WO2008053495A1 - A novel crystalline form of atorvastatin sodium - Google Patents

A novel crystalline form of atorvastatin sodium Download PDF

Info

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
Authority
WO
WIPO (PCT)
Prior art keywords
atorvastatin
sodium
crystalline form
atorvastatin sodium
salt
Prior art date
Application number
PCT/IN2007/000398
Other languages
French (fr)
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/en

Links

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%.

Landscapes

  • 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

A novel crystalline form of atorvastatin sodium. The said crystalline atorvastatin sodium has characteristic X-ray powder diffraction pattern and is highly pure with purity above 99.5%.

Description

A NOVEL CRYSTALLINE FORM OF ATORVASTATIN SODIUM
FIELD OF THE INVENTION
The present invention relates to a novel crystalline form of atorvastatin sodium.
BACKGROUND OF THE INVENTION
Atorvastatin, chemically known as [R-(R*, R*)]-2-(4-fluorophenyl)-β, δ-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)-β,δ-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.
Atorvastatin, the pure [R(R* ,R*)] enantiomer of 2-(4-fluorophenyl)-β, δ-dihydroxy-5- (1- methylethyl)-3-phenyl-4- [(phenylamino)carbonyl]-lH-pyrrole- 1-heptanoic acid and its hemi-calcium salt were first disclosed in US patent No. 5,273,995.
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 CaQ2.2H2O. Atorvastatin hemi-calcium salt was further purified by recrystallization from a 5:3 mixture of ethyl acetate and hexane. Thus, atorvastatin sodium is the useful precursor in the manufacture of atorvastatin hemi- calcium salt. However, there is no disclosure in the prior art on crystalline form(s) of the sodium salt of atorvastatin first disclosed in US Patent No. 5,273,995.
Processes for preparing atorvastatin salts, atorvastatin lactone, and key intermediates are disclosed in US Patent Nos. 6,777,552; 6,528,661; 5,298,627; 5,003,080; 5,097,045; 5,124,482; 5,149,837; 5,216,174; 5245,047; 5,280,126; and Baumann, K.I, et al. Tetrahedron Letters, 33, 2283-2284, (1992).
The process to manufacture atorvastatin and its salts disclosed in US Patent Nos. 5,298,627, and 5,273,995 teaches to convert the sodium salt to calcium salt by treating with calcium chloride or calcium acetate without isolation and purification of the sodium salt obtained by hydrolyzing the lactone/ester/amide intermediate with methanolic sodium hydroxide.
The prior art conversions of the t-butyl ester or the lactone intermediate to hemi-calcium salt goes via in situ formation of sodium salt and conversion to calcium salt without isolation. This affects the purity of the calcium salt and also decreases its solubility.
There are no reports of isolating and utilizing the crystalline sodium salt. The inventors have now found that it is advantageous to isolate the crystalline sodium salt as it reduces the impurities in the atorvastatin hemi calcium salt which is the ultimate product
OBJECT OF THE INVENTION
Thus it is an object of the present invention to provide a novel crystalline form of atorvastatin sodium that has advantageous physical properties useful in the manufacture of atorvastatin hemi-calcium salt. SUMMARY OF THE INVENTION
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 inventors found that the isolation of the atorvastatin sodium salt get rid of the inorganic impurities that reduce the solubility of the atorvastatin hemicalcium salt.
Accordingly, the present invention provides a novel crystalline form of atorvastatin sodium, having high storage stability, high purity of greater than 99.5%,
Description of the accompanying drawings
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 0C under relative humidity of 75%.
The crystalline atorvastatin sodium salt of the present invention is prepared as depicted in the following process Scheme- 1.
Figure imgf000005_0001
dil.HCI lsopropyl alcohol
Figure imgf000005_0002
Scheme 1
The invention is further illustrated by the following non-limiting examples. EXAMPLE
To a stirred mixture of t-butyl ester intermediate (III) (100 gm, 0.153 moles) and isopropanol (1500 ml) kept at about 25-30 0C, dilute HCl (15 ml, 0.15 w/v) was added and warmed to 40- 45 0C till the ester intermediate (III) disappeared as indicated by HPLC. After the ester was completely hydrolyzed sodium hydroxide (14.67 gm, 0.367 moles) in water (110 ml) was added and refluxed to 78-82 0C till the diol ester (II) was completely converted to sodium salt. The reaction mixture was cooled to 25-30 0C and stirred for about 3 hours. 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 0C for about an hour, cooled to 25-30 0C, and then stirred for 1-2 hours, filtered under N2 atmosphere and dried under vacuum to obtain crystalline atorvastatin sodium of purity 99.6%. Melting point: 136.7-139.2 0C.
The, purification of the crude atorvastatin sodium may be repeated one or more time to get crystalline form with purity above 99.6%.

Claims

1. Crystalline atorvastatin sodium.
2. Crystalline atorvastatin sodium as claimed in claim 1 having characteristic X-ray powder diffraction pattern given in Figure- 1.
3. Crystalline atorvastatin sodium as claimed in claim 1 or 2 with a purity of above
PCT/IN2007/000398 2006-10-30 2007-09-10 A novel crystalline form of atorvastatin sodium WO2008053495A1 (en)

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 (en) 2008-05-08

Family

ID=38969838

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/IN2007/000398 WO2008053495A1 (en) 2006-10-30 2007-09-10 A novel crystalline form of atorvastatin sodium

Country Status (1)

Country Link
WO (1) WO2008053495A1 (en)

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2009023260A2 (en) * 2007-08-15 2009-02-19 Teva Pharmaceutical Industries Ltd. An improved process for synthesis of pyrrole derivative, an intermediate for atorvastatin
CN102070504A (en) * 2010-12-23 2011-05-25 蚌埠丰原医药科技发展有限公司 Method for preparing atorvastatin sodium
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 (en) * 2005-08-15 2006-03-22 浙江新东港药业股份有限公司 Process for preparing high purity crystal atorvastatin sodium
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 (en) * 2005-08-15 2007-02-22 Arrow International Limited Crystalline and amorphous sodium atorvastatin
WO2007052296A2 (en) * 2005-08-23 2007-05-10 Kopran Research Laboratories Ltd A process of preparing amorphous atorvastatin calcium
WO2007118873A2 (en) * 2006-04-14 2007-10-25 Krka, Tovarna Zdravil, D.D., Novo Mesto Polymorphs of atorvastatin sodium and magnesium salts

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 (en) * 2005-08-15 2006-03-22 浙江新东港药业股份有限公司 Process for preparing high purity crystal atorvastatin sodium
WO2007020413A1 (en) * 2005-08-15 2007-02-22 Arrow International Limited Crystalline and amorphous sodium atorvastatin
WO2007052296A2 (en) * 2005-08-23 2007-05-10 Kopran Research Laboratories Ltd A process of preparing amorphous atorvastatin calcium
WO2007118873A2 (en) * 2006-04-14 2007-10-25 Krka, Tovarna Zdravil, D.D., Novo Mesto Polymorphs of atorvastatin sodium and magnesium salts

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 (en) * 2007-08-15 2009-02-19 Teva Pharmaceutical Industries Ltd. An improved process for synthesis of pyrrole derivative, an intermediate for atorvastatin
WO2009023260A3 (en) * 2007-08-15 2009-10-15 Teva Pharmaceutical Industries Ltd. An improved process for synthesis of pyrrole derivative, an intermediate for atorvastatin
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 (en) * 2010-12-23 2011-05-25 蚌埠丰原医药科技发展有限公司 Method for preparing atorvastatin sodium

Similar Documents

Publication Publication Date Title
EP1351963B1 (en) A process for the synthesis of atorvastatin form v and phenylboronates as intermediate compounds
FI94339C (en) Process for the preparation of pharmaceutically acceptable [R- (R *, R *)] - 2- (4-fluorophenyl) -, - dihydroxy-5- (1-methylethyl) -3-phenyl-4 - [(phenylamino) carbonyl] -1H- for the preparation of pyrrole-1-heptanoic acid and its pharmaceutically acceptable salts
SK281110B6 (en) Process for preparing trans-6-[2-(substituted-pyrrol-1- -yl)alkyl]pyran-2-ones
US7812179B2 (en) Process for the preparation of atorvastatin and intermediates
WO2007099552A2 (en) Novel crystalline form of atovastatin hemi-magnesium
WO2008053495A1 (en) A novel crystalline form of atorvastatin sodium
US8188300B2 (en) Atorvastatin calcium propylene glycol solvates
EP1922315B1 (en) Preparation of an atorvastatin intermediate
US7615647B2 (en) Process for producing atorvastatin hemicalcium
WO2007096751A1 (en) Process for the preparation of atorvastatin calcium
US20090099371A1 (en) Process for the preparation of amorphous atorvastatin calcium salt
US7361772B2 (en) Process for the production of atorvastatin calcium
Stach et al. Synthesis of some impurities and/or degradation products of atorvastatin
WO2005073187A1 (en) Improved process for the preparation of amorphous atorvastatin calcium
US20050165242A1 (en) Process for the preparation of amorphous atorvastatin calcium
EP2616454B1 (en) Esters of hexanoic acids as intermediates for the preparation of atorvastatin
WO2008053312A2 (en) Process for preparing amorphous atorvastatin hemi calcium salt and its intermediate
IE20050594A1 (en) A process for preparing atorvastatin lactone
WO2006048888A1 (en) Novel process for the preparation of amorphous atorvastatin calcium salt
WO2005033078A1 (en) Process for the production of atorvastatin calcium

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 07805647

Country of ref document: EP

Kind code of ref document: A1

DPE1 Request for preliminary examination filed after expiration of 19th month from priority date (pct application filed from 20040101)
NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 07805647

Country of ref document: EP

Kind code of ref document: A1