EP2220071A2 - Sunitinib-hemi-l-malat, polymorphe und herstellung davon, polymorphe von racemischem sunitinib-malat, sunitinib base und äpfelsäure enthaltende zusammensetzungen und herstellung davon - Google Patents
Sunitinib-hemi-l-malat, polymorphe und herstellung davon, polymorphe von racemischem sunitinib-malat, sunitinib base und äpfelsäure enthaltende zusammensetzungen und herstellung davonInfo
- Publication number
- EP2220071A2 EP2220071A2 EP08851719A EP08851719A EP2220071A2 EP 2220071 A2 EP2220071 A2 EP 2220071A2 EP 08851719 A EP08851719 A EP 08851719A EP 08851719 A EP08851719 A EP 08851719A EP 2220071 A2 EP2220071 A2 EP 2220071A2
- Authority
- EP
- European Patent Office
- Prior art keywords
- sunitinib
- malate
- theta
- pxrd pattern
- degrees
- 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- Withdrawn
Links
- WINHZLLDWRZWRT-ATVHPVEESA-N sunitinib Chemical compound CCN(CC)CCNC(=O)C1=C(C)NC(\C=C/2C3=CC(F)=CC=C3NC\2=O)=C1C WINHZLLDWRZWRT-ATVHPVEESA-N 0.000 title claims abstract description 328
- 239000002147 L01XE04 - Sunitinib Substances 0.000 title claims abstract description 95
- 229960001796 sunitinib Drugs 0.000 title claims abstract description 92
- LBWFXVZLPYTWQI-IPOVEDGCSA-N n-[2-(diethylamino)ethyl]-5-[(z)-(5-fluoro-2-oxo-1h-indol-3-ylidene)methyl]-2,4-dimethyl-1h-pyrrole-3-carboxamide;(2s)-2-hydroxybutanedioic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O.CCN(CC)CCNC(=O)C1=C(C)NC(\C=C/2C3=CC(F)=CC=C3NC\2=O)=C1C LBWFXVZLPYTWQI-IPOVEDGCSA-N 0.000 title claims abstract description 85
- 229960002812 sunitinib malate Drugs 0.000 title claims abstract description 68
- 229940049920 malate Drugs 0.000 title claims description 6
- BJEPYKJPYRNKOW-UHFFFAOYSA-N alpha-hydroxysuccinic acid Natural products OC(=O)C(O)CC(O)=O BJEPYKJPYRNKOW-UHFFFAOYSA-N 0.000 title abstract description 211
- 238000002360 preparation method Methods 0.000 title abstract description 48
- BJEPYKJPYRNKOW-REOHCLBHSA-N (S)-malic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O BJEPYKJPYRNKOW-REOHCLBHSA-N 0.000 title description 352
- 235000011090 malic acid Nutrition 0.000 title description 171
- 239000001630 malic acid Substances 0.000 title description 2
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 17
- 238000001144 powder X-ray diffraction data Methods 0.000 claims description 236
- 238000001460 carbon-13 nuclear magnetic resonance spectrum Methods 0.000 claims description 47
- 239000000126 substance Substances 0.000 claims description 43
- 239000007787 solid Substances 0.000 claims description 21
- 230000001747 exhibiting effect Effects 0.000 claims description 15
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 10
- 238000004519 manufacturing process Methods 0.000 claims description 9
- 239000003814 drug Substances 0.000 claims description 8
- 208000006265 Renal cell carcinoma Diseases 0.000 claims description 7
- 206010028980 Neoplasm Diseases 0.000 claims description 6
- 238000001757 thermogravimetry curve Methods 0.000 claims description 2
- 239000000203 mixture Substances 0.000 abstract description 279
- 238000000034 method Methods 0.000 abstract description 41
- 229940116298 l- malic acid Drugs 0.000 description 178
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 74
- 239000000243 solution Substances 0.000 description 70
- 238000010438 heat treatment Methods 0.000 description 49
- 239000002904 solvent Substances 0.000 description 49
- 238000000634 powder X-ray diffraction Methods 0.000 description 43
- 239000000725 suspension Substances 0.000 description 22
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 21
- 239000007864 aqueous solution Substances 0.000 description 19
- 238000001816 cooling Methods 0.000 description 19
- 239000002002 slurry Substances 0.000 description 19
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 18
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 15
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 14
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 14
- 238000001704 evaporation Methods 0.000 description 13
- 238000004090 dissolution Methods 0.000 description 12
- 238000001914 filtration Methods 0.000 description 12
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 11
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 10
- 230000008020 evaporation Effects 0.000 description 10
- 238000012792 lyophilization process Methods 0.000 description 10
- 238000003756 stirring Methods 0.000 description 10
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 9
- 238000006243 chemical reaction Methods 0.000 description 9
- 238000001035 drying Methods 0.000 description 8
- 239000000843 powder Substances 0.000 description 8
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 7
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 7
- 239000013078 crystal Substances 0.000 description 7
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 7
- 238000005406 washing Methods 0.000 description 7
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 6
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 6
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 6
- 238000001938 differential scanning calorimetry curve Methods 0.000 description 5
- 239000000047 product Substances 0.000 description 5
- 239000011541 reaction mixture Substances 0.000 description 5
- -1 t-butyl methyl Chemical group 0.000 description 5
- NTIZESTWPVYFNL-UHFFFAOYSA-N Methyl isobutyl ketone Chemical compound CC(C)CC(C)=O NTIZESTWPVYFNL-UHFFFAOYSA-N 0.000 description 4
- UIHCLUNTQKBZGK-UHFFFAOYSA-N Methyl isobutyl ketone Natural products CCC(C)C(C)=O UIHCLUNTQKBZGK-UHFFFAOYSA-N 0.000 description 4
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 4
- 239000008346 aqueous phase Substances 0.000 description 4
- 238000004108 freeze drying Methods 0.000 description 4
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 4
- 229940043265 methyl isobutyl ketone Drugs 0.000 description 4
- 239000004570 mortar (masonry) Substances 0.000 description 4
- 229910052757 nitrogen Inorganic materials 0.000 description 4
- 239000012071 phase Substances 0.000 description 4
- 230000000704 physical effect Effects 0.000 description 4
- 238000001556 precipitation Methods 0.000 description 4
- 238000011084 recovery Methods 0.000 description 4
- 238000010992 reflux Methods 0.000 description 4
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 4
- WNXJIVFYUVYPPR-UHFFFAOYSA-N 1,3-dioxolane Chemical compound C1COCO1 WNXJIVFYUVYPPR-UHFFFAOYSA-N 0.000 description 3
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 3
- JWUJQDFVADABEY-UHFFFAOYSA-N 2-methyltetrahydrofuran Chemical compound CC1CCCO1 JWUJQDFVADABEY-UHFFFAOYSA-N 0.000 description 3
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 3
- RWRDLPDLKQPQOW-UHFFFAOYSA-N Pyrrolidine Chemical compound C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 description 3
- 229910021529 ammonia Inorganic materials 0.000 description 3
- 235000011114 ammonium hydroxide Nutrition 0.000 description 3
- 230000015572 biosynthetic process Effects 0.000 description 3
- 238000009835 boiling Methods 0.000 description 3
- UDGSVBYJWHOHNN-UHFFFAOYSA-N n',n'-diethylethane-1,2-diamine Chemical compound CCN(CC)CCN UDGSVBYJWHOHNN-UHFFFAOYSA-N 0.000 description 3
- 229940034785 sutent Drugs 0.000 description 3
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- 238000005004 MAS NMR spectroscopy Methods 0.000 description 2
- 238000005481 NMR spectroscopy Methods 0.000 description 2
- MCMNRKCIXSYSNV-UHFFFAOYSA-N Zirconium dioxide Chemical compound O=[Zr]=O MCMNRKCIXSYSNV-UHFFFAOYSA-N 0.000 description 2
- 238000010521 absorption reaction Methods 0.000 description 2
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 2
- 238000007710 freezing Methods 0.000 description 2
- 230000008014 freezing Effects 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
- 238000005259 measurement Methods 0.000 description 2
- 238000002844 melting Methods 0.000 description 2
- 230000008018 melting Effects 0.000 description 2
- 238000002156 mixing Methods 0.000 description 2
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 2
- 239000012074 organic phase Substances 0.000 description 2
- 239000003960 organic solvent Substances 0.000 description 2
- 239000002244 precipitate Substances 0.000 description 2
- 230000001376 precipitating effect Effects 0.000 description 2
- 150000003839 salts Chemical class 0.000 description 2
- 239000007858 starting material Substances 0.000 description 2
- 238000003786 synthesis reaction Methods 0.000 description 2
- 238000002604 ultrasonography Methods 0.000 description 2
- DDIIYGHHUMKDGI-UHFFFAOYSA-N 5-fluoro-1,3-dihydroindol-2-one Chemical compound FC1=CC=C2NC(=O)CC2=C1 DDIIYGHHUMKDGI-UHFFFAOYSA-N 0.000 description 1
- HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 description 1
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonium chloride Substances [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 1
- 229920002785 Croscarmellose sodium Polymers 0.000 description 1
- 229910016523 CuKa Inorganic materials 0.000 description 1
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 description 1
- 206010061818 Disease progression Diseases 0.000 description 1
- 206010051066 Gastrointestinal stromal tumour Diseases 0.000 description 1
- 229930195725 Mannitol Natural products 0.000 description 1
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 description 1
- 229920003080 Povidone K 25 Polymers 0.000 description 1
- 150000004937 Sunitinib derivatives Chemical class 0.000 description 1
- 238000002441 X-ray diffraction Methods 0.000 description 1
- 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 1
- 239000000908 ammonium hydroxide Substances 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 239000012736 aqueous medium Substances 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 239000006059 cover glass Substances 0.000 description 1
- 229960001681 croscarmellose sodium Drugs 0.000 description 1
- 238000005384 cross polarization magic-angle spinning Methods 0.000 description 1
- 235000010947 crosslinked sodium carboxy methyl cellulose Nutrition 0.000 description 1
- 239000013058 crude material Substances 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- 238000000354 decomposition reaction Methods 0.000 description 1
- 230000002939 deleterious effect Effects 0.000 description 1
- 238000000113 differential scanning calorimetry Methods 0.000 description 1
- 230000005750 disease progression Effects 0.000 description 1
- UZUODNWWWUQRIR-UHFFFAOYSA-L disodium;3-aminonaphthalene-1,5-disulfonate Chemical compound [Na+].[Na+].C1=CC=C(S([O-])(=O)=O)C2=CC(N)=CC(S([O-])(=O)=O)=C21 UZUODNWWWUQRIR-UHFFFAOYSA-L 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- 210000004051 gastric juice Anatomy 0.000 description 1
- 201000011243 gastrointestinal stromal tumor Diseases 0.000 description 1
- 210000001035 gastrointestinal tract Anatomy 0.000 description 1
- 239000007887 hard shell capsule Substances 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 229960003685 imatinib mesylate Drugs 0.000 description 1
- YLMAHDNUQAMNNX-UHFFFAOYSA-N imatinib methanesulfonate Chemical compound CS(O)(=O)=O.C1CN(C)CCN1CC1=CC=C(C(=O)NC=2C=C(NC=3N=C(C=CN=3)C=3C=NC=CC=3)C(C)=CC=2)C=C1 YLMAHDNUQAMNNX-UHFFFAOYSA-N 0.000 description 1
- 239000005414 inactive ingredient Substances 0.000 description 1
- 230000009878 intermolecular interaction Effects 0.000 description 1
- 210000000936 intestine Anatomy 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 235000019359 magnesium stearate Nutrition 0.000 description 1
- 229940099690 malic acid Drugs 0.000 description 1
- 239000000594 mannitol Substances 0.000 description 1
- 235000010355 mannitol Nutrition 0.000 description 1
- 229960001855 mannitol Drugs 0.000 description 1
- 238000004949 mass spectrometry Methods 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 229940124303 multikinase inhibitor Drugs 0.000 description 1
- 238000000655 nuclear magnetic resonance spectrum Methods 0.000 description 1
- 239000000825 pharmaceutical preparation Substances 0.000 description 1
- 229940127557 pharmaceutical product Drugs 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 230000005855 radiation Effects 0.000 description 1
- 238000000371 solid-state nuclear magnetic resonance spectroscopy Methods 0.000 description 1
- 239000012453 solvate Substances 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 210000002784 stomach Anatomy 0.000 description 1
- 238000002411 thermogravimetry Methods 0.000 description 1
- 230000007704 transition Effects 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
- C07D403/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
Definitions
- the invention encompasses Sunitinib hemi-L-malate. In one embodiment, the invention encompasses a crystalline form of sunitinib hemi-
- Figure 8 illustrates a powder X-ray diffraction pattern of composition I containing Sunitinib base and L-malic acid.
- Figure 8a illustrates a powder X-ray diffraction pattern of composition I containing
- Figure lla illustrates a powder X-ray diffraction pattern of composition L containing Sunitinib base and L-malic acid (zoomed).
- Figure 21 illustrates a DSC thermogram of of sunitinib hemi-L-malate form U.
- Figure 37 illustrate a powder XRD pattern of crystalline Sunitinib base Form II.
- Sunitinib base characterized by crystalline Sunitinib base characterized by data selected from a group consisting of a PXRD pattern having any 5 peaks selected from the list consisting of: 3.8, 7.8, 9.0, 10.2, 11.8, 15.8, 17.9, 20.3, 26.1 and 26.8 deg ⁇ 0.2 degrees 2-theta, a PXRD pattern having peaks at about 9.0 and 26.1 ⁇ 0.2 degrees 2-theta and any 3 peaks at positions selected from the group consisting of 3.8, 7.8, 10.2, 11.8, 15.8, 17.9, 20.3 and 26.8 deg ⁇ 0.2 degrees 2-thetaa PXRD pattern as depicted in Figure 37 and combination thereof.
- the crystalline racemic sunitinib malate Form A can be further characterized by data selected from the group consisting of: a PXRD pattern having peaks at about 5.7, 8.0, 12.5, 14.7 and 18.3 ⁇ 0.2 degrees 2-theta; a PXRD pattern having peaks at about 5.7, 8.0, 9.3, 24.7 and 18.3 ⁇ 0.2 degrees 2-theta; and a PXRD pattern having a single peak at about 27.4 ⁇ 0.2 degrees 2-theta.
- the crystalline racemic sunitinib malate Form A can be prepared by a process comprising reacting Sunitinib base and racemic malic acid in ethanol to obtain a suspension comprising the said crystalline form.
- the said solution is maintained at the said temperature for a period of about 15 minutes to about 2 hours. More preferably, the said solution is maintained at the said temperature for a period of about 30 minutes.
- the present inventions encompasses crystalline sunitinib hemi-L-malate designated form E characterized by a PXRD pattern having peaks at about 6.8 and 11.3 ⁇ 0.2 degrees 2-theta and any 3 peaks at positions selected from the group consisting of: 3.7, 11.9, 15.1, 25.9 and 26.6 ⁇ 0.2 degrees 2-theta.
- Crystalline sunitinib hemi-L-malate can be further characterized by data selected from the group consisting of: a PXRD pattern having peaks at about 3.7, 6.8, 11.3, 11.9 and 25.9 ⁇ 0.2 degrees 2-theta.
- the aqueous solution is provided by combining sunitinib base, water and L- malic acid, and heating the combination.
- the heating is done to a temperature of about 100 0 C.
- L-malic acid in water to obtain a solution, and lyophilizing the solution; wherein the ratio of L-malic acid to water is about 34:1 w/v, respectively.
- the invention encompasses a composition containing Sunitinib base and L-malic acid characterized by data selected from a group consisting of a PXRD pattern having any 5 peaks at positions selected from the group consisting of: 6.0, 7.7, 9.2, 12.3, 14.5, 23.0 and 27.3 ⁇ 0.2 degrees 2-theta, a PXRD pattern as depicted in Figure 12, a PXRD pattern as depicted in Figure 12a and combination thereof.
- This composition can be designated as composition M.
- composition M can be further characterized by data selected from the group consisting of: a PXRD pattern having peaks at about 6.0, 9.2, 14.5, 23.0 and 27.3 ⁇ 0.2 degrees 2-theta; and a PXRD pattern having peaks at about 7.7, 9.2, 12.3, 14.5 and 23.0 ⁇ 0.2 degrees 2-theta.
- Composition M can be prepared by a process comprising heating Sunitinib malate to a temperature of about 50°C to 100°C. Preferably, heating is done to a temperature of about 8O 0 C. Preferably, heating is done for a period of about 30 minutes to about 4 hours. More preferably, heating is done for a period of about 2 hours.
- Composition N can be prepared by a process comprising dissolving sunitinib malate in a mixture of dioxane and water, and lyophilizing the solution. In the lyophilization process, the said solution is subjected to a pressure of less than about one atmosphere, to remove solvent.
- composition O can be further characterized by a PXRD pattern having four peaks at about 6.0, 7.4, 8.9 and 11.9 ⁇ 0.2 degrees 2-theta.
- the composition O can be prepared by a process comprising combining sunitinib base, L-malic acid, and a mixture of water, and tetrahydrofuran and evaporating the solvent.
- the solution is provided by combining sunitinib base, L-malic acid and a mixture of water and dioxane, and heating the said combination to obtain a solution.
- the invention encompasses a composition containing Sunitinib base and L-malic acid characterized by data selected from a group consisting of a PXRD pattern any 5 peaks at positions selected from the group consisting of: 3.4, 5.6, 9.6, 10.3,
- the invention encompasses a composition containing Sunitinib base and L-malic acid, characterized by a PXRD pattern having peaks at about 8.5 and 11.3 ⁇ 0.2 degrees 2-theta and any 3 peaks selected from a group consisting of 14.2, 23.2, 24.0 and 26.9 ⁇ 0.2 degrees 2-theta.
- Example 10 Preparation of composition H containing sunitinib base and L-malic acid. To sunitinib base (form VII, 300 mg) and L-malic acid (101 mg) was added TBME 10 ml) and the slurry was heated 10 min to reflux temperature facilitating formation of the titled composition (368 mg).
- Example 13 Preparation of composition O containing sunitinib base and L-malic acid.
- Sunitinib base (form X, dried 70°C, 2 h, 1 mBar, 150 mg)
- L-malic acid 50 mg in 3 ml of water, 1:1 molar
- THF 8 ml
- boiling to dissolution allowed to evaporate at 20°C to dryness in an open baker.
- Sunitinib base was dissolved in water (250 g) at about 40° by adjusting the pH to 1.5 with IN HCl. The solution was extracted with methyl isobutyl ketone (100 g), the phases were separated and to the aqueous phase dimethylacetamide (20 g) was added. Under strong stirring, the solution was adjusted to pH 8.5 by addition of 25% ammonium hydroxide solution. After one hour the suspension was filtered and the cake was rinsed with 200 g of water. The product was dried at 70° under vacuum overnight to give 12.6 g (56%) of Sunitinib base Form II.
- Sunitinib Base obtained by reaction of Sunitinib activated carboxylic acid derivative with excess of N,N'-diethylaminoethylamine in tetrahydrofuran, were dissolved with 150g of water and 5Og of HCl IM. The solution was washed with methyl isobutyl ketone at 50°C and then precipitated with ammonia 30% in water to pH 9, the product was filtered and dried in oven under vacuum at 60 0 C for 16 hours.
- the stirred suspension was cooled at room temperature for 2 hours and filtered; the cake was washed with 5O g of toluene and dried at 50° under vacuum overnight.
Landscapes
- Organic Chemistry (AREA)
- Chemical & Material Sciences (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| EP10166182A EP2253629A1 (de) | 2007-11-21 | 2008-11-21 | Polymorphe von racemischem Sunitinib-Malat, Zusammensetzungen enthaltend diese and ihre Herstellung |
Applications Claiming Priority (23)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US98956007P | 2007-11-21 | 2007-11-21 | |
| US3016708P | 2008-02-20 | 2008-02-20 | |
| US3177308P | 2008-02-27 | 2008-02-27 | |
| US4143908P | 2008-04-01 | 2008-04-01 | |
| US4213808P | 2008-04-03 | 2008-04-03 | |
| US4519608P | 2008-04-15 | 2008-04-15 | |
| US4846708P | 2008-04-28 | 2008-04-28 | |
| US4846008P | 2008-04-28 | 2008-04-28 | |
| US5805308P | 2008-06-02 | 2008-06-02 | |
| US5841708P | 2008-06-03 | 2008-06-03 | |
| US5908808P | 2008-06-05 | 2008-06-05 | |
| US5922208P | 2008-06-05 | 2008-06-05 | |
| US6106908P | 2008-06-12 | 2008-06-12 | |
| US6192008P | 2008-06-16 | 2008-06-16 | |
| US7865008P | 2008-07-07 | 2008-07-07 | |
| US8240508P | 2008-07-21 | 2008-07-21 | |
| US8415608P | 2008-07-28 | 2008-07-28 | |
| US8599108P | 2008-08-04 | 2008-08-04 | |
| US8785908P | 2008-08-11 | 2008-08-11 | |
| US8855408P | 2008-08-13 | 2008-08-13 | |
| US10152708P | 2008-09-30 | 2008-09-30 | |
| US10807808P | 2008-10-24 | 2008-10-24 | |
| PCT/US2008/084386 WO2009067686A2 (en) | 2007-11-21 | 2008-11-21 | Sunitinib hemi-l-malate, polymorphs and preparation thereof, polymorphs of racemic sunitinib malate, compositins containing sunitinib base and malic acid and preparation thereof |
Related Child Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| EP10166182.5 Division-Into | 2010-06-16 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| EP2220071A2 true EP2220071A2 (de) | 2010-08-25 |
Family
ID=40668097
Family Applications (3)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| EP08851719A Withdrawn EP2220071A2 (de) | 2007-11-21 | 2008-11-21 | Sunitinib-hemi-l-malat, polymorphe und herstellung davon, polymorphe von racemischem sunitinib-malat, sunitinib base und äpfelsäure enthaltende zusammensetzungen und herstellung davon |
| EP10166182A Withdrawn EP2253629A1 (de) | 2007-11-21 | 2008-11-21 | Polymorphe von racemischem Sunitinib-Malat, Zusammensetzungen enthaltend diese and ihre Herstellung |
| EP08852503A Withdrawn EP2220072A2 (de) | 2007-11-21 | 2008-11-21 | Polymorphe von sunitinib-base und verfahren zu deren herstellung |
Family Applications After (2)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| EP10166182A Withdrawn EP2253629A1 (de) | 2007-11-21 | 2008-11-21 | Polymorphe von racemischem Sunitinib-Malat, Zusammensetzungen enthaltend diese and ihre Herstellung |
| EP08852503A Withdrawn EP2220072A2 (de) | 2007-11-21 | 2008-11-21 | Polymorphe von sunitinib-base und verfahren zu deren herstellung |
Country Status (4)
| Country | Link |
|---|---|
| EP (3) | EP2220071A2 (de) |
| KR (1) | KR20100069705A (de) |
| CA (2) | CA2699306A1 (de) |
| WO (2) | WO2009067674A2 (de) |
Families Citing this family (22)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CA2720164A1 (en) * | 2008-03-31 | 2009-10-08 | Teva Pharmaceutical Industries Ltd. | Processes for preparing sunitinib and salts thereof |
| KR20100135910A (ko) | 2008-04-16 | 2010-12-27 | 낫코 파마 리미티드 | 수니티닙 염기의 신규한 다형 형태 |
| WO2009156837A2 (en) * | 2008-06-26 | 2009-12-30 | Medichem, S.A. | Amorphous form of a 3-pyrrole substituted 2-indolinone malate salt |
| CN102203085A (zh) * | 2008-07-10 | 2011-09-28 | 基因里克斯(英国)有限公司 | 用于制备苹果酸舒尼替尼晶体形式的新方法 |
| WO2010011834A2 (en) * | 2008-07-24 | 2010-01-28 | Teva Pharmaceutical Industries Ltd. | Sunitinib and salts thereof and their polymorphs |
| EP2342195B1 (de) | 2008-07-24 | 2014-09-10 | Medichem, S.A. | Kristalline formen eines 3-pyrrolsubstituierten 2-indolinonmalatsalzes |
| CA2735084A1 (en) * | 2008-08-25 | 2010-03-04 | Generics [Uk] Limited | Novel polymorphs of sunitinib and processes for their preparation |
| CN102197035A (zh) * | 2008-08-25 | 2011-09-21 | 基因里克斯(英国)有限公司 | 舒尼替尼的结晶形式及其制备方法 |
| EP2181991A1 (de) | 2008-10-28 | 2010-05-05 | LEK Pharmaceuticals D.D. | Neuartige Sunitinib-Salze |
| EP2186809A1 (de) * | 2008-11-13 | 2010-05-19 | LEK Pharmaceuticals D.D. | Neue kristalline Form von Sunitinib-Malat |
| CA2774634A1 (en) | 2009-09-16 | 2011-03-24 | Ranbaxy Laboratories Limited | Salts of sunitinib |
| EP2499133A2 (de) * | 2009-11-12 | 2012-09-19 | Ranbaxy Laboratories Limited | Verfahren zur herstellung einer kristallinen form i von l-apfelsäuresalz aus sunitinib |
| US8916716B2 (en) | 2009-11-19 | 2014-12-23 | Ranbaxy Laboratories Limited | Process for the preparation of crystalline form II of L-malic acid salt of sunitinib |
| WO2011092664A1 (en) | 2010-01-29 | 2011-08-04 | Ranbaxy Laboratories Limited | Crystalline forms of l-malic acid salt of sunitinib |
| WO2011100325A2 (en) | 2010-02-09 | 2011-08-18 | Sicor Inc. | Polymorphs of sunitinib salts |
| AU2011222470A1 (en) | 2010-03-04 | 2012-09-27 | Ranbaxy Laboratories Limited | Process for the direct preparation of malic acid salt of sunitinib |
| US20160185760A1 (en) | 2010-03-18 | 2016-06-30 | Ranbaxy Laboratories Limited | Process for the preparation of malic acid salt of sunitinib |
| CN103833733B (zh) * | 2012-11-21 | 2017-08-25 | 广东东阳光药业有限公司 | 一种替尼类药物新晶型 |
| PT3039424T (pt) | 2013-08-28 | 2020-09-03 | Crown Bioscience Inc Taicang | Assinaturas de expressão genética que permitem prever a resposta de um sujeito a um inibidor multiquinase e métodos de utilização do mesmo |
| CA2838587A1 (en) * | 2013-10-18 | 2015-04-18 | Hari Babu Matta | Pure crystalline form ii of l-malic acid salt of sunitinib and processes for its preparation |
| RU2567535C1 (ru) * | 2014-10-01 | 2015-11-10 | Олег Ростиславович Михайлов | КРИСТАЛЛИЧЕСКАЯ ε-МОДИФИКАЦИЯ N-[2-(ДИЭТИЛАМИНО)ЭТИЛ]-5-[(Z)-(5-ФТОР-1,2-ДИГИДРО-2-ОКСО-3Н-ИНДОЛ-3-ИЛИДЕН)МЕТИЛ]-2,4-ДИМЕТИЛ-1Н-ПИРРОЛ-3-КАРБОКСАМИД МАЛАТА, СПОСОБ ЕЕ ПОЛУЧЕНИЯ И ФАРМАЦЕВТИЧЕСКАЯ КОМПОЗИЦИЯ НА ЕЕ ОСНОВЕ |
| WO2020216450A1 (en) | 2019-04-25 | 2020-10-29 | Synthon B.V. | Pharmaceutical composition comprising amorphous sunitinib |
Family Cites Families (11)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| SI1255752T1 (sl) * | 2000-02-15 | 2007-12-31 | Pharmacia & Upjohn Co Llc | S pirolom substituirani zaviralci 2-indolinon protein kinaza |
| GEP20063777B (en) | 2001-08-15 | 2006-03-27 | Upjohn Co | Crystals Including Malic Acid Salt of N-[2-(Diethylamino) Ethyl]-5-[(5-Fluoro-2-Oxo-3h-Indole-3-Ylidene) Methyl]-2, 4-Dimethyl-1h-Pyrrole-3-Carboxamide, Processes for Its Preparation and Compositions Thereof |
| EP1476443A2 (de) * | 2002-02-15 | 2004-11-17 | PHARMACIA & UPJOHN COMPANY | Prozess zur herstellung von indolinon-derivativen |
| PY0323128A (es) * | 2002-09-10 | 2012-12-03 | Pharmacia Italia Spa | Formulacion sólida que comprende un compuesto de indolina, útil en el tratamiento de trastornos relacionados con proteina de quinasas |
| US20060009510A1 (en) * | 2004-07-09 | 2006-01-12 | Pharmacia & Upjohn Company Llc | Method of synthesizing indolinone compounds |
| RU2007141654A (ru) * | 2005-05-12 | 2009-05-20 | Пфайзер Инк. (US) | Противоопухолевая комбинированная терапия, в которой используется сунитиниб-малат |
| CN101939314B (zh) * | 2007-12-12 | 2014-04-02 | 麦迪凯姆股份公司 | 3-吡咯取代的2-吲哚酮的多晶型物 |
| EP2098521A1 (de) * | 2008-03-06 | 2009-09-09 | Ratiopharm GmbH | Kristalline Formen von N-[2-(diethylamino)-Ethyl]-5-[Fluor-1,2-dihydro-2-oxo-3H-Indol-3-yliden)methyl]-2,4-Dimethyl-1H-Pyroll-3-Carboxamid und Verfahren zu ihrer Herstellung |
| KR20100135910A (ko) * | 2008-04-16 | 2010-12-27 | 낫코 파마 리미티드 | 수니티닙 염기의 신규한 다형 형태 |
| KR20110036055A (ko) * | 2008-06-23 | 2011-04-06 | 낫코 파마 리미티드 | 고순도의 수니티닙 및 이의 약학적으로 허용가능한 염의 개선된 제조 방법 |
| AU2009265360A1 (en) * | 2008-07-02 | 2010-01-07 | Generics [Uk] Limited | Preparation of 3-pyrrole substituted 2-indolinone derivatives |
-
2008
- 2008-11-21 EP EP08851719A patent/EP2220071A2/de not_active Withdrawn
- 2008-11-21 CA CA2699306A patent/CA2699306A1/en not_active Abandoned
- 2008-11-21 CA CA2699305A patent/CA2699305A1/en not_active Abandoned
- 2008-11-21 EP EP10166182A patent/EP2253629A1/de not_active Withdrawn
- 2008-11-21 WO PCT/US2008/084366 patent/WO2009067674A2/en not_active Ceased
- 2008-11-21 EP EP08852503A patent/EP2220072A2/de not_active Withdrawn
- 2008-11-21 WO PCT/US2008/084386 patent/WO2009067686A2/en not_active Ceased
- 2008-11-21 KR KR1020107010188A patent/KR20100069705A/ko not_active Ceased
Non-Patent Citations (1)
| Title |
|---|
| See references of WO2009067686A2 * |
Also Published As
| Publication number | Publication date |
|---|---|
| EP2253629A1 (de) | 2010-11-24 |
| WO2009067686A3 (en) | 2009-11-12 |
| WO2009067674A2 (en) | 2009-05-28 |
| CA2699306A1 (en) | 2009-05-28 |
| WO2009067674A3 (en) | 2009-08-27 |
| CA2699305A1 (en) | 2009-05-28 |
| KR20100069705A (ko) | 2010-06-24 |
| WO2009067686A8 (en) | 2009-07-16 |
| EP2220072A2 (de) | 2010-08-25 |
| WO2009067686A2 (en) | 2009-05-28 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| EP2253629A1 (de) | Polymorphe von racemischem Sunitinib-Malat, Zusammensetzungen enthaltend diese and ihre Herstellung | |
| US8703967B2 (en) | Crystal form of sunitinib malate | |
| EP2247585B1 (de) | Kristalline formen von n-[2-(diethylamino-)ethyl]-5-[(5-fluor-1,2-dihydro-2-oxo-3h-indol-3-yliden-)methyl]-2,4-dimethyl-1h-pyrrol-3-carboxamid und verfahren zu ihrer herstellung | |
| US20090221595A1 (en) | Crystalline form of sitagliptin | |
| EP2207777A2 (de) | Dasatinib-polymorphe und verfahren zu ihrer herstellung | |
| JP2011512396A (ja) | 新規な多形およびその調製方法 | |
| US7759481B2 (en) | Solid state forms of 5-azacytidine and processes for preparation thereof | |
| EP2297092A1 (de) | Polymorphe und amorphe formen von lacosamid und amorphe zusammensetzungen | |
| US8252805B2 (en) | Forms of lapatinib ditosylate and processes for preparation thereof | |
| EP4153551A1 (de) | Festkörperformen von tapinarof | |
| WO2010027848A2 (en) | Forms of lapatinib compounds and processes for the preparation thereof | |
| US20210163498A1 (en) | Solid state forms of lorlatinib and their preparation | |
| US20100256392A1 (en) | Polymorphs of sunitinib base and processes for preparation thereof | |
| WO2011100325A2 (en) | Polymorphs of sunitinib salts | |
| US20090030207A1 (en) | Polymorphs of Dolasetron base and process for preparation thereof | |
| WO2008081475A2 (en) | Novel crystalline forms of zolmitriptan |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PUAI | Public reference made under article 153(3) epc to a published international application that has entered the european phase |
Free format text: ORIGINAL CODE: 0009012 |
|
| 17P | Request for examination filed |
Effective date: 20100526 |
|
| AK | Designated contracting states |
Kind code of ref document: A2 Designated state(s): AT BE BG CH CY CZ DE DK EE ES FI FR GB GR HR HU IE IS IT LI LT LU LV MC MT NL NO PL PT RO SE SI SK TR |
|
| AX | Request for extension of the european patent |
Extension state: AL BA MK RS |
|
| DAX | Request for extension of the european patent (deleted) | ||
| 17Q | First examination report despatched |
Effective date: 20120301 |
|
| STAA | Information on the status of an ep patent application or granted ep patent |
Free format text: STATUS: THE APPLICATION IS DEEMED TO BE WITHDRAWN |
|
| 18D | Application deemed to be withdrawn |
Effective date: 20120601 |