WO2006048893A2 - Processus de synthese de composes statine a particules de grande taille - Google Patents

Processus de synthese de composes statine a particules de grande taille Download PDF

Info

Publication number
WO2006048893A2
WO2006048893A2 PCT/IN2005/000359 IN2005000359W WO2006048893A2 WO 2006048893 A2 WO2006048893 A2 WO 2006048893A2 IN 2005000359 W IN2005000359 W IN 2005000359W WO 2006048893 A2 WO2006048893 A2 WO 2006048893A2
Authority
WO
WIPO (PCT)
Prior art keywords
amorphous
solvent
microns
atorvastatin calcium
solution
Prior art date
Application number
PCT/IN2005/000359
Other languages
English (en)
Other versions
WO2006048893A3 (fr
Inventor
Sanjay Suri
Gurdeep Singh Sarin
Original Assignee
Morepen 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 Morepen Laboratories Limited filed Critical Morepen Laboratories Limited
Publication of WO2006048893A2 publication Critical patent/WO2006048893A2/fr
Publication of WO2006048893A3 publication Critical patent/WO2006048893A3/fr

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/10—Indoles; Hydrogenated indoles with substituted hydrocarbon radicals attached to carbon atoms of the hetero ring
    • C07D209/18—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D209/24—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals with an alkyl or cycloalkyl radical attached to the ring nitrogen atom
    • 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 relates to A Process for the synthesis of large particle size statin compounds.
  • This invention particularly relates to a process for the synthesis of large particle size amorphous forms of statin compounds, HMG co-reductase inhibitors such as Atorvastatin, Fluvastatin and their salts such as Atorvastatin calcium and Fluvastatin sodium. More particularly, the invention relates to an improved process for synthesis of large particle size amorphous forms of alkali metal salts of Atorvastatin and Fluvastatin. Specifically, the process is simple, cost effective, reproducible, environment friendly and easy to scale up for industrial manufacture while maintaining the quality of the title product. Further, the process produces the title compounds with low residual solvent levels and displaying dissolution characteristics which are equivalent to that of milled and micronized samples of amorphous Atorvastatin calcium eliminating the use of expensive instruments like freeze or spray dryers or sonicators.
  • Atorvastatin Calcium and Fluvastatin Sodium are members of a class of drug called statins which are considered to be therapeutically most effective drugs available for the treatment of hyperlipidemia and hypocholesterolemia.
  • Atorvastatin calcium is known by its chemical name as [R-(R*, R*)]-2-(4-
  • Atorvastatin Calcium is a white to off white amorphous or crystalline powder that is partially soluble in water and soluble in alcohols like methanol, ethanol, acetonitrile, acetone, tetrahydrofuran, dimethylformamide, dimethylacetamide and dimethylsulfoxide etc.
  • Fluvastatin Sodium is R*, S*(E)-( ⁇ )-7-[3-(4-Fluorophenyl)-l-(l-methylethyl)-lH- indol-2-yl]-3, 5-dihydroxy-6-heptanoic acid mono sodium salt and is a racemic mixture of the 3R, 5S and 3S, 5R dihydroxy enantiomers.
  • the empirical formula of Fluvastatin sodium is C 24 H 2 SFNNaO 4 and its molecular weight is 433.50.
  • Fluvastatin Sodium is white to pale yellow amorphous or crystalline powder that is soluble in water and alcohols like methanol, ethanol, n-propanol and iso-propanol, aliphatic ketones like acetone, ethyl methyl ketone, methyl isobutyl ketone, diethyl ketone, tetrahydrofuran, dimethylformamide, and dimethylsulfoxide etc. Its 1% aqueous solution exhibits pH in the range of 8 to 10. Structural formulas of both Atorvastatin calcium and Fluvastatin sodium are displayed below.
  • Atorvastatin Calcium (I) Fluvastatin Sodi ⁇ m(II)
  • Prior art known to the inventor include PCT WO 2003018547A2 for preparing amorphous Atorvastatin Calcium wherein nonpolar water immesible antisolvent like diisopropylether was added to a solution of Atorvastatin Calcium in halogenated solvent like methylene dichloride. Though the method provided amorphous Atorvastatin Calcium with excellent physical characteristics and could be easily filtered and displayed low levels of residual solvents in head space gas chromatographic analysis it is posing problems in pilot plant scale up.
  • Samples of amorphous Atorvastatin Calcium prepared via freeze drying and spray drying (PCT WO 030783790) of methanolic solutions of Atorvastatin Calcium display very fine particle size and their DlO, D50 and D90 values have been measured to be 1 micron, 6 microns and 11 microns respectively.
  • WO01/28999 advocates preparation of atorvastatin through crystallization of crude atorvastatin from alkanol with 2-4 carbon atoms.
  • the solvent used is ethanol, n-propanol, iso propanpl, n-butanol, preferably isopropanpl or ethanol or mixture thereof. Further, the solvent is removed by drying in vacuo.
  • the starting material used is prepared in accordance with US Patent NO. 5,273,995.
  • PCT WO 02057228 Al teaches preparing Atorvastatin by adding either solvent to antisolvent or antisolvent to solvent wherein both are nonhydroxylic in nature. Generally these are THF and diisopropyl.
  • the patent further advises removing of solvents by drying the product in vacuum tray wherein vacuum applied is 650 mm/Hg.
  • the patent claims avoiding use of hydrocarbon and implementing industrially feasible operation.
  • PCT WO 03/078,379 Al describes process for the generation of amorphous
  • Atorvastatin calcium via freeze drying a methanolic solution of Atorvastatin calcium which display very fine particle size and their dio, dso and ago values have been measured to be 1 micron, 6 microns and 11 microns respectively.
  • Atorvastatin for obtaining amorphous form Atorvastatin for obtaining amorphous form.
  • US 6,087,511 discloses the preparation of amorphous Atorvastatin calcium by evaporating a solution of tetrahydrofuran under vacuum and then breaking the foamy material via mechanical agitation.
  • PCT WO 03/099,785 Al claims use of complete removal of non-hydroxylic solvent like acetone under vacuum to afford amorphous Atorvastatin calcium which displays reduced residual solvent levels of less than 5000 ppm whereas PCT WO 03/005,384 Al mentions the process of generation of amorphous Atorvastatin calcium via vacuum evaporation of ethyl acetate.
  • PCT WO 03068739 Al discloses a process comprising of dissolving the atorvastatin in a hydroxylic solvent and removing the solvent by freeze drying.
  • the solvent used is methanol. Further the patent claims particular particle size.
  • the process comprises dissolving atorvastatin in water miscible solvent , adding the said solution to water under stirring followed by filtering and drying under vacuum.
  • the solvents employed are THF, DMSO, DMF, dimethylacetamide and N-methylpyrrolidone sulfone.
  • amorphous Atorvastatin Calcium that generally, include precipitation of amorphous form (a) from a mixture of polar protic solvents like alcohols and water immiscible solvents like aliphatic ethers, (b) from a mixture of polar aprotic solvent like THF and non polar water immiscible solvents like aliphatic hydrocarbons like cyclohexane, n-hexanes, n-heptane and aliphatic ethers and several permutation and combination of these solvents.
  • polar protic solvents like alcohols and water immiscible solvents like aliphatic ethers
  • non polar water immiscible solvents like aliphatic hydrocarbons like cyclohexane, n-hexanes, n-heptane and aliphatic ethers and several permutation and combination of these solvents.
  • sophisticated and expensive techniques like freeze and/or spray drying and sonication have also been utilized
  • amorphous Atorvastatin Calcium has been its poor filterability characteristics due to the very fine particle size, which in addition to loss of resulting material due to passing of the material through filter bags also require long time to isolate thus leading to longer time cycle. Further, it has been observed that amorphous Atorvastatin Calcium starts deteroating over a period of 3 — 6 months and extensive decomposition occures over a period of 9-12 months under normal storage conditions. Also the extent of decomposition depends upon the method of its preparation, the type and quantity of the residual solvents present in the API. The particle size of the material may also contribute to the stability of the crystalline and amorphous forms.
  • the fine particle size amorphous Atorvastatin Calcium is expected to be relatively less stable than the amorphous atorvastatin with larger particle since the fine particle has larger surface area which being disordered in crystal orientation will decompose faster when expose to light and air.
  • Atorvastatin Calcium US 5,686,104; US 6,126, 971 and EP 1,336,405 are stabilized by the adding a definite amount of alkaline earth metal salts like calcium and magnesium carbonates, calcium and magnesium hydroxides etc whereas those of Fluvastatin Sodium (US 5,356,896; US 6,242,003 Bl and US 2001/0,043,950 Al) are stabilized with pharmaceutically acceptable alkali metal carbonates or bicarbonates salts like sodium/ potassium carbonate or bicarbonate along with additional excipients.
  • the semi crystalline forms designated as XC, XCI, XCII, XCIV, XCV, XVI, XVII 5 XVIII, XCIX, C, CI, CII, CIII, CIV and CV display XRD patterns which clearly indicate them to be mixtures of amorphous and different crystalline forms.
  • amorphous Fluvastatin sodium can be generated from a mixture of 1, 4-dioxane and cyclohexane and from a cooled solution of iso-propanol.
  • amorphous Fluvastatin sodium can also be isolated from a mixture of methanol and cyclohexane by directly reacting the methyl ester (VI) of Fluvastatin with sodium hydroxide.
  • VI methyl ester
  • the patent does not display XRD patterns of any one of the above mentioned amorphous samples although more than 80 crystalline and semi-crystalline forms of Fluvastatin sodium along with their XRD patterns are reported therein.
  • Atorvastatin calcium and Fluvastatin sodium we have found out that subjecting alcoholic solution of Atorvastatin calcium and Fluvastatin sodium to vacuum drying results in the generation of amorphous material larger size particles. Additionally the sequence of addition of ingredients, ratio of ingredients and technique used for isolation helps in procuring large particle size Atorvastatin calcium and Fluvastatin sodium. Moreover, the amorphous form of Atorvastatin calcium and Fluvastatin sodium thus obtained are easily filterable and display lower levels of residual solvent.
  • the samples may be anhydrous or may contain water up to 8 to 10%.
  • the present invention provides a process for preparing large particle size amorphous form of statin compounds particularly Atorvastatin calcium & Fluvastatin Sodium obviating the disadvantages associated with the existing processes
  • Other object of the present invention is to provide a process for preparing amorphous statin compounds particularly Atorvastatin calcium & Fluvastatin Sodium obviating the disadvantages associated with the existing processes
  • Other object of the present invention is to provide a process for preparing amorphous
  • Atorvastatin Calcium and Fluvastatin Sodium with superior filtration characteristics.
  • Another object of the present invention is to provide a process for preparing amorphous
  • Atorvastatin Calcium and Fluvastatin Sodium with low residual solvent levels are included in the composition.
  • Yet other object of the present invention is to provide a process for preparing amorphous Atorvastatin Calcium and Fluvastatin Sodium displaying dissolution characteristics, which are equivalent to that of milled and micronized samples of amorphous Atorvastatin Calcium prepared from other routes.
  • Still another object of the invention is also to provide an improved process for the preparation of an amorphous forms of statins, specifically Atorvastatin Calcium and Fluvastatin Sodium which is 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.
  • Yet another object of the invention is also to provide an improved process for the preparation of amorphous forms of statins, specifically Atorvastatin Calcium and Fluvastatin Sodium, which reduces if not eliminates the loss of material due to small particle size. Further it also reduces reaction time.
  • the process for amorphous forms of Atorvastatin Calcium and Fluvastatin Sodium have merits of easy and rapid isolation and precipitation with residual solvent limits well below ICH guidelines. Moreover, the process does not require any special infrastructure and stringent operating conditions or skilled personnel.
  • Fig. Ill displays XRD pattern of amorphous Atorvastatin Calcium prepared via addition of diisopropyl ether to a solution of Atorvastatin Calcium in dichloromethane .
  • Fig. IV displays XRD pattern of amorphous Atorvastatin Calcium prepared via addition of solution of Atorvastatin Calcium in ethyl acetate to n-hexane.
  • Fig. V displays XRD pattern of amorphous Atorvastatin Calcium prepared via evaporation of methanolic solution under vacuum.
  • Fig. VI displays XRD pattern of amorphous Fluvastatin Sodium prepared via evaporation of methanolic solution under vacuum.
  • Fig. VtI displays XRD pattern of amorphous Fluvastatin Sodium prepared via evaporation of tetrahydrofuran solution under vacuum.
  • Fig. VIII displays XRD pattern of amorphous Fluvastatin Sodium prepared addition of n- heptane to solution of Fluvastatin Sodium in tetrahydrofuran and water and from methanol and diisopropyl ether.
  • Fig. IX displays XRD pattern of Fluvastatin Sodium prepared from tetrahydrofuran, water and diisopropyl ether.
  • the present invention provides a process for the synthesis of large particle size statin compounds comprising preparing solution of desired statin, optionally obtained on conversion of its respective intermediates by any known conventional methods, in organic solvent; mixing the said solution with antisolvent under stirring, with or without evaporating the solvent, isolating the title compound followed by drying under vacuum, wherein the organic solvent used is halogenated organic solvent or aliphatic solvents and antisolvent is non-polar ethereal solvent.
  • the statins include without limiting to atorvastatin, fluvastatin either crystalline or amorphous.
  • One of the embodiments of the present invention is to provide a process wherein the halogenated organic solvent used may be dichloromethane, dichloroethane, or chloroform and aliphatic solvents used may be lower aliphatic alcohols with Cl to C3 when statins are atorvastatin and lower aliphatic alcohols, aliphatic ketones, ethers, hydrocarbon solvents like n-pentane, n-hexane, hexanes, cyclohexane, n-heptane, heptanes, cycloheptane when statins are fluvastatins and may be added in an amount ranging from 2 to 100 times preferably 3 to 10 times w.r.t. starting material.
  • the ethereal solvent used may be such as aliphatic ethers exemplified by diethyl ether, diisopropyl ether, dibutyl ether or methyl tertiary butyl ether.
  • the mixing may be carried out by adding either solution of statin to antisolvent or antisolvent to solution of statin preferably adding solution of statins to antisolvent.
  • the evaporation of solvent is preferably performed under vacuum at 50 to 6O 0 C so as to get the solvent concentrated to 3 to 20 preferably 5 to 10 times.
  • the title compound may be isolated by centrifugation.
  • Drying is conducted under vacuum of 0.2 to 10 mm of Hg preferably 5 to 10 mm of Hg at 20 to 9O 0 C preferably 50 to 6O 0 C for 6 to 100 hours preferably 18 to 36 hours.
  • the amorphous Atorvastatin calcium thus synthesized displays particle size in the range of dso between 125 to 300 microns and dgo between 300 to 500 microns and the amorphous Fluvastatin sodium, thus synthesized displays particle size in the range of dio between 10 to 75 microns, dso is between 75 to 250 microns and dgo is between 250 to 500 microns
  • the detailed description and examples further illustrate the process. However it should not limit the scope of the invention.
  • the quantity of halogenated solvent used for dissolution of the starting Atorvastatin calcium may be between 2 to 100 times v/w of Atorvastatin calcium dissolved and the quantity of the anti-solvent used for precipitation may be between 10 to 500 times and the temperature during precipitation may be between -25 to +45 0 C.
  • the sample of amorphous Atorvastatin calcium thus obtained displays XRD pattern as shown in FIG IV. Most preferably Atorvastatin calcium is dissolved in 5 to 10 times of dichloromethane, 20 to 35 times v/w of the diisopropyl ether is used as an anti-solvent w. r. t.
  • addition of the anti-solvent is most preferably carried out at +5 to 25 0 C over a period of 5 min to 2 hrs, preferably 10 min to 1 hr and the reaction mixture is stirred for 5 min to 6 hrs, preferably 10 min to 1 hr.
  • the amorphous Atorvastatin calcium is dried at 20 to 9O 0 C, preferably at 45 to 65 0 C under vacuum for 6 tolOO hrs, preferably, 18 to 36 hrs.
  • the intermediate lactone (V)/FIG II is reacted with aqueous calcium hydroxide in water miscible solvents like tetrahydrofuran and after the reaction is over, the mixture is poured into water and extracted into a halogenated solvent like dichloromethane, chloroform or dichloroethane, preferably dichloromethane and washed with water.
  • a halogenated solvent like dichloromethane, chloroform or dichloroethane, preferably dichloromethane and washed with water.
  • amorphous Atorvastatin calcium which may be anhydrous or may contain up to 10 % w/w, preferably between 1 to 4.5 % w/w water and display acceptable residual solvents levels as per ICH guide lines
  • amorphous Atorvastatin calcium with larger particle size can be manufactured by evaporating a solution of Atorvastatin calcium in alcoholic solvents like methanol or ethanol under vacuum at ambient temperature.
  • the solvent is evaporated at 10 to 7O 0 C, preferably at 30 to 6O 0 C and the vacuum during evaporation may vary between 200 to 300 mm of Hg and the final vacuum during evaporation is between 20 to 50 mm of Hg at 20 to 6O 0 C, preferably at 25 to 5O 0 C.
  • Atorvastatin Calcium thus obtained is further dried under high vacuum of 5 to 10 mm of Hg at 20 to 90 0 C, preferably at 45 to 65 0 C and then straight away used for preparing different dosage forms.
  • the sample displays XRD pattern as shown in FIG V
  • the above vacuum dried material may be washed with aliphatic hydrocarbon solvents like n-hexane, cyclohexane, n-heptane, aliphatic ethers like diethyl ether, diisopropyl ether, and methyl tertiary butyl ether, filtered and then dried at 45 to 65 0 C under vacuum of 5 to 10 mm of Hg. All the samples displayed XRD patterns corresponding to the amorphous form and exhibited excellent flowability characteristics and acceptable levels of residual solvent as per ICH guidelines.
  • amorphous Atorvastatin calcium after drying and normal crushing with pestle followed by sifting through a ordinary tea filter displayed particle size in the range of dso between 125 to 300 microns and d 9 o between 300 to 500 microns
  • dissolution characteristics of the amorphous Atorvastatin calcium in common solvents like in methanol, ethanol, acetone, tetrahydrofuran (THF), dimethyl sulfoxide (DMSO), dimethylformamide (DMF) and dimethylacetamide (DMT) were comparable to that of milled samples of amorphous Atorvastatin calcium prepared via other reported processes.
  • ester derivative (III)/ FIG 2 upon successive treatment with dilute acid like hydrochloric acid in alcohols like methanol or ethanol, alkali metal hydroxides, preferably with sodium hydroxide, neutralization with dilute hydrochloric acid to pH of around 7.2 to 8.5, reaction with calcium salts like calcium acetate or calcium chloride followed by complete evaporation of the alcoholic solvent under vacuum, washing of the aqueous layer with methyl tertiary butyl ether, extraction of the aqueous layer with halogenated solvents like dichloromethane, chloroform or dichloroethane, preferably dichloromethane, washing with water, complete evaporation of dichloromethane and dissolution of the viscous or semi-powdered material in alcoholic solvent, preferably methanol, fine filtration evaporation of solvent and drying under the conditions and optional washing with aliphatic alkenes or ethers and drying as described above affords amorphous Atorvastatin calcium which
  • the intermediate lactone (V) is reacted with aqueous calcium hydroxide in water miscible solvents like tetrahydrofuran and then extracted into a halogenated solvent like dichloromethane, chloroform or dichloroethane, preferably dichloromethane, washed with water, complete evaporation of dichloromethane, dissolution of the viscous or semi-powdered material in alcoholic solvents, preferably methanol, fine filtration, evaporation of solvent and drying under the conditions and optional washing with aliphatic alkanes or ethers and drying as described above affords amorphous Atorvastatin calcium which after normal crushing with pestle followed by sifting through a ordinary tea filter displayed particle size in the range of dso between 125-300 microns and ago between 300 to 500 microns and acceptable residual solvents levels as per ICH guide lines.
  • a halogenated solvent like dichloromethane, chloroform or dichloroethane,
  • the innovation described herein this application therefore substantiates providing simple and inexpensive method for preparing amorphous Atorvastatin calcium with relatively larger particle size which may_be anhydrous or may contain water up to 10 % w/w and display acceptable residual solvents levels as per ICH guide lines. Preferably they contain water between 1 to 4.5 % w/w of water. As and when required the samples of large particle size Atorvastatin calcium can be milled or micronized to generate amorphous samples of the desired fine particle size.
  • amorphous Fluvastatin sodium can be generated by subjecting a solution of any one of the several crystalline and semi-crystalline forms of Fluvastatin sodium dissolved in methanol and small amounts of water to evaporation under vacuum to obtain a viscous oily residue which is then finally dried at 45 to 65 0 C under vacuum.
  • Amorphous Fluvastatin sodium is also obtained if methanol is replaced with acetone and tetrahydrofuran.
  • the quantity of solvents used to dissolve Fluvastatin sodium may vary between 2 to 50 times, preferably 3 to 7 times and the solvent is distilled off on a water bath at 10 to 8O 0 C, preferably at 30 to 60 0 C and the final drying of amorphous Fluvastatin sodium is carried out under high vacuum of 2 to 5 mm of Hg at 20 to 80 0 C, preferably at 45 to 65 0 C over a period of 12 to 72 hrs, preferably 18 to 36 hrs.
  • the samples of amorphous Fluvastatin sodium thus produced show excellent filterability and desired texture particularly when vacuum dried amorphous products are stirred with aliphatic alkanes like n-pentane, n-hexane, hexanes, cyclohexane, n- heptane, heptanes, cycloheptane and aliphatic ethers like diethyl ether, diisopropyl ether, methyl tertiary butyl ether, filtered and dried under vacuum at 50 to 65 0 C.
  • aliphatic alkanes like n-pentane, n-hexane, hexanes, cyclohexane, n- heptane, heptanes, cycloheptane and aliphatic ethers like diethyl ether, diisopropyl ether, methyl tertiary butyl ether, filtered and dried under vacuum
  • the off white to yellow samples of amorphous Fluvastatin sodium exhibit particle size wherein di 0 is between 10 to 75 microns, dso is between 75 to 250 microns and d ⁇ o is between 250 to 500 microns, display acceptable levels of residual solvent contents and are soluble in water, methanol, THF and acetone.
  • the samples of amorphous Fluvastatin sodium displays XRD pattern as shown in FIG VI (from methanol) and FIG VII (from THF).
  • the advanced intermediate (+) erythro-(E)-7-[3'-(4"-fluorophenyl)-r- (l"-methylethyl)indole-2'-yl]-3,5-dihydroxy hept-6-enoate (VI)/FIG-3 can be directly converted into amorphous Fluvastatin sodium in the following manner.
  • the diol ester (VI) is reacted with aqueous solution of 1.025 to 1.1 molar equivalents of sodium hydroxide in alcoholic solvents like methanol or ethanol, preferably methanol.
  • reaction mixture is optionally extracted with aliphatic alkanes like n-hexane or n-heptane, the solvent is evaporated under vacuum as per the conditions described above and optionally washed with aliphatic alkanes or aliphatic ethers, preferably with diisopropyl ether and dried under vacuum to afford amorphous Fluvastatin sodium.
  • the quantity of alcoholic solvents used may vary between 2 to 50 times, preferably 3 to 7 times and the solvent is completely distilled off on a water bath at 10 to 8O 0 C, most preferably at 30 to 60 0 C and the final drying of amorphous Fluvastatin sodium is carried out under high vacuum of 2 to 5 mm of Hg at 20 to 75 0 C, most preferably at 45 to 65 0 C over a period of 12 to 72 hrs, preferably 18 to 36 hrs.
  • Amorphous Fluvastatin sodium can also be obtained by adding n-heptane to a stirred solution of any crystalline or semi-crystalline form of Fluvastatin sodium in THF at +5 to 35 0 C.
  • Amorphous Fluvastatin sodium is also precipitated when the solution of Fluvastatin Sodium in THF is slowly added to n-heptane (i. e. reverse addition) at +5 to 35 0 C.
  • the precipitation is performed at 10 to 2O 0 C and the product after filtration is dried under high vacuum of 2 to 5 mm of Hg at 20 to 75 0 C, preferably at 45 to 65 0 C to yield amorphous Fluvastatin sodium as off white to pale yellow-to- yellow powder and displays acceptable level of residual solvent contents.
  • the precipitation of the amorphous Fluvastatin sodium may also be performed with other common aliphatic solvents like n-pentane, n-hexane, hexanes, cyclohexane, . n- heptane, heptanes, cycloheptane and aliphatic ethers like diethyl ether, diisopropyl ether, methyl tertiary butyl ether.
  • the sample of amorphous Fluvastatin sodium displays XRD pattern as shown in FIG VIII-(THF water and n-heptane) and FIG IX (THF, water and diisopropyl ether)
  • the diol ester intermediate (VI) can be directly converted into amorphous Fluvastatin sodium by reacting with aqueous solution of 1.025 to 1.1 molar equivalents of sodium hydroxide in alcoholic solvents like methanol or ethanol, preferably methanol and the solvent is evaporated under vacuum and the residue thus obtained is dissolved in 2 to 25 times, preferably in 3 to 7 times tetrahydrofuran.
  • the samples of amorphous Fluvastatin sodium prepared above display residual solvent levels as per ICH guidelines and may be anhydrous or may contain water up to 12 %, preferably between 2 to 8 5 w/w.
  • Atorvastatin calcium and its precursor intermediate ester (III) and lactone (V) were prepared as described in US 5,273,995 or US 5,003,080)
  • Example 1 Atorvastatin calcium (2.0 kg, amorphous or any reported crystalline form) was dissolved in dichloromethane ( 70.0 It. ) at 40 to 42 0 C and filtered through hyflow bed to remove the un-dissolved particles.
  • Dichloromethane was distilled off at normal pressure and the volume of the solution was reduced to approx 14 It, filtered through Whatman paper, cooled to 10 to 15 0 C, fine filtered diisopropyl ether (60.0 It.) was added slowly keeping the temperature below 15 0 C and mixture was stirred for 15 min at 10 to 15 0 C.
  • the precipitated solid was then centrifuged, washed with cooled diisopropyl ether (2.0 It, 10 0 C ) and dried under vacuum at 55 to 6O 0 C for 24 hrs to obtain amorphous Atorvastatin calcium as a white to off white powder which displays XRD pattern as shown in FIG III.
  • the reaction mixture was initially stirred at 15 to 2O 0 C for 4 hrs and then at 25 to 30 0 C for 8 hrs when the HPLC indicated the reaction to be complete.
  • Sodium hydroxide 0.375 kg in 3.75 It of water
  • solvent was distilled off under vacuum at 55 to 6O 0 C, water (6.0 It) and methanol ( 1.5 It.) were added to the residue, the mixture was extracted twice with methyl tertiary butyl ether ( 7.5 It and 2.5 It.
  • the solution was cooled to 10 to 15 0 C and fine filtered diisopropyl ether (45.0 It) was slowly added to the mixture keeping the temperature below 15 0 C.
  • the mixture was stirred for 30 min at 10 to 15 0 C, centrifuged, washed with cold diisopropyl ether (1.5 It) and dried under vacuum at 55 at 6O 0 C for 24 hrs to obtain amorphous Atorvastatin Calcium as white to off white powder.
  • Example 3 To lactone intermediate (V) ( 100 g, 0.185 mol) dissolved in methanol ( 500 ml ) was slowly added sodium hydroxide ( 8.0 g dissolved in 80 ml water ) at 25 to 30 0 C and the reaction mass was stirred at 45 to 5O 0 C for 2 hrs when the HPLC indicated the reaction to be complete. Methanol was distilled off under vacuum, water (100.0 ml) and methanol (100.0 ml) were added and the solution was extracted twice with methyl tertiary butyl ether ( 500 ml and 125 ml each), the combined MTBE layer was washed with a mixture of water ( 90 ml) and methanol (10 ml).
  • the pH of the combined aqueous layer was adjusted to 7.8 to "6.2 with 6N hydrochloric acid and the mixture was diluted with methanol (1.0 It ) and then suspension of calcium acetate (16.0 g in 1.0 It water) was added to the reaction mixture at 25 to 3O 0 C.
  • the mixture was then poured into water ( 2.0 It ), extracted with dichloromethane ( 2 x 1.5 It) and the combined dichloromethane layer was concentrated at 40 to 42 0 C to approx 700 ml.
  • the concentrated solution was fine filtered through Whatman filter, cooled to 10 to 15 0 C and diisopropyl ether (3.0 It) was slowly added keeping the temperature below 15 0 C.
  • Example 4 The lactone (V) ( 100.0 g, 0.185 mol) was dissolved in THF (500 ml) and reacted with the suspension of calcium hydroxide ( 18.68 g, 0.185 mol) in water ( 100 ml) and stirred at 45 to 5O 0 C.
  • Atorvastatin Calcium (100.0 g, amorphous or any crystalline form) was dissolved in methanol ( 500 ml), charcoal (5.0 g) was added and the mixture was stirred at 45 to 5O 0 C for 30 min and then successively filtered through hyflow and Whatman filter paper. Most of methanol was then distilled off under vacuum on water bath at 40 to 45 0 C to obtain a viscous residue which was then finally dried under high vacuum at 35 to 4O 0 C to afford white solid material.
  • the white powder thus obtained was further dried in a vacuum oven at 55 to 6O 0 C for 24 hrs to remove maximum of the alcoholic solvent, crushed lightly with a stopper and sieved through a common tea filter to yield white to off white amorphous Atorvastatin calcium with a particle size in the range of dso between 125 to 300 microns and ds>o between 300 to 500 microns. Yield: 95.1 g (95.1 % recovery); Purity (HPLC): 99.33%; Assay (HPLC): 99.05 %. Calcium content: 3.53%; Moisture content (by K. F): 1.48 %; Residual solvents: Methanol ⁇ 0.2%.
  • Example 6 To a stirred suspension of the ester (III) ( 100.0 g ) in methanol ( 220 ml) at 15 to 20 0 C, dilute hydrochloric acid ( 200.0 ml, 2N solution) was added. The reaction mixture was initially stirred at 15 to 20 0 C for 4 hrs and then at 25 to 30 for 6 to 8 hrs when the HPLC indicated the reaction to be complete. Sodium hydroxide (25.O g in 200 ml of water ) was added to the mixture till the pH of the solution had reached approximately 12 and stirred.
  • dilute hydrochloric acid 200.0 ml, 2N solution
  • Part B The second part of the mixture was diluted with water (500 ml), extracted with dichloromethane ( 2 x 1.0 It), the combined dichloromethane layer was washed with water (100 ml) and dichloromethane was distilled off completely to obtain a viscous residue. The residue was dissolved in methanol (250 ml) and the solution was successively filtered through hyflow bed and Whatman filter paper to remove the un- dissolved particles. The solvent was then distilled under vacuum as described in Example 5 to afford, after sieving through a tea filter funnel, white to off white amorphous Atorvastatin Calcium with a particle size in the range of dso between 125 to 300 microns and d 90 between 300 to 500 microns.
  • Example 7 To lactone (V) ( 100.0 g, 1.2 mol) dissolved in methanol ( 500 ml ) was slowly added sodium hydroxide ( 8.0 g dissolved in 80 ml water ) at 25 to 30 0 C) and the reaction mass was stirred at 45 to 5O 0 C for 2 hrs when the TLC indicated the reaction to be complete. The solvent was then distilled off under vacuum, water (100 ml) and methanol (100 ml) were added, the solution was extracted twice with methyl tertiary butyl ether ( 500 ml and 125 ml each) and the combined MTBE layer was washed with a mixture of water ( 90 ml) and methanol (10 ml).
  • the pH of the combined aqueous layer was adjusted to between 7.8 to 8.2 with 6N hydrochloric acid and the mixture was diluted with methanol (1.0 It) and then solution of calcium acetate (16.0 g in 100 ml of water) was added to the reaction mixture at 25 to 3O 0 C .
  • the reaction mixture was then poured into water (2.0 It ) and extracted with dichloromethane (2 x 1.5 It) and the combined dichloromethane layer was distilled off completely at 40 to 42 0 C .
  • Example 5 The solvent was then distilled under vacuum as described in Example 5 to afford, after sieving through a tea filter funnel, white to off white amorphous Atorvastatin Calcium with a particle size in the range of d 5 o between 125 to 300 microns and d ⁇ io between 300 to 500 microns. Yield: 98.2 g (91.82%); Purity (HPLC): 99.58%; Assay (HPLC): 99.27 %; Calcium content: 3.52 %; Moisture content (by K. F):1.41 %; Residual solvents: Methanol ⁇ 0.2%, Dichloromethane ⁇ 0.01%, THF ⁇ 0.05%.
  • the samples of amorphous Atorvastatin calcium described in the Examples 5 to 8, above may be further stirred with aliphatic alkanes like n-pentane, n-hexane, hexanes, cyclohexane, n-heptane, heptanes, cycloheptane and aliphatic ethers like diethyl ether, diisopropyl ether, dibutyl ether or methyl tertiary butyl ether and dried under vacuum at 55 to 6O 0 C to obtain white to off white amorphous Atorvastatin calcium with a particle size in the range of ⁇ s 0 between 125 to 300 microns and dgo between 300 to 500 microns.
  • N-Heptane and Methyl tertiary butyl ether are the preferred solvents and the samples thus obtained display superior flowability characteristics and lower residual solvent levels as per ICH guide lines.
  • the starting Fluvastatin sodium and its precursor methyl ester derivative (VI) used were . prepared as described in US 4,739,073 or US 5,354,722, or PCT WO 97/49,681 and its equivalent / EP 0,907,639 or in 2004/113,291 A2 and PCT WO 2004/113,292 A2).
  • the off white to yellow powder thus obtained was further dried at 55 to 6O 0 C under vacuum (1 to 5 mm of Hg) in a vacuum oven for 36 hrs to remove maximum of the alcoholic solvent, crushed with a stopper and sieved through a tea funnel to obtain off white to yellow amorphous Fluvastatin Sodium with particle size in the range wherein dio is 10 to 75 microns, dso is between 75 to 250 microns and dpo is between 250 to 500 microns. Yield: 23.0 g (92 % recovery); Purity (HPLC): 99.77 %; Assay (HPLC): 99.33 %; Moisture content: 3.63% (w/w by K.
  • Example 10 Crystalline form A or form B or any other crystalline form of Fluvastatin Sodium ( 10.0 g) was dissolved in tetrahydrofuran (45 ml), charcoal (0.5 g) was added and the mixture was stirred at 40 to 45 0 C for 30 min and the solution was successively filtered through hyflow and Whatman filter paper to remove the suspended particles.
  • Example 9 The solvent was then distilled under vacuum as described in Example 9 to afford, after sieving through a tea filter funnel, off white to yellow amorphous Fluvastatin Sodium with a particle size in the range of dio is 10 to 75 microns, d 50 is between 75 to 250 microns and dgo is between 250 to 500 microns. Yield: 9.0 g ( 90 % recovery); Purity (HPLC): 99.72 %; Assay (HPLC): 99.15 %; Moisture content: 4.55% (w/w by K. F.).
  • Example 11 To a stirred suspension of Methyl (+)erythro-(E)-7-[3'-(4"- fluorophenyl)-l'-(l"-methylethyl)indole-2'-yl]-3,5-dihydroxy hept-6-enoate (VI) (Methyl ester of Fluvastatin Sodium ) ( 25.0 g/ 0.058 mol) in methanol (115 ml), sodium hydroxide ( 2.5 g/0.06 mol) dissolved in water (10 ml) was added. The reaction mixture was heated to 30 to 35°C and stirred at the same temperature till reaction was complete (TLC ).
  • VI Methyl (+)erythro-(E)-7-[3'-(4"- fluorophenyl)-l'-(l"-methylethyl)indole-2'-yl]-3,5-dihydroxy hept-6-enoate (VI) (Methyl ester of Fluvastat
  • the clear reaction mixture was extracted with n- heptane (2 x 250 ml) and the methanolic layer was separated, fine filtered and the solvent was then distilled under vacuum and dried at 55 to 60 0 C under vacuum ( 1 to 5 mm of Hg) for 36 hrs as described in Example 9 to afford, after sieving through a tea filter funnel, off white to pale yellow amorphous Fluvastatin Sodium with particle size in the range wherein dio is 10 to 75 microns, d 5 o is between 75 to 250 microns and d 90 is between 250 to 500 microns.
  • the above powder may be further stirred with aliphatic alkanes like n- pentane, n-hexane, hexanes, cyclohexane, n-heptane, heptanes, cycloheptane and aliphatic ethers like diethyl ether, diisopropyl ether, methyl tertiary-butyl ether and dried at 55 to 60 0 C under vacuum ( 1 to 5 mm of Hg) for 24 hrs to obtain pale yellow to yellow amorphous Fluvastatin Sodium with a particle size in the range wherein dio is 10 to 75 microns, dso is between 75 to 250 microns and d 9 o is between 250 to 500 microns.
  • the sample displays XRD pattern as displayed in the FIG VI.
  • Example 12 Crystalline Form A or Form B or any other crystalline form of Fluvastatin sodium ( 10 .0 g, was dissolved in tetrahydrofuran (50 ml) and water (5 ml), the solution was filtered through Whatman filter paper and n-heptane (500 ml) was slowly added to the solution at 10 to 15 0 C and the mixture was stirred at that temperature for 3 hrs.
  • aliphatic alkanes like n-pentane, n-hexane, hexanes, cyclohexane, n-heptane, heptanes, cycloheptane and aliphatic ethers like diethyl ether, diisopropyl ether, methyl tertiary butyl ether also provide amorphous Fluvastatin Sodium which displays XRD pattern as shown in FIG VIH.
  • Example 13 Crystalline Form A or Form B or any other crystalline form of Fluvastatin Sodium (10.0 g) was dissolved in methanol ( 45 ml) and water ( 5 ml) at 30 to 35 0 C and the solution was slowly added to diisopropyl ether (500 ml) at 0 to +5 0 C and the mixture was stirred at 0 +5 0 C for 1 hr.
  • Example 14 To a stirred suspension of Methyl ( ⁇ )erythro-(E)-7-[3'-(4"- fluorophenyl)-r-(l"-methylethyl)indole-2'-yl]-3,5-dihydroxy hept-6-enoate (VI) (Methyl ester of Fluvastatin Sodium ) ( 25.0 g/ 0.058 mol) in methanol (115 ml), sodium hydroxide ( 2.5 g/0.06 mol) dissolved in water (10 ml) was added. The reaction mixture was heated to 30 to 35°C and stirred at the same temperature till reaction was complete (TLC monitoring, Methyl ester of Fluvastatin Sodium NMT 0.1%).
  • VI Methyl ester of Fluvastatin Sodium
  • the clear reaction mixture was extracted with n-heptane (2 x 250 ml) and the methanolic layer was separated, fine filtered and distilled off under vacuum to obtain a viscous residue which was then finally dried under high vacuum to obtain the solid material.
  • the off white to yellow powder thus obtained was dissolved in tetrahydrofuran (125 ml), filtered to remove the suspended particles, cooled to 10 to 15 0 C and n-Heptane (2.0 It) was slowly added and the mixture was stirred at that temperature for 3 hrs.
  • the process results in large size particles of Statins particularly Atorvastatin calcium and Fluvastatin sodium.
  • the process results in large size particles of Statins particularly Atorvastatin calcium and Fluvastatin sodium with better filterability.
  • the process results in large size particles of Statins particularly Atorvastatin calcium and Fluvastatin with low-level residual solvents conforming to ICH guidelines.
  • the process was 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 process does not require any special infrastructure and stringent operating conditions.

Landscapes

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

Abstract

La présente invention concerne un processus de synthèse de composés statine à particules de grande taille qui consiste à ajouter une solution du composé statine souhaité de forme cristalline ou de forme amorphe, éventuellement obtenu de leurs intermédiaires par des procédés connus, de solvant organiques en anti-solvant, par mélange, le solvant étant éventuellement évaporé, à isoler le composé cité par centrifugation suivie par le séchage sous vide. Ce processus est plus particulièrement destiné à la synthèse du calcium d'atorvastatine et du sodium de fluvastatine.
PCT/IN2005/000359 2004-11-05 2005-11-03 Processus de synthese de composes statine a particules de grande taille WO2006048893A2 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
IN2206/DEL/2004 2004-11-05
IN2206DE2004 2004-11-05

Publications (2)

Publication Number Publication Date
WO2006048893A2 true WO2006048893A2 (fr) 2006-05-11
WO2006048893A3 WO2006048893A3 (fr) 2006-07-13

Family

ID=36120262

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/IN2005/000359 WO2006048893A2 (fr) 2004-11-05 2005-11-03 Processus de synthese de composes statine a particules de grande taille

Country Status (1)

Country Link
WO (1) WO2006048893A2 (fr)

Cited By (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2006109147A1 (fr) * 2005-04-12 2006-10-19 Glenmark Pharmaceuticals Limited Fluvastatine amorphe pratiquement pure, procede de preparation et compositions pharmaceutiques qui la contiennent
CN100429202C (zh) * 2006-06-30 2008-10-29 浙江新东港药业股份有限公司 一种无定形氟伐他汀钠的制备方法
ES2321571A1 (es) * 2007-07-18 2009-06-08 Ercros Industrial, S.A. Solvatos de fluvastatina sodica y su utilizacion como intermedios en la obtencion de fluvastatina sodica amorfa.
WO2011131601A1 (fr) * 2010-04-19 2011-10-27 Dsm Ip Assets B.V. Production d'atorvastatine à faible teneur en impuretés lactones
WO2011154009A1 (fr) * 2010-06-10 2011-12-15 Lifecycle Pharma A/S Composition comprenant un principe actif sous une forme amorphe et une substance poreuse adsorbante
CN102351771A (zh) * 2011-08-11 2012-02-15 天津市汉康医药生物技术有限公司 高生物利用度的阿托伐他汀钙化合物
CN103108863A (zh) * 2010-04-19 2013-05-15 中化帝斯曼制药有限公司荷兰公司 低醚杂质的阿托伐他汀的制备
CN106432033A (zh) * 2016-10-21 2017-02-22 江苏阿尔法药业有限公司 一种无定形阿托伐他汀钙的制备方法
CN115043769A (zh) * 2022-06-28 2022-09-13 江苏阿尔法药业股份有限公司 一种阿托伐他汀钙的制备方法

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2001042209A1 (fr) * 1999-12-10 2001-06-14 Lek Pharmaceutical And Chemical Company D.D. Procede de preparation d'atorvastatine amorphe
WO2003018547A2 (fr) * 2001-08-31 2003-03-06 Morepen Laboratories Ltd. Procede ameliore de preparation d'un sel d'atorvastatine calcique amorphe (2:1)
WO2003068739A1 (fr) * 2002-02-01 2003-08-21 Zentiva A.S. Procede de fabrication d'une forme amorphe du sel d'hemicalcium d'acide (3r, 5r) 7-[3-phenyl-4-phenylcarbamoyl-2-(4-fluorophenyl)-5-isopropyl-pyrrol-l-yl]-3, 5-dihydroxyheptanoique (atorvastatine)

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2001042209A1 (fr) * 1999-12-10 2001-06-14 Lek Pharmaceutical And Chemical Company D.D. Procede de preparation d'atorvastatine amorphe
WO2003018547A2 (fr) * 2001-08-31 2003-03-06 Morepen Laboratories Ltd. Procede ameliore de preparation d'un sel d'atorvastatine calcique amorphe (2:1)
WO2003068739A1 (fr) * 2002-02-01 2003-08-21 Zentiva A.S. Procede de fabrication d'une forme amorphe du sel d'hemicalcium d'acide (3r, 5r) 7-[3-phenyl-4-phenylcarbamoyl-2-(4-fluorophenyl)-5-isopropyl-pyrrol-l-yl]-3, 5-dihydroxyheptanoique (atorvastatine)

Cited By (12)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2006109147A1 (fr) * 2005-04-12 2006-10-19 Glenmark Pharmaceuticals Limited Fluvastatine amorphe pratiquement pure, procede de preparation et compositions pharmaceutiques qui la contiennent
CN100429202C (zh) * 2006-06-30 2008-10-29 浙江新东港药业股份有限公司 一种无定形氟伐他汀钠的制备方法
ES2321571A1 (es) * 2007-07-18 2009-06-08 Ercros Industrial, S.A. Solvatos de fluvastatina sodica y su utilizacion como intermedios en la obtencion de fluvastatina sodica amorfa.
WO2011131601A1 (fr) * 2010-04-19 2011-10-27 Dsm Ip Assets B.V. Production d'atorvastatine à faible teneur en impuretés lactones
CN102858740A (zh) * 2010-04-19 2013-01-02 中化帝斯曼制药有限公司荷兰公司 低内酯杂质的阿托伐他汀的制备
CN103108863A (zh) * 2010-04-19 2013-05-15 中化帝斯曼制药有限公司荷兰公司 低醚杂质的阿托伐他汀的制备
CN103108863B (zh) * 2010-04-19 2015-08-19 中化帝斯曼制药有限公司荷兰公司 低醚杂质的阿托伐他汀的制备
WO2011154009A1 (fr) * 2010-06-10 2011-12-15 Lifecycle Pharma A/S Composition comprenant un principe actif sous une forme amorphe et une substance poreuse adsorbante
CN102351771A (zh) * 2011-08-11 2012-02-15 天津市汉康医药生物技术有限公司 高生物利用度的阿托伐他汀钙化合物
CN102351771B (zh) * 2011-08-11 2013-07-03 天津市汉康医药生物技术有限公司 高生物利用度的阿托伐他汀钙化合物
CN106432033A (zh) * 2016-10-21 2017-02-22 江苏阿尔法药业有限公司 一种无定形阿托伐他汀钙的制备方法
CN115043769A (zh) * 2022-06-28 2022-09-13 江苏阿尔法药业股份有限公司 一种阿托伐他汀钙的制备方法

Also Published As

Publication number Publication date
WO2006048893A3 (fr) 2006-07-13

Similar Documents

Publication Publication Date Title
WO2006048893A2 (fr) Processus de synthese de composes statine a particules de grande taille
ES2437157T3 (es) Proceso para preparar la forma I de atorvastatina hemicálcica
KR100790766B1 (ko) 아토르바스타틴의 결정 형태, 이의 제조방법 및 이를 포함하는 약제학적 조성물
JP4234429B2 (ja) 水酸化カルシウムによる〔Ｒ（Ｒ＊，Ｒ＊）〕−２−（４−フルオロフェニル）−β，δ−ジヒドロキシ−５−（１−メチルエチル）−３−フェニル−４−〔（フェニルアミノ）カルボニル〕−１Ｈ−ピロール−１−ヘプタン酸エステルの加水分解
KR20020063190A (ko) 아토르바스타틴 칼슘의 다형태
KR20030077003A (ko) 비결정 아토르바스타틴 칼슘의 제조방법
IL160077A (en) Processes for preparing calcium salt forms of statins
KR20070092993A (ko) 플루바스타틴 나트륨 결정형 ｘｉｖ, ｌｘｘｉｉｉ,ｌｘｘｉｘ, ｌｘｘｘ 및 ｌｘｘｘｖｉｉ, 이의 제조 방법,이를 포함하는 조성물 및 이를 사용하는 방법
EP1562583A1 (fr) Forme vi de calcium d'atorvastatine ou hydrates de cette derniere
EP1732886A1 (fr) Polymorphes d'ester de tert-butyle d'atorvastatine et leur utilisation en tant qu'intermediaires dans la preparation d'atorvastatine
KR100829268B1 (ko) 비정질 아토바스타틴 칼슘의 제조 방법
JP2007507497A (ja) フルバスタチンナトリウムの多形の調製方法
US20100260851A1 (en) Novel Polymorph of Atorvastatin Calcium and Use Thereof for the Preparation of Amorphous Atorvastatin Calcium
MX2007013612A (es) Proceso para preparar una forma cristalina de hemi-calcio de atorvastatina.
WO2006048894A1 (fr) Nouvelles formes cristallines de calcium d'atorvastatine et procedes de fabrication
WO2005073187A1 (fr) Procede ameliore de preparation d'atorvastatine calcique amorphe
WO2006109147A1 (fr) Fluvastatine amorphe pratiquement pure, procede de preparation et compositions pharmaceutiques qui la contiennent
KR20080005230A (ko) 플루바스타틴 나트륨 신규 형태 및 이의 제조 방법
RU2294924C2 (ru) Форма vi аторвастатина кальция или ее гидраты

Legal Events

Date Code Title Description
AK Designated states

Kind code of ref document: A2

Designated state(s): AE AG AL AM AT AU AZ BA BB BG BR BW BY BZ CA CH CN CO CR CU CZ DE DK DM DZ EC EE EG ES FI GB GD GE GH GM HR HU ID IL IN IS JP KE KG KM KN KP KR KZ LC LK LR LS LT LU LV LY MA MD MG MK MN MW MX MZ NA NG NI NO NZ OM PG PH PL PT RO RU SC SD SE SG SK SL SM SY TJ TM TN TR TT TZ UA UG US UZ VC VN YU ZA ZM ZW

AL Designated countries for regional patents

Kind code of ref document: A2

Designated state(s): BW GH GM KE LS MW MZ NA SD SL SZ TZ UG ZM ZW AM AZ BY KG KZ MD RU TJ TM AT BE BG CH CY CZ DE DK EE ES FI FR GB GR HU IE IS IT LT LU LV MC NL PL PT RO SE SI SK TR BF BJ CF CG CI CM GA GN GQ GW ML MR NE SN TD TG

121 Ep: the epo has been informed by wipo that ep was designated in this application
NENP Non-entry into the national phase in:

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 05812688

Country of ref document: EP

Kind code of ref document: A2