WO2006035295A1 - Procede de purification de lovastatine - Google Patents

Procede de purification de lovastatine Download PDF

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Publication number
WO2006035295A1
WO2006035295A1 PCT/IB2005/002863 IB2005002863W WO2006035295A1 WO 2006035295 A1 WO2006035295 A1 WO 2006035295A1 IB 2005002863 W IB2005002863 W IB 2005002863W WO 2006035295 A1 WO2006035295 A1 WO 2006035295A1
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WO
WIPO (PCT)
Prior art keywords
lovastatin
impurity
substantially pure
less
recovering
Prior art date
Application number
PCT/IB2005/002863
Other languages
English (en)
Inventor
Parveen Kumar
Ashoke Mitra
Hitesh Kumar Malviya
Original Assignee
Ranbaxy Laboratories 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 Ranbaxy Laboratories Limited filed Critical Ranbaxy Laboratories Limited
Publication of WO2006035295A1 publication Critical patent/WO2006035295A1/fr

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D309/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings
    • C07D309/16—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
    • C07D309/28—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member 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
    • C07D309/30—Oxygen atoms, e.g. delta-lactones
    • 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 field of the invention relates to a process for the preparation of lovastatin. More particularly, it relates to the preparation of lovastatin substantially free of dihydrolovastatin.
  • the invention also relates to pharmaceutical compositions that include the lovastatin substantially free of dihydrolovastatin and use of said compositions for treating hypercholesterolemia.
  • lovastatin is ( ⁇ S,3R,7S,SS,8aR)-8- ⁇ 2-[(2R,4R)-4-hyd ⁇ oxy-6- oxotetrahydro-2H-pyran-2-yl]ethyl ⁇ -3,7-dimethyl-l,2,3,7,8,8a-hexahydronaphthalen-l-yl (25)-2-methylbutanoate having the structural Formula I.
  • the lovastatin which is an inactive lactone, is hydrolyzed to the corresponding /3-hydroxyacid form.
  • HMG-CoA 3-hydroxy-3- methylglutaryl-coenzyme A
  • Hypercholesterolemia is known to be a major risk factor for atherosclerosis.
  • Complications of cardiovascular disease such as myocardial infarction, stroke, and peripheral vascular disease result in many deaths in developed countries.
  • a decrease in plasma LDL levels has been shown to reduce the risk of cardiovascular disease.
  • Statins are by far the most therapeutically effective drugs for reducing the plasma LDL levels.
  • Statins include for example, lovastatin, compactin, pravastatin, simvastatin which are essentially fermentation based and rosuvastatin, fluvastatin and atorvastatin which are totally synthetic statins.
  • Lovastatin is one of the first statins described in the literature for example, in U.S. Patent Nos. 4,231,938; 4,294,846 and 4,294,926.
  • Several processes are reported for recovering lovastatin from fermentation broth which suggest use of different solvents for extraction, recrystallization, use of different chromatographic methods for purification of lovastatin, and the like for example, in U.S. Patent No. 4,916,239; 4,231,938; International Publication Nos. (PCT) WO 92/16276; WO 00/63411; WO 03/48149; and European Patent No. 033536.
  • the level of Impurity A in lovastatin harvest broth ranges from about 8% to 11% w/w relative to lovastatin. Since impurity is present in such a high amount in the broth, it is very difficult to remove this impurity A in the lovastatin drug product. None of the reported processes provide pure lovastatin with levels of impurity A less than 0.25%. Summary of the Invention
  • substantially pure lovastatin having less than 0.25% w/w relative to lovastatin of impurity A of Formula II.
  • a pharmaceutical composition that includes a therapeutically effective amount of the substantially pure lovastatin; and one or more pharmaceutically acceptable carriers, excipients or diluents.
  • a process for the preparation of substantially pure lovastatin having less than 0.25% w/w relative to lovastatin of impurity A includes:
  • a process for removal of impurity A from lovastatin includes dissolving lovastatin in toluene, isolating lovastatin and recrystallizing from one or more solvents.
  • the process may include further purification of the product obtained.
  • the process may produce the substantially pure lovastatin having less than 0.25% of impurity A. hi particular, it may produce the lovastatin having less than 0.2% of impurity A.
  • a method for treating hypercholesteremia in a warm-blooded animal comprising providing a pharmaceutical composition to the warm-blooded animal that includes the substantially pure lovastatin.
  • the inventors have developed a process for the preparation of substantially pure lovastatin having less than 0.25% of impurity A by HPLC.
  • the process includes obtaining a solution of lovastatin in toluene; recovering lovastatin; recrystallizing from one or more solvents; and recovering the substantially pure lovastatin by the removal of the solvents.
  • compositions that contain the substantially pure lovastatin having less than 0.25% of impurity A for example, less than 0.2%, in admixture with one or more solid or liquid pharmaceutical diluents, carriers, and/or excipients.
  • the solution of lovastatin may be obtained by dissolving lovastatin in toluene.
  • a solution may be obtained directly from fermentation broth.
  • the solution of lovastatin in toluene may be obtained by heating. It may be heated from about 40°C to about 12O 0 C, for example from about 50 0 C to about 100 0 C. It may be heated from about 10 minutes to about 24 hours. More particularly, it may be heated for about 2-3 hours.
  • the solution may be filtered to remove any undissolved foreign particulate matter.
  • any of the methods known in the art can be employed for isolation of lovastatin from the fermentation broth.
  • it may be isolated from the fermentation broth in the form of an in-situ aqueous process stream employing the method described in International Publication No. (PCT) patent application WO 02/ 00615.
  • the lovastatin may be recovered by a technique which includes, for example, distillation, distillation under vacuum, cooling, evaporation, filtration, filtration under vacuum, decantation and centrifugation.
  • the lovastatin thus recovered may be further purified or additionally purified, by employing commonly practiced recrystallization techniques using solvent / antisolvent mixture to obtain substantially pure lovastatin.
  • lovastatin substantially free of impurity A refers to lovastatin containing less than 0.25% w/w of impurity A relative to lovastatin.
  • the substantially pure lovastatin of the invention has purity greater than 98%.
  • solvent includes any solvent or solvent mixture in which lovastatin, is soluble, including, for example, lower alkanol, polar aprotic solvents, and mixtures thereof.
  • alkanol include those primary, secondary and tertiary alcohols having from one to six carbon atoms.
  • Suitable lower alkanol solvents include methanol, ethanol, n-propanol, and isopropanol.
  • a suitable polar aprotic solvent includes one or more of N,N-dimethylformamide, N,N-dimethylacetamide, dimethylsulphoxide, acetonitrile and N-methylpyrrolidone. Mixtures of all of these solvents are also contemplated.
  • a suitable anti-solvent can be added to the clear solution to precipitate the substantially pure lovastatin.
  • anti-solvent includes any solvent in which lovastatin is insoluble or poorly soluble or practically insoluble or partially soluble, including, for example, cyclopentane, cyclohexane, cycloheptane, hexane, petroleum ether, heptane, water, or mixtures thereof.
  • the resulting pure lovastatin may be formulated into ordinary dosage forms such as, for example, tablets, capsules, pills, solutions, etc. In these cases, the medicaments can be prepared by conventional methods with conventional pharmaceutical excipients.
  • the lovastatin can be administered for the prevention and treatment of hypocholesterolemia in a warm-blooded animal.
  • a warm-blooded animal is a member of the animal kingdom possessed of a homeostatic mechanism and includes mammals and birds.
  • the lovastatin is generally administered as part of a pharmaceutical composition with a pharmaceutically acceptable carrier, diluent or excipient and optionally other therapeutic ingredients.
  • a pharmaceutically acceptable carrier diluent or excipient and optionally other therapeutic ingredients.
  • the lovastatin may be conventionally formulated into tablets, capsules, suspensions, dispersions, injectables and other pharmaceutical forms. Any suitable route of administration may be employed, such as, for example, peroral or parenteral.
  • Fermentation broth (12 L) was acidified to pH 2.0 with sulphuric acid (2N) .
  • the acidified broth was heated to 5O 0 C and was stirred at room temperature for 24 hours.
  • the broth was filtered and the mycelial cake was extracted twice with toluene (6 L + 5 L).
  • the toluene extract was washed with sodium bicarbonate solution (5% aqueous).
  • the washed toluene extract was concentrated under vacuum at about 50 0 C.
  • the concentrate was cooled to 5 - 10°C and stirred further for 1 hour.
  • the slurry so obtained was filtered and dried to yield 100 gm of lovastatin powder.
  • lovastatin 80 gm of the lovastatin was dissolved in toluene (16OmL) at +95 °C and the clear homogenous solution was stirred for 10 to 15 minutes and then cooled to +27°C. The slurry was stirred at room temperature for 2 hours and then cooled to +5 0 C and again stirred at this temperature for 2 hours. The cooled slurry was filtered and the wet cake washed with pre-cooled (5°C) toluene (16OmL). The whole operation from the dissolution of lovastatin in toluene till filtration and washing with pre-cooled toluene was repeated again with wet cake. The wet cake was dried under vacuum at temperature +45 0 C ⁇ 2°C, to get lovastatin
  • Lovastatin (20 gm) obtained through example 1; having 97.98 % purity and 0.56 % impurity A (w/w of lovastatin) was taken in dimethylsulphoxide (30OmL) at +26 0 C. The resultant mixture was stirred for 30 minutes to get a clear solution. To the clear solution, deionized water (58mL) was added drop wise till precipitation started. The slurry was stirred for 60 minutes at room temperature and consequently cooled to +1O 0 C. The cooled slurry was stirred for 60 minutes and filtered. The wet cake was washed with pre-cooled deionized water and dried at temperature +45°C under vacuum to get substantially pure lovastatin.
  • Lovastatin (20 gm) obtained through example 1; having 97.98 % purity and 0.56 % impurity A was taken in 10OmL of acetonitrile. The slurry was heated to +6O 0 C till a clear solution was observed. To the clear solution, 4OmL of deionized water was added at +6O 0 C. The temperature of the solution was brought to room temperature (+26 0 C) and stirred for further 60 minutes. The slurry was cooled to +10 0 C and stirred for 60 minutes. The product was filtered and washed with pre-cooled deionized water (4OmL). The wet cake was dried under vacuum at temperature +45°C, till constant weight was obtained.
  • An aqueous fermentation broth containing 9.6% of impurity A (w/w, relative to lovastatin) was used for recovery of crude lovastatin by a process as provided in Example 1.
  • Lovastatin (10 gm) containing 3.92% impurity A was added to 5OmL of toluene and the slurry was heated to +95 0 C to get a clear solution.
  • the clear homogenous solution was stirred at + 95 0 C for 10 to 15 minutes and then cooled to room temperature (+ 27°C), when lovastatin lactone crystallized.
  • the slurry was stirred at room temperature for 2 hours.
  • the slurry was then cooled to +5 0 C and stirred at this temperature for 2 hours.

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

Abstract

L'invention porte sur un procédé de préparation de lovastatine. Plus précisément, elle se rapporte à la préparation de lovastatine ne contenant pratiquement pas de dihydrolovastatine. L'invention concerne aussi des compositions pharmaceutiques comprenant la lovastatine qui ne contient pratiquement pas de dihydrolovastatine, ainsi que l'utilisation de ces compositions dans le traitement de l'hypercholestérolémie.
PCT/IB2005/002863 2004-09-27 2005-09-27 Procede de purification de lovastatine WO2006035295A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
IN1850/DEL/2004 2004-09-27
IN1850DE2004 2004-09-27

Publications (1)

Publication Number Publication Date
WO2006035295A1 true WO2006035295A1 (fr) 2006-04-06

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PCT/IB2005/002863 WO2006035295A1 (fr) 2004-09-27 2005-09-27 Procede de purification de lovastatine

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1954653A2 (fr) * 2005-11-23 2008-08-13 Merck & Co., Inc. Procede de generation de solide amorphe pour agents pharmaceutiques insolubles dans l'eau
EP2597092A1 (fr) 2011-11-24 2013-05-29 Sterling Biotech Limited Procédé de purification de la lovastatine

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1992016276A1 (fr) * 1991-03-13 1992-10-01 Merck & Co., Inc. PROCEDE DE PURIFICATION D'INHIBITEURS DE HMG-CoA REDUCTASE
EP0556699A1 (fr) * 1992-02-10 1993-08-25 Novopharm Ltd. Souches fongiques et leurs utilisation dans la production d'antibiotiques

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1992016276A1 (fr) * 1991-03-13 1992-10-01 Merck & Co., Inc. PROCEDE DE PURIFICATION D'INHIBITEURS DE HMG-CoA REDUCTASE
EP0556699A1 (fr) * 1992-02-10 1993-08-25 Novopharm Ltd. Souches fongiques et leurs utilisation dans la production d'antibiotiques

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1954653A2 (fr) * 2005-11-23 2008-08-13 Merck & Co., Inc. Procede de generation de solide amorphe pour agents pharmaceutiques insolubles dans l'eau
EP1954653A4 (fr) * 2005-11-23 2010-11-03 Merck Sharp & Dohme Procede de generation de solide amorphe pour agents pharmaceutiques insolubles dans l'eau
EP2597092A1 (fr) 2011-11-24 2013-05-29 Sterling Biotech Limited Procédé de purification de la lovastatine

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