WO2009090544A2 - Procédé de production d'atorvastatine calcique amorphe - Google Patents

Procédé de production d'atorvastatine calcique amorphe Download PDF

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Publication number
WO2009090544A2
WO2009090544A2 PCT/IB2009/000068 IB2009000068W WO2009090544A2 WO 2009090544 A2 WO2009090544 A2 WO 2009090544A2 IB 2009000068 W IB2009000068 W IB 2009000068W WO 2009090544 A2 WO2009090544 A2 WO 2009090544A2
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WO
WIPO (PCT)
Prior art keywords
atorvastatin calcium
amorphous atorvastatin
sealed container
amorphous
process according
Prior art date
Legal status (The legal status 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 status listed.)
Ceased
Application number
PCT/IB2009/000068
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English (en)
Other versions
WO2009090544A3 (fr
Inventor
P. V. Srinivas Rao
Yogendra Kumar Chauhan
Tushar Kumar Srivastava
Purna Chandra Ray
Om Dutt Tyagi
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Mylan Laboratories Ltd
Original Assignee
Matrix Laboratories Ltd
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 Matrix Laboratories Ltd filed Critical Matrix Laboratories Ltd
Publication of WO2009090544A2 publication Critical patent/WO2009090544A2/fr
Publication of WO2009090544A3 publication Critical patent/WO2009090544A3/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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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

Definitions

  • This invention in general relates to a synthetic HMG-CoA reductase inhibitor. More particularly, the present invention provides an improved process for producing amorphous form of atorvastatin calcium and a method of packaging thereof.
  • Atorvastatin calcium a synthetic HMG-CoA reductase inhibitor, is used for the treatment of hyperlipidemia and hypercholesterolemia, both of which are risk factors for arteriosclerosis and coronary heart disease, open dihydroxy carboxylic acid, lactone and various salt forms of atorvastatin have been synthesized for use in the treatment of aforementioned diseases.
  • Atorvastatin in its calcium salt form i.e. [R(R*,R*)]-2-(4-fluorophenyl)- ⁇ , ⁇ - dihydroxy-5 -(l-methylethyl)-3 -phenyl-4- [(phenylamino)carbonyl] - 1 H-pyrrole- 1 - heptanoic acid calcium salt (2:1) having formula I is more preferable for developing formulations and has been recommended as a drug.
  • US Patent No. 5,273,995 discloses that R-enantiomer of the ring-opened acid form of trans-5-(4-fluorophenyl)-2-(l-methylethyl)-N,4-diphenyl-l-[2-(tetrahydro-4- hydroxy-6-oxo-2H-pyran-2-yl)ethyl]-lH-pyrrole-3-carboxamide exhibits inhibition of the biosynthesis of cholesterol.
  • the amorphous forms of pharmaceutical substances exhibit different dissolution characteristics and bioavailability patterns compared to the crystalline forms (Konno T., Chem. Phar. Bull. 1990, 38, 2003-2007).
  • Amorphous form of the atorvastatin calcium is more soluble than the crystalline forms, thereby resulting in increased bioavailability.
  • the bioavailability is one of the key parameters in determining the form of the substance to be used in a pharmaceutical formulation.
  • the amorphous atorvastatin calcium is an unstable substance, which is susceptible to moisture and picks up moisture easily when exposed to atmosphere. Moreover, the reaction of atorvastatin with atmospheric oxygen leads to the formation of the sulfoxide impurity. The susceptibility of the amorphous atorvastatin calcium leads to deviation of the drug product from regulatory purity requirements even prior to the product reaching the patient.
  • the present invention provides an improved process for producing amorphous atorvastatin calcium, which obviates the drawback associated in the prior arts.
  • an improved process for producing amorphous atorvastatin calcium comprises of dissolving crystalline Form M of atorvastatin calcium in ester solvent, treating with anti solvent and isolating amorphous atorvastatin calcium.
  • a method for packaging amorphous atorvastatin calcium comprises of placing atorvastatin calcium in low density polyethylene ("LDPE”) sealed container under an inert atmosphere, placing the sealed container, a desiccant and an oxygen adsorbent in a second sealed container, placing the second sealed container in a triple laminated bag and sealing and enclosing the triple laminated bag in a closed high density polyethylene (“HDPE”) container.
  • LDPE low density polyethylene
  • HDPE high density polyethylene
  • Figure 1 illustrates the powder XRD pattern of amorphous atorvastatin calcium.
  • the present invention describes an improved process for producing the amorphous atorvastatin calcium.
  • the process for producing the amorphous atorvastatin calcium comprises dissolving crystalline Form M of atorvastatin calcium in an ester solvent, treating with an anti solvent and isolating the resultant amorphous atorvastatin calcium.
  • the ester solvent employed in the process is ethyl acetate.
  • the atorvastatin calcium Form M is dissolved in the ester solvent at elevated temperature preferably 40-60 0 C.
  • the ami solvent used in the process is hydrocarbon selected from the group consisting of hexane, pentane, heptane, cyclohexane or mixture thereof, preferably pentane.
  • the anti solvent is added at a temperature 5-25 0 C and subsequently isolating pure amorphous atorvastatin calcium.
  • atorvastatin calcium Form M can be prepared by treating atorvastatin hemi-calcium amorphous form or form-I or mixture of any polymorphic forms with alcohol, preferably methanol at room temperature to reflux temperature preferably at temperature of 15 to 35 0 C for a period of 2 hrs to 30 hrs preferably for about 4hrs to 18 hrs. After the precipitation of form M, it can be isolated as per the conventional methods.
  • the amorphous atorvastatin calcium prepared by the process of the invention is packaged in a way to reduce the uptake of moisture and formation of oxidized products, thereby increasing the shelf life of the product.
  • the method for packaging amorphous atorvastatin calcium comprises of placing the amorphous atorvastatin calcium in low density polyethylene ("LDPE") sealed container under an inert atmosphere, placing the sealed container, a desiccant and an oxygen adsorbent in a second sealed container, placing the second sealed container in a triple laminated bag and sealing and enclosing the triple laminated bag in a closed high density polyethylene (“HDPE”) container.
  • the oxygen adsorbent employed in the package includes any material that can adsorb or dissolve oxygen with/without reaction and provide the stability and thereby increasing the shelf life of the product.
  • the said polymorphs of the present invention are characterized by their X-ray powder diffraction pattern.
  • the X-ray diffraction patterns of said 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 4OkV and 3OmA. The experiments were conducted over the 2 ⁇ range of 2.0°-50.0°, 0.030° step size and 50 seconds step time.
  • Example 1 Process for the preparation of amorphous atorvastatin calcium
  • Atorvastatin calcium Form M 150 gms of Atorvastatin calcium Form M was taken in 750 mL of Ethyl acetate. Reaction mass was heated to 50-55 °C. Then reaction mass was cooled to 10- 15 0 C. Slowly 750 mL of n-Pentane was added. The obtained solid was filtered and dried to yield 135-138 gms of pure amorphous Atorvastatin calcium.

Landscapes

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

Abstract

L'invention concerne un procédé amélioré pour la production d'atorvastatine calcique amorphe ainsi qu'un procédé de conditionnement associé.
PCT/IB2009/000068 2008-01-16 2009-01-15 Procédé de production d'atorvastatine calcique amorphe Ceased WO2009090544A2 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
IN138CH2008 2008-01-16
IN138/CHE/2008 2008-01-16

Publications (2)

Publication Number Publication Date
WO2009090544A2 true WO2009090544A2 (fr) 2009-07-23
WO2009090544A3 WO2009090544A3 (fr) 2009-11-19

Family

ID=40885714

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/IB2009/000068 Ceased WO2009090544A2 (fr) 2008-01-16 2009-01-15 Procédé de production d'atorvastatine calcique amorphe

Country Status (1)

Country Link
WO (1) WO2009090544A2 (fr)

Family Cites Families (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
IN190564B (fr) * 2001-04-11 2003-08-09 Cadila Heathcare Ltd
WO2005090301A1 (fr) * 2004-03-17 2005-09-29 Ranbaxy Laboratories Limited Forme cristalline d'hemi-calcium d'atorvastatine
EP1793815A4 (fr) * 2004-09-30 2010-12-29 Reddys Lab Ltd Dr Atorvastatine calcique amorphe

Also Published As

Publication number Publication date
WO2009090544A3 (fr) 2009-11-19

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