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WO2011089559A1 - Nouvelle forme polymorphe de sels d'atorvastatine - Google Patents

Nouvelle forme polymorphe de sels d'atorvastatine Download PDF

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Publication number
WO2011089559A1
WO2011089559A1 PCT/IB2011/050253 IB2011050253W WO2011089559A1 WO 2011089559 A1 WO2011089559 A1 WO 2011089559A1 IB 2011050253 W IB2011050253 W IB 2011050253W WO 2011089559 A1 WO2011089559 A1 WO 2011089559A1
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WO
WIPO (PCT)
Prior art keywords
atorvastatin
salt
dicyclohexylethylenediamine
iii
sodium
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/IB2011/050253
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English (en)
Inventor
Buchi Reddy Reguri
Misra Dharmendra
Peter Paul Raj Medabalimi
Ganesan Subramaniam
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.)
Orchid Pharma Ltd
Original Assignee
Orchid Chemicals and Pharmaceuticals 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 Orchid Chemicals and Pharmaceuticals Ltd filed Critical Orchid Chemicals and Pharmaceuticals Ltd
Publication of WO2011089559A1 publication Critical patent/WO2011089559A1/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
    • C07D207/36—Oxygen or sulfur atoms
    • C07D207/40—2,5-Pyrrolidine-diones
    • C07D207/416—2,5-Pyrrolidine-diones 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 other ring carbon atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • 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

  • Atorvastatin of formula (I) or its salts preferably hemicalcium salt with purity greater than 99.5% using novel salts of Atorvastatin such as N,N- dicyclohexylethylenediamine salt of Atorvastatin and novel polymorph of Atorvastatin sodium salt.
  • the invention also provides a process for preparatin said salts with increased purity and good yield.
  • the novel salt according to the present invention are useful in the preparation of Atorvastatin calcium.
  • Atorvastatin hemicalcium is a synthetic lipid-lowering agent. It is a 3- hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitor. This enzyme catalyzes the conversion of HMG-CoA to mevalonate, an early and rate- limiting step in cholesterol biosynthesis. Inhibition of the enzyme decreases de novo cholesterol synthesis, increasing expression of low-density lipoprotein receptors (LDL receptors) on hepatocytes. This increases LDL uptake by the hepatocytes, decreasing the amount of LDL-cholesterol in the blood.
  • LDL receptors low-density lipoprotein receptors
  • Atorvastatin Like other statins, Atorvastatin also reduces blood levels of triglycerides and slightly increases levels of HDL-cholesterol.
  • the chemical designation for Atorvastatin hemicalcium is [R- (R*, R*)]-2-(4-fluorophenyl)- , ⁇ -dihydroxy-5- (l-methylethyl)-3-phenyl-4- [(phenylamino) carbonyl]-lH-pyrrole-l-heptanoic acid, calcium salt (2: 1) trihydrate. This is marketed under the brand name of LIPITOR ®
  • US patent No. 5,273,995 discloses the mono-sodium, mono-potassium, hemi-calcium, ammonium and N-methylglucamine salts of atorvastatin and also discloses the preparation of atorvastatin hemicalcium salt from atorvastatin sodium. This patent isolates Atorvastatin hemicalcium by dissolving hemi calcium in ethyl acetate followed by addition of hexane to yield amorphous form of Atorvastatin calcium.
  • WO 97/003958 discloses the teaching of amorphous atorvastatin which has unsuitable filtration and drying for large scale production and discloses that the said amorphous form must be protected from heat, light, oxygen and moisture.
  • US patent No. 6,838,566 discloses various amine salts of statin derivatives including Atrovastatin, for the preparation of medicament using the said amine salt. Though this patent covers various organic amines, this patent does not provide preparation method of all the amine salts except TBA and DCHA. This patent does not disclose the purity and stability of diamines salts.
  • US patent No. 7,615,647 discloses the various amines salt of atorvastatin and its also teaches the preparation of atorvastatin calcium salt from atorvastatin amine salt. However the purity of amine salt and the hemicalcium slat obtained from the said amine salt is less than 99.5%. Other than the Atorvastatin ammonium salt the organic amine salt of Atorvastatin prepared according to the present invention has purity in the range of 94- 96%.
  • US patent No. 7,534,810 discloses various atorvastatin amine salt and new crystalline form of atorvastatin sodium salt in view of preparing pharmaceutical composition using these salts.
  • GB2424880 discloses atorvastatin sodium form I and form II.
  • WO2007118873 discloses atorvastatin sodium of form I, II, III, IV V and amorphous form, the said forms are used for preparing pharmaceutical composition.
  • WO2008053495 discloses the preparation of novel crystalline form of atorvastatin sodium. These publication no where provide enablement for the preparation of Atorvastatin calcium using these sodium salt disclosed in the specification.
  • US20070066679 discloses crystalline atorvastatin sodium of form I by treating of amorphous atorvastatin sodium with 85% ethanol solution and acetone.
  • US20070066678 discloses crystalline atorvastatin sodium of form II by treating of amorphous atorvastatin sodium with 85% ethanol solution and butanone.
  • the above said literature provides the Atorvastatin sodium or amine salt for the preparation of pharmaceutical composition.
  • There are number of literatures provides a process for the preparation of amorphous Atorvastatin, but said preparation are fails to produce the amorphous form of Atorvastatin having purity greater than 99.5%.
  • And number of literature utilizes the isolation of Atorvastatin in crystalline hemicalcium salt and converts said form into amorphous to achieve the purity.
  • Atorvastatin calcium particularly in the amorphous form
  • the primary objective of the present invention is to provide the process for preparing Atorvastatin hemicalcium having good purity, greater than 99.5% and stability.
  • Another objective of the present invention is to provide novel polymorph of Atorvastatin sodium with good stability, purity and yield.
  • Yet another objective of the invention is to provide Atorvastatin N'N'- dicyclohexylethylenediamine salt with good stability, purity and yield.
  • a first aspect of the present invention directed to an improved process for the preparation of Atorvastatin hemicalcium salt having purity greater than 99.5% which comprising the steps of:
  • Atorvastatin as ⁇ , ⁇ -dicyclohexylethylenediamine or as a sodium salt having the PXRD pattern as described in Fig-1;
  • step (iii) into Atorvastatin of formula (I) or its hemicalcium salt.
  • the present invention directed to novel polymorph of Atorvastatin sodium salt having substantially the same X-ray diffractogram as set out in FIG. 1.
  • a fourth aspect of the inventions directed to crystalline form of ⁇ , ⁇ -dicyclohexylethylenediamine salt of Atorvastatin having substantially the same X-ray diffractogram as set out in FIG. 2.
  • the present invention directed to a process for preparing crystalline form of ⁇ , ⁇ -dicyclohexylethylenediamine salt of Atorvastatin which comprising the steps of:
  • step (i) treating the step (i) solution with N,N-dicyclohexylethylenediamine or its salt;
  • Atorvastatin N,N-dicyclohexylethylenediamine salt isolating Atorvastatin N,N-dicyclohexylethylenediamine salt.
  • FIG. 1 shows X-ray powder diffraction pattern of crystalline form of atorvastatin sodium according to the present invention.
  • Fig. 2 shows X-ray powder diffraction pattern of atorvastatin N'N'-dicyclohexyl ethylenediamine salt according to the present invention.
  • Fig 3 shows amorphous Atorvastatin hemicalcium obtained as intermediate in Method A of Example 3.
  • Fig 4 shows final amorphous Atorvastatin hemicalcium obtained from the present invention.
  • Atorvastatin hemicalcium from atorvastatin ester of formula (III), particularly tert-buty ester, having purity greater than 99.5% by HPLC.
  • the purity of Atorvastatin hemicalcium is achieved by way isolating the Atorvastatin as N, N- dicyclohexylethylenediamine salt of Atorvastatin or as crystalline sodium salt Atorvastatin having PXRD similar to Fig- 1.
  • Atorvastatin ester of formula (III) includes lower alky ester, for example tert-butyl ester.
  • N, N- dicyclohexylethylenediamine salt of Atorvastatin can be isolated either as an amorphous form or in crystalline form.
  • the isolated ⁇ , ⁇ -dicyclohexylethylenediamine salt has high storage stability and purity greater than 99.5%, particularly 99.6%, more particularly >99.7%.
  • the said salt is easy to handle in industrial scale and easy to filter. It should be noted that all amine salt of Atorvastatin does not have said property, some of them are difficult to isolate because of pasty nature, some of them does not have storage stability and some of them are difficult to filter. None of the literature per se discloses the N,N- dicyclohexylethylenediamine salt of Atorvastatin and constitute one of the novelty of the present invention.
  • Suitable amine salts require through investigation of many factors, including but not limited to (i) stability & purity of the amine salt (ii) yield and quality of atorvastatin that are prepared from these amine salt ⁇ with certain amine the quality of amine salt of Atorvastatin salt is either inferior or the amine salt of atorvastatin is less stable owing to the basicity of amines ⁇ (iii) preparation of atorvastatin from the atorvastatin amine salt for example certain amine require strong acid for cleavage of the salt, which affects the quality of final API (iv) cost involved in the manufacturing. Applicant points out the manufacturing cost associated with the preparation of ⁇ , ⁇ '-dicyclohexylethylenediamine salt is much less.
  • the reported amine salt fails to produce the Atorvastatin with purity greater than 99.5%.
  • the isolation of Atorvastatin as ⁇ , ⁇ '- dicyclohexylethylenediamine salt produce the Atorvastatin with purity greater than 99.5% and the manufacturing cost according to the present invention is less and gives economical advantage to the present process.
  • crystalline N,N- dicyclohexylethylenediamme salt of Atorvastatin is characterized by having a powder X-ray diffraction pattern with peaks at 6.4, 7.7, 9.3, 10.3, 11.0, 12.7, 15.6, 16.0, 16.9, 17.6, 18.7, 19.2, 19.3, 19.8, 20.1, 20.7, 21.0, 22.0, 22.6, 23.0, 23.4, 23.8, 24.5, 24.8, 25.6, 26.0, 26.3, 26.7, 27.1, 27.8, 28.2, 28.5 and 29.3. ⁇ 0.2 degrees 2 ⁇ .
  • Atorvastatin is characterized by having a powder X-ray diffraction pattern with peaks at 4.53, 5.53, 5.99, 8.19, 8.64, 9.59, 10.28, 10.62, 11.09, 12.00, 13.08, 13.66, 14.12, 15.26, 16.34, 16.73, 17.38, 17.58, 18.10, 18.54, 19.30, 19.56, 19.94, 20.76, 21.45, 21.92, 22.35, 23.27, 23.62 23.95, 24.45, 24.77, 25.22, 26.54, 26.86, 27.78, 28.07, 28.96, 29.52, 30.03 and 30.70. ⁇ 0.2 degrees 2 ⁇ .
  • the solvent used in step (i) in the preparation of N, N dicyclohexylethylenediamme salt is selected from ethyl acetate, isopropylacetate, dichloromethane, toluene and mixture thereof.
  • the hydrolysis of atorvastatin ester of formula (III) is performed in conventional manner using an alcoholic solvent system such as methanol, ethanol, isopropanol and the like or mixture thereof , and the percentage of aqueous sodium hydroxide used in step (i) is in the range of 20-80%; preferably in the range of 40-60%.
  • the solvent is removed by distillation, preferably by vacuum distillation, from residue atorvastatin is isolated as ⁇ , ⁇ -dicyclohexylethylenediamine salt or as sodium salt having PXRD pattern as shown in the Fig-1.
  • Atorvastatin ⁇ , ⁇ -dicyclohexylethylenediamine salt is done by adjusting the reaction mass pH to about 4.5 to 6.5 followed by treating with ⁇ , ⁇ -dicyclohexylethylenediamine or its acetate salt in a solvent system that does not disturb the course of the reaction.
  • the Atorvastatin sodium is isolated directly from the reaction mass by treating the residue obtained with solvent selected from acetonitrile, THF, and the like, preferably acetonitrile.
  • solvent selected from acetonitrile, THF, and the like preferably acetonitrile.
  • co-crystal of Atorvastatin sodium can be isolated by conventional co-crystal methods.
  • Atorvastatin as ⁇ , ⁇ -dicyclohexylethylenediamine salt or as sodium salt having the PXRD pattern as shown in Fig- 1 has purity greater than 99.5%, which indirectly helps to produce the Atorvastatin hemiclacium having purity greater than 99.5%, preferably 99.8%.
  • the novel salt prepared according to the present invention is converted to Atorvastatin hemi calcium salt according the procedure reported in the prior art or by following procedure provided in the examples.
  • amorphous atorvastatin hemicalcium can be done by removing the solvent from the solution by any desired technique, such as agitated thin film drying, rotational evaporation (such as using a RVD), spin-flash drying, fluid-bed drying, Vacuum tray drying or other techniques known to those skilled in the art.
  • the obtained atorvastatin N'N'-dicyclohexylethylenediamine salt was treated with methanol/water/MTBE mixture and stirred for 30 minutes at 25°-35°C.
  • the pH of the reaction mass was adjusted to 5-5.3 using 10% HCL.
  • calcium chloride solution was added and maintained for 10-12 hours.
  • the reaction mixture distilled under vacuum upto 6 to 8 volumes at less than 40°C and maintained for 30 minutes at room temperature.
  • the obtained material was filtered, washed with water and dried under vacuum at 40°C for 24 hours to yield Atorvastatin hemicalcium with purity greater than 99.75%.
  • atorvastatin sodium was added methanol/water/MTBE at 25-30 °C and the pH was adjusted to 7.5-8.5.
  • the reaction mass temperature was raised and followed by addition of calcium chloride solution (0.5 to 0.6 mol).
  • the reaction mass temperature was cooled to 30 °C and stirred. Partially distilled and the precipitated product was filtered and sucks dried to yield amorphous Atorvastatin calcium as described in Fig-3 was dissolved in ethyl acetate at 55-65 °C and water was added over it. Ethyl acetate layer separated and distilled upto 3-7 volume under reduced pressure.
  • Heptane was added slowly in to the solution containing atorvastatin calcium at 25°-30°C (alternatively the reaction mass in ethyl acetate in to heptane).
  • the solid obtained was filtered and washed with n-heptane and dried under vacuum at 40-45°C yielded Atorvastatin calcium in amorphous nature. Purity > 99.78 % by HPLC RS method.
  • Mobile phase A Mix 720ml of buffer (Dissolve 1.54 g-of Ammonium acetate in 1000 mL of water.
  • atorvastatin sodium was added methanol/water/MTBE at 25-30 °C and the pH was adjusted to 7.5-8.5 using 50 % HC1 at 20-30 °C. To that was added calcium chloride solution at 20-30 °C and stirred. Reaction mass partially distilled under reduced pressure. To the reaction mass, ethylacetate was added over it and layer separated. Water was added over to the obtained ethylacetate layer at 30°- 40°C, stirred and layer separated. The separated ethylacetate layer was distilled upto 3-7 volume under reduced pressure.
  • Heptane was added slowly in to the solution containing atorvastatin calcium at 25°-30°C (alternatively the reaction mass in ethyl acetate in to heptane).
  • the solid obtained was filtered and washed with n-heptane and dried under vacuum at 40-45°C yielded Atorvastatin calcium in amorphous nature. Purity > 99.65 % by HPLC RS method.
  • Heptane preferably degassed heptane (or hexane, cyclohexane)
  • atorvastatin calcium 25°-30°C (alternatively the reaction mass in ethyl acetate into heptane).
  • the solid obtained was filtered and washed with n-heptane and dried under vacuum at 40°-45°C yielded Atorvastatin calcium in amorphous nature. Purity ⁇ 99.3 % by HPLC RS method.
  • the amorphous material obtained from method A or method B or method C was added to methanol (or acetone or ethyl acetate), preferably degassed methanol, at 25-30 °C under stirring and the resulting mixture was degassed by bubbling nitrogen through it, optionally in the presence of butylated hydroxyl anisole and butylated hydroxyl toluene and filtered through hyflow bed.
  • the obtained filterate was concentrated under reduced pressure and then transferred to RVD (Rotatory vacumm dryer) and the amorphous powder obtained was dried further in VTD (Vacuum try dryer) at 40°-45°C.
  • RVD Rotary vacumm dryer
  • VTD Vauum try dryer
  • the amorphous atorvastatin hemicalcium obtained is packed under inert condition, i.e. nitrogen atmosphere in a polybags preferably gas non-permeable plastic bags, or metal container or glass container.
  • the amorphous material obtained from method A or method B or method C was added to methanol (or acetone) at 25-30 °C under stirring and the resulting mixture was degassed by bubbling nitrogen through it, optionally in the presence of butylated hydroxyl anisole and/or butylated hydroxyl toluene and filtered through hyflow bed.
  • the obtained filterate was feeded to agitated thin film dryer and dried under vacuum at 35°-45°C.
  • the obtained solution was distilled partially transferred to Tray and dried under vacuum at 35°-45°C.

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Abstract

La présente invention concerne un procédé perfectionné de préparation d'atorvastatine de formule (I) ou de ses sels, de préférence le sel hémicalcique, avec une pureté supérieure à 99,5 %, à l'aide des nouveaux sels d'atorvastatine tels que le sel de N,N-dicyclohexyléthylènediamine d'atorvastatine et le nouveau polymorphe du sel sodique d'atorvastatine.
PCT/IB2011/050253 2010-01-22 2011-01-20 Nouvelle forme polymorphe de sels d'atorvastatine Ceased WO2011089559A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
IN151CH2010 2010-01-22
IN151/CHE/2010 2010-01-22

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WO2011089559A1 true WO2011089559A1 (fr) 2011-07-28

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Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2000017150A1 (fr) * 1998-09-18 2000-03-30 Lek Pharmaceutical And Chemical Company D.D. NOUVEAUX SELS D'INHIBITEURS DE LA HMG-CoA REDUCTASE
WO2003082816A1 (fr) * 2002-03-28 2003-10-09 Richter Gedeon Vegyészeti Gyár Rt. Nouveaux sels d'atorvastatine et compositions pharmaceutiques les contenant
WO2005105738A2 (fr) * 2004-05-05 2005-11-10 Pfizer Products Inc. Formes salines d'acide [r-(r*, r*)]-2-(4-fluorophenyl)-beta, delta-dihydroxy-5-(1-methylethyl)-3-phenyl-4-[(phenylamino)carbonyl]-1h-pyrrole-1-heptanoique
WO2006092037A1 (fr) * 2005-03-01 2006-09-08 Apotex Pharmachem Inc. Procédé de fabrication d’hémicalcium d’atorvastatine

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2000017150A1 (fr) * 1998-09-18 2000-03-30 Lek Pharmaceutical And Chemical Company D.D. NOUVEAUX SELS D'INHIBITEURS DE LA HMG-CoA REDUCTASE
WO2003082816A1 (fr) * 2002-03-28 2003-10-09 Richter Gedeon Vegyészeti Gyár Rt. Nouveaux sels d'atorvastatine et compositions pharmaceutiques les contenant
WO2005105738A2 (fr) * 2004-05-05 2005-11-10 Pfizer Products Inc. Formes salines d'acide [r-(r*, r*)]-2-(4-fluorophenyl)-beta, delta-dihydroxy-5-(1-methylethyl)-3-phenyl-4-[(phenylamino)carbonyl]-1h-pyrrole-1-heptanoique
WO2006092037A1 (fr) * 2005-03-01 2006-09-08 Apotex Pharmachem Inc. Procédé de fabrication d’hémicalcium d’atorvastatine

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
CAIRA M.R. ET AL.: "Crystalline Polymorphism of Organic Compounds", TOPICS IN CURRENT CHEMISTRY, vol. 198, 1998, pages 163 - 208, XP001156954, DOI: doi:10.1007/3-540-69178-2_5 *

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