WO2003070702A1 - Nouvelles formes cristallines d'hemi-calcium d'atorvastatine - Google Patents

Nouvelles formes cristallines d'hemi-calcium d'atorvastatine Download PDF

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WO2003070702A1
WO2003070702A1 PCT/US2003/005384 US0305384W WO03070702A1 WO 2003070702 A1 WO2003070702 A1 WO 2003070702A1 US 0305384 W US0305384 W US 0305384W WO 03070702 A1 WO03070702 A1 WO 03070702A1
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Prior art keywords
calcium
atorvastatin hemi
characteristic
solid crystalline
solvates
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PCT/US2003/005384
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English (en)
Inventor
Limor Tessler
Judith Aronhime
Revital Lifshitz-Liron
Dalia Maidan-Hanoch
Nir Hasson
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Teva Pharmaceutical Industries Ltd.
Teva Pharmaceuticals Usa, Inc.
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Priority to CA002475864A priority Critical patent/CA2475864A1/fr
Priority to AU2003217653A priority patent/AU2003217653A1/en
Priority to DE03713610T priority patent/DE03713610T1/de
Priority to KR1020047012591A priority patent/KR100724515B1/ko
Priority to JP2003569609A priority patent/JP2005519076A/ja
Priority to EP03713610A priority patent/EP1480950A4/fr
Priority to MXPA04007939A priority patent/MXPA04007939A/es
Publication of WO2003070702A1 publication Critical patent/WO2003070702A1/fr
Priority to IS7402A priority patent/IS7402A/is
Priority to HR20040768A priority patent/HRP20040768A2/hr
Priority to NO20043842A priority patent/NO20043842L/no

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    • 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
    • C07D207/32—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 only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • C07D207/325—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 only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms with substituted hydrocarbon radicals directly attached to the ring nitrogen atom
    • C07D207/327—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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/06—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a carbon chain containing only aliphatic 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • 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

  • the present invention relates to crystalline polymorphic forms of atorvastatin hemi- calcium and novel processes for preparing crystalline forms of atorvastatin hemi-calcium.
  • Atorvastatin ([R-(R*,R*)]-2-(4-fluorophenyl)- ⁇ , ⁇ -dihydroxy-5-(l-methylethyl)-3- phenyl-4-[(phenylamino)carbonyl]-lH-pyrrole-l-heptanoic acid), depicted in lactone form in formula (I) and its calcium salt of formula (11) are well known in the art, and described, inter alia, in U.S. Patents Nos. 4,681,893, 5,273,995, and in copending USSN 60/166,153, filed November 17, 2000, all of which are herein incorporated by reference.
  • Statin drugs are currently the most therapeutically effective drugs available for reducing low density lipoprotein (LDL) particle concentration in the blood stream of patients at risk for cardiovascular disease.
  • LDL low density lipoprotein
  • a high level of LDL in the bloodstream has been linked to the formation of coronary lesions which obstruct the flow of blood and can rupture and promote thrombosis.
  • Goodman and Gilman The Pharmacological Basis of Therapeutics 879 (9th ed. 1996). Reducing plasma LDL levels has been shown to reduce the risk of clinical events in patients with cardiovascular disease and patients who are free of cardiovascular disease but who have hypercholesterolemia. Scandinavian Simvastatin Survival Study Group, 1994; Lipid Research Clinics Program, 1984a, 1984b.
  • statin drugs The mechanism of action of statin drugs has been elucidated in some detail. They interfere with the synthesis of cholesterol and other sterols in the liver by competitively inhibiting the 3-hydroxy-3-methyl-glutaryl-coenzyme A reductase enzyme ("HMG-CoA reductase"). HMG-CoA reductase catalyzes the conversion HMG to mevalonate, which is the rate determining step in the biosynthesis of cholesterol, and so, its inhibition leads to a reduction in the concentration of cholesterol in the liver. Very low density lipoprotein (NLDL) is the biological vehicle for transporting cholesterol and triglycerides from the liver to peripheral cells.
  • NLDL Very low density lipoprotein
  • VLDL is catabolized in the peripheral cells which releases fatty acids which may be stored in adopcytes or oxidized by muscle.
  • the NLDL is converted to intermediate density lipoprotein (DDL), which is either removed by an LDL receptor, or is converted to LDL.
  • DDL intermediate density lipoprotein
  • Decreased production of cholesterol leads to an increase in the number of LDL receptors and corresponding reduction in the production of LDL particles by metabolism of DDL.
  • Atorvastatin hemi-calcium salt trihydrate is marketed under the name LIPITOR by Warner-Lambert Co. Atorvastatin was first disclosed to the public and claimed in U.S.
  • the hemi-calcium salt depicted in formula (H) is disclosed in U.S. Patent No. 5,273,995.
  • the '995 patent teaches that the hemi-calcium salt is obtained by crystallization from a brine solution resulting from the transposition of the sodium salt with CaCl 2 and further purified by recrystallization from a 5 :3 mixture of ethyl acetate and hexane.
  • the present invention provides new crystal forms of atorvastatin hemi-calcium in both solvated and hydrated states. The occurrence of different crystal forms (polymorphism) is a property of some molecules and molecular complexes.
  • a single molecule like the atorvastatin in formula (I) or the salt complex of formula (IT), may give rise to a variety of solids having distinct physical properties like melting point, X-ray diffraction pattern, infrared absorption fingerprint and NMR spectrum.
  • the differences in the physical properties of polymorphs result from the orientation and intermolecular interactions of adjacent molecules (complexes) in the bulk solid. Accordingly, polymorphs are distinct solids sharing the same molecular formula yet having distinct advantageous and/or disadvantageous physical properties compared to other forms in the polymorph family.
  • One of the most important physical properties of pharmaceutical polymorphs is their solubility in aqueous solution, particularly their solubility in the gastric juices of a patient.
  • Form I is characterized by powder X-ray diffraction pattern having peaks at 9.150, 9.470, 10.266, 10.560, 11.853, 12.195, 17.075, 19.485, 21.626, 21.960, 22.748, 23.335, 23.734, 24.438, 28.915 and 29.234 degrees two-theta.
  • atorvastatin hemi-calcium Form VHI produces a powder X-ray diffraction pattern using conventional CuK ⁇ radiation having peaks at 6.9, 9.3, 9.6, 16.3, 17.1, 19.2, 20.0, 21.6, 22.4, 23,9, 24.7, 25.6, and 26.5 ⁇ 0.2 degrees 20. Additional peaks have been observed at 4.8, 5.2, 5.9, 7.0, 8.0, 9.3, 9.6, 10.4, 11.9, 16.3, 17.1(broad), 17.9, 18.6, 19.2, 20.0, 20.8, 21.1, 21.6, 22.4, 22.8, 23.9, 24.7, 25.6, 26.5, 29.0 ⁇ 0.2 degrees two-theta.
  • Form VHI Synchrotron X-ray powder diffraction analysis was performed on Form VHI to determine its crystal system and unit cell dimensions.
  • Atorvastatin hemi-calcium Form VHI produces a cross-polarization, magic angle spinning solid-state 13 C NMR spectrum with resonances at the following chemical shift positions:: 17.8, 20.0, 24.8, 25.2, 26.1, 40.3, 40.8, 41.5, 43.4, 44.1, 46.1, 70.8, 73.3, 114.1, 116.0, 119.5, 120.1, 121.8, 122.8, 126.6, 128.8, 129.2, 134.2 , 135.1, 137.0, 138.3, 139.8, 159.8, 166.4, 178.8, 186.5 ppm.
  • Form VHI is characterized by a solid-state 13 C nuclear magnetic resonance having the following chemical shifts differences between the lowest ppm resonance and other resonances: 2.2, 7.0, 7.4, 8.3, 22.5, 23.0, 23.7, 25.6, 26.3, 28.3, 53.0, 55.5, 96.3, 98.2, 101.7, 102.3, 104.0, 105.0, 108.8, 111.0, 111.4, 116.4, 117.3, 119.2, 120.5, 122.0, 142.0, 148.6, 161.0 and 168.7.
  • Atorvastatin hemi-calcium Form VHI can exist as an ethanol solvate containing up to about 3 % ethanol by weight. Samples of atorvastatin hemi-calcium Form VHI also can contain up to 7% water as determined by Karl Fisher analysis.
  • atorvastatin hemi-calcium Form VHI may be obtained by slurrying atorvastatin hemi-calcium in a mixture of ethanol and water at elevated temperature, preferably about 78-80 °C.
  • Form VHI may be obtained starting from Form V by treating Form V with a mixture of EtOH:H 2 O, preferably in the ratio of about 5:1 at an elevated temperature below reflux, preferably 78-80°C.
  • An especially preferred EtOH:H 2 O mixture for that process contains about 4 % by volume water in ethanol.
  • atorvastatin Form V gradually dissolves and at the point of 78-80°C turbidity, with or without seeding, is observed. At this point the suspension is immediately cooled to room temperature.
  • the '378 publication teaches that Form VHI may be obtained by treating atorvastatin hemi-calcium in EtOH, preferably absolute EtOH, at elevated temperature, preferably boiling EtOH.
  • atorvastatin dissolves and reprecipitates.
  • MeOH may be added at reflux. Added MeOH may adversely affect the yield, but may improve the chemical purity of the product.
  • Starting materials for preparing Form VHI by this process can be crystalline forms of atorvastatin hemi-calcium, preferably Forms I and V and mixtures thereof or amorphous atorvastatin hemi-calcium.
  • the quantity of EtOH or mixture thereof with water is preferably in the range of from about 10 to about 100 ml g "1 , more preferably about 20 to about 80 ml g "1 .
  • Form VHI also may be prepared by suspending atorvastatin hemi-calcium in certain 1-butanol/water and ethanol/water mixtures for a period of time sufficient to cause the conversion of the atorvastatin hemi-calcium to Form VHI.
  • 1-Butanol/water mixtures should contain about 20% 1-butanol by volume at elevated temperature, preferably at reflux temperature.
  • atorvastatin hemi-calcium Form C produces a powder X-ray diffraction pattern using conventional CuK ⁇ radiation having peaks at 4.7,
  • Atorvastatin hemi-calcium Form LX produces a cross-polarization, magic angle spinning solid-state 13 C NMR spectrum with resonances at the following chemical shift positions: 18.0, 20.4, 24.9, 26.1, 40.4, 46.4, 71.0, 73.4, 114.3, 116.0, 119.5, 120.2, 121.7, 122.8, 126.7, 128.6, 129.4, 134.3, 135.1, 136.8, 138.3, 139.4, 159.9, 166.3, 178.4, 186.6 ppm.
  • Form IX is characterized by a solid-state !3 C nuclear resonance having the following chemical shifts differences between the lowest ppm resonance and other resonances: 2.4, 6.9, 8.1, 22.4, 28.4, 53.0, 55.4, 96.3, 98.0, 101.5, 102.2, 103.7, 104.8, 108.7, 110.6, 111.4, 116.3, 117.1, 118.8, 120.3, 121.4, 141.9, 148.3, 160.4, 168.6.
  • Form LX may be prepared by slurrying atorvastatin hemi-calcium in butanol and isolating Form IX by, for example, filtration or decantation of the butanol, preferably by filtration.
  • Preferred temperature ranges for the slurrying are from 78 °C to the reflux temperature of the solvent.
  • Recovery of atorvastatin hemi-calcium salt from the slurry can be enhanced by addition of an anti-solvent to the slurry before isolating Form IX.
  • Preferred anti-solvents include isopropanol and ⁇ -hexane.
  • Starting materials for preparing Form DC by this process can be crystalline or amorphous atorvastatin hemi-calcium, preferably Forms I and V and mixtures thereof.
  • Form IX may be prepared by suspending Form VHI in ethanol, preferably absolute ethanol, at room temperature for a period of time sufficient to convert form VHI to Form LX, which may range from a few hours to 24 hours and typically requires about 16 hours. Thereafter, Form C is recovered from the suspension.
  • Form DC also may be prepared by maintaining Form VHI under a humid atmosphere.
  • Form LX also may be prepared by suspending atorvastatin hemi-calcium Form V in mixtures of 1 -butanol and either ethanol or water at reflux temperature for a period of time sufficient to convert Form V into Form DC and recovering Form LX from the suspension.
  • the mixtures Preferably contain about 50 volume percent of each component.
  • Form I remedies some of the deficiencies of the amorphous material in terms of manufacturability, there remains a need for yet further improvement in these properties as well as improvements in other properties such as flowability, vapor impermeability and solubility. Further, the discovery of new crystalline polymorphic forms of a drug enlarges the repertoire of materials that a formulation scientist has with which to design a pharmaceutical dosage form of a drug with a targeted release profile or other desired characteristic.
  • FIG. 1 is a characteristic powder X-ray diffraction pattern of atorvastatin hemi- calcium Form DC obtained using a conventional X-ray generator with a copper anode.
  • Fig. 2 is a characteristic powder X-ray diffraction pattern of atorvastatin hemi- calcium Form LXa obtained using a conventional X-ray generator with a copper anode.
  • Fig. 3 is a characteristic powder X-ray diffraction pattern of atorvastatin hemi- calcium Form XIV obtained using a conventional X-ray generator with a copper anode.
  • Fig. 4 is a characteristic powder X-ray diffraction pattern of atorvastatin hemi- calcium Form XVI obtained using a conventional X-ray generator with a copper anode.
  • Fig. 5 is a characteristic powder X-ray diffraction pattern of atorvastatin hemi- calcium Form XVH.
  • the present invention provides new solid crystalline forms of atorvastatin hemi- calcium, and solvates and hydrates thereof. More particularly, the present invention provides novel solid crystalline atorvastatin hemi-calcium characterized by a powder X-ray diffraction pattern obtained using conventional CuK ⁇ radiation having peaks at 9.3 and 9.5 ⁇ 0.2 degrees two-theta. In addition, small peaks are observed atl5.7, 20.5, 21.1, 22.8, 23.8, 24.0, 25.3, 26.4, 26.8,
  • the present invention provides novel solid crystalline atorvastatin hemi-calcium characterized by a powder X-ray diffraction pattern obtained using conventional CuK ⁇ radiation having peaks at 7.6, 9.8, 16.5, 29.4 ⁇ 0.2 degrees two-theta and novel processes for its preparation.
  • the present invention provides a novel crystalline form of atorvastatin hemi-calcium characterized by a powder X-ray diffraction pattern obtained using conventional CuK ⁇ radiation having peaks at 16.5, 21.9, 29.5 ⁇ 0.2 degrees two-theta and novel processes for its preparation.
  • the present invention provides a novel crystalline form of atorvastatin hemi-calcium characterized by a powder X-ray diffraction pattern obtained using conventional CuK ⁇ radiation by typical X-Ray peaks at 7.8, 9.5, 10.2, 18.2, 19.1,
  • the present invention provides a novel process for preparing atorvastatin hemi-calcium Form VHI.
  • the present invention provides a novel process for preparing atorvastatin hemi-calcium Form IX.
  • the invention provides compositions and dosage forms comprising the novel solid crystalline atorvastatin hemi-calcium and their mixtures along with a pharmaceutically acceptable carrier, as well as methods of treating hyperlipidemia with the new forms.
  • Some crystalline forms of atorvastatin hemi-calcium of the present invention exist in a solvated state and hydrated state. Hydrates have been analyzed by Karl-Fisher and thermogravimetric analysis.
  • atorvastatin hemi-calcium Form DC can be produced using mixtures of 1 -butanol and either ethanol or water. It has now been found that suspending atorvastatin hemi-calcium Form V in mixtures of 1 -butanol and water, wherein one or the other diluent is predominant in the mixture, will yield a more highly pure and crystalline atorvastatin hemi-calcium product. This product has been denominated Form LXa. Atorvastatin hemi-calcium Form IXa is characterized by its PXRD pattern (Fig.
  • Atorvastatin hemi-calcium Form DCa is considered to be an especially crystalline, filterable and pure material having similar internal structure to Form DC, hence the designation Form IXa.
  • Form DCa can be prepared by suspending atorvastatin hemi- calcium Form V in mixtures of 1 -butanol and water in which either the 1 -butanol or water constitutes from about 85% to about 95%>, more preferably about 90%>, of the mixture. The suspension can be heated to accelerate conversion of Form V to Form IXa. Sixteen hours at about 85 °C is generally sufficient. Under these conditions, yields as high as 95% can be obtained and the impurity level of the material can be significantly reduced.
  • the impurity content of the starting atorvastatin hemi-calcium can be reduced by about 50%> or more.
  • Form DC can be obtained in about 0.7% chemical purity when starting with Form V of about 1.3% chemical purity.
  • Chemical purity was measured by high performance liquid chromatography ("HPLC"). HPLC was performed on a Spherisorb ® S5, C8 column, 250x4.6 mm with gradient elution: Solvent A 0.05M KH 3 PO 4 adjusted to pH 5 with IN KOH:acetonitrile: methanohTHF (62:26:8:4); Solvent B: methanol. The HPLC system was equipped with Waters ® pumps and a UV detector set to detect at 254 nm.
  • Form V is suspended in a mixture of 90%> 1 -butanol and 10% water (v/v). The mixture is used in an amount of about 20 milliliters per gram of Form V. The suspension is refluxed at 90 °C for about 16 hours, after which time Form V is transformed into Form DC, which is then be recovered from the suspension by conventional means, like filtration. According to another specific procedure, Form V is suspended in a mixture of 10%>
  • the present invention further provides a novel polymorph of atorvastatin hemi- calcium that has been denominated Form XIV.
  • Atorvastatin hemi-calcium Form XIV is characterized by a powder X-ray diffraction pattern obtained using conventional CuK ⁇ radiation (FIG. 3) having peaks at 7.6, 9.8, 16.5, 18.1, 20.0, 20.4, 21.9, 22.4, 23.6, 29.4 ⁇ 0.2 degrees two-theta. The most characteristic peaks are those at 7.6, 9.8, 16.5, 29.4 ⁇ 0.2 degrees two-theta.
  • Form XTV can be obtained from a suspension of atorvastatin hemi-calcium in water.
  • atorvastatin hemi- calcium Form I precipitates when calcium acetate is added to a solution of atorvastatin sodium in water. It is also said that Form I can be prepared by suspending amorphous atorvastatin hemi-calcium in water.
  • Example 1 a mixture formed from atorvastatin sodium and calcium acetate in water was seeded with Form I shortly after addition of the calcium acetate solution and, thereafter, Form I was obtained.
  • Form XIV is readily distinguishable from Form I (which is also obtained by precipitation from water, but with seeding with Form I) by the peaks at 7.6, 16.5, 20.0 and 19.4 degrees two-theta, which peaks are absent from the PXRD pattern of Form I.
  • Atorvastatin hemi-calcium Form XTV can be prepared by suspending atorvastatin hemi-calcium in water until a fine suspension forms and then allowing the suspension to stand undisturbed until the fine crystals transform substantially into white flakes.
  • the flakes can be separated from the suspension by conventional means, like decanting or filtering (either with or without suction and they do not clog the filter) and washing the crystals.
  • the crystals of the fine suspension are very small giving the suspension the appearance of an emulsion.
  • the transformation from fine suspension to flakes is readily apparent from visual inspection of the suspension. Preferred process parameters are as follows.
  • the preferred starting material is atorvastatin hemi-calcium Form V.
  • the fine suspension typically forms over a period of from about 2 to about 10 hours, on average about 5 hours.
  • the fine suspension transforms into white flakes over about one to about five days, with longer time periods being preferred for more complete conversion and a more easily filterable product.
  • Other conditions which lead to the production of Form X1N may be discovered but presently the best method known is by suspending atorvastatin hemi-calcium in water that is not agitated and has not been seeded with a different polymorph of atorvastatin.
  • Form XIV has been obtained in our laboratory without seeding of any kind.
  • Form XIV crystals can be transformed into another crystal form without contact with solvent.
  • This new form has been denominated Form XVI.
  • Form XVI is characterized by a powder X-ray diffraction pattern obtained using conventional CuK ⁇ radiation (FIG. 4) having peaks at 7.7, 9.9, 16.5, 17.7, 18.3, 20.0, 21.9, 29.5 ⁇ 0.2 degrees two-theta. The most characteristic peaks are at 16.5, 21.9, 29.5 ⁇ 0.2 degrees two-theta.
  • Form XVI may be produced by maintaining Form XIV at from about 20° C to about 50°C, preferably about 22°C or room temperature, and preferably exposed to air. Preferably, Form XIV is maintained under these conditions for about three hours. Other conditions under which Form XVI is formed may be empirically determined. It is only possible to give methods which have so far been found suitable for producing it.
  • the present invention further provides a hydrated form of atorvastatin hemi- calcium that has been denominated Form XVH.
  • Form XVH has been isolated as the immediate product obtained by precipitation from wet ethanol.
  • U.S. Patent Application Publication No. 2992/0183378 alternatively, see International Publication No.
  • Form VHI can be prepared from a dispersion of Form V in a mixture of 96% ethanol/water at a temperature of about 70 °C.
  • the precipitated material prior to being dried, is obtained in Form XVH.
  • Atorvastatin hemi-calcium Form XVH is characterized by a powder X-ray diffraction pattern obtained using conventional CuK ⁇ radiation by typical X-Ray peaks at 19.1, 20.6, 21.4 and 23.6 ⁇ 0.2 degrees two-theta.
  • Form XVH is also characterized by the typical X-Ray powder diffraction pattern of FIG. 5.
  • Form XVH is distinguishable from Form VHI (the material obtained by complete drying of material obtained by precipitation from 96% ethanol/4%) water) by the peak pattern in the range of 9-10, 18-25 degrees two-theta.
  • Form NIH exhibits two strong peaks at 19.2 and 20.0 ⁇ 0.2 degrees 20, while Form XNH has one strong peak at 19.1 ⁇ 0.2 degrees 20, but no comparably strong peak at 20 ⁇ 0.2 degrees 20.
  • Atorvastatin hemi-calcium Form XVH may be produced by suspending atorvastatin hemi-calcium Form V in a mixture of 96%> ethanol and 4% water (v/v) and heating to about 78-80°C, followed by cooling.
  • Form XVH can be isolated immediately after the material starts to precipitate in the mixture at reflux temperature, or after all the material is precipitated, after the material is cooled down to room temperature, or after all the solid is isolated from the mother liquor (for instance by filtration).
  • Form XVH Although there may be other ways to obtain Form XVH, the best way presently known is to suspend atorvastatin hemi- calcium Form V in at least about 500 milliliters or more of a mixture of about 96%> ethanol and about 4% water (v/v) and refluxing the suspension, followed by cooling. The solids are then recovered by conventional means such as filtering or decanting as Form XVH. Additional experimental details are provided in Example 6. The volume of the reactor should be at least about 1 liter.
  • the present invention also provides novel processes for preparing known forms of atorvastatin hemi-calcium.
  • Atorvastatin hemi-calcium Form I may be produced by heating Form XTV to about 50° C or above, preferably about 65 °C. Preferably, Form XIV is maintained at elevated temperature for about 15 hours.
  • conventional drying of Form XVH transforms it into Form VHI.
  • conventional drying it is meant the methods of drying routinely used by those skilled in the art in the pharmaceutical industry. Any drying type of equipment conventionally used in the pharmaceutical industry is suitable for this purpose.
  • a drying temperature in the range of about 40-70 °C (in temperature steps or in one temperature only) is preferred.
  • the amount of time required to convert Form XVH to Form VHI depends on the quantity of material employed. Vacuum may be preferably used to convert Form XVH to Form VHI by drying. Preparation of Form VHI also may be achieved by drying Form XVH at temperatures lower than 40 °C, down to room temperature.
  • atorvastatin hemi-calcium Form DC can be prepared by suspending Form V in a mixture of 50% 1 -butanol and 50% of another organic solvent(s) like acetone, 2-propanol, tetrahydrofuran, 1-propanol and methyl t-butyl ether. The mixture is used in an amount of about 20 milliliters per gram of Form V. The suspension is heated to reflux temperature for about 16 hours, after which time Form V is transformed into Form IX, which can then be recovered from the suspension by conventional means.
  • organic solvent(s) like acetone, 2-propanol, tetrahydrofuran, 1-propanol and methyl t-butyl ether.
  • the mixture is used in an amount of about 20 milliliters per gram of Form V.
  • the suspension is heated to reflux temperature for about 16 hours, after which time Form V is transformed into Form IX, which can then be recovered from the suspension by conventional means.
  • Atorvastatin hemi-calcium Forms DCa, XIV, XNI and XNH are useful for reducing the plasma low density lipoprotein level of a patient suffering from or susceptible to hypercholesterolemia.
  • it will typically be administered to human patients in a unit dose of from about 0.5 mg to about 100 mg.
  • a dose of from about 2.5 to about 80 mg per day, more particularly from about 2.5 to about 20 mg per day causes a lowering of the plasma low density lipoprotein level in human patients. Whether such lowering is sufficient or whether the dose or dose frequency should be increased is a determination that is within the skill level of appropriately trained medical personnel.
  • a further aspect of the present invention is a pharmaceutical composition and dosage form containing the novel forms of atorvastatin hemi-calcium.
  • compositions of the invention include powders, granulates, aggregates and other solid compositions comprising novel Forms DCa, X1N, XNI and XNH of atorvastatin hemi-calcium.
  • Forms DCa, XIN, XNI and XNH solid compositions that are contemplated by the present invention may further include diluents, such as cellulose- derived materials like powdered cellulose, microcrystalline cellulose, microfine cellulose, methyl cellulose, ethyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropylmethyl cellulose, carboxymethyl cellulose salts and other substituted and unsubstituted celluloses; starch; pregelatinized starch; inorganic diluents like calcium carbonate and calcium diphosphate and other diluents known to the pharmaceutical industry.
  • suitable diluents include waxes, sugars and sugar alcohols like mannitol and sorbito
  • excipients that are within the contemplation of the present invention include binders, such as acacia gum, pregelatinized starch, sodium alginate, glucose and other binders used in wet and dry granulation and direct compression tableting processes.
  • Excipients that also maybe present in a solid composition of Forms IXa, XIV, XVI and XVH atorvastatin hemi-calcium further include disintegrants like sodium starch glycolate, crospovidone, low-substituted hydroxypropyl cellulose and others.
  • excipients may include tableting lubricants like magnesium and calcium stearate and sodium stearyl fumarate; flavorings; sweeteners; preservatives; pharmaceutically acceptable dyes and glidants such as silicon dioxide.
  • the dosages include dosages suitable for oral, buccal, rectal, parenteral (including subcutaneous, intramuscular, and intravenous), inhalant and ophthalmic administration.
  • parenteral including subcutaneous, intramuscular, and intravenous
  • inhalant and ophthalmic administration are examples of the most suitable route in any given case.
  • Dosages may be conveniently presented in unit dosage form and prepared by any of the methods well-known in the art of pharmacy.
  • Dosage forms include solid dosage forms, like tablets, powders, capsules, suppositories, sachets, troches and losenges as well as liquid suspensions and elixirs. While the description is not intended to be limiting, the invention is also not intended to pertain to true solutions of atorvastatin hemi-calcium whereupon the properties that distinguish the solid forms of atorvastatin hemi-calcium are lost. However, the use of the novel forms to prepare such solutions (e.g. so as to deliver, in addition to atorvastatin, a solvate to said solution in a certain ratio with a solvate) is considered to be within the contemplation of the invention.
  • Capsule dosages will contain the solid composition within a capsule which may be made of gelatin or other conventional encapsulating material.
  • Tablets and powders may be coated. Tablets and powders may be coated with an enteric coating.
  • the enteric coated powder forms may have coatings comprising phthalic acid cellulose acetate, hydroxypropylmethyl-cellulose phthalate, polyvinyl alcohol phthalate, carboxymethylethylcellulose, a copolymer of styrene and maleic acid, a copolymer of methacrylic acid and methyl methacrylate, and like materials, and if desired, they maybe employed with suitable plasticizers and/or extending agents.
  • a coated tablet may have a coating on the surface of the tablet or may be a tablet comprising a powder or granules with an enteric-coating.
  • Preferred unit dosages of the pharmaceutical compositions of this invention typically contain from 0.5 to 100 mg of the novel atorvastatin hemi-calcium Forms DCa, XIN, XNI and XVH or mixtures thereof with each other or other forms of atorvastatin hemi-calcium. More usually, the combined weight of the atorvastatin hemi-calcium forms of a unit dosage are from 2.5 mg. to 80 mg.
  • Example 1 Atorvastatin hemi-calcium salt Form V (5 g) was suspended in a mixture of 1- butanol (90ml) and water (10ml) at reflux temperature (85°C) for 16 hours. The mixture was then cooled to room temperature and then to 0°C using an ice-bath. The product was isolated by filtration and dried at 65°C in a vacuum oven for 24 hours to give 4.73g (95%) of Atorvastatin hemi-calcium crystalline Form DCa.
  • Example 2 Atorvastatin hemi-calcium salt Form V (5 g) was suspended in a mixture of 1- butanol (10ml) and water (90ml) at reflux temperature for 16 hours. The mixture was then cooled to room temperature and then to 0°C using an ice-bath. The product was isolated by filtration and dried at 65°C in a vacuum oven for 24 hours to give atorvastatin hemi- calcium crystalline Form IXa.
  • Example 3 Atorvastatin hemi-calcium Form V (1 g) was introduced into a 500 ml beaker. Water (240 ml) was added. The suspension was mixed for 5 hours. A fine suspension appeared. It was left standing undisturbed for three days. After three days white flakes formed in the suspension. The suspension was then filtered and analyzed by XRD as is.
  • Example 4 A small aliquot of form XIV was exposed to the air at room temperature for three hours, and then analyzed by XRD. The resulting form is Form XVI.
  • Example 6 About 20 kg of Atorvastatin hemi-calcium Form V was added to a hot solution (about 70°C) of ethanol (about 600 liters). The resulting quantity of water in ethanol should be about 4%> , and it is adjusted according to the initial moisture level of Form V.
  • the mixture was refluxed for about 2.5 hours.
  • the mixture was cooled to 15-20°C and stirred at this temperature for at least 3 hours.
  • the solid was filtered, washed with 96%> ethanol.
  • the material was then analyzed by powder X-Ray diffraction and found to contain form XVH. Conventional drying at 40-70 °C produced atorvastatin hemi-calcium
  • Example 7 Atorvastatin hemi-calcium salt Form V (1 g) in 1-BuOH (10ml) and EtOH (10ml) was heated to reflux for 1 h. The mixture was then cooled to room temperature and stirred at this temperature for additional 16 hrs. Filtration and drying at 65 °C for 24 hrs gave 0.98g (98%) of atorvastatin hemi-calcium Form DC.
  • Example 8 Atorvastatin hemi-calcium salt Form V (5 g) was suspended in a mixture of 1- butanol (50ml) and Acetone (50ml) at reflux temperature (71°C) for 17 hours. The mixture was then cooled to room temperature and then to 0°C using an ice-bath. The product was isolated by filtration and dried at 65°C in a vacuum oven for 24 hours to give 4.6g (93%) of Atorvastatin hemi-calcium salt Form DC.
  • Atorvastatin hemi-calcium salt Form V (5 g) was suspended in a mixture of 1- butanol (50ml) and IPA (50ml) at reflux temperature (91.5°C) for 15 hours. The mixture was then cooled to room temperature and then to 0°C using an ice-bath. The product was isolated by filtration and dried at 65°C in a vacuum oven for 24 hours to give 4.7g (94%) of Atorvastatin hemi-calcium salt Form IX.
  • Example 10 Atorvastatin hemi-calcium salt Form V (5 g) was suspended in a mixture of 1- butanol (50ml) and THF (50ml) at reflux temperature (80°C) for 15 hours. The mixture was then cooled to room temperature and then to 0°C using an ice-bath. The product was isolated by filtration and dried at 65°C in a vacuum oven for 24 hours to give 2.4g (48%) of Atorvastatin hemi-calcium salt Form DC.
  • Example 11 Atorvastatin hemi-calcium salt Form V (5 g) was suspended in a mixture of 1- butanol (50ml) and 1-propanol (50ml) at reflux temperature (95°C) for 16 hours. The mixture was then cooled to room temperature and then to 0°C using an ice-bath. The product was isolated by filtration and dried at 65°C in a vacuum oven for 24 hours to give 4.8g (96%o) of Atorvastatin hemi-calcium salt Form DC.
  • Example 12 Atorvastatin hemi-calcium salt Form V (5 g) was suspended in a mixture of 1- butanol (50ml) and MTBE (50ml) at reflux temperature (73°C) for 16 hours. The mixture was then cooled to room temperature and then to 0°C using an ice-bath. The product was isolated by filtration and dried at 65°C in a vacuum oven for 24 hours to give 4.8g (97%) of Atorvastatin hemi-calcium salt Form DC.

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Abstract

La présente invention concerne de nouvelles formes d'atorvastatine, appelées formes IXa, XIV, XVI et XVII, et leurs procédés de préparation, ainsi que des procédés de préparation des formes I, XIII et IX d'hémi-calcium d'atorvastatine.
PCT/US2003/005384 2002-02-15 2003-02-19 Nouvelles formes cristallines d'hemi-calcium d'atorvastatine WO2003070702A1 (fr)

Priority Applications (10)

Application Number Priority Date Filing Date Title
CA002475864A CA2475864A1 (fr) 2002-02-15 2003-02-19 Nouvelles formes cristallines d'hemi-calcium d'atorvastatine
AU2003217653A AU2003217653A1 (en) 2002-02-15 2003-02-19 Novel crystal forms of atorvastatin hemi-calcium and processes for their preparation, as well as novel processes for preparing atorvastatin hemi-calcium forms i, viii and ix
DE03713610T DE03713610T1 (de) 2002-02-15 2003-02-19 Neue kristallformen von atorvastatin-hemicalcium und verfahren zu deren herstellung, sowie neue verfahren zur herstellung der formen i, viii und ix von atorvastatin-hemicalcium
KR1020047012591A KR100724515B1 (ko) 2002-02-15 2003-02-19 아토르바스타틴 헤미칼슘의 신규한 결정형, 이의 제조 방법 및 아토르바스타틴 헤미칼슘 i형, viii형 및 ix형을 제조하는 신규한 방법
JP2003569609A JP2005519076A (ja) 2002-02-15 2003-02-19 アトルバスタチンヘミカルシウムの新規結晶形態およびその調製方法ならびにアトルバスタチンヘミカルシウム形態ｉ、ｖｉｉｉおよびｉｘの新規調製方法
EP03713610A EP1480950A4 (fr) 2002-02-15 2003-02-19 Nouvelles formes cristallines d'hemi-calcium d'atorvastatine et procedes pour leur preparation, ainsi que procedes nouveaux pour la preparation des formes i,viii et ix d'hemi-calcium d'atorvastatine
MXPA04007939A MXPA04007939A (es) 2002-02-15 2003-02-19 Formas cristalinas novedosas de hemi-calcio de atorvastatina y procesos para su preparacion; procesos novedosos para la preparacion de hemi-calcio de atorvastatina en sus formas i, viii i ix.
IS7402A IS7402A (is) 2002-02-15 2004-08-13 Ný kristölluð form atorvastatínhálfkalsíums og aðferðir til að framleiða þau, auk nýrra aðferða tilað framleiða atorvastatínhálfkalsíum form I, VIIIog IX
HR20040768A HRP20040768A2 (en) 2002-02-15 2004-08-25 Novel crystal forms of atorvastatin hemi-calcium and processes for their preparation, as well as novel processes for preparing atorvastatin hemi-calcium forms i, viii and ix
NO20043842A NO20043842L (no) 2002-02-15 2004-09-14 Nye krystallformer av atorvastatinhemikalsium og fremgangsmater for fremstilling derav, savel som nye fremgangsmater for fremstilling av atorvastatinhemikalsiumform I, VIII og IX

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US60/357,181 2002-02-15
US42532502P 2002-11-12 2002-11-12
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CA (1) CA2475864A1 (fr)
DE (1) DE03713610T1 (fr)
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Cited By (18)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2004043918A2 (fr) * 2002-11-12 2004-05-27 Teva Pharmaceutical Industries Ltd. Nouvelles formes cristallines d'atorvastatine hemi-calcium et leurs procedes de preparation ainsi que de nouveaux procedes de preparation d'autres formes
WO2004050618A2 (fr) * 2002-11-28 2004-06-17 Teva Pharmaceutical Industries Ltd. Forme cristalline
WO2004110409A1 (fr) 2003-06-12 2004-12-23 Warner-Lambert Company Llc Compositions pharmaceutiques d'atorvastatine
US6992194B2 (en) 2000-11-30 2006-01-31 Teva Pharmaceutical Industries, Ltd. Crystal forms of atorvastatin hemi-calcium and processes for their preparation as well as novel processes for preparing other forms
WO2006012499A2 (fr) * 2004-07-22 2006-02-02 Teva Pharmaceutical Industries Ltd. Nouvelles formes cristallines d'hemi-calcium d'atorvastatine et leurs procedes de preparation
WO2006011041A2 (fr) * 2004-07-20 2006-02-02 Warner-Lambert Company Llc Nouvelles formes de [r-(r*,r*)]-2-(4-fluorophenyl)-bet a, gamma-dihydroxy-5-(1-methylethyl)-3-phenyl-4-[(phenylamino)carbonyl]-1h-pyrrole-1-hept acide anoique sel de calcium (2:1)
WO2006048894A1 (fr) * 2004-11-05 2006-05-11 Morepen Laboratories Limited Nouvelles formes cristallines de calcium d'atorvastatine et procedes de fabrication
US7122681B2 (en) 2002-02-19 2006-10-17 Teva Pharmaceutical Industries, Ltd. Desolvation process for the production of atorvastatin hemi-calcium essentially free of bound organic solvent
WO2007057755A1 (fr) 2005-11-21 2007-05-24 Warner-Lambert Company Llc Nouvelles formes d’acide [r-(r*,r*)]-2-(4-fluorophenyl)-b,b-dihydroxy-5-(1-methylethyl)-3-phenyl-4-[(phenylamino)carbonyl]-1h-pyrrole-1-heptanoique magnesium
WO2007070667A2 (fr) * 2005-12-13 2007-06-21 Teva Pharmaceutical Industries Ltd. Forme cristalline d’hemi-calcium d’atorvastatine et procedes de fabrication de celle-ci
US7411075B1 (en) 2000-11-16 2008-08-12 Teva Pharmaceutical Industries Ltd. Polymorphic form of atorvastatin calcium
JP2008534669A (ja) * 2005-04-08 2008-08-28 エギシュ ヂョヂセルヂャール ニルヴァーノサン ミケデ レースヴェーニタールササーグ 新規な結晶性のアトルバスタチンヘミカルシウム塩の多形相
WO2008108572A1 (fr) * 2007-03-02 2008-09-12 Dong-A Pharm. Co., Ltd. Nouvelles formes cristallines de dérivés d'acide pyrrolylheptanoïque
US7655692B2 (en) 2003-06-12 2010-02-02 Pfizer Inc. Process for forming amorphous atorvastatin
EP2420488A1 (fr) 2010-07-28 2012-02-22 Kyongbo pharmaceutical, Co., Ltd Nouvelle formule cristalline de sel hémicalcium atorvastanine, hydrate associé et son procédé de production
CN105055357A (zh) * 2015-09-25 2015-11-18 青岛华之草医药科技有限公司 一种治疗高胆固醇血症的药物阿托伐他汀钙组合物片剂
KR20170024602A (ko) * 2017-02-24 2017-03-07 주식회사 경보제약 아토바스타틴 헤미칼슘염의 신규한 결정형, 이의 수화물, 및 그의 제조방법
US11065237B2 (en) 2013-11-15 2021-07-20 Akebia Therapeutics, Inc. Solid forms of {[5-(3-chlorophenyl)-3-hydroxypyridine-2-carbonyl]amino}acetic acid, compositions, and uses thereof

Families Citing this family (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20070265456A1 (en) * 2006-05-09 2007-11-15 Judith Aronhime Novel crystal forms of atorvastatin hemi-calcium and processes for their preparation as well as novel processes for preparing other forms
KR101324862B1 (ko) * 2011-07-12 2013-11-01 (주)에이에스텍 클로피도그렐 황산수소염의 구형 입자, 이를 포함하는 약학적 조성물 및 이의 제조방법

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6087511A (en) * 1996-07-16 2000-07-11 Warner-Lambert Company Process for the production of amorphous [R-(R*,R*)]-2-(4-fluorophenyl)-β,δ-dihydroxy-5-(1-methylethyl )-3-phenyl-4-[(phenylamino)carbonyl]-1H-pyrrole-1-heptanoic acid) calcium salt (2:1)

Family Cites Families (14)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
ATE284868T1 (de) * 1995-07-17 2005-01-15 Warner Lambert Co Kristaline (r-(r*,r*))-2-(4-fluorphenyl)-beta, delta-dihydroxy-5-(1-methylethyl)-3-phenyl-4- ((phenylamino)carbonyl)-1h-pyrrol-1- heptancarbonsäure hemi calcium sslz (atorvastatin)
HRP960313B1 (en) * 1995-07-17 2002-08-31 Warner Lambert Co Form iii crystalline (r- (r*, r*)-2- (4-fluorophenyl) -beta-delta-hydroxy-5-(1-methylethyl) -3-phenyl-4- ((phenylamino) carbonyl -1h-pyrrole-1-heptanoic acid calcium salt (2:1)
PT1535613E (pt) * 1999-11-17 2010-10-04 Teva Pharma Processo de preparação de uma forma polimórfica de atorvastatina de cálcio
ATE320415T1 (de) * 1999-12-17 2006-04-15 Pfizer Science & Tech Ltd Verfahren zur herstellung von kristallin atorvastin kalcium
HUP0203708A3 (en) * 1999-12-17 2003-11-28 Warner Lambert Res & Dev Ie A factory scale process for producing crystalline atorvastatin trihydrate hemi calcium salt
CA2426632C (fr) * 2000-11-03 2008-08-05 Teva Pharmaceutical Industries, Ltd. Atorvastatine hemicalcique forme vii
IL156055A0 (en) * 2000-11-30 2003-12-23 Teva Pharma Novel crystal forms of atorvastatin hemi calcium and processes for their preparation as well as novel processes for preparing other forms
MXPA03005879A (es) * 2000-12-27 2003-09-10 Ciba Sc Holding Ag Formas cristalinas de atorvastatina.
WO2002057229A1 (fr) * 2001-01-19 2002-07-25 Biocon India Limited FORME V CRISTALLINE DE SEL HEMICALCIQUE D'ACIDE [R-(R*,R*)]-2-(4-FLUOROPHENYL)-ß,$G(D)-DIHYDROXY-5-(1-METHYLETHYL)-3-PHENYL-4-[(PHENYLAMINO)CARBONYL]-1H-PYRROLE-1-HEPTANOIQUE (ATORVASTATINE)
CA2450111C (fr) * 2001-06-29 2006-02-07 Warner-Lambert Company Llc Formes cristallines de sel hemicalcique d'acide [r-(r*,r*)]-2-(4-fluorophenyl)-beta,delta-dihydroxy-5-(1-methylethyl)-3-phenyl-4-[(phenylamino)carbonyl]-1h-pyrrole-1-heptanoique (2:1)(atorvastatine)
WO2003011826A1 (fr) * 2001-07-30 2003-02-13 Dr. Reddy's Laboratories Ltd. Formes cristallines vi et vii de calcium d'atorvastatine
UA77990C2 (en) * 2001-12-12 2007-02-15 Crystalline calcium salt of (2:1) [r-(r*,r*)]-2-(4-fluorophenyl)-?,?-dihydroxy-5-(1-methylethyl)-3-phenyl-4-[(phenylamino)carbonyl]-1h-pyrroleheptanic acid
JP2006503024A (ja) * 2002-09-03 2006-01-26 モレペン、ラボラトリーズ、リミテッド Ｖｉ型アトルバスタチンカルシウムまたはその水和物
AU2003297594A1 (en) * 2002-11-28 2004-06-23 Teva Pharmaceutical Industries Ltd. Crystalline form f of atorvastatin hemi-calcium salt

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6087511A (en) * 1996-07-16 2000-07-11 Warner-Lambert Company Process for the production of amorphous [R-(R*,R*)]-2-(4-fluorophenyl)-β,δ-dihydroxy-5-(1-methylethyl )-3-phenyl-4-[(phenylamino)carbonyl]-1H-pyrrole-1-heptanoic acid) calcium salt (2:1)

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See also references of EP1480950A4 *

Cited By (46)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7732623B2 (en) 1999-11-17 2010-06-08 Teva Pharmaceutical Industries Ltd. Polymorphic form of atorvastatin calcium
US7411075B1 (en) 2000-11-16 2008-08-12 Teva Pharmaceutical Industries Ltd. Polymorphic form of atorvastatin calcium
US7468444B2 (en) 2000-11-30 2008-12-23 Teva Pharmaceutical Industries Ltd. Crystal forms of atorvastatin hemi-calcium and processes for their preparation as well as novel processes for preparing other forms
US7151183B2 (en) 2000-11-30 2006-12-19 Teva Pharmaceutical Industries Ltd. Processes for preparing amorphous atorvastatin hemi-calcium
US7342120B2 (en) 2000-11-30 2008-03-11 Teva Pharmaceutical Industries, Ltd. Crystal forms of atorvastatin hemi-calcium and processes for their preparation as well as novel processes for preparing other forms
US6992194B2 (en) 2000-11-30 2006-01-31 Teva Pharmaceutical Industries, Ltd. Crystal forms of atorvastatin hemi-calcium and processes for their preparation as well as novel processes for preparing other forms
US7256212B2 (en) 2000-11-30 2007-08-14 Teva Pharmaceutical Industries Ltd. Crystal forms of atorvastatin hemi-calcium and processes for their preparation as well as novel processes for preparing other forms
US7456297B2 (en) 2000-11-30 2008-11-25 Teva Pharmaceutical Industries Ltd. Crystal forms of atorvastatin hemi-calcium and processes for their preparation as well as novel processes for preparing other forms
US7501450B2 (en) 2000-11-30 2009-03-10 Teva Pharaceutical Industries Ltd. Crystal forms of atorvastatin hemi-calcium and processes for their preparation as well as novel processes for preparing other forms
US7488750B2 (en) 2000-11-30 2009-02-10 Teva Pharmaceutical Industries Ltd. Crystal forms of atorvastatin hemi-calcium and processes for their preparation as well as novel processes for preparing other forms
US7189861B2 (en) 2000-11-30 2007-03-13 Teva Pharmaceutical Industries, Ltd. Processes for preparing amorphous atorvastatin hemi-calcium
US7161012B2 (en) 2000-11-30 2007-01-09 Teva Pharmaceutical Industries Ltd. Processes for preparing amorphous atorvastatin hemi-calcium
US7144916B2 (en) 2000-11-30 2006-12-05 Teva Pharmaceutical Industries Ltd. Crystal forms of atorvastatin hemi-calcium and processes for their preparation as well as novel processes for preparing other forms
US7122681B2 (en) 2002-02-19 2006-10-17 Teva Pharmaceutical Industries, Ltd. Desolvation process for the production of atorvastatin hemi-calcium essentially free of bound organic solvent
WO2004043918A2 (fr) * 2002-11-12 2004-05-27 Teva Pharmaceutical Industries Ltd. Nouvelles formes cristallines d'atorvastatine hemi-calcium et leurs procedes de preparation ainsi que de nouveaux procedes de preparation d'autres formes
WO2004043918A3 (fr) * 2002-11-12 2004-07-15 Teva Pharma Nouvelles formes cristallines d'atorvastatine hemi-calcium et leurs procedes de preparation ainsi que de nouveaux procedes de preparation d'autres formes
WO2004050618A3 (fr) * 2002-11-28 2004-07-15 Teva Pharma Forme cristalline
WO2004050618A2 (fr) * 2002-11-28 2004-06-17 Teva Pharmaceutical Industries Ltd. Forme cristalline
US7655692B2 (en) 2003-06-12 2010-02-02 Pfizer Inc. Process for forming amorphous atorvastatin
EP1977738A1 (fr) 2003-06-12 2008-10-08 Warner-Lambert Company LLC Compositions pharmaceutiques d'atorvastatine, qui sont produites sans procédé de granulation
WO2004110409A1 (fr) 2003-06-12 2004-12-23 Warner-Lambert Company Llc Compositions pharmaceutiques d'atorvastatine
US9790177B2 (en) 2004-07-20 2017-10-17 Warner-Lambert Company Llc Forms of [R-(R*,R*)]-2-(4-fluorophenyl)-beta, gamma-dihydroxy-5-(1-methylethyl)-3-phenyl-4-[(phenylamino)carbonyl]-1H-pyrrole-1-heptanoic acid calcium salt (2:1)
US9199932B2 (en) 2004-07-20 2015-12-01 Warner-Lambert Company Llc Forms of [R-(R*,R*)]-2-(4-fluorophenyl)-β,δ-dihydroxy-5-(1-methylethyl)-3-phenyl-4-[(phenylamino)carbonyl]-1H-pyrrole-1-heptanoic acid calcium salt (2:1)
US8895758B2 (en) 2004-07-20 2014-11-25 Warner-Lambert Company Llc Forms of [R-(R*,R*)]-2-(4-fluorophenyl)-β, δ-Dihydroxy-5-(1-methylethyl)-3-phenyl-4-[(phenylamino)carbonyl]-1H-pyrrole-1-heptanoic acid calcium salt (2:1)
US9481647B2 (en) 2004-07-20 2016-11-01 Warner-Lambert Company Llc Forms of [R-(R*,R*)]-2-(4-fluorophenyl)-β, δ-dihydroxy-5-(1-methylethyl)-3-Phenyl-4-[(phenylamino)carbonyl]-1H-pyrrole-1-heptanoic acid calcium salt (2:1)
US8026376B2 (en) 2004-07-20 2011-09-27 Pfizer, Inc. Forms of [R-(R*,R*)]-2-(4-fluorophenyl)-β,δ-dihydroxy-5-(1-methylethyl)-3-phenyl-4-[(phenylamino)carbonyl]-1H-pyrrole-1-heptanoicacid calcium salt (2:1)
WO2006011041A3 (fr) * 2004-07-20 2006-06-22 Warner Lambert Co Nouvelles formes de [r-(r*,r*)]-2-(4-fluorophenyl)-bet a, gamma-dihydroxy-5-(1-methylethyl)-3-phenyl-4-[(phenylamino)carbonyl]-1h-pyrrole-1-hept acide anoique sel de calcium (2:1)
WO2006011041A2 (fr) * 2004-07-20 2006-02-02 Warner-Lambert Company Llc Nouvelles formes de [r-(r*,r*)]-2-(4-fluorophenyl)-bet a, gamma-dihydroxy-5-(1-methylethyl)-3-phenyl-4-[(phenylamino)carbonyl]-1h-pyrrole-1-hept acide anoique sel de calcium (2:1)
US8563750B2 (en) 2004-07-20 2013-10-22 Warner-Lambert Company Llc Forms of [R-(R*,R*)]-2-(4-fluorophenyl)-β,δ-dihydroxy-5-(1-methylethyl)-3-phenyl-4-[(phenylmino)carbonyl]-1H-pyrrole-1-heptanoic acid calcium salt (2:1)
WO2006012499A3 (fr) * 2004-07-22 2006-07-20 Teva Pharma Nouvelles formes cristallines d'hemi-calcium d'atorvastatine et leurs procedes de preparation
WO2006012499A2 (fr) * 2004-07-22 2006-02-02 Teva Pharmaceutical Industries Ltd. Nouvelles formes cristallines d'hemi-calcium d'atorvastatine et leurs procedes de preparation
WO2006048894A1 (fr) * 2004-11-05 2006-05-11 Morepen Laboratories Limited Nouvelles formes cristallines de calcium d'atorvastatine et procedes de fabrication
JP2008534669A (ja) * 2005-04-08 2008-08-28 エギシュ ヂョヂセルヂャール ニルヴァーノサン ミケデ レースヴェーニタールササーグ 新規な結晶性のアトルバスタチンヘミカルシウム塩の多形相
WO2007057755A1 (fr) 2005-11-21 2007-05-24 Warner-Lambert Company Llc Nouvelles formes d’acide [r-(r*,r*)]-2-(4-fluorophenyl)-b,b-dihydroxy-5-(1-methylethyl)-3-phenyl-4-[(phenylamino)carbonyl]-1h-pyrrole-1-heptanoique magnesium
WO2007070667A2 (fr) * 2005-12-13 2007-06-21 Teva Pharmaceutical Industries Ltd. Forme cristalline d’hemi-calcium d’atorvastatine et procedes de fabrication de celle-ci
WO2007070667A3 (fr) * 2005-12-13 2007-08-02 Teva Pharma Forme cristalline d’hemi-calcium d’atorvastatine et procedes de fabrication de celle-ci
US8080672B2 (en) 2005-12-13 2011-12-20 Teva Pharmaceutical Industries Ltd. Crystal form of atorvastatin hemi-calcium and processes for preparation thereof
KR101012917B1 (ko) 2007-03-02 2011-02-08 동아제약주식회사 피롤 헵탄산 화합물의 신규한 결정형
WO2008108572A1 (fr) * 2007-03-02 2008-09-12 Dong-A Pharm. Co., Ltd. Nouvelles formes cristallines de dérivés d'acide pyrrolylheptanoïque
EP2420488A1 (fr) 2010-07-28 2012-02-22 Kyongbo pharmaceutical, Co., Ltd Nouvelle formule cristalline de sel hémicalcium atorvastanine, hydrate associé et son procédé de production
US10252993B2 (en) 2010-07-28 2019-04-09 Kyongbo Pharm Crystalline form of atorvastatin hemi-calcium salt, hydrate thereof, and method of producing the same
US11065237B2 (en) 2013-11-15 2021-07-20 Akebia Therapeutics, Inc. Solid forms of {[5-(3-chlorophenyl)-3-hydroxypyridine-2-carbonyl]amino}acetic acid, compositions, and uses thereof
US11690836B2 (en) 2013-11-15 2023-07-04 Akebia Therapeutics, Inc. Solid forms of {[5-(3-chlorophenyl)-3-hydroxypyridine-2-carbonyl]amino}acetic acid, compositions, and uses thereof
CN105055357A (zh) * 2015-09-25 2015-11-18 青岛华之草医药科技有限公司 一种治疗高胆固醇血症的药物阿托伐他汀钙组合物片剂
KR20170024602A (ko) * 2017-02-24 2017-03-07 주식회사 경보제약 아토바스타틴 헤미칼슘염의 신규한 결정형, 이의 수화물, 및 그의 제조방법
KR101723783B1 (ko) 2017-02-24 2017-04-07 주식회사 경보제약 아토바스타틴 헤미칼슘염의 신규한 결정형, 이의 수화물, 및 그의 제조방법

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CA2475864A1 (fr) 2003-08-28
ES2241507T1 (es) 2005-11-01
JP2005519076A (ja) 2005-06-30
PL372303A1 (en) 2005-07-11
DE03713610T1 (de) 2005-10-20
NO20043842L (no) 2004-09-14
CN1646490A (zh) 2005-07-27
HRP20040768A2 (en) 2005-06-30
MXPA04007939A (es) 2004-11-26
KR100724515B1 (ko) 2007-06-04
EP1480950A4 (fr) 2005-05-18
CN100406436C (zh) 2008-07-30
IS7402A (is) 2004-08-13

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