EP1572643A2 - Forme cristalline du sel hemi calcique de l'atorvastatine - Google Patents

Forme cristalline du sel hemi calcique de l'atorvastatine

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Publication number
EP1572643A2
EP1572643A2 EP03812471A EP03812471A EP1572643A2 EP 1572643 A2 EP1572643 A2 EP 1572643A2 EP 03812471 A EP03812471 A EP 03812471A EP 03812471 A EP03812471 A EP 03812471A EP 1572643 A2 EP1572643 A2 EP 1572643A2
Authority
EP
European Patent Office
Prior art keywords
phenylamino
fluorophenyl
dihydroxy
delta
beta
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.)
Withdrawn
Application number
EP03812471A
Other languages
German (de)
English (en)
Inventor
Fritz Blatter
Martin Szelagiewicz
Paul Adriaan Van Der Schaaf
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.)
Teva Pharmaceutical Industries Ltd
Original Assignee
Teva Pharmaceutical Industries 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
Priority claimed from EP02406037A external-priority patent/EP1424324A1/fr
Application filed by Teva Pharmaceutical Industries Ltd filed Critical Teva Pharmaceutical Industries Ltd
Priority to EP03812471A priority Critical patent/EP1572643A2/fr
Publication of EP1572643A2 publication Critical patent/EP1572643A2/fr
Withdrawn legal-status Critical Current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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/06—Antihyperlipidemics

Definitions

  • the present invention is directed to a crystalline form of Atorvastatin calcium, processes for the preparation thereof and pharmaceutical compositions comprising this crystalline form.
  • Atorvastatin calcium is known by the chemical name, [R-(R * ,R * )J-2-(4-fluorophenyl)-beta,delta-dihydroxy- 5-(1 -methylethyl)-3-phenyl-4-[(phenylamino)carbonyl]-1 H-pyrroIe-1 -heptanoic acid calcium salt (2:1).
  • Atorvastatin has the following formula:
  • Atorvastatin calcium is an orally-active hypocholesterolaemic, a liver-selective HMG-CoA reductase inhibitor.
  • Processes for the preparation of Atorvastatin calcium are described in US-A-5,273,995, US-A-5,298,627, US-A-6,087,511 , US-A-6,274,740, WO-A-97/03960, WO- A-02/059087, WO-A-02/072073, and in the publications by P.L. Brower et al. in Tetrahedron Letters (1992), vol. 33, pages 2279-2282, K.L. Baumann et al. in Tetrahedron Letters (1992), vol. 33, pages 2283-2284 and A. Graul et al. in Drugs of the Future (1997), vol. 22, pages 956-968.
  • This calcium salt (2:1) is desirable since it enables Atorvastatin calcium to be conveniently formulated.
  • the processes in the above mentioned patents and publications result in the preparation of amorphous Atorvastatin calcium.
  • Atorvastatin calcium in a reproducible, pure and crystalline form to enable formulations to meet exacting pharmaceutical requirements and specifications. Furthermore, it is economically desirable that the product is stable for extended periods of time without the need for specialized storage conditions.
  • Atorvastatin calcium salt (2:1) herein designated as Form F.
  • This novel form of the present invention can be prepared in ecological friendly solvents and has a good thermal stability combined with good solubility characteristics.
  • the present invention is directed to the polymorphic Form F of Atorvastatin calcium salt (2:1 ).
  • the crystalline polymorph F exhibits a characteristic X-ray powder diffraction pattern with characteristic peaks expressed in d-values (A) at
  • Table 1 d-spacings and 2 ⁇ angles for Form F.
  • the polymorphic Form F of Atorvastatin calcium is especially characterized by a powder X- ray diffraction pattern substantially as depicted in Figure 1.
  • the crystalline polymorph F exhibits a characteristic 13 C CP-MAS solid state NMR spectrum with chemical shifts (in parts per million, with peak intensity in arbitrary units in brackets) at 188.2 (2.5), 184.3 (2.2), 177.4 (2.8), 167.5 (2.9), 162.6 (2.4), 161.0 (3.9), 139.8 (6.5), 138.2 (4.3), 135.8 (5.1), 134.1 (4.0), 132.0 (8.4), 131.2 (7.3), 130.5 (14.0), 129.0 (9.5), 128.0 (6.6), 127.2 (4.6), 125.5 (2.9), 124.0 (4.9), 123.5 (4.7), 122.8 (4.8), 122.1 (6.2), 120.7 (5.4), 117.6 (4.1), 116.6 (4.1), 115.2 (3.6), 112.8 (1.6), 72.9 (4.8), 71.7 (5.2), 69.4 (6.5), 67.1 (4.9), 63.2 (0.7), 46.3 (10.4), 44.1 (12.6), 40.6 (7.6), 36.4 (0.7), 32.1 (3.8), 31.1 (1.3), 28.2 (5.3
  • the polymorphic Form F of Atorvastatin calcium is especially characterized by a 13 C CP- MAS solid state NMR spectrum as depicted in Figure 2. Furthermore, the present invention is directed to processes for the preparation of Form F of Atorvastatin calcium.
  • Form F can generally be prepared by adding Form A to a ketone solvent, especially acetone. It is preferred that the ketone solvent contains as a further solvent some water. The amount of water is preferably about 1 to 30%, more preferably about 5 to 20%, especially about 10 to 20% by volume of the suspension. It is preferred that the suspension is treated at temperatures between 10 and 60°C, preferably at temperatures of 20 to 40°C, especially for a longer periods of time, like 10 to 40 hours. It is further preferred that nucleation of Form F is induced at a temperature of 40 to 60°C, especially at about 60°C, and subsequent ripening and equilibration is performed at temperatures between 20 and 40°C. If desired, during the preparation process seeding with Form F can be carried out.
  • Form F can, for example, be isolated by filtration and dried in air or in vacuum.
  • the above mentioned process can also be carried out using another crystalline form or the amorphous form of atorvastatin calcium.
  • Examples of other crystalline forms are Forms I, II, III, IV, V, VI, VII, VIII, IX, X, XI, XII, A, B1 , B2, C, D and E, which are disclosed and characterized in the references given hereinbefore.
  • Preferred forms for this purpose are Form A (see for example WO-A-02/051804; last but one paragraph of page 2; page 4, last but one paragraph to page 5, first paragraph; Examples 2, 8 and 9; Fig.
  • Form B1 see for example WO-A-02/051804; the paragraph bridging pages 2 and 3; page 5, second paragraph; Example 3; and Fig. 3).
  • Form B2 see for example WO-A-02/051804; page 3, second paragraph; page 5, third paragraph; Example 4; and Fig. 3.
  • Form F can also be prepared from Atorvastatin lactone upon subsequent reaction with NaOH to form Atorvastatin sodium followed by reaction with CaCI 2 in a ketone solvent, especially in acetone. It is preferred that the ketone solvent contains as a further solvent some water. The amount of water is preferably about 1 to 30%. If desired, during the preparation process seeding with Form F can be carried out.
  • Form F can also be prepared directly from Atorvastatin lactone upon reaction with a calcium(ll) salt, like Ca(OH) 2 or Ca(OAc) 2 , in a ketone solvent, especially in acetone. It is preferred that the ketone solution contains as a further solvent some water. The amount of water is preferably about 1 to 30%. If desired, during the preparation process seeding with Form F can be carried out.
  • Form F can also be prepared by adding a concentrated solution of Atorvastatin calcium in an organic solvent, like tetrahydrofuran, to a ketone solvent, especially acetone. It is preferred that the ketone solution contains as a further solvent some water. The amount of water is preferably about 1 to 30%. If desired, during the preparation process seeding with Form F can be carried out.
  • ketone solvent of the preparation processes given above it is preferred to use C 3 - C 8 ketones, especially acetone.
  • Another object of the present invention are crystalline forms of atorvastatin calcium which are essentially free of residual organic solvent.
  • Preferred are Forms I to XII and A, B1 , B2, C, D, E and F which are essentially free of residual organic solvent.
  • Highly preferred are Forms B1 , B2 and F, especially Form F.
  • Forms I to XII and A, B1 , B2, C, D, E are disclosed in the references given above.
  • the following preparations of forms which are essentially free of residual organic solvents can be applied to any form of Atorvastatin calcium. It is preferred that the crystalline forms contain less than 0.5% by weight of residual organic solvent. Highly preferred are amounts of residual organic solvents of less than 5000 ppm, especially less than 2000 ppm.
  • residual organic solvents of less than 400 ppm, especially less than 200 ppm.
  • residual organic solvents are aceton, ethylacetate, tetrahydrofuran, ethanol, methanol, acetonitrile and hexane.
  • the crystalline polymorph F of [R-(R*,R*)]-2-(4-fluorophenyl)-beta,delta- dihydroxy-5-(1 -methylethyl)-3-phenyl-4-[(phenylamino)carbonyl]-1 H-pyrrole-1 -heptanoic acid calcium salt (2:1) which is essentially free of residual organic solvents exhibits a characteristic X-ray powder diffraction pattern with characteristic peaks expressed in d- values (A) at 31.9 (w), 24.3 (s), 16.3 (w), 13.1 (vw), 12.1 (w), 11.4 (m), 10.2 (s), 8.7 (s), 8.1 (vw), 7.1 (w), 6.9 (w), 6.5 (m), 5.98 (vw), 5.60 (vw), 5.21 (m), 5.00 (m), 4.80 (m), 4.56 (vs), 4.32 (w), 4.23 (m), 4.00 (m), 3.72 (m), 3.48 (m); wherein
  • the crystalline polymorph F of [R-(R * ,R * )]-2-(4-fluorophenyl)-beta,delta-dihydroxy-5-(1- methylethyl)-3-phenyl-4-[(phenylamino)carbonyl]-1 H-pyrrole-1 -heptanoic acid calcium salt (2:1) which is essentially free of residual organic solvents is especially characterized by an X-ray powder diffraction pattern substantially as depicted in figure 3.
  • the crystalline polymorphs F have a water content of up to 5% by weight (independently whether the polymorphs are essentially free of residual organic solvents or not).
  • Another object of the present invention are processes for the preparation of crystalline forms of atorvastatin calcium which are essentially free of residual organic solvent.
  • Preferred are processes for the preparation of Forms I to XII and A, B1 , B2, C, D, E and F which are essentially free of residual organic solvent.
  • Highly preferred are processes for the preparation of Forms B1 , B2 and F, especially Form F, which are essentially free of residual organic solvent.
  • Forms I to XII and A, B1 , B2, C, D, E are disclosed in the references given above. The following preparations of forms which are essentially free of residual organic solvents can be applied to any form of Atorvastatin calcium.
  • the present invention is related to processes for the preparation of crystalline forms of atorvastatin calcium essentially free of residual organic solvent by exposing the crystalline form of atorvastatin calcium to an atmosphere with a defined relative air humidity.
  • a corresponding process for the preparation of Form F is preferred.
  • atorvastatin calcium essentially free of residual organic solvent can be prepared by exposure to an inert gas flow with a defined relative air humidity (to exchange residual organic solvent with water).
  • a corresponding process for the preparation of Form F is preferred.
  • Form F can be generally prepared essentially free of residual organic solvent by storage of this form in an atmosphere with a relative air humidity of 5 to 100%, preferably 40 to 80%, or by treating this form with a gas stream with a relative air humidity of 5 to 100%, preferably 40 to 80%.
  • compositions comprising an effective amount of crystalline polymorphic Form F, and a pharmaceutically acceptable carrier.
  • the polymorphic Form F may be used as single component or as mixtures with other polymorphic forms or the amorphous form of atorvastatin calcium.
  • Atorvastatin calcium it is preferred that it contains 25-100% by weight, especially 50- 100% by weight of the novel form, based on the total amount of Atorvastatin calcium.
  • an amount of the novel polymorphic form of Atorvastatin calcium is 75- 100% by weight, especially 90-100% by weight. Highly preferred is an amount of 95-100% by weight.
  • compositions of the present invention include powders, granulates, aggregates and other solid compositions comprising polymorphic Form F.
  • 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 sorbitol, acrylate polymers and copolymers, as well as pectin, dextrin and gelatin.
  • 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.
  • 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 may be present in the solid compositions 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.
  • oral the most preferred route of the present invention is oral.
  • the 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 calcium whereupon the properties that distinguish the solid form of Atorvastatin calcium are lost. However, the use of the novel form to prepare such solutions 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 may be 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 1 to 100 mg of the novel Atorvastatin calcium form or mixtures with other forms of Atorvastatin calcium (including the amorphous form). More usually, the combined weight of the Atorvastatin calcium forms of a unit dosage are from 5 mg to 80 mg, for example 10, 20 or 40 mg.
  • Atorvastatin calcium Form A 277 mg are added to 11 ml of a mixture of acetone and water (80:20 v/v). This suspension is stirred at ambient temperature for about ten minutes, leading to almost complete dissolution of Form A. When the resulting slightly turbid, opalescent solution is stirred at 40°C for about 14 hours, a white precipitate is formed. This precipitate is separated by filtration and dried at 60°C for 2 hours. Yield: 153 mg (55%). Analysis by powder X-ray diffraction shows that the obtained sample is Atorvastatin calcium Form F as shown in Figure 1. Karl Fischer titration of the sample after X-ray diffraction reveals a water content of 2.0 %.
  • Atorvastatin calcium Form A 303 mg are added to a mixture of 10 ml acetone and 1 ml of water. This mixture is stirred at ambient temperature for about 15 minutes which leads to almost complete dissolution of the solid. The slightly turbid, opalescent solution/suspension is stirred at 40°C for 22 hours. Within this time a thick precipitate is formed. This suspension is thoroughly stirred at 50°C for about 15 minutes, then the mixture is cooled to 20°C while stirring is continued for another 4 hours. Then the suspension is filtrated and dried at 80°C for 3 hours (300 mbar). An X-ray powder diffraction study shows the product to be polymorphic Form F.
  • Atorvastatin calcium Form I 500 mg are suspended in 15 ml of acetone and water mixture (80:20 v/v). This suspension is shortly stirred at 60°C giving a clear solution which becomes immediately turbid. This turbid suspension is stirred for an additional 16 hours at 40°C. The resulting precipitate is filtered, washed with 2 ml of the acetone/water mixture and dried for 1 hour at 50°C/800 mbar. Yield 400 mg (80%). An X-ray powder diffraction study shows the product to be polymorphic Form F.
  • Atorvastatin calcium Form F as obtained in example 4 was placed in a U-shaped glass tube in a oven at 60°C. This glass tube was purged with a nitrogen flow with a relative air humidity of ca. 50% for a period of 16 hours. Analysis by Karl Fischer titration reveals a water content of 2.5%, and analysis by GC-head space chromatography reveals an acetone content of less than 0.05%.
  • Atorvastatin calcium Form F as obtained in example 4 was placed in a desiccator over a saturated NaCI solution at room temperature, i.e. in an atmosphere with a relative air humidity of 75%, for 44 hours.
  • Analysis by Karl Fischer titration reveals a water content of 2.7%
  • analysis by GC-head space chromatography reveals an acetone content of less than 0.05%.
  • Further analysis by X-ray powder diffraction and i3 C CP-MAS solid state NMR spectroscopy shows that the crystal structure of Atorvastatin Form F was essentially retained under the given conditions, see Figures 3 and 4, respectively.
  • the X-ray source is operated at 45 kV and 45 mA. Spectra are recorded at a step size of 0.02° with a counting time of 2.4 seconds per step.
  • the accuracy of the 2 theta values of conventionally recorded powder X-ray diffraction patterns is generally +/- 0.2°.
  • about 40 mg of substance was prepared into circular shaped quartz sample holders of 0.5 mm depth and 10 mm width.
  • the 13 C CP-MAS solid state NMR spectra were recorded on a Bruker Avance-600 NMR spectrometer operating at 600 MHz proton resonance frequency. Samples were filled into 4 mm rotors without further pretreatment. Bruker xwinnmr version 3.1 was used to acquire the spectra. All spectra were recorded with variable-amplitude (linear ramp) cross polarization from the protons and using high-power proton decoupling (100 KHz field strength using the XiX decoupling scheme). The MAS frequency was set to 15 KHz and stabilized to within 5 Hz. 3072 transients with 4096 complex data points each (acquisition time 41 ms) were added.
  • the recycle delay was set to 3 sec leading to a measurement time of about 3 hours.
  • the data analysis was carried out using MATLAB version 6.5.
  • the first 200 complex data points of the acquired signal (FID) were Fourier transformed using a cosine-squared window function and zero filling to 32768 data points leading to an optimized signal-to-noise ratio and spectral resolution.
  • the digital resolution in the frequency domain is 1.53 Hz.
  • the spectra were referenced to an external standard using uniformly 13 C/ 15 N labeled alanine by setting the resonance frequency of the C ⁇ to 51.9 ppm. Under these measurement conditions and above described data evaluation the accuracy of the NMR shifts as presented is +/- 0.05 ppm.
  • Figure 1 is a characteristic X-ray powder diffraction pattern for Form F.
  • Figure 2 is a characteristic 13 C CP-MAS solid state NMR spectrum of Form F.
  • Figure 3 is a characteristic X-ray powder diffraction pattern for Form F essentially free of residual organic solvent.
  • Figure 4 is a characteristic 13 C CP-MAS solid state NMR spectrum of Form F essentially free of residual organic solvent.

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Abstract

La présente invention concerne la forme polymorphe F de calcium d'atorvastatine, des procédés de sa préparation et de compositions pharmaceutiques comportant cette forme cristalline.
EP03812471A 2002-11-28 2003-11-26 Forme cristalline du sel hemi calcique de l'atorvastatine Withdrawn EP1572643A2 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
EP03812471A EP1572643A2 (fr) 2002-11-28 2003-11-26 Forme cristalline du sel hemi calcique de l'atorvastatine

Applications Claiming Priority (6)

Application Number Priority Date Filing Date Title
EP02406037A EP1424324A1 (fr) 2002-11-28 2002-11-28 Forme cristalline F de calcium d'atorvastatine
EP02406037 2002-11-28
EP03405110 2003-02-20
EP03405110 2003-02-20
PCT/US2003/038090 WO2004050618A2 (fr) 2002-11-28 2003-11-26 Forme cristalline
EP03812471A EP1572643A2 (fr) 2002-11-28 2003-11-26 Forme cristalline du sel hemi calcique de l'atorvastatine

Publications (1)

Publication Number Publication Date
EP1572643A2 true EP1572643A2 (fr) 2005-09-14

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Family Applications (1)

Application Number Title Priority Date Filing Date
EP03812471A Withdrawn EP1572643A2 (fr) 2002-11-28 2003-11-26 Forme cristalline du sel hemi calcique de l'atorvastatine

Country Status (4)

Country Link
EP (1) EP1572643A2 (fr)
AU (1) AU2003297594A1 (fr)
CA (1) CA2508871C (fr)
WO (1) WO2004050618A2 (fr)

Families Citing this family (14)

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Publication number Priority date Publication date Assignee Title
US7411075B1 (en) 2000-11-16 2008-08-12 Teva Pharmaceutical Industries Ltd. Polymorphic form of atorvastatin calcium
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
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
PL372303A1 (en) * 2002-02-15 2005-07-11 Teva Pharmaceutical Industries Ltd. 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
JP5000502B2 (ja) * 2004-07-16 2012-08-15 レツク・フアーマシユーテイカルズ・デー・デー アトルバスタチンカルシウムの酸化分解生成物
CA2672554C (fr) 2004-07-20 2012-01-03 Warner-Lambert Company Llc Nouvelles formes de [r-(r*,r*)]-2-(4-fluorophenyl).beta.,.delta.-dihydroxy-5-(isopropyl)-3-phenyl-4-[(phenylamino)carbonyl]-1h-pyrrole-1-heptanoatede calcium (2:1)
DE05774589T1 (de) * 2004-07-22 2007-08-09 Teva Pharmaceutical Industries Ltd. Neue kristallformen von atorvastatin-hemi-calcium und verfahren zu deren herstellung
CN101124230A (zh) * 2004-09-28 2008-02-13 特瓦制药工业有限公司 制备基本无杂质的阿托伐他汀钙形式的方法
WO2006048894A1 (fr) * 2004-11-05 2006-05-11 Morepen Laboratories Limited Nouvelles formes cristallines de calcium d'atorvastatine et procedes de fabrication
BRPI0610344A2 (pt) 2005-12-13 2016-11-29 Teva Pharma forma cristalizada do atorvastatin hemi-calcium, processo para sua preparação, produto famacêutico derivado e seu uso medicinal
WO2008002655A2 (fr) * 2006-06-28 2008-01-03 Teva Pharmaceutical Industries Ltd. Formes cristallines d'atorvastatine
WO2008108572A1 (fr) * 2007-03-02 2008-09-12 Dong-A Pharm. Co., Ltd. Nouvelles formes cristallines de dérivés d'acide pyrrolylheptanoïque
EP2185527A2 (fr) * 2007-07-11 2010-05-19 Actavis Group PTC EHF Nouveau polymorphe d'atorvastatine calcium et son utilisation pour la préparation d'atorvastatine calcium amorphe
TWI665190B (zh) 2013-11-15 2019-07-11 阿克比治療有限公司 ｛［５－（３－氯苯基）－３－羥基吡啶－２－羰基］胺基｝乙酸之固體型式，其組合物及用途

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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

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CA2508871C (fr) 2008-09-09
AU2003297594A1 (en) 2004-06-23
WO2004050618A8 (fr) 2005-07-14
CA2508871A1 (fr) 2004-06-17
WO2004050618A3 (fr) 2004-07-15
AU2003297594A8 (en) 2004-06-23

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