WO2008053495A1 - Nouvelle forme cristalline d'atorvastatine sodique - Google Patents

Nouvelle forme cristalline d'atorvastatine sodique Download PDF

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Publication number
WO2008053495A1
WO2008053495A1 PCT/IN2007/000398 IN2007000398W WO2008053495A1 WO 2008053495 A1 WO2008053495 A1 WO 2008053495A1 IN 2007000398 W IN2007000398 W IN 2007000398W WO 2008053495 A1 WO2008053495 A1 WO 2008053495A1
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WO
WIPO (PCT)
Prior art keywords
atorvastatin
sodium
crystalline form
atorvastatin sodium
salt
Prior art date
Application number
PCT/IN2007/000398
Other languages
English (en)
Inventor
Rajesh Kumar Thaper
Kumodini Kashinath Mahakal
Shreenivas Digamber Gundale
Hemraj Mahadeorao Lande
Valmik Shankar Shinde
Original Assignee
Lupin 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 Lupin Limited filed Critical Lupin Limited
Publication of WO2008053495A1 publication Critical patent/WO2008053495A1/fr

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Classifications

    • 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

  • the present invention relates to a novel crystalline form of atorvastatin sodium.
  • Atorvastatin chemically known as [R-(R*, R*)]-2-(4-fluorophenyl)- ⁇ , ⁇ -dihydroxy-5- (1- methylethyl)-3-phenyl-4- [(phenylamino)carbonyl]-lH-pyrrole-l-heptanoic acid is an HMG- CoA reductase inhibitor and is used as an antihypercholesterolemic agent.
  • Atorvastatin is marketed as the hemi-calcium salt trihydrate under the brand name LIPITOR.
  • Atorvastatin was first disclosed and claimed in US . Patent No. 4,681,893, as the racemic lactone, i.e., trans-5- (4-fluorophenyl)-2-(l-methylethyl)-N, 4-diphenyl-l- [2-tetrahydro-4- hydroxy-6-oxo-2H-pyran-2-yl) ethyl] -lH-pyrrole-carboxamide.
  • the patent teaches a method of synthesizing the racemic atorvastatin lactone and sodium salt of (R*, R*)-2-(4- fluorophenyi)- ⁇ , ⁇ -dihydroxy-5- (l-methylethyl)-3-phenyl-4- [(phenylamino)carbonyl]-lH- pyrrole- 1-heptanoic acid ("racemic atorvastatin sodium”) by treating the racemic lactone with sodium hydroxide in mixture of THF and water.
  • the US Patent 5,273,995 teaches a method of making the calcium salt of atorvastatin by first treating the atorvastatin lactone with sodium hydroxide in a mixture of methanol and water to get the sodium salt and treating the sodium salt with slight excess of CaQ 2 .2H 2 O.
  • Atorvastatin hemi-calcium salt was further purified by recrystallization from a 5:3 mixture of ethyl acetate and hexane.
  • atorvastatin sodium is the useful precursor in the manufacture of atorvastatin hemi- calcium salt.
  • the present inventors have found that isolation of the sodium salt of atorvastatin and its subsequent conversion to hemi-calcium salt significantly improved the purity of atorvastatin hemi-calcium salt.
  • the present invention provides a novel crystalline form of atorvastatin sodium, having high storage stability, high purity of greater than 99.5%,
  • Figure 1 powder X-ray diffraction pattern of the crystalline atorvastatiun sodium of present invention
  • Figure 2 DSC of the crystalline atorvastatin sodium of present invention
  • the crystalline atorvastatin sodium of present invention is characterized by a powder X-ray diffraction pattern given in the Figure- 1 and DSC given in Figure-2.
  • the crystalline atorvastatin sodium was stable for 3 months when stored at 40 0 C under relative humidity of 75%.
  • the crystalline atorvastatin sodium salt of the present invention is prepared as depicted in the following process Scheme- 1. dil.HCI lsopropyl alcohol
  • the crude sodium salt was washed with isopropanol (2 x 100 ml).
  • the wet sodium salt was then charged into 1000 ml of isopropanol containing 5% water and heated to 78-82 0 C for about an hour, cooled to 25-30 0 C, and then stirred for 1-2 hours, filtered under N 2 atmosphere and dried under vacuum to obtain crystalline atorvastatin sodium of purity 99.6%. Melting point: 136.7-139.2 0 C.
  • The, purification of the crude atorvastatin sodium may be repeated one or more time to get crystalline form with purity above 99.6%.

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

Abstract

L'invention concerne une nouvelle forme cristalline d'atorvastatine sodique qui présente un motif caractéristique de diffraction des rayons X sur poudre et qui possède une pureté supérieure à 99,5 %.
PCT/IN2007/000398 2006-10-30 2007-09-10 Nouvelle forme cristalline d'atorvastatine sodique WO2008053495A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
IN1143KO2006 2006-10-30
IN1143/KOL/2006 2006-10-30

Publications (1)

Publication Number Publication Date
WO2008053495A1 true WO2008053495A1 (fr) 2008-05-08

Family

ID=38969838

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/IN2007/000398 WO2008053495A1 (fr) 2006-10-30 2007-09-10 Nouvelle forme cristalline d'atorvastatine sodique

Country Status (1)

Country Link
WO (1) WO2008053495A1 (fr)

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2009023260A2 (fr) * 2007-08-15 2009-02-19 Teva Pharmaceutical Industries Ltd. Procédé amélioré de synthèse de dérivé pyrrole, intermédiaire d'atorvastatine
CN102070504A (zh) * 2010-12-23 2011-05-25 蚌埠丰原医药科技发展有限公司 阿托伐他汀钠的制备方法
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

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1749247A (zh) * 2005-08-15 2006-03-22 浙江新东港药业股份有限公司 高纯度结晶型阿伐他汀钠的制备方法
GB2424880A (en) * 2005-04-06 2006-10-11 Generics Crystalline forms of atorvastatin sodium, processes for their preparation and their use in inhibiting HMG-CoA reductase
WO2007020413A1 (fr) * 2005-08-15 2007-02-22 Arrow International Limited Atorvastatine de sodium amorphe cristalline
WO2007052296A2 (fr) * 2005-08-23 2007-05-10 Kopran Research Laboratories Ltd Procede de preparation de calcium d'atorvastatine amorphe
WO2007118873A2 (fr) * 2006-04-14 2007-10-25 Krka, Tovarna Zdravil, D.D., Novo Mesto Polymorphes de sels d'atorvastatine

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB2424880A (en) * 2005-04-06 2006-10-11 Generics Crystalline forms of atorvastatin sodium, processes for their preparation and their use in inhibiting HMG-CoA reductase
CN1749247A (zh) * 2005-08-15 2006-03-22 浙江新东港药业股份有限公司 高纯度结晶型阿伐他汀钠的制备方法
WO2007020413A1 (fr) * 2005-08-15 2007-02-22 Arrow International Limited Atorvastatine de sodium amorphe cristalline
WO2007052296A2 (fr) * 2005-08-23 2007-05-10 Kopran Research Laboratories Ltd Procede de preparation de calcium d'atorvastatine amorphe
WO2007118873A2 (fr) * 2006-04-14 2007-10-25 Krka, Tovarna Zdravil, D.D., Novo Mesto Polymorphes de sels d'atorvastatine

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
CHEN Z ET AL: "Process for preparing high purity crystal atorvastatin sodium used as medicine for treating cardiac and cerebral vascular diseases", WPI / THOMSON, 2006, XP002440592 *
ZHOU ET AL: "Method for preparation of high purity crystal atorvastatin sodium for treating cardiovascular and cerebrovascular diseases", CA, 2006, XP002400831 *

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2009023260A2 (fr) * 2007-08-15 2009-02-19 Teva Pharmaceutical Industries Ltd. Procédé amélioré de synthèse de dérivé pyrrole, intermédiaire d'atorvastatine
WO2009023260A3 (fr) * 2007-08-15 2009-10-15 Teva Pharmaceutical Industries Ltd. Procédé amélioré de synthèse de dérivé pyrrole, intermédiaire d'atorvastatine
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
CN102070504A (zh) * 2010-12-23 2011-05-25 蚌埠丰原医药科技发展有限公司 阿托伐他汀钠的制备方法

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