WO1997003959A1 - Crystalline [r-(r*,r*)]-2-(4-fluorophenyl)-beta,delta-dihydroxy-5-(1-methylethyl)-3-phenyl-4-[(phenylamino)carbonyl]-1h-pyrrole-1-heptanoic acid hemi calcium salt (atorvastatin) - Google Patents
Crystalline [r-(r*,r*)]-2-(4-fluorophenyl)-beta,delta-dihydroxy-5-(1-methylethyl)-3-phenyl-4-[(phenylamino)carbonyl]-1h-pyrrole-1-heptanoic acid hemi calcium salt (atorvastatin) Download PDFInfo
- Publication number
- WO1997003959A1 WO1997003959A1 PCT/US1996/011368 US9611368W WO9703959A1 WO 1997003959 A1 WO1997003959 A1 WO 1997003959A1 US 9611368 W US9611368 W US 9611368W WO 9703959 A1 WO9703959 A1 WO 9703959A1
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- WIPO (PCT)
- Prior art keywords
- atorvastatin
- crystalline form
- broad
- process according
- crystalline
- Prior art date
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- XUKUURHRXDUEBC-KAYWLYCHSA-N Atorvastatin Chemical compound C=1C=CC=CC=1C1=C(C=2C=CC(F)=CC=2)N(CC[C@@H](O)C[C@@H](O)CC(O)=O)C(C(C)C)=C1C(=O)NC1=CC=CC=C1 XUKUURHRXDUEBC-KAYWLYCHSA-N 0.000 title claims abstract description 119
- 159000000007 calcium salts Chemical class 0.000 title claims abstract description 14
- XUKUURHRXDUEBC-UHFFFAOYSA-N Atorvastatin Natural products C=1C=CC=CC=1C1=C(C=2C=CC(F)=CC=2)N(CCC(O)CC(O)CC(O)=O)C(C(C)C)=C1C(=O)NC1=CC=CC=C1 XUKUURHRXDUEBC-UHFFFAOYSA-N 0.000 title claims description 117
- 229960005370 atorvastatin Drugs 0.000 title claims description 117
- 238000000034 method Methods 0.000 claims abstract description 35
- 238000002360 preparation method Methods 0.000 claims abstract description 19
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 10
- 238000000634 powder X-ray diffraction Methods 0.000 claims abstract description 9
- 208000035150 Hypercholesterolemia Diseases 0.000 claims abstract 2
- 208000031226 Hyperlipidaemia Diseases 0.000 claims abstract 2
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical group OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 57
- 239000000126 substance Substances 0.000 claims description 21
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 claims description 19
- 239000000203 mixture Substances 0.000 claims description 19
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 19
- 150000001875 compounds Chemical class 0.000 claims description 15
- 238000009987 spinning Methods 0.000 claims description 15
- 238000000655 nuclear magnetic resonance spectrum Methods 0.000 claims description 13
- -1 alkali metal salt Chemical class 0.000 claims description 12
- 238000000227 grinding Methods 0.000 claims description 12
- 150000004677 hydrates Chemical class 0.000 claims description 12
- 239000007864 aqueous solution Substances 0.000 claims description 10
- 125000003118 aryl group Chemical group 0.000 claims description 9
- 125000000325 methylidene group Chemical group [H]C([H])=* 0.000 claims description 9
- 159000000000 sodium salts Chemical class 0.000 claims description 9
- 239000003826 tablet Substances 0.000 claims description 9
- 230000005855 radiation Effects 0.000 claims description 8
- VSGNNIFQASZAOI-UHFFFAOYSA-L calcium acetate Chemical group [Ca+2].CC([O-])=O.CC([O-])=O VSGNNIFQASZAOI-UHFFFAOYSA-L 0.000 claims description 7
- 239000001639 calcium acetate Substances 0.000 claims description 7
- 229960005147 calcium acetate Drugs 0.000 claims description 7
- 235000011092 calcium acetate Nutrition 0.000 claims description 7
- 239000002775 capsule Substances 0.000 claims description 7
- 239000006184 cosolvent Substances 0.000 claims description 7
- 239000003085 diluting agent Substances 0.000 claims description 7
- 239000000843 powder Substances 0.000 claims description 7
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 6
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 6
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 6
- 150000001447 alkali salts Chemical class 0.000 claims description 6
- 239000002552 dosage form Substances 0.000 claims description 6
- 125000001255 4-fluorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1F 0.000 claims description 5
- 239000007937 lozenge Substances 0.000 claims description 5
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 claims description 4
- 239000000829 suppository Substances 0.000 claims description 3
- 241000792859 Enema Species 0.000 claims description 2
- 229910052783 alkali metal Inorganic materials 0.000 claims description 2
- 229910021529 ammonia Inorganic materials 0.000 claims description 2
- 239000007920 enema Substances 0.000 claims description 2
- 229940079360 enema for constipation Drugs 0.000 claims description 2
- 230000014759 maintenance of location Effects 0.000 claims description 2
- 150000004684 trihydrates Chemical class 0.000 claims description 2
- 239000000546 pharmaceutical excipient Substances 0.000 claims 6
- 238000000371 solid-state nuclear magnetic resonance spectroscopy Methods 0.000 abstract description 4
- 239000003795 chemical substances by application Substances 0.000 abstract description 2
- 239000000243 solution Substances 0.000 description 18
- 239000007787 solid Substances 0.000 description 12
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
- 238000001914 filtration Methods 0.000 description 5
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 5
- 239000007788 liquid Substances 0.000 description 5
- 239000002904 solvent Substances 0.000 description 5
- 239000012044 organic layer Substances 0.000 description 4
- 238000001228 spectrum Methods 0.000 description 4
- 239000007858 starting material Substances 0.000 description 4
- OUCSEDFVYPBLLF-KAYWLYCHSA-N 5-(4-fluorophenyl)-1-[2-[(2r,4r)-4-hydroxy-6-oxooxan-2-yl]ethyl]-n,4-diphenyl-2-propan-2-ylpyrrole-3-carboxamide Chemical compound C=1C=CC=CC=1C1=C(C=2C=CC(F)=CC=2)N(CC[C@H]2OC(=O)C[C@H](O)C2)C(C(C)C)=C1C(=O)NC1=CC=CC=C1 OUCSEDFVYPBLLF-KAYWLYCHSA-N 0.000 description 3
- 239000003529 anticholesteremic agent Substances 0.000 description 3
- 239000003524 antilipemic agent Substances 0.000 description 3
- 229910052799 carbon Inorganic materials 0.000 description 3
- 125000004432 carbon atom Chemical class C* 0.000 description 3
- 238000006243 chemical reaction Methods 0.000 description 3
- 238000001816 cooling Methods 0.000 description 3
- 238000002425 crystallisation Methods 0.000 description 3
- 230000008025 crystallization Effects 0.000 description 3
- 239000000796 flavoring agent Substances 0.000 description 3
- 230000000055 hyoplipidemic effect Effects 0.000 description 3
- 239000000463 material Substances 0.000 description 3
- 239000000047 product Substances 0.000 description 3
- 239000000725 suspension Substances 0.000 description 3
- 238000005004 MAS NMR spectroscopy Methods 0.000 description 2
- 238000005481 NMR spectroscopy Methods 0.000 description 2
- XUIMIQQOPSSXEZ-UHFFFAOYSA-N Silicon Chemical compound [Si] XUIMIQQOPSSXEZ-UHFFFAOYSA-N 0.000 description 2
- 238000002441 X-ray diffraction Methods 0.000 description 2
- DPXJVFZANSGRMM-UHFFFAOYSA-N acetic acid;2,3,4,5,6-pentahydroxyhexanal;sodium Chemical compound [Na].CC(O)=O.OCC(O)C(O)C(O)C(O)C=O DPXJVFZANSGRMM-UHFFFAOYSA-N 0.000 description 2
- 239000001768 carboxy methyl cellulose Substances 0.000 description 2
- 239000000969 carrier Substances 0.000 description 2
- 229940110456 cocoa butter Drugs 0.000 description 2
- 235000019868 cocoa butter Nutrition 0.000 description 2
- 239000003086 colorant Substances 0.000 description 2
- 238000005388 cross polarization Methods 0.000 description 2
- UOENAPUPIPQFOY-UHFFFAOYSA-J dicalcium tetraacetate hydrate Chemical compound O.C(C)(=O)[O-].[Ca+2].[Ca+2].C(C)(=O)[O-].C(C)(=O)[O-].C(C)(=O)[O-] UOENAPUPIPQFOY-UHFFFAOYSA-J 0.000 description 2
- 239000003937 drug carrier Substances 0.000 description 2
- 238000001035 drying Methods 0.000 description 2
- 239000000839 emulsion Substances 0.000 description 2
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 2
- 235000019634 flavors Nutrition 0.000 description 2
- 238000009472 formulation Methods 0.000 description 2
- 239000003112 inhibitor Substances 0.000 description 2
- 238000002347 injection Methods 0.000 description 2
- 239000007924 injection Substances 0.000 description 2
- 238000011031 large-scale manufacturing process Methods 0.000 description 2
- 239000010410 layer Substances 0.000 description 2
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- 238000002844 melting Methods 0.000 description 2
- 230000008018 melting Effects 0.000 description 2
- 229920000609 methyl cellulose Polymers 0.000 description 2
- 239000001923 methylcellulose Substances 0.000 description 2
- 235000010981 methylcellulose Nutrition 0.000 description 2
- DNIAPMSPPWPWGF-UHFFFAOYSA-N monopropylene glycol Natural products CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 2
- 239000004570 mortar (masonry) Substances 0.000 description 2
- 239000006187 pill Substances 0.000 description 2
- 229910052710 silicon Inorganic materials 0.000 description 2
- 239000010703 silicon Substances 0.000 description 2
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N silicon dioxide Inorganic materials O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 2
- 239000002002 slurry Substances 0.000 description 2
- 235000019812 sodium carboxymethyl cellulose Nutrition 0.000 description 2
- 229920001027 sodium carboxymethylcellulose Polymers 0.000 description 2
- 239000003381 stabilizer Substances 0.000 description 2
- 239000000375 suspending agent Substances 0.000 description 2
- 239000002562 thickening agent Substances 0.000 description 2
- CABVTRNMFUVUDM-VRHQGPGLSA-N (3S)-3-hydroxy-3-methylglutaryl-CoA Chemical compound O[C@@H]1[C@H](OP(O)(O)=O)[C@@H](COP(O)(=O)OP(O)(=O)OCC(C)(C)[C@@H](O)C(=O)NCCC(=O)NCCSC(=O)C[C@@](O)(CC(O)=O)C)O[C@H]1N1C2=NC=NC(N)=C2N=C1 CABVTRNMFUVUDM-VRHQGPGLSA-N 0.000 description 1
- 102100029077 3-hydroxy-3-methylglutaryl-coenzyme A reductase Human genes 0.000 description 1
- 101710158485 3-hydroxy-3-methylglutaryl-coenzyme A reductase Proteins 0.000 description 1
- 241000416162 Astragalus gummifer Species 0.000 description 1
- MGNZXYYWBUKAII-UHFFFAOYSA-N C1C=CC=CC1 Chemical compound C1C=CC=CC1 MGNZXYYWBUKAII-UHFFFAOYSA-N 0.000 description 1
- 0 C=*c1ccccc1 Chemical compound C=*c1ccccc1 0.000 description 1
- UGFAIRIUMAVXCW-UHFFFAOYSA-N Carbon monoxide Chemical compound [O+]#[C-] UGFAIRIUMAVXCW-UHFFFAOYSA-N 0.000 description 1
- 229910016523 CuKa Inorganic materials 0.000 description 1
- 239000004375 Dextrin Substances 0.000 description 1
- 229920001353 Dextrin Polymers 0.000 description 1
- 102000004190 Enzymes Human genes 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- 108010010803 Gelatin Proteins 0.000 description 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 1
- WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 description 1
- 239000002202 Polyethylene glycol Substances 0.000 description 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- 229920002472 Starch Polymers 0.000 description 1
- 229920001615 Tragacanth Polymers 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 125000000217 alkyl group Chemical group 0.000 description 1
- 229910052782 aluminium Inorganic materials 0.000 description 1
- XAGFODPZIPBFFR-UHFFFAOYSA-N aluminium Chemical compound [Al] XAGFODPZIPBFFR-UHFFFAOYSA-N 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 125000002490 anilino group Chemical group [H]N(*)C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 1
- 239000007900 aqueous suspension Substances 0.000 description 1
- 235000021311 artificial sweeteners Nutrition 0.000 description 1
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 1
- 239000011230 binding agent Substances 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 239000000872 buffer Substances 0.000 description 1
- 239000000306 component Substances 0.000 description 1
- 239000011549 crystallization solution Substances 0.000 description 1
- 235000019425 dextrin Nutrition 0.000 description 1
- 235000014113 dietary fatty acids Nutrition 0.000 description 1
- 239000002270 dispersing agent Substances 0.000 description 1
- 238000004821 distillation Methods 0.000 description 1
- 238000009826 distribution Methods 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 239000000194 fatty acid Substances 0.000 description 1
- 229930195729 fatty acid Natural products 0.000 description 1
- 230000002349 favourable effect Effects 0.000 description 1
- 235000013355 food flavoring agent Nutrition 0.000 description 1
- 229920000159 gelatin Polymers 0.000 description 1
- 239000008273 gelatin Substances 0.000 description 1
- 235000019322 gelatine Nutrition 0.000 description 1
- 235000011852 gelatine desserts Nutrition 0.000 description 1
- 239000008187 granular material Substances 0.000 description 1
- 239000008240 homogeneous mixture Substances 0.000 description 1
- 239000000543 intermediate Substances 0.000 description 1
- 238000002955 isolation Methods 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- 229910052744 lithium Inorganic materials 0.000 description 1
- 239000000314 lubricant Substances 0.000 description 1
- ZLNQQNXFFQJAID-UHFFFAOYSA-L magnesium carbonate Chemical compound [Mg+2].[O-]C([O-])=O ZLNQQNXFFQJAID-UHFFFAOYSA-L 0.000 description 1
- 239000001095 magnesium carbonate Substances 0.000 description 1
- 229910000021 magnesium carbonate Inorganic materials 0.000 description 1
- 235000019359 magnesium stearate Nutrition 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 235000021096 natural sweeteners Nutrition 0.000 description 1
- 239000006186 oral dosage form Substances 0.000 description 1
- 229910052760 oxygen Inorganic materials 0.000 description 1
- 239000001301 oxygen Substances 0.000 description 1
- 239000006201 parenteral dosage form Substances 0.000 description 1
- 239000002245 particle Substances 0.000 description 1
- 239000001814 pectin Substances 0.000 description 1
- 235000010987 pectin Nutrition 0.000 description 1
- 229920001277 pectin Polymers 0.000 description 1
- 239000008177 pharmaceutical agent Substances 0.000 description 1
- 239000000825 pharmaceutical preparation Substances 0.000 description 1
- 229920001223 polyethylene glycol Polymers 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 239000003755 preservative agent Substances 0.000 description 1
- ALDITMKAAPLVJK-UHFFFAOYSA-N prop-1-ene;hydrate Chemical group O.CC=C ALDITMKAAPLVJK-UHFFFAOYSA-N 0.000 description 1
- 239000010453 quartz Substances 0.000 description 1
- 239000011347 resin Substances 0.000 description 1
- 229920005989 resin Polymers 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 238000007873 sieving Methods 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 239000007909 solid dosage form Substances 0.000 description 1
- 230000000087 stabilizing effect Effects 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 238000003860 storage Methods 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- BOJSDHZZKKYWAS-UHFFFAOYSA-N tetrakis(trimethylsilyl)silane Chemical compound C[Si](C)(C)[Si]([Si](C)(C)C)([Si](C)(C)C)[Si](C)(C)C BOJSDHZZKKYWAS-UHFFFAOYSA-N 0.000 description 1
- 229940124597 therapeutic agent Drugs 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 239000000196 tragacanth Substances 0.000 description 1
- 235000010487 tragacanth Nutrition 0.000 description 1
- 229940116362 tragacanth Drugs 0.000 description 1
- 239000011345 viscous material Substances 0.000 description 1
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
-
- 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
- A61P3/12—Drugs for disorders of the metabolism for electrolyte homeostasis
- A61P3/14—Drugs for disorders of the metabolism for electrolyte homeostasis for calcium homeostasis
-
- 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
Definitions
- the present invention relates to novel crystalline forms of atorvastatin which is known by the chemical name [R- (R*,R*) ] -2- (4-fluorophenyl) - ⁇ , ⁇ -dihydroxy-5- (1- methylethyl) -3- henyl-4- [ (phenylamino)carbonyl] -IH- pyrrole-1-heptanoic acid hemi calcium salt useful as pharmaceutical agents, to methods for their production and isolation, to pharmaceutical compositions which include these compounds and a pharmaceutically acceptable carrier, and to pharmaceutical methods of treatment.
- atorvastatin which is known by the chemical name [R- (R*,R*) ] -2- (4-fluorophenyl) - ⁇ , ⁇ -dihydroxy-5- (1- methylethyl) -3- henyl-4- [ (phenylamino)carbonyl] -IH- pyrrole-1-heptanoic acid hemi calcium salt useful as pharmaceutical agents, to methods
- novel crystalline compounds of the present invention are useful as inhibitors of the enzyme 3-hydroxy-3-methylglutaryl-coenzyme A reductase (H G-CoA reductase) and are thus useful hypolipidemic and hypocholesterolemic agents.
- H G-CoA reductase 3-hydroxy-3-methylglutaryl-coenzyme A reductase
- United States Patent Number 5,273,995 discloses the enantiomer having the R form of the ring-opened acid of trans-5-(4-fluorophenyl) -2- (1-methylethyl) -N,4- diphenyl-1- [ (2-tetrahydro-4-hydroxy-6-oxo-2H-pyran- 2-yl)ethyl] -IH-pyrrole-3-carboxamide, i.e.
- Atorvastatin is prepared as its calcium salt, i.e., [R-(R*,R*)]-2-(4-fluorophenyl)- ⁇ , ⁇ -dihydroxy-5- (1-methylethyl) -3-phenyl-4- [ (phenylamino)carbonyl] -1H- pyrrole-1-heptanoic acid calcium salt (2:1).
- the calcium salt is desirable since it enables atorvastatin to be conveniently formulated in, for example, tablets, capsules, lozenges, powders, and the like for oral administration. Additionally, there is a need to produce atorvastatin in a pure and crystalline form to enable formulations to meet exacting pharmaceutical requirements and specifications.
- atorvastatin is produced needs to be one which is amenable to large- scale production. Additionally, it is desirable that the product should be in a form that is readily filterable and easily dried. Finally, it is economically desirable that the product be stable for extended periods of time without the need for specialized storage conditions.
- atorvastatin can be prepared in crystalline form.
- the present invention provides atorvastatin in new crystalline forms designated Form I, Form II, and Form IV.
- Form I atorvastatin consists of smaller particles and a more uniform size distribution than the previous amorphous product and exhibits more favorable filtration and drying characteristics . Additionally, Form I atorvastatin is purer and more stable than the amorphous produc .
- the present invention is directed to crystalline Form I atorvastatin and hydrates thereof characterized by the following X-ray powder diffraction pattern expressed in terms of the 2 ⁇ , d-spacings, and relative intensities with a relative intensity of >20% measured after 2 minutes of grinding and measured on a Siemens D-500 diffractometer with CuK ⁇ radiation:
- the present invention is directed to crystalline Form I atorvastatin and hydrates thereof characterized by the following solid-state 13 C nuclear magnetic resonance spectrum wherein chemical shift is expressed in parts per million measured on a Bruker A -250 spectrometer: Assignment (7 kHz) Chemical Shift
- crystalline Form I atorvastatin is a trihydrate.
- the present invention is directed to crystalline Form II atorvastatin and hydrates thereof characterized by the following X-ray powder diffraction pattern expressed in terms of the 2 ⁇ , d-spacings, and relative intensities with a relative intensity of >20% measured after 2 minutes of grinding and measured on a Siemens D-500 diffractometer with CuK ⁇ radiation:
- the second aspect of the present invention is directed to crystalline Form II atorvastatin and hydrates thereof characterized by the following solid-state 13 C nuclear magnetic resonance spectrum wherein chemical shift is expressed in parts per million measured on a Bruker AX-250 spectrometer: Assignment Chemical Shift
- the present invention is directed to crystalline Form IV atorvastatin and hydrates thereof characterized by the following X-ray powder diffraction pattern expressed in terms of the 2 ⁇ , d-spacings, and relative intensities with a relative intensity of >15% measured on a Siemens D-500 diffractometer with CuK ⁇ radiation:
- the fourth aspect of the present invention is directed to Form IV atorvastatin and hydrates thereof characterized by the following solid-state 13 C nuclear magnetic resonance spectrum wherein chemical shift is expressed as parts per million measured on a Bruker AX-250 spectrometer: Assignment Chemical Shift
- a still further embodiment of the present invention is a pharmaceutical composition for administering an effective amount of crystalline Form I, Form II, or Form IV atorvastatin in unit dosage form in the treatment methods mentioned above.
- the present invention is directed to methods for production of Form I, Form II, or Form IV atorvastatin.
- Crystalline Form I, Form II, or Form IV atorvastatin may be characterized by their X-ray powder diffraction patterns and/or by their solid state nuclear magnetic resonance spectra (NMR) .
- Forms I, II, or Form IV atorvastatin were characterized by their X-ray powder diffraction pattern.
- the X-ray diffraction patterns of Forms I, II, and Form IV atorvastatin were measured on a Siemens D-500 diffractometer with CuK a season radiation.
- the silicon standard is run each day to check the X-ray tube alignment.
- Ground Form II atorvastatin was sieved through a 230 mesh screen before analysis by x-ray diffraction.
- Table 1 lists the 2 ⁇ , d-spacings, and relative intensities of all lines in the unground sample with a relative intensity of >20% for crystalline Form I atorvastatin. Table 1 also lists the relative intensities of the same lines in a diffractogram measured after 2 minutes of grinding. The intensities of the sample ground for 2 minutes are more representative of the diffraction pattern without preferred orientation. It should also be noted that the computer-generated, unrounded numbers are listed in this table.
- the second relative intensity column gives the relative intensities of the diffraction lines on the original diffractogram after 2 minutes of grinding.
- Table 2 lists the 2 ⁇ , d-spacings, and relative intensities of all lines in the ground/sieved sample with a relative intensity of >20% for crystalline Form II atorvastatin. It should also be noted that the computer-generated unrounded numbers are listed in this table.
- Table 3 lists the 2 ⁇ , d-spacings, and relative intensities of all lines in the unground sample with a relative intensity of >15% for crystalline Form IV atorvastatin. It should also be noted that the computer-generated unrounded numbers are listed in this table. TABLE 3. Intensities and Peak Locations of All
- Table 4 shows the solid-state NMR spectrum for crystalline Form I atorvastatin.
- Table 5 shows the solid-state NMR spectrum for crystalline Form II atorvastatin. TABLE 5. Carbon Atom Assignment and Chemical Shift for Form II Atorvastatin
- Table 6 shows the solid-state NMR spectrum for crystalline Form IV atorvastatin.
- Crystalline Form I, Form II, and Form IV atorvastatin of the present invention may exist in anhydrous forms as well as hydrated forms. In general, the hydrated forms, are equivalent to unhydrated forms and are intended to be encompassed within the scope of the present invention.
- Crystalline Form I atorvastatin contains about 1 to 8 mol of water. Preferably, Form I atorvastatin contains 3 mol of water.
- the present invention provides a process for the preparation of crystalline Form I atorvastatin which comprises crystallizing atorvastatin from a solution in solvents under conditions which yield crystalline Form I atorvastatin.
- crystalline Form I atorvastatin may be prepared by crystallization under controlled conditions.
- it can be prepared either from an aqueous solution of the corresponding basic salt such as, an alkali metal salt, for example, lithium, potassium, sodium, and the like; ammonia or an amine salt; preferably, the sodium salt by addition of a calcium salt, such as, for example, calcium acetate and the like, or by suspending amorphous atorvastatin in water.
- a hydroxylic co-solvent such as, for example, a lower alkanol, for example methanol and the like, is preferred.
- one preferred preparation involves treating a solution of the sodium salt in water containing not less than about 5% v/v methanol, preferably about 5% to 33% v/v methanol, particularly preferred about 10% to 15% v/v methanol, with an aqueous solution of calcium acetate, preferably at an elevated temperature at up to about 70°C such as, for example, about 45-60°C, particularly preferred about 47-52°C. It is preferable to use calcium acetate and, in general, 1 mole of calcium acetate to 2 moles of the sodium salt of atorvastatin.
- calcium salt formation as well as crystallization should preferably be carried out at an elevated temperature, for example within the above ⁇ mentioned temperature ranges. It has been found that it may be advantageous to include in the starting solution a small amount of methyl tert-butyl ether (MTBE) such as, for example, about 7% w/w. It has frequently been found desirable to add "seeds" of crystalline Form I atorvastatin to the crystallization solution in order to consistently produce crystalline Form I atorvastatin.
- MTBE methyl tert-butyl ether
- the desired crystalline Form I atorvastatin may be obtained by suspending the solid in water containing up to about 40% v/v, such as, for example, about 0% to 20% v/v, particularly preferred about 5% to 15% v/v co-solvent such as, for example, methanol, ethanol, 2-propanol, acetone, and the like until conversion to the required form is complete, followed by filtration. It has frequently been found desirable to add "seeds" of crystalline Form I atorvastatin to the suspension in order to ensure complete conversion to crystalline Form I atorvastatin.
- a water-wet cake consisting principally of amorphous atorvastatin can be heated at elevated temperatures such as, for example, up to about 75°C, particularly preferred about 65-70°C, until a significant amount of crystalline Form I atorvastatin is present, whereupon the amorphous/ crystalline Form I mixture can be slurried as described above.
- Crystalline Form I atorvastatin is significantly easier to isolate than amorphous atorvastatin and can be filtered from the crystallization medium after cooling, and washed and dried. For example, filtration of a 50 mL slurry of crystalline Form I atorvastatin was complete within 10 seconds. A similarly sized sample of amorphous atorvastatin took more than an hour to filter.
- the present invention also provides a process for the preparation of crystalline Form II atorvastatin which comprises suspending atorvastatin in solvents under conditions which yield crystalline Form II atorvastatin.
- Form II of crystalline atorvastatin is formed may be empirically determined and it is only possible to give a method which has been found to be suitable in practice.
- the desired Form II of crystalline atorvastatin may be obtained by suspending the solid in methanol containing about 40% to about 50% water until conversion to the required form is complete, followed by filtration.
- the present invention also provides a process for the preparation of crystalline Form IV atorvastatin which comprises crystallizing atorvastatin from a solution thereof in solvents under conditions which yield crystalline Form IV atorvastatin.
- Form IV of crystalline atorvastatin is formed may be empirically determined and it is only possible to give a method which has been found to be suitable in practice.
- the desired Form IV of crystalline atorvastatin may be obtained by dissolving the solid in methanol whereupon crystalline Form IV precipitates .
- the compounds of the present invention can be prepared and administered in a wide variety of oral and parenteral dosage forms.
- the compounds of the present invention can be administered by injection, that is, intravenously, intramuscularly, intracutaneously, subcutaneously, intraduodenally, or intraperitoneally.
- the compounds of the present invention can be administered by inhalation, for example, intranasally.
- the compounds of the present invention can be administered transdermally. It will be obvious to those skilled in the art that the following dosage forms may comprise as the active component, either compounds or a corresponding pharmaceutically acceptable salt of a compound of the present invention.
- pharmaceutically acceptable carriers can be either solid or liquid.
- Solid form preparations include powders, tablets, pills, capsules, cachets, suppositories, and dispersible granules.
- a solid carrier can be one or more substances which may also act as diluents, flavoring agents, solubilizers, lubricants, suspending agents, binders, preservatives, tablet disintegrating agents, or an encapsulating material.
- the carrier is a finely divided solid which is in a mixture with the finely divided active component.
- the active component is mixed with the carrier having the necessary binding properties in suitable proportions and compacted in the shape and size desired.
- the powders and tablets preferably contain from two or ten to about seventy percent of the active compound.
- Suitable carriers are magnesium carbonate, magnesium stearate, talc, sugar, lactose, pectin, dextrin, starch, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose, a low melting wax, cocoa butter, and the like.
- the term "preparation” is intended to include the formulation of the active compound with encapsulating material as a carrier providing a capsule in which the active component, with or without other carriers, is surrounded by a carrier, which is thus in association with it. Similarly, cachets and lozenges are included.
- Tablets, powders, capsules, pills, cachets, and lozenges can be used as solid dosage forms suitable for oral administration.
- a low melting wax such as a mixture of fatty acid glycerides or cocoa butter
- the active component is dispersed homogeneously therein, as by stirring.
- the molten homogenous mixture is then poured into convenient sized molds, allowed to cool, and thereby to solidify.
- Liquid form preparations include solutions, suspensions, retention enemas, and emulsions, for example water or water propylene glycol solutions .
- liquid preparations can be formulated in solution in aqueous polyethylene glycol solution.
- Aqueous solutions suitable for oral use can be prepared by dissolving the active component in water and adding suitable colorants, flavors, stabilizing, and thickening agents as desired.
- Aqueous suspensions suitable for oral use can be made by dispersing the finely divided active component in water with viscous material, such as natural or synthetic gums, resins, methylcellulose, sodium carboxymethylcellulose, and other well-known suspending agents .
- viscous material such as natural or synthetic gums, resins, methylcellulose, sodium carboxymethylcellulose, and other well-known suspending agents .
- solid form preparations which are intended to be converted, shortly before use, to liquid form preparations for oral administration.
- Such liquid forms include solutions, suspensions, and emulsions.
- These preparations may contain, in addition to the active component, colorants, flavors, stabilizers, buffers, artificial and natural sweeteners, dispersants, thickeners, solubilizing agents, and the like.
- the pharmaceutical preparation is preferably in unit dosage form.
- the preparation is subdivided into unit doses containing appropriate quantities of the active component.
- the unit dosage form can be a packaged preparation, the package containing discrete quantities of preparation, such as packeted tablets, capsules, and powders in vials or ampoules.
- the unit dosage form can be a capsule, tablet, cachet, or lozenge itself, or it can be the appropriate number of any of these in packaged form.
- the quantity of active component in a unit dose preparation may be varied or adjusted from 0.5 mg to 100 mg, preferably 2.5 mg to 80 mg according to the particular application and the potency of the active component.
- the composition can, if desired, also contain other compatible therapeutic agents .
- the crystalline Forms I, II, and Form IV atorvastatin utilized in the pharmaceutical method of this invention are administered at the initial dosage of about 2.5 mg to about 80 mg daily.
- a daily dose range of about 2.5 mg to about 20 mg is preferred.
- the dosages may be varied depending upon the requirements of the patient, the severity of the condition being treated, and the compound being employed. Determination of the proper dosage for a particular situation is within the skill of the art. Generally, treatment is initiated with smaller dosages which are less than the optimum dose of the compound. Thereafter, the dosage is increased by small increments until the optimum effect under the circumstance is reached. For convenience, the total daily dosage may be divided and administered in portions during the day if desired.
- Amorphous atorvastatin (9 g) and crystalline Form I atorvastatin (1 g) are stirred at about 40°C in a mixture of water (170 mL) and methanol (30 mL) for a total of 17 hours. The mixture is filtered, rinsed with water, and dried at 70°C under reduced pressure to give crystalline Form I atorvastatin (9.7 g) .
Abstract
Description
Claims
Priority Applications (31)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US08/945,812 US5969156A (en) | 1995-07-17 | 1996-07-08 | Crystalline [R- (R*,R*)]-2-(4-Dfluorophenyl)-β,δ-dihydroxy-5-(1-methylethyl)- 3-phenyl-4-[(phenylamino)carbonyl]-1H-pyrrole-1-heptanoic acid hemi calcium salt (atorvastatin) |
BR9609872A BR9609872A (en) | 1995-07-17 | 1996-07-08 | Hemi calcium salt of (R- (R * R *)) - 2- (4-fluorophenyl -) - beta delta-dihydroxy-5- (1-methylethyl) -3-phenyl-4- [(phenylamino) carbonyl ] -1H- pyrrole-1heptanoic (atorvastatin) and ristaline |
SK62-98A SK284202B6 (en) | 1995-07-17 | 1996-07-08 | crystalline [R-(R*,R*)]-2-(4-fluorophenyl)-beta,delta-dihydroxy- 5-(1-methylethyl)-3-phenyl-4-[(phenylamino)carbonyl]-1H-pyrrole- 1-heptanoic acid hemi calcium salt (atorvastatin) |
EP96924368A EP0848705B1 (en) | 1995-07-17 | 1996-07-08 | Crystalline r-(r*,r*)]-2-(4-fluorophenyl)-beta,delta-dihydroxy-5-(1-methylethyl)-3-phenyl-4- (phenylamino)carbonyl]-1h-pyrrole-1-heptanoic acid hemi calcium salt (atorvastatin) |
IL128864A IL128864A (en) | 1995-07-17 | 1996-07-08 | Crystalline form ii atorvastatin and hydrates thereof, methods for its preparation and pharmaceutical compositions containing it |
MX9709099A MX9709099A (en) | 1995-07-17 | 1996-07-08 | Crystalline [r-(r*,r*)]-2-(4-fluorophenyl)-beta,delta-dihydroxy-5-(1-met hylethyl)-3-phenyl-4-[(phenylamino)carbonyl]-1h-pyrrole-1-he ptanoic acid hemi calcium salt (atorvastatin). |
DK01116338T DK1148049T3 (en) | 1995-07-17 | 1996-07-08 | Crystalline [R- (R *, R *)] - 2- (4-fluorophenyl) -beta, delta-dihydroxy-5- (1-methylethyl) -3-phenyl-4- [(phenylamino) carbonyl] -1H- pyrrole-1-heptanoic acid hemicalcium salt (ATORVASTATIN) |
RO98-00061A RO120070B1 (en) | 1995-07-17 | 1996-07-08 | Crystalline forms of [r-(r*,r*)]-2-(4-fluorophenyl)-beta, delta-dihydroxy-5-(1-methylethyl)-3-phenyl-4-[(phenylamino)carbonyl]-1h-pyrrole-1-heptanoic acid hemi calcium salt (atorvastatin) |
AT01116338T ATE284868T1 (en) | 1995-07-17 | 1996-07-08 | KRISTALINE (R-(R*,R*))-2-(4-FLUOROPHENYL)-BETA, DELTA-DIHYDROXY-5-(1-METHYLETHYL)-3-PHENYL-4-((PHENYLAMINO)CARBONYL)-1H- PYRROLE-1-HEPTANCARBOXIC ACID HEMI CALCIUM SSLZ (ATORVASTATIN) |
JP50671097A JP3296564B2 (en) | 1995-07-17 | 1996-07-08 | Crystalline [R- (R ▲ *, R ▲ *)]-2- (4-fluorophenyl) -β, δ-dihydroxy-5- (1-methylethyl) -3-phenyl-4 -[(Phenylamino) carbonyl] -1H-pyrrole-1-heptanoic acid hemicalcium salt (atorvastatin) |
SI9630355T SI0848705T1 (en) | 1995-07-17 | 1996-07-08 | Crystalline r-(r*,r*))-2-(4-fluorophenyl)-beta,delta-dihydroxy-5-(1-methylethyl)-3-phenyl-4- (phenylamino)carbonyl)-1h-pyrrole-1-heptanoic acid hemi calcium salt (atorvastatin) |
AT96924368T ATE208375T1 (en) | 1995-07-17 | 1996-07-08 | CRYSTALLINE (R-(R*,R*))-2-(4-FLUOROPHENYL)-BETA, DELTA-DIHYDROXY-5-(1-METHYLETHYL)-3-PHENYL-4-((PHENYLAMINO)CARBONYL)-1H- PYRROLE-1-HEPTANCARBOXIC ACID HEMI CALCIUM SALT (ATORVASTATIN) |
PL324496A PL193479B1 (en) | 1995-07-17 | 1996-07-08 | Crystalline fsemi-calcinous salt of [r-(r*,r*)]-2-(4-fluorophenyl)-dihydroxy-5-(1-methylethyl)-3-phenyl-4-[(phenylamino)carbonyl]-1h-pyrrolo-1-enantanic acid (atorvastatin) |
IL128862A IL128862A (en) | 1995-07-17 | 1996-07-08 | CRYSTALLINE [R-(R*R*)] - 2 - (4 - FLUOROPHENYL) - ??, Ó¬á - DELTA-DIHYDROXY - 5 - (1 - METHYLETHYL) - 3 - PHENYL - 4 - (PHENYLAMINO) CARBONYL] - 1H - PYRROLE - 1 - HEPTANOIC ACID HEMI CALCIUM SALT (ATORVASTATIN)HYDRATE |
IL128865A IL128865A (en) | 1995-07-17 | 1996-07-08 | Crystalline form iv atorvastatin and hydrates thereof, methods for its preparation and pharmacetical compositions containing it |
DK96924368T DK0848705T3 (en) | 1995-07-17 | 1996-07-08 | Crystalline [R- (R *, R *)] - 2- (4-fluorophenyl) -beta, delta-dihydroxy-5- (1-methylethyl) -3-phenyl-4 - [(phenylamino) carbonyl] -1H- pyrrole-1-heptanoic acid hemicalcium salt (atorvastatin) |
AU64842/96A AU725424B2 (en) | 1995-07-17 | 1996-07-08 | Crystalline (R-(R*,R*))-2-(4-fluorophenyl)-beta,delta-dihydroxy-5- (1-methylethyl)-3-phenyl-4-((phenylamino)carbonyl)-1H- pyrrole-1-heptanoic acid hemi calcium salt (atorvastatin) |
EE9800015A EE03606B1 (en) | 1995-07-17 | 1996-07-08 | Crystalline [R- (R *, R *)] - 2- (4-fluorophenyl) -beta, delta-dihydroxy-5- (1-methylethyl) -3-phenyl-4 - [(phenylamino) carbonyl] -1H- pyrrole-1-heptanoic acid calcium calcium (atorvastatin) |
HU9900678A HU223599B1 (en) | 1995-07-17 | 1996-07-08 | Forms i,ii and iv crystalline [r-(r*,r*)]-2-(4-fluorophenyl)-beta,delta-dihydroxy-5(1-methyl-ethil)-3-phenyl-4-[(phenylamino)-carbonyl]-1h-pyrrole-1-heptanoic acid hemi calcium salt hydrate (atorvastatin-hydrate), and pharmaceutical compositions ... |
NZ312907A NZ312907A (en) | 1995-07-17 | 1996-07-08 | Crystalline [r-(r*,r*)]-2-(4-fluorophenyl)-beta,delta-dihydroxy-5-(1-methylethyl |
DE69616808T DE69616808T2 (en) | 1995-07-17 | 1996-07-08 | CRYSTALLINES (R- (R *, R *)) - 2- (4-FLUORPHENYL) BETA, DELTA-DIHYDROXY-5- (1-METHYLETHYL) -3-PHENYL-4 - ((PHENYLAMINO) CARBONYL) -1H- PYRROL-1-HEPTANIC CARBONIC ACID HEMI CALCIUM SALT (ATORVASTATIN) |
IL12211896A IL122118A (en) | 1995-07-17 | 1996-07-08 | Crystalline form I atorvastatin pharmaceutical compositions containing it and process for its preparation |
EA199800130A EA000474B1 (en) | 1995-07-17 | 1996-07-08 | Crystalline [r-(r*, r*)]-2-(4-fluorophenyl)-beta, delta-dihydroxy-5-(1-methylethyl)-3-phenyl-4-[(phenylamino)carbonyl]-1h-pyrrole-1-heptanoic acid hemi calcium salt (atorvastatin) |
CA002220018A CA2220018C (en) | 1995-07-17 | 1996-07-08 | Crystalline [r-(r*,r*)]-2-(4-fluorophenyl)-beta,delta-dihydroxy-5-(1-methylethyl)-3-phenyl-4-[(phenylamino)carbonyl]-1h-pyrrole-1-heptanoic acid hemi calcium salt (atorvastatin) |
UA98020824A UA51661C2 (en) | 1995-07-17 | 1996-08-07 | crystalline forms of ACID CALCIUM SALT [R-(R*,R*)]-2-(4-fluorophenyl)-<sub>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,</sub><sub>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-dihydroxy-5-(l-methylethyl)-3-phenyl-4-[(phenylamIno)carbonyl]-lH-pyrrole-1-heptanoic acid (ATORVASTATIN) and a pharmaceutical composition on their base |
BG102187A BG63630B1 (en) | 1995-07-17 | 1998-01-14 | Crystalline hemicalcium salt of [r-(r*, r*)]-2-(4-fluorophenyl)-beta,delta -dihydroxy-5-(1-methyletyl)-3-phenyl-4-[(phenylamino)carbonyl]-1h- pyrol-1-heptane acid (atorvastatin) |
NO980207A NO309898B1 (en) | 1995-07-17 | 1998-01-16 | Crystalline Form I [R- (R *, R *)] - 2- (4-fluorophenyl) - <beta>, <delta> -dihydroxy-5- (1-methylethyl) -3-phenyl-4 - [(phenylamino ) carbonyl] -1H-pyrrole-1-heptanoic acid hemicalcium salt |
HK98113380A HK1018052A1 (en) | 1995-07-17 | 1998-12-15 | Crystalline [r-(r*,r*)]-2-(4-fluorophenyl)-beta, delta-dihydroxy-5-(1-methylethyl)-3-phenyl-4-[(phenylamino)carbonyl)-1h-pyrrole-1-heptanoic acid hemi calcium salt (atorvastatin) |
IL177376A IL177376A0 (en) | 1995-07-17 | 2006-08-08 | Crystalline (r-r*r*)-2-(4-fluorophenyl)-beta-delta-dihydroxy-5-(1-methylethyl)3-phenyl-4-(phenylamino)carbonyl)-ih-pyrrole-1-heptanoic acid hemi calcium salt ( atorvastatin) |
IL177377A IL177377A0 (en) | 1995-07-17 | 2006-08-08 | Crystalline (r-r*r*)-2-(4-fluorophenyl)-beta-delta-dihydroxy-5-(1-methylethyl)3-phenyl-4-(phenylamino)carbonyl)-ih-pyrrole-1-heptanoic acid hemi calcium salt ( atorvastatin) |
IL203847A IL203847A0 (en) | 1995-07-17 | 2010-02-09 | Crystalline [r-(r*,r*)]-2-(4-fluorophenyl)-beta,delta-dihydroxy-5-(1-methylethyl)-3-phenyl-4-[(phenylamino)carbonyl]-1h-pyrrole-1-heptanoic acid hemi calcium salt (atorvastatin) |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
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US145295P | 1995-07-17 | 1995-07-17 | |
US60/001,452 | 1995-07-17 |
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Application Number | Title | Priority Date | Filing Date |
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PCT/US1996/011368 WO1997003959A1 (en) | 1995-07-17 | 1996-07-08 | Crystalline [r-(r*,r*)]-2-(4-fluorophenyl)-beta,delta-dihydroxy-5-(1-methylethyl)-3-phenyl-4-[(phenylamino)carbonyl]-1h-pyrrole-1-heptanoic acid hemi calcium salt (atorvastatin) |
Country Status (38)
Country | Link |
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US (1) | US5969156A (en) |
EP (2) | EP1148049B1 (en) |
JP (4) | JP3296564B2 (en) |
KR (2) | KR100431038B1 (en) |
CN (1) | CN1087288C (en) |
AR (2) | AR003459A1 (en) |
AT (3) | ATE208375T1 (en) |
AU (1) | AU725424B2 (en) |
BG (1) | BG63630B1 (en) |
BR (1) | BR9609872A (en) |
CA (1) | CA2220018C (en) |
CO (1) | CO4700443A1 (en) |
CY (1) | CY2358B1 (en) |
CZ (3) | CZ294740B6 (en) |
DE (2) | DE69634054T2 (en) |
DK (2) | DK1148049T3 (en) |
EA (1) | EA000474B1 (en) |
EE (1) | EE03606B1 (en) |
ES (2) | ES2167587T3 (en) |
GE (1) | GEP20002029B (en) |
HK (1) | HK1018052A1 (en) |
HR (1) | HRP960339B1 (en) |
HU (1) | HU223599B1 (en) |
IL (7) | IL122118A (en) |
MX (1) | MX9709099A (en) |
NO (1) | NO309898B1 (en) |
NZ (1) | NZ312907A (en) |
PE (1) | PE1898A1 (en) |
PL (1) | PL193479B1 (en) |
PT (2) | PT1148049E (en) |
RO (1) | RO120070B1 (en) |
SI (2) | SI0848705T1 (en) |
SK (1) | SK284202B6 (en) |
TW (1) | TW486467B (en) |
UA (1) | UA51661C2 (en) |
UY (2) | UY24285A1 (en) |
WO (1) | WO1997003959A1 (en) |
ZA (1) | ZA966044B (en) |
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WO2000071116A1 (en) * | 1999-05-25 | 2000-11-30 | Ranbaxy Laboratories Limited | Process for the production of amorphous atorvastatin calcium |
WO2001044181A1 (en) * | 1999-12-17 | 2001-06-21 | Warner Lambert Research And Development Ireland Limited | A process for producing crystalline atorvastatin calcium |
US6294516B1 (en) * | 2000-04-26 | 2001-09-25 | Colgate-Palmolive Co. | Wash cycle unit dose softener |
WO2001093860A1 (en) * | 2000-06-09 | 2001-12-13 | Lek Pharmaceuticals D.D. | Stabilized pharmaceutically effective composition and pharmaceutical formulation comprising the same |
WO2002041834A2 (en) * | 2000-11-03 | 2002-05-30 | Teva Pharmaceutical Industries, Ltd. | Atorvastatin hemi-calcium form vii |
WO2002051804A1 (en) * | 2000-12-27 | 2002-07-04 | Ciba Specialty Chemicals Holding Inc. | Crystalline forms of atorvastatin |
WO2002057229A1 (en) * | 2001-01-19 | 2002-07-25 | Biocon India Limited | FORM V CRYSTALLINE [R-(R*,R*)]-2-(4-FLUOROPHENYL)-ß,$G(D)-DIHYDROXY-5-(1-METHYLETHYL)-3-PHENYL-4-[(PHENYLAMINO)CARBONYL]-1H-PYRROLE-1- HEPTANOIC ACID HEMI CALCIUM SALT. (ATORVASTATIN) |
WO2002072073A2 (en) * | 2001-03-14 | 2002-09-19 | Lek Pharmaceutical And Chemical Company D.D. | Pharmaceutical formulation comprising atorvastatin calcium |
WO2003004470A1 (en) * | 2001-06-29 | 2003-01-16 | Warner-Lambert Company Llc | Crystalline forms of 'r-(r*,r*)!-2-(4-fluorophenyl)-beta, delta-dihydroxy-5-(1-methylethyl)-3-phenyl-4-'phenylamino)carbonyl!-1h-pyrrole-1-heptanoic acid calcium salt (2:1) (atorvastatin) |
WO2003011826A1 (en) * | 2001-07-30 | 2003-02-13 | Dr. Reddy's Laboratories Ltd. | Crystalline forms vi and vii of atorvastatin calcium |
WO2003024959A1 (en) * | 2001-09-14 | 2003-03-27 | EGIS Gyógyszergyár Rt. | Polymorphs of a 1-pyrrole derivative, intermediate for the preparation of atorvastatin |
US6569461B1 (en) | 1999-03-08 | 2003-05-27 | Merck & Co., Inc. | Dihydroxy open-acid and salts of HMG-CoA reductase inhibitors |
US6613916B2 (en) | 1999-12-10 | 2003-09-02 | Lek Pharmaceuticals D.D. | Process for the preparation of amorphous atorvastatin |
WO2003082816A1 (en) * | 2002-03-28 | 2003-10-09 | Richter Gedeon Vegyészeti Gyár Rt. | New atorvastatin salts and pharmaceutical compositions containing them |
EP1363621A1 (en) * | 2000-11-30 | 2003-11-26 | Teva Pharmaceutical Industries Ltd. | Novel crystal forms of atorvastatin hemi-calcium and processes for their preparation as well as novel processes for preparing other forms |
WO2004043918A2 (en) * | 2002-11-12 | 2004-05-27 | Teva Pharmaceutical Industries Ltd. | Novel crystal forms of atorvastatin hemi-calcium and processes for their preparation as well as novel processes for preparing other forms |
EP1424324A1 (en) * | 2002-11-28 | 2004-06-02 | Teva Pharmaceutical Industries Limited | Crystalline form F of Atorvastatin hemi-calcium salt |
US6750353B2 (en) | 2001-01-23 | 2004-06-15 | Lek Pharmaceutical & Chemical Co. D.D. | Preparation of pharmaceutically acceptable atorvastatin salts in non-crystalline form |
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