4-[(phenylamino)carbonyl]-1h-pyrrole-heptanoique
WO2003070702A1 (fr) * 2002-02-15 2003-08-28 Teva Pharmaceutical Industries Ltd. Nouvelles formes cristallines d'hemi-calcium d'atorvastatine
US20030212279A1 (en) * 2000-11-30 2003-11-13 Limor Tessler Novel crystal forms of atorvastatin hemi-calcium and processes for their preparation as well as novel processes for preparing other forms
WO2004022053A1 (fr) * 2002-09-03 2004-03-18 Morepen Laboratories Limited Forme vi de calcium d'atorvastatine ou hydrates de cette derniere
WO2004050618A2 (fr) * 2002-11-28 2004-06-17 Teva Pharmaceutical Industries Ltd. Forme cristalline

Patent Citations (15)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1997003958A1 (fr) * 1995-07-17 1997-02-06 Warner-Lambert Company Forme cristalline iii d'hemi-sel de calcium d'acide [r-(r*,r*)]-2(4-fluorophenyl)-beta-delta-dihydroxy-5-(1-methylethyl)-3-phenyl-4-[(phenylamino)carbonyl]-1h-pyrrole-1-heptanoique (atorvastatine)
WO1997003959A1 (fr) * 1995-07-17 1997-02-06 Warner-Lambert Company Formes cristallines d'hemi-sel de calcium d'acide [r-(r*,r*)]-2-(4-fluorophenyl)-beta,delta-dihydroxy-5-(1-methylethyl)-3-phenyl-4-[(phenylamino)carbonyl]-1h-pyrrole-1-heptanoique (atorvastatine)
WO2001036384A1 (fr) * 1999-11-17 2001-05-25 Teva Pharmaceutical Industries Ltd. Forme polymorphe de calcium d'atorvastatine
WO2002041834A2 (fr) * 2000-11-03 2002-05-30 Teva Pharmaceutical Industries, Ltd. Atorvastatine hemicalcique forme vii
US20030212279A1 (en) * 2000-11-30 2003-11-13 Limor Tessler Novel crystal forms of atorvastatin hemi-calcium and processes for their preparation as well as novel processes for preparing other forms
WO2002043732A1 (fr) * 2000-11-30 2002-06-06 Teva Pharmaceutical Industries Ltd. Nouvelles formes cristallines d'hemi-calcium d'atorvastatine et leurs procedes de preparation, et nouveaux procedes de preparation d'autres formes
WO2002051804A1 (fr) * 2000-12-27 2002-07-04 Ciba Specialty Chemicals Holding Inc. Formes cristallines d'atorvastatine
WO2003004470A1 (fr) * 2001-06-29 2003-01-16 Warner-Lambert Company Llc Formes cristallines de sel hemicalcique d'acide [r-(r*,r*)]-2-(4-fluorophenyl)-beta,delta-dihydroxy-5-(1-methylethyl)-3-phenyl-4-[(phenylamino)carbonyl]-1h-pyrrole-1-heptanoique (atorvastatine)
US6605729B1 (en) * 2001-06-29 2003-08-12 Warner-Lambert Company Crystalline forms of [R-(R*,R*)]-2-(4-fluorophenyl)-β,δ-dihydroxy-5-(1-methylethyl)-3-phenyl-4-[(phenylamino)carbonyl]-1H-pyrrole-1-heptanoic acid calcium salt (2:1)
WO2003011826A1 (fr) * 2001-07-30 2003-02-13 Dr. Reddy's Laboratories Ltd. Formes cristallines vi et vii de calcium d'atorvastatine
WO2003050085A1 (fr) * 2001-12-12 2003-06-19 Ivax Corporation Sel de calcium cristallin (2:1)de l'acide [r-(r*,r*)]-2-(4-fluorophenyl)-$g(b),$g(d)-dihydroxy-5-(1-methylethyl)-3-phenyl-4-[(phenylamino)carbonyl]-1h-pyrrole-heptanoique
WO2003070702A1 (fr) * 2002-02-15 2003-08-28 Teva Pharmaceutical Industries Ltd. Nouvelles formes cristallines d'hemi-calcium d'atorvastatine
WO2004022053A1 (fr) * 2002-09-03 2004-03-18 Morepen Laboratories Limited Forme vi de calcium d'atorvastatine ou hydrates de cette derniere
WO2004043918A2 (fr) * 2002-11-12 2004-05-27 Teva Pharmaceutical Industries Ltd. Nouvelles formes cristallines d'atorvastatine hemi-calcium et leurs procedes de preparation ainsi que de nouveaux procedes de preparation d'autres formes
WO2004050618A2 (fr) * 2002-11-28 2004-06-17 Teva Pharmaceutical Industries Ltd. Forme cristalline

Cited By (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2007070667A2 (fr) * 2005-12-13 2007-06-21 Teva Pharmaceutical Industries Ltd. Forme cristalline d’hemi-calcium d’atorvastatine et procedes de fabrication de celle-ci
WO2007070667A3 (fr) * 2005-12-13 2007-08-02 Teva Pharma Forme cristalline d’hemi-calcium d’atorvastatine et procedes de fabrication de celle-ci
US8080672B2 (en) 2005-12-13 2011-12-20 Teva Pharmaceutical Industries Ltd. Crystal form of atorvastatin hemi-calcium and processes for preparation thereof
JP2010520273A (ja) * 2007-03-02 2010-06-10 ドン・ア・ファーム・カンパニー・リミテッド ピロリルヘプタン酸誘導体の新規な結晶形態
JP2011219437A (ja) * 2010-04-14 2011-11-04 Towa Yakuhin Kk 結晶性形態ｔｗ−１のアトルバスタチンヘミカルシウム水和物とその製造方法
JP2012031130A (ja) * 2010-07-28 2012-02-16 Kyongbo Pharm Co Ltd アトルバスタチンヘミカルシウム塩の新規な結晶形、その水和物、及びその製造方法
EP2420488A1 (fr) * 2010-07-28 2012-02-22 Kyongbo pharmaceutical, Co., Ltd Nouvelle formule cristalline de sel hémicalcium atorvastanine, hydrate associé et son procédé de production
US10252993B2 (en) 2010-07-28 2019-04-09 Kyongbo Pharm Crystalline form of atorvastatin hemi-calcium salt, hydrate thereof, and method of producing the same

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