WO2022271109A1 - New polymorph of vismodegib and method for its preparation - Google Patents
New polymorph of vismodegib and method for its preparation Download PDFInfo
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- WO2022271109A1 WO2022271109A1 PCT/TR2021/050644 TR2021050644W WO2022271109A1 WO 2022271109 A1 WO2022271109 A1 WO 2022271109A1 TR 2021050644 W TR2021050644 W TR 2021050644W WO 2022271109 A1 WO2022271109 A1 WO 2022271109A1
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- WO
- WIPO (PCT)
- Prior art keywords
- vismodegib
- crystalline form
- stirred
- mixture
- equiv
- Prior art date
Links
- BPQMGSKTAYIVFO-UHFFFAOYSA-N vismodegib Chemical compound ClC1=CC(S(=O)(=O)C)=CC=C1C(=O)NC1=CC=C(Cl)C(C=2N=CC=CC=2)=C1 BPQMGSKTAYIVFO-UHFFFAOYSA-N 0.000 title claims abstract description 95
- 229960004449 vismodegib Drugs 0.000 title claims abstract description 91
- 238000000034 method Methods 0.000 title claims description 12
- 238000002360 preparation method Methods 0.000 title abstract description 10
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 8
- 238000000634 powder X-ray diffraction Methods 0.000 claims abstract description 7
- 206010004146 Basal cell carcinoma Diseases 0.000 claims description 5
- 239000003814 drug Substances 0.000 claims description 4
- 238000004519 manufacturing process Methods 0.000 claims description 4
- 238000001938 differential scanning calorimetry curve Methods 0.000 claims description 2
- 238000002329 infrared spectrum Methods 0.000 claims description 2
- 239000000546 pharmaceutical excipient Substances 0.000 claims 1
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 90
- 239000000203 mixture Substances 0.000 description 54
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 36
- 239000000047 product Substances 0.000 description 31
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 30
- 229960004592 isopropanol Drugs 0.000 description 30
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 24
- 238000004128 high performance liquid chromatography Methods 0.000 description 21
- 238000003756 stirring Methods 0.000 description 19
- 239000013078 crystal Substances 0.000 description 18
- 238000001816 cooling Methods 0.000 description 16
- 238000001914 filtration Methods 0.000 description 14
- 239000008186 active pharmaceutical agent Substances 0.000 description 11
- 239000002904 solvent Substances 0.000 description 11
- QWVLHTCIAZPQAY-UHFFFAOYSA-N 4-chloro-3-pyridin-2-ylaniline Chemical compound NC1=CC=C(Cl)C(C=2N=CC=CC=2)=C1 QWVLHTCIAZPQAY-UHFFFAOYSA-N 0.000 description 10
- 238000006243 chemical reaction Methods 0.000 description 10
- CTTWSFIIFMWHLQ-UHFFFAOYSA-N 2-chloro-4-methylsulfonylbenzoic acid Chemical compound CS(=O)(=O)C1=CC=C(C(O)=O)C(Cl)=C1 CTTWSFIIFMWHLQ-UHFFFAOYSA-N 0.000 description 9
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 9
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 9
- 239000011541 reaction mixture Substances 0.000 description 8
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 8
- 239000012043 crude product Substances 0.000 description 7
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 7
- 239000000126 substance Substances 0.000 description 7
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 6
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 6
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 description 6
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 6
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 6
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 description 6
- 238000005033 Fourier transform infrared spectroscopy Methods 0.000 description 5
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 5
- 238000000113 differential scanning calorimetry Methods 0.000 description 5
- 238000010438 heat treatment Methods 0.000 description 5
- 239000000825 pharmaceutical preparation Substances 0.000 description 5
- 229940127557 pharmaceutical product Drugs 0.000 description 5
- 230000008569 process Effects 0.000 description 5
- 239000007787 solid Substances 0.000 description 5
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 4
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 4
- 229940079593 drug Drugs 0.000 description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 3
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 3
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 3
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 3
- AMQJEAYHLZJPGS-UHFFFAOYSA-N N-Pentanol Chemical compound CCCCCO AMQJEAYHLZJPGS-UHFFFAOYSA-N 0.000 description 3
- DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 description 3
- BTANRVKWQNVYAZ-UHFFFAOYSA-N butan-2-ol Chemical compound CCC(C)O BTANRVKWQNVYAZ-UHFFFAOYSA-N 0.000 description 3
- 239000012535 impurity Substances 0.000 description 3
- 239000002245 particle Substances 0.000 description 3
- 238000003860 storage Methods 0.000 description 3
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 3
- 230000009466 transformation Effects 0.000 description 3
- 229940044613 1-propanol Drugs 0.000 description 2
- ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-Butanone Chemical compound CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 description 2
- DLFVBJFMPXGRIB-UHFFFAOYSA-N Acetamide Chemical compound CC(N)=O DLFVBJFMPXGRIB-UHFFFAOYSA-N 0.000 description 2
- ZHNUHDYFZUAESO-UHFFFAOYSA-N Formamide Chemical compound NC=O ZHNUHDYFZUAESO-UHFFFAOYSA-N 0.000 description 2
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 2
- PXHVJJICTQNCMI-UHFFFAOYSA-N Nickel Chemical compound [Ni] PXHVJJICTQNCMI-UHFFFAOYSA-N 0.000 description 2
- XBDQKXXYIPTUBI-UHFFFAOYSA-M Propionate Chemical compound CCC([O-])=O XBDQKXXYIPTUBI-UHFFFAOYSA-M 0.000 description 2
- 239000004480 active ingredient Substances 0.000 description 2
- 239000013543 active substance Substances 0.000 description 2
- 238000005102 attenuated total reflection Methods 0.000 description 2
- MVPPADPHJFYWMZ-UHFFFAOYSA-N chlorobenzene Chemical compound ClC1=CC=CC=C1 MVPPADPHJFYWMZ-UHFFFAOYSA-N 0.000 description 2
- 230000008878 coupling Effects 0.000 description 2
- 238000010168 coupling process Methods 0.000 description 2
- 238000005859 coupling reaction Methods 0.000 description 2
- DMEGYFMYUHOHGS-UHFFFAOYSA-N cycloheptane Chemical compound C1CCCCCC1 DMEGYFMYUHOHGS-UHFFFAOYSA-N 0.000 description 2
- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 2
- 238000004090 dissolution Methods 0.000 description 2
- 238000009472 formulation Methods 0.000 description 2
- 239000012458 free base Substances 0.000 description 2
- ZSIAUFGUXNUGDI-UHFFFAOYSA-N hexan-1-ol Chemical compound CCCCCCO ZSIAUFGUXNUGDI-UHFFFAOYSA-N 0.000 description 2
- ZXEKIIBDNHEJCQ-UHFFFAOYSA-N isobutanol Chemical compound CC(C)CO ZXEKIIBDNHEJCQ-UHFFFAOYSA-N 0.000 description 2
- JMMWKPVZQRWMSS-UHFFFAOYSA-N isopropanol acetate Natural products CC(C)OC(C)=O JMMWKPVZQRWMSS-UHFFFAOYSA-N 0.000 description 2
- 229940011051 isopropyl acetate Drugs 0.000 description 2
- GWYFCOCPABKNJV-UHFFFAOYSA-N isovaleric acid Chemical compound CC(C)CC(O)=O GWYFCOCPABKNJV-UHFFFAOYSA-N 0.000 description 2
- 229940126601 medicinal product Drugs 0.000 description 2
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 2
- JYVLIDXNZAXMDK-UHFFFAOYSA-N pentan-2-ol Chemical compound CCCC(C)O JYVLIDXNZAXMDK-UHFFFAOYSA-N 0.000 description 2
- XNLICIUVMPYHGG-UHFFFAOYSA-N pentan-2-one Chemical compound CCCC(C)=O XNLICIUVMPYHGG-UHFFFAOYSA-N 0.000 description 2
- FDPIMTJIUBPUKL-UHFFFAOYSA-N pentan-3-one Chemical compound CCC(=O)CC FDPIMTJIUBPUKL-UHFFFAOYSA-N 0.000 description 2
- 230000000704 physical effect Effects 0.000 description 2
- 239000000843 powder Substances 0.000 description 2
- 238000012545 processing Methods 0.000 description 2
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 2
- 230000005855 radiation Effects 0.000 description 2
- 238000010992 reflux Methods 0.000 description 2
- 239000012453 solvate Substances 0.000 description 2
- 238000001356 surgical procedure Methods 0.000 description 2
- VZGDMQKNWNREIO-UHFFFAOYSA-N tetrachloromethane Chemical compound ClC(Cl)(Cl)Cl VZGDMQKNWNREIO-UHFFFAOYSA-N 0.000 description 2
- 230000001225 therapeutic effect Effects 0.000 description 2
- 238000001757 thermogravimetry curve Methods 0.000 description 2
- 238000000844 transformation Methods 0.000 description 2
- DNIAPMSPPWPWGF-GSVOUGTGSA-N (R)-(-)-Propylene glycol Chemical compound C[C@@H](O)CO DNIAPMSPPWPWGF-GSVOUGTGSA-N 0.000 description 1
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 description 1
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 1
- DURPTKYDGMDSBL-UHFFFAOYSA-N 1-butoxybutane Chemical compound CCCCOCCCC DURPTKYDGMDSBL-UHFFFAOYSA-N 0.000 description 1
- XNWFRZJHXBZDAG-UHFFFAOYSA-N 2-METHOXYETHANOL Chemical compound COCCO XNWFRZJHXBZDAG-UHFFFAOYSA-N 0.000 description 1
- QQZOPKMRPOGIEB-UHFFFAOYSA-N 2-Oxohexane Chemical compound CCCCC(C)=O QQZOPKMRPOGIEB-UHFFFAOYSA-N 0.000 description 1
- CLCPHXRHYYEUME-UHFFFAOYSA-N 2-chloro-4-methylsulfonylbenzoyl chloride Chemical compound CS(=O)(=O)C1=CC=C(C(Cl)=O)C(Cl)=C1 CLCPHXRHYYEUME-UHFFFAOYSA-N 0.000 description 1
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 description 1
- DKPFZGUDAPQIHT-UHFFFAOYSA-N Butyl acetate Natural products CCCCOC(C)=O DKPFZGUDAPQIHT-UHFFFAOYSA-N 0.000 description 1
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 description 1
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 description 1
- NTIZESTWPVYFNL-UHFFFAOYSA-N Methyl isobutyl ketone Chemical compound CC(C)CC(C)=O NTIZESTWPVYFNL-UHFFFAOYSA-N 0.000 description 1
- UIHCLUNTQKBZGK-UHFFFAOYSA-N Methyl isobutyl ketone Natural products CCC(C)C(C)=O UIHCLUNTQKBZGK-UHFFFAOYSA-N 0.000 description 1
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 1
- LKJPYSCBVHEWIU-UHFFFAOYSA-N N-[4-cyano-3-(trifluoromethyl)phenyl]-3-[(4-fluorophenyl)sulfonyl]-2-hydroxy-2-methylpropanamide Chemical compound C=1C=C(C#N)C(C(F)(F)F)=CC=1NC(=O)C(O)(C)CS(=O)(=O)C1=CC=C(F)C=C1 LKJPYSCBVHEWIU-UHFFFAOYSA-N 0.000 description 1
- 206010028980 Neoplasm Diseases 0.000 description 1
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 description 1
- 235000011054 acetic acid Nutrition 0.000 description 1
- KXKVLQRXCPHEJC-UHFFFAOYSA-N acetic acid trimethyl ester Natural products COC(C)=O KXKVLQRXCPHEJC-UHFFFAOYSA-N 0.000 description 1
- 230000002411 adverse Effects 0.000 description 1
- 238000005280 amorphization Methods 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 229940043232 butyl acetate Drugs 0.000 description 1
- 201000011510 cancer Diseases 0.000 description 1
- 230000015556 catabolic process Effects 0.000 description 1
- 230000008859 change Effects 0.000 description 1
- 238000007906 compression Methods 0.000 description 1
- 230000006835 compression Effects 0.000 description 1
- WJTCGQSWYFHTAC-UHFFFAOYSA-N cyclooctane Chemical compound C1CCCCCCC1 WJTCGQSWYFHTAC-UHFFFAOYSA-N 0.000 description 1
- 239000004914 cyclooctane Substances 0.000 description 1
- 238000006731 degradation reaction Methods 0.000 description 1
- 230000018044 dehydration Effects 0.000 description 1
- 238000006297 dehydration reaction Methods 0.000 description 1
- 238000004807 desolvation Methods 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 239000003937 drug carrier Substances 0.000 description 1
- 238000012362 drug development process Methods 0.000 description 1
- 229940014684 erivedge Drugs 0.000 description 1
- 229940093499 ethyl acetate Drugs 0.000 description 1
- 238000005755 formation reaction Methods 0.000 description 1
- 235000019253 formic acid Nutrition 0.000 description 1
- WBJINCZRORDGAQ-UHFFFAOYSA-N formic acid ethyl ester Natural products CCOC=O WBJINCZRORDGAQ-UHFFFAOYSA-N 0.000 description 1
- 230000009477 glass transition Effects 0.000 description 1
- 238000000227 grinding Methods 0.000 description 1
- FUZZWVXGSFPDMH-UHFFFAOYSA-N hexanoic acid Chemical compound CCCCCC(O)=O FUZZWVXGSFPDMH-UHFFFAOYSA-N 0.000 description 1
- 230000036571 hydration Effects 0.000 description 1
- 238000006703 hydration reaction Methods 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 239000000543 intermediate Substances 0.000 description 1
- 230000009878 intermolecular interaction Effects 0.000 description 1
- GJRQTCIYDGXPES-UHFFFAOYSA-N iso-butyl acetate Natural products CC(C)COC(C)=O GJRQTCIYDGXPES-UHFFFAOYSA-N 0.000 description 1
- FGKJLKRYENPLQH-UHFFFAOYSA-M isocaproate Chemical compound CC(C)CCC([O-])=O FGKJLKRYENPLQH-UHFFFAOYSA-M 0.000 description 1
- OQAGVSWESNCJJT-UHFFFAOYSA-N isovaleric acid methyl ester Natural products COC(=O)CC(C)C OQAGVSWESNCJJT-UHFFFAOYSA-N 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 230000001394 metastastic effect Effects 0.000 description 1
- 206010061289 metastatic neoplasm Diseases 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 230000002906 microbiologic effect Effects 0.000 description 1
- 238000003801 milling Methods 0.000 description 1
- DNIAPMSPPWPWGF-UHFFFAOYSA-N monopropylene glycol Natural products CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 1
- YKYONYBAUNKHLG-UHFFFAOYSA-N n-Propyl acetate Natural products CCCOC(C)=O YKYONYBAUNKHLG-UHFFFAOYSA-N 0.000 description 1
- 229910052759 nickel Inorganic materials 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 235000019260 propionic acid Nutrition 0.000 description 1
- 229940090181 propyl acetate Drugs 0.000 description 1
- 235000013772 propylene glycol Nutrition 0.000 description 1
- IUVKMZGDUIUOCP-BTNSXGMBSA-N quinbolone Chemical compound O([C@H]1CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)CC[C@@]21C)C1=CCCC1 IUVKMZGDUIUOCP-BTNSXGMBSA-N 0.000 description 1
- -1 reaction steps Substances 0.000 description 1
- 238000012827 research and development Methods 0.000 description 1
- 238000005070 sampling Methods 0.000 description 1
- 239000002002 slurry Substances 0.000 description 1
- 230000008410 smoothened signaling pathway Effects 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 238000013112 stability test Methods 0.000 description 1
- HXJUTPCZVOIRIF-UHFFFAOYSA-N sulfolane Chemical compound O=S1(=O)CCCC1 HXJUTPCZVOIRIF-UHFFFAOYSA-N 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- WMOVHXAZOJBABW-UHFFFAOYSA-N tert-butyl acetate Chemical compound CC(=O)OC(C)(C)C WMOVHXAZOJBABW-UHFFFAOYSA-N 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- 230000002110 toxicologic effect Effects 0.000 description 1
- 231100000027 toxicology Toxicity 0.000 description 1
- NQPDZGIKBAWPEJ-UHFFFAOYSA-N valeric acid Chemical compound CCCCC(O)=O NQPDZGIKBAWPEJ-UHFFFAOYSA-N 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
- 239000003643 water by type Substances 0.000 description 1
- 238000005550 wet granulation Methods 0.000 description 1
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Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
- C07D213/36—Radicals substituted by singly-bound nitrogen atoms
- C07D213/40—Acylated substituent nitrogen atom
Definitions
- the present invention relates to a novel crystalline polymorphic form of vismodegib designated as Form X and process for its preparation.
- the invention further relates to pharmaceutical compositions comprising Form X and use of Form X in the treatment of cancer.
- Vismodegib is an oral Hedgehog signaling pathway inhibitor, which is approved for treatment of adults with metastatic basal cell carcinoma, or with locally advanced basal cell carcinoma that has recurred following surgery or who are not candidates for surgery and who are not candidates for radiation. Vismodegib is marketed by Genentech under the brand name ERIVEDGE ® . Vismodegib is chemically designated as 2-chloro- V-(4-chloro-3-(pyridin-2- yl)phenyl)-4-(methylsulfonyl)benzamide and represented by the following chemical structure;
- vismodegib The preparation and therapeutic use of vismodegib have been described for the first time in European patent EP 1789390, according to which vismodegib is prepared by coupling 4- chloro-3-(pyridin-2-yl)aniline and 2-chloro-4-methylsulfonylbenzoic acid or by coupling 4- chloro-3-(pyridin-2-yl)aniline and 2-chloro-4-(methylsulfonyl)benzoyl chloride. Vismodegib may exist in different polymorphic forms.
- European patent EP 1789390 discloses a crystalline free base of vismodegib, but polymorphic form of crystalline form is not defined or characterized. On the other hand, process for the preparation of said crystalline free base of vismodegib in European patent EP 1789390 was repeated in WO 2014195977. According to the teachings of European patent EP 1789390, prior art form of vismodegib was obtained by crystallizing vismodegib with acetone and ethyl acetate, then by recrystallizing from hot slurry of isopropyl acetate. The crystalline polymorphic form of vismodegib obtained by said process designated as Form I. The X-ray powder diffractogram (XRPD) of Form I was shown in Figure 1 of WO 2014195977.
- XRPD X-ray powder diffractogram
- WO2014195977 further discloses two polymorphic forms of vismodegib labeled as Form II, Form III and preparation thereof.
- the object of the present invention is to provide a new polymorphic form of vismodegib and process for the preparation of this novel polymorphic form of vismodegib.
- Another object of the present invention is to provide pharmaceutical compositions comprising new polymorphic form of vismodegib.
- Active pharmaceutical ingredients are individual components or mixture of components that are used as a part of a finished pharmaceutical drug or medicinal product, where they provide the pharmacological activity.
- Polymorphism the occurrence of different crystal forms, is a property of some molecules and molecular complexes. A single molecule, may give rise to a variety of crystalline forms having distinct crystal structures and physical properties. The difference in the physical properties of different crystalline forms results from the orientation and intermolecular interactions of adjacent molecules or complexes in the bulk solid.
- composition is affected by polymorphic form of the pharmaceutically active substance.
- invention relates to a novel solid form of vismodegib.
- this new form of vismodegib besides being stable, meet the pharmaceutical requirements such as storage, shelf life, solubility and high purity.
- a first aspect of the present invention relates to a novel polymorphic form of vismodegib.
- This new anhydrous form hereinafter is referred as crystalline Form X of vismodegib.
- Form X is characterized by an XRPD pattern having characteristic peaks at 9.37 ⁇ 0.2, 11.49 ⁇ 0.2, 15.70 ⁇ 0.2, 16.56 ⁇ 0.2, 18.84 ⁇ 0.2, 18.95 ⁇ 0.2 and 23.85 ⁇ 0.2 degree 2-theta.
- Form X of vismodegib can be characterized by an XRPD pattern with characteristic peaks at 10.61 ⁇ 0.2, 12.10 ⁇ 0.2, 15.94 ⁇ 0.2, 17.27 ⁇ 0.2, 21.36 ⁇ 0.2, 23.56 ⁇ 0.2, 25.85 ⁇ 0.2 and 28.42 ⁇ 0.2 degree 2-theta.
- Form X is characterized by a powder X-ray diffraction pattern, as shown in figure 1.
- Form X is also characterized by an IR spectrum, as shown in figure 3 and characterized by a DSC thermogram, as shown in figure 4.
- a second aspect of the present invention relates to a process for preparing novel polymorphic Form X of vismodegib.
- the Form X according to the present invention may be obtained by: a) providing a solution of dissolving vismodegib in a suitable organic solvent, b) heating and stirring the solution at a suitable temperature, c) cooling the solution to room temperature, d) filtering and isolating the obtained solid, e) washing the obtained solid as pure crystalline vismodegib designated as Form X with C1-C5 alcohol.
- suitable solvent in step (a) is selected from, 2-propanol, 1 -propanol, 1 -butanol, 2- butanol, tert-butyl alcohol, 1-pentanol, 2-pentanol, amyl alcohol, ethylene glycol, glycerol, acetone, butanone, 2-pentanone, 3-pentanone, methyl butyl ketone, methyl isobutyl ketone, ethyl formate, methyl acetate, ethyl acetate, propyl acetate, isopropyl acetate, butyl acetate, isobutyl acetate, tert- butyl acetate, toluene, xylene, chloroform, dichloromethane, carbon tetrachloride, ethylene dichloride, chlorobenzene, acetonitrile, diethyl ether, diisopropyl ether, tert-but
- the suitable temperature used in step (b) is selected from room temperature to reflux temperature of the solvent used.
- the process of the present invention affords Form X of vismodegib in high purity and high yield.
- the Form X of vismodegib is obtained having purity greater than 99% by area percentage in HPLC.
- Stability plays an important role in the drug development process. Stability of a pharmaceutical product may be defined as the capability of that particular formulation, in a specific container or closure system, to remain within its chemical, physical, microbiological, therapeutic and toxicological specifications to assure its attributed quality, e.g., identity, purity, strength etc. until drug expiry.
- Stability of a pharmaceutical product is strongly influenced by changes in solid-state form of the API.
- the changes in solid state form of the API may be resulted from the conditions of product manufacturing process. Examples of processing that may cause polymorphic changes including grinding, milling, heating, and applying compression. Manufacturing conditions that include a solvent (e.g., wet granulation, polymorphs in solution, and polymorphs in suspension) may facilitate changes in the solid-state form of API.
- solvent e.g., wet granulation, polymorphs in solution, and polymorphs in suspension
- These variations comprising polymorphic transformations, hydrate/solvate formations and dehydration/desolvation reactions in the solid-state form of API, may cause stability problems in finished pharmaceutical products. Therefore, crystalline stability of API has a critical role on satisfying the essentialities of qualified pharmaceutical product and stable polymorphs of API should be used in pharmaceutical formulations.
- crystalline stability of Form X of vismodegib was investigated under the following conditions: a sample was kept in an open flask at 105 °C for 30 days, packed samples were kept at 40 °C under 75% relative humidity (RH) and at 25 °C under 60% relative humidity (RH) for 6 months.
- the crystalline stability referred here is the stability of a polymorphic form of API with respect to polymorph transformations, hydration, or amorphization through time under these conditions.
- Crystalline Form X showed crystalline stability under dry heating at 105 °C for 30 days, at 40 °C / 75% RH and at 25 °C / 60% RH for 6 months.
- the chemical stability of crystalline Form X of vismodegib is also important and its stability in finished product at room-temperature storage can be predicted from shorter-term storage under accelerated conditions of high temperature and humidity.
- samples of obtained crystalline Form X of vismodegib were kept under dry heating in open flask at 105 °C for 30 days in an oven, and in FDPE pack at 40 °C & 75% RH and at 25 °C & 60% RH for 6 months in stability chambers to test chemical stability.
- the chemical stability of the samples was determined by HPFC method. Table 1 shows the stability results of vismodegib Form X prepared according to the present invention. Form X samples stayed stable under all conditions without any change in the impurity profile and without increase in the impurity amounts.
- a third aspect of the present invention relates to pharmaceutical compositions comprising crystalline Form X of vismodegib along with a pharmaceutically acceptable carrier.
- Fig. 1 shows the X-Ray Powder Diffraction (XRPD) pattern of crystalline Form X of vismodegib as obtained in example 1
- Fig. 2 shows the X-Ray Powder Diffraction (XRPD) pattern of crystalline Form X of vismodegib as obtained in example 4
- Fig. 3 shows the Attenuated Total Reflectance Fourier Transform Infrared (ATR-FTIR) spectra of crystalline Form X of vismodegib
- Fig. 4 shows the Differential Scanning Calorimetry (DSC) thermogram of crystalline Form X of vismodegib
- DSC Differential scanning calorimetry thermograms were obtained using a differential scanning calorimeter (TA instrument, Waters, USA) by using the following instrument parameters; start temperature: 25 °C, final temperature: 350 °C and heating rate: 10 °C/min.
- Samples were measured as neat by ATR (Attenuated Total Reflectance) on Shimadzu FTIR Spectrometer IR Prestige-21 (Shimadzu Corporation, Kyoto, Japan) in the range of 600 - 4000 cm -1 with 20 scans and 4 cm -1 resolution.
- X-Ray powder diffractograms were measured using a Shimadzu LabX XRD-6100 X-ray diffractometer (Shimadzu Corporation, Japan) by using the following instrument parameters;
- Scan range 3.00 - 40.00°
- Scan mode Continuous scan Scan speed: 2.07min
- Sampling pitch 0.020°
- HBTU (2.78 g, 7.3 mmol, 1.5 equiv.) and triethylamine (2.05 mL, 14.7 mmol, 3.0 equiv.) were added into a mixture of 2-chloro-4-(methylsulfonyl)benzoic acid (1.26 g, 5.3 mmol, 1.1 equiv.) and dichloromethane (20 mL), stirred at 20 - 25 °C for 20 min. Then, 4-chloro-3- (pyridin-2-yl)aniline (1.0 g, 4.8 mmol, 1.0 equiv.) was added. The reaction mixture was stirred at 20 - 25 °C for 24 h.
- HBTU 27.8 g, 73 mmol, 1.5 equiv.
- triethylamine 20.5 mL, 147 mmol, 3.0 equiv.
- 2-chloro-4-(methylsulfonyl)benzoic acid 12.6 g, 53.7 mmol, 1.1 equiv.
- 4-chloro-3- (pyridin-2-yl)aniline (10.0 g, 48.8 mmol, 1.0 equiv.) was added and the reaction mixture was stirred at 20 - 25 °C for 24 h.
- HBTU 138.9 g, 366 mmol, 1.5 equiv.
- triethylamine 100.0 mL, 717 mmol, 3.0 equiv.
- 2-chloro-4-(methylsulfonyl)benzoic acid 74.5 g, 317 mmol, 1.3 equiv.
- 4-chloro-3- (pyridin-2-yl)aniline 50.0 g, 244 mmol, 1.0 equiv.
- HBTU 13.89 g, 36.6 mmol, 1.5 equiv.
- triethylamine 10.2 mL, 73.2 mmol, 3.0 equiv.
- 2-chloro-4-(methylsulfonyl)benzoic acid 7.45 g, 31.7 mmol, 1.3 equiv.
- 4-chloro-3- (pyridin-2-yl)aniline 5.0 g, 24.4 mmol, 1.0 equiv.
- HBTU 13.89 g, 36.6 mmol, 1.5 equiv.
- triethylamine 10.2 mF, 73.2 mmol, 3.0 equiv.
- 2-chloro-4-(methylsulfonyl)benzoic acid 7.45 g, 31.7 mmol, 1.3 equiv.
- 4-chloro-3-(pyridin-2- yl)aniline 5.0 g, 24.4 mmol, 1.0 equiv.
- HBTU 13.89 g, 36.6 mmol, 1.5 equiv.
- triethylamine 10.2 mL, 73.2 mmol, 3.0 equiv.
- 2-chloro-4-(methylsulfonyl)benzoic acid 7.45 g, 31.7 mmol, 1.3 equiv.
- 4-chloro-3-(pyridin- 2-yl)aniline 5.0 g, 24.4 mmol, 1.0 equiv.
- HBTU 13.89 g, 36.6 mmol, 1.5 equiv.
- triethylamine 10.2 mL, 73.2 mmol, 3.0 equiv.
- 2-chloro-4-(methylsulfonyl)benzoic acid 7.45 g, 31.7 mmol, 1.3 equiv.
- 4-chloro-3-(pyridin- 2-yl)aniline 5.0 g, 24.4 mmol, 1.0 equiv.
Abstract
The present invention relates to a new crystalline polymorphic Form X of vismodegib and its preparation. Preferably, the new crystalline polymorphic Form X of vismodegib is characterized by an XRPD pattern having characteristic peaks at 9.37 ± 0.2, 11.49 ± 0.2, 15.70 ± 0.2, 16.56 ± 0.2, 18.84 ± 0.2, 18.95 ± 0.2 and 23.85 ± 0.2 degree 2-theta. The present invention also provides pharmaceutical compositions comprising Form X of vismodegib, and medical use of Form X of vismodegib.
Description
NEW POLYMORPH OF VISMODEGIB AND METHOD FOR ITS PREPARATION
Technical Field
The present invention relates to a novel crystalline polymorphic form of vismodegib designated as Form X and process for its preparation.
The invention further relates to pharmaceutical compositions comprising Form X and use of Form X in the treatment of cancer.
Background Art
Vismodegib is an oral Hedgehog signaling pathway inhibitor, which is approved for treatment of adults with metastatic basal cell carcinoma, or with locally advanced basal cell carcinoma that has recurred following surgery or who are not candidates for surgery and who are not candidates for radiation. Vismodegib is marketed by Genentech under the brand name ERIVEDGE®. Vismodegib is chemically designated as 2-chloro- V-(4-chloro-3-(pyridin-2- yl)phenyl)-4-(methylsulfonyl)benzamide and represented by the following chemical structure;
The preparation and therapeutic use of vismodegib have been described for the first time in European patent EP 1789390, according to which vismodegib is prepared by coupling 4- chloro-3-(pyridin-2-yl)aniline and 2-chloro-4-methylsulfonylbenzoic acid or by coupling 4- chloro-3-(pyridin-2-yl)aniline and 2-chloro-4-(methylsulfonyl)benzoyl chloride. Vismodegib may exist in different polymorphic forms.
European patent EP 1789390 discloses a crystalline free base of vismodegib, but polymorphic form of crystalline form is not defined or characterized. On the other hand, process for the preparation of said crystalline free base of vismodegib in European patent EP 1789390 was repeated in WO 2014195977. According to the teachings of European patent EP 1789390, prior art form of vismodegib was obtained by crystallizing vismodegib with acetone and ethyl acetate, then by recrystallizing from hot slurry of isopropyl acetate. The crystalline
polymorphic form of vismodegib obtained by said process designated as Form I. The X-ray powder diffractogram (XRPD) of Form I was shown in Figure 1 of WO 2014195977.
WO2014195977 further discloses two polymorphic forms of vismodegib labeled as Form II, Form III and preparation thereof.
One another crystalline vismodegib polymorph Form SV has been disclosed in WO 2014147504.
The discovery of a new polymorph of an active ingredient provides an opportunity to improve its characteristics, increasing the possibilities available to a formulation specialist when developing a new pharmaceutical form, a drug with a particular release profile or a specific dissolution degree.
Based on these considerations, there still appears a need for new polymorphs of vismodegib having further improved physical and/or chemical properties. Hence it was thought worthwhile by the inventors of the present application to explore pharmaceutically novel polymorphs of vismodegib with good chemical purity and improved stability characteristics, which may further improve the characteristics of vismodegib in finished medicinal product.
Summary of the invention
The object of the present invention is to provide a new polymorphic form of vismodegib and process for the preparation of this novel polymorphic form of vismodegib.
Another object of the present invention is to provide pharmaceutical compositions comprising new polymorphic form of vismodegib.
Technical Problem
Active pharmaceutical ingredients (APIs) are individual components or mixture of components that are used as a part of a finished pharmaceutical drug or medicinal product, where they provide the pharmacological activity.
Research and development projects in the pharmaceutical industry mainly aim to investigate different possible synthetic routes, key intermediates, reaction steps, impurity profile, particle size, particle shape and polymorphism to produce these APIs with higher efficiency. Polymorphism, the occurrence of different crystal forms, is a property of some molecules and molecular complexes. A single molecule, may give rise to a variety of crystalline forms having distinct crystal structures and physical properties. The difference in the physical properties of different crystalline forms results from the orientation and intermolecular
interactions of adjacent molecules or complexes in the bulk solid.
The relationship between polymorphic forms of pharmaceutically active substance and pharmaceutical product is well known in the pharmaceutical industry. Pharmaceutical formulation is affected by polymorphic form of the pharmaceutically active substance.
It is a well known fact that different polymorphic forms of the same drug may have substantial differences in certain pharmaceutically important properties such as dissolution characteristics, bioavailability patterns, handling properties, solubility, flow characteristics and stability. These different physical forms may also have different particle size, hardness and glass transition temperatures.
The discovery of new polymorphic forms and solvates of an active pharmaceutical ingredient provides a new opportunity to improve the performance characteristics of pharmaceutical finished product, the development of new polymorphic forms is always encouraged.
Therefore, there is a need to develop novel polymorphic forms of vismodegib having advantageous properties which are useful and well suitable for the preparation of various pharmaceutical compositions.
Solution to Problem
In an embodiment invention relates to a novel solid form of vismodegib.
In another embodiment, this new form of vismodegib, besides being stable, meet the pharmaceutical requirements such as storage, shelf life, solubility and high purity.
Description of embodiments
A first aspect of the present invention relates to a novel polymorphic form of vismodegib. This new anhydrous form hereinafter is referred as crystalline Form X of vismodegib. Form X is characterized by an XRPD pattern having characteristic peaks at 9.37 ± 0.2, 11.49 ± 0.2, 15.70 ± 0.2, 16.56 ± 0.2, 18.84 ± 0.2, 18.95 ± 0.2 and 23.85 ± 0.2 degree 2-theta. Furthermore, Form X of vismodegib can be characterized by an XRPD pattern with characteristic peaks at 10.61 ± 0.2, 12.10 ± 0.2, 15.94 ± 0.2, 17.27 ± 0.2, 21.36 ± 0.2, 23.56 ± 0.2, 25.85 ± 0.2 and 28.42 ± 0.2 degree 2-theta.
Form X is characterized by a powder X-ray diffraction pattern, as shown in figure 1.
Form X is also characterized by an IR spectrum, as shown in figure 3 and characterized by a DSC thermogram, as shown in figure 4.
A second aspect of the present invention relates to a process for preparing novel polymorphic Form X of vismodegib.
The Form X according to the present invention may be obtained by: a) providing a solution of dissolving vismodegib in a suitable organic solvent, b) heating and stirring the solution at a suitable temperature, c) cooling the solution to room temperature, d) filtering and isolating the obtained solid, e) washing the obtained solid as pure crystalline vismodegib designated as Form X with C1-C5 alcohol.
Wherein suitable solvent in step (a) is selected from, 2-propanol, 1 -propanol, 1 -butanol, 2- butanol, tert-butyl alcohol, 1-pentanol, 2-pentanol, amyl alcohol, ethylene glycol, glycerol, acetone, butanone, 2-pentanone, 3-pentanone, methyl butyl ketone, methyl isobutyl ketone, ethyl formate, methyl acetate, ethyl acetate, propyl acetate, isopropyl acetate, butyl acetate, isobutyl acetate, tert- butyl acetate, toluene, xylene, chloroform, dichloromethane, carbon tetrachloride, ethylene dichloride, chlorobenzene, acetonitrile, diethyl ether, diisopropyl ether, tert-butyl methyl ether, dibutyl ether, tetrahydrofuran (THF), 1,4-dioxane, 2-methoxyethanol, A,A-di methyl forma midc (DMF), N, N- d i m c t h y 1 ac c t a m i dc (DMAc), N- m c t h y 1 p y ro 1 i do n c (NMP), pyridine, dimethylsulfoxide (DMSO), sulfolane, formamide, acetamide, propanamide, pyridine, formic acid, acetic acid, propionic acid, hexane, heptane, cyclohexane, cycloheptane and cyclooctane or mixtures thereof.
The suitable temperature used in step (b) is selected from room temperature to reflux temperature of the solvent used.
The degree of purity of the active ingredient and the resulting possible changes of the efficacy, further important properties for the pharmaceutical processing can be affected in an adverse manner.
The process of the present invention affords Form X of vismodegib in high purity and high yield. The Form X of vismodegib is obtained having purity greater than 99% by area percentage in HPLC.
Stability plays an important role in the drug development process. Stability of a pharmaceutical product may be defined as the capability of that particular formulation, in a
specific container or closure system, to remain within its chemical, physical, microbiological, therapeutic and toxicological specifications to assure its attributed quality, e.g., identity, purity, strength etc. until drug expiry.
Stability of a pharmaceutical product is strongly influenced by changes in solid-state form of the API. The changes in solid state form of the API may be resulted from the conditions of product manufacturing process. Examples of processing that may cause polymorphic changes including grinding, milling, heating, and applying compression. Manufacturing conditions that include a solvent (e.g., wet granulation, polymorphs in solution, and polymorphs in suspension) may facilitate changes in the solid-state form of API. These variations comprising polymorphic transformations, hydrate/solvate formations and dehydration/desolvation reactions in the solid-state form of API, may cause stability problems in finished pharmaceutical products. Therefore, crystalline stability of API has a critical role on satisfying the essentialities of qualified pharmaceutical product and stable polymorphs of API should be used in pharmaceutical formulations.
For this aspect, crystalline stability of Form X of vismodegib was investigated under the following conditions: a sample was kept in an open flask at 105 °C for 30 days, packed samples were kept at 40 °C under 75% relative humidity (RH) and at 25 °C under 60% relative humidity (RH) for 6 months. The crystalline stability referred here, is the stability of a polymorphic form of API with respect to polymorph transformations, hydration, or amorphization through time under these conditions.
The crystalline stability of vismodegib Form X was investigated and determined by X-ray powder diffraction method. Results showed that any polymorphic transformation to another crystal form or any degradation in crystalline Form X did not occur. Crystalline Form X showed crystalline stability under dry heating at 105 °C for 30 days, at 40 °C / 75% RH and at 25 °C / 60% RH for 6 months.
The chemical stability of crystalline Form X of vismodegib is also important and its stability in finished product at room-temperature storage can be predicted from shorter-term storage under accelerated conditions of high temperature and humidity. In the present invention, samples of obtained crystalline Form X of vismodegib were kept under dry heating in open flask at 105 °C for 30 days in an oven, and in FDPE pack at 40 °C & 75% RH and at 25 °C & 60% RH for 6 months in stability chambers to test chemical stability. The chemical stability of the samples was determined by HPFC method.
Table 1 shows the stability results of vismodegib Form X prepared according to the present invention. Form X samples stayed stable under all conditions without any change in the impurity profile and without increase in the impurity amounts.
A third aspect of the present invention relates to pharmaceutical compositions comprising crystalline Form X of vismodegib along with a pharmaceutically acceptable carrier.
Brief description of the drawings: Fig. 1 shows the X-Ray Powder Diffraction (XRPD) pattern of crystalline Form X of vismodegib as obtained in example 1
Fig. 2 shows the X-Ray Powder Diffraction (XRPD) pattern of crystalline Form X of vismodegib as obtained in example 4
Fig. 3 shows the Attenuated Total Reflectance Fourier Transform Infrared (ATR-FTIR) spectra of crystalline Form X of vismodegib
Fig. 4 shows the Differential Scanning Calorimetry (DSC) thermogram of crystalline Form X of vismodegib
Instrumental parameters: DSC parameters:
Differential scanning calorimetry (DSC) thermograms were obtained using a differential scanning calorimeter (TA instrument, Waters, USA) by using the following instrument
parameters; start temperature: 25 °C, final temperature: 350 °C and heating rate: 10 °C/min.
FTIR parameters:
Samples were measured as neat by ATR (Attenuated Total Reflectance) on Shimadzu FTIR Spectrometer IR Prestige-21 (Shimadzu Corporation, Kyoto, Japan) in the range of 600 - 4000 cm-1 with 20 scans and 4 cm-1 resolution.
PXRD Method of Analysis:
X-Ray powder diffractograms were measured using a Shimadzu LabX XRD-6100 X-ray diffractometer (Shimadzu Corporation, Japan) by using the following instrument parameters;
The measurement conditions were as follows:
Radiation: Cu (1.5406 A) Filter for Kb: Nickel Voltage: 40.0 kV Current: 30.0 mA
Scan range: 3.00 - 40.00° Scan mode: Continuous scan Scan speed: 2.07min Sampling pitch: 0.020°
Following examples are provided to enable one skilled in the art to practice the invention and are merely illustrative of the invention. The examples should not be read as limiting the scope of the invention.
EXAMPLES
Preparation of new crystalline Form X of vismodegib Example 1
HBTU (2.78 g, 7.3 mmol, 1.5 equiv.) and triethylamine (2.05 mL, 14.7 mmol, 3.0 equiv.) were added into a mixture of 2-chloro-4-(methylsulfonyl)benzoic acid (1.26 g, 5.3 mmol, 1.1 equiv.) and dichloromethane (20 mL), stirred at 20 - 25 °C for 20 min. Then, 4-chloro-3- (pyridin-2-yl)aniline (1.0 g, 4.8 mmol, 1.0 equiv.) was added. The reaction mixture was stirred at 20 - 25 °C for 24 h. After completion of the reaction, water (10 mL) was added, the
solvent was evaporated in vacuo. Methanol (5 mL) was added onto the residue and the mixture was heated, stirred at 70 °C for 2 h. After cooling and stirring for 1 h at 20 - 25 °C, the mixture was filtered. The product crystals were washed with 2-propanol. Crude product in methanol (15 mL) was heated to 70 °C and stirred at this temperature for 3 h. After cooling and stirring for 1 day at 20 - 25 °C, the mixture was filtered, the product crystals were washed with 2-propanol and dried to afford white to off-white crystalline Form X of vismodegib (1.5 g, 72.8%, 99.65% HPLC purity). XRD, DSC, FTIR.
Example 2
HBTU (27.8 g, 73 mmol, 1.5 equiv.) and triethylamine (20.5 mL, 147 mmol, 3.0 equiv.) were added into a dichloromethane (100 mL) mixture of 2-chloro-4-(methylsulfonyl)benzoic acid (12.6 g, 53.7 mmol, 1.1 equiv.) and stirred at 20 - 25 °C for 20 min. Then, 4-chloro-3- (pyridin-2-yl)aniline (10.0 g, 48.8 mmol, 1.0 equiv.) was added and the reaction mixture was stirred at 20 - 25 °C for 24 h. After completion of the reaction, water (40 mL) was added and the solvent was evaporated in vacuo. Methanol (20 mL) was added onto the residue and the mixture was heated and stirred at 70 °C for 2 h. After cooling and stirring for 1 h at 20 - 25 °C, the mixture was filtered and product crystals were washed with 2-propanol. Methanol (35 mL) mixture of crude product was heated to 70 °C and stirred at this temperature for 2 h. After cooling and stirring for 1 h at 20 - 25 °C, the mixture was filtered, the product crystals were washed with 2-propanol and dried to afford white to off-white crystalline Form X of vismodegib (15.7 g, 76.3%, 99.71% HPLC purity). XRD, DSC, FTIR
Example 3
HBTU (138.9 g, 366 mmol, 1.5 equiv.) and triethylamine (100.0 mL, 717 mmol, 3.0 equiv.) were added into a dichloromethane (300 mL) mixture of 2-chloro-4-(methylsulfonyl)benzoic acid (74.5 g, 317 mmol, 1.3 equiv.) and stirred at 20 - 25 °C for 1 h. Then, 4-chloro-3- (pyridin-2-yl)aniline (50.0 g, 244 mmol, 1.0 equiv.) was added and the reaction mixture was stirred at 22 - 25 °C overnight. After completion of the reaction, water (160 mL) was added and the solvent was evaporated in vacuo. Methanol (80 mL) was added onto the residue and the mixture was heated and stirred at 70 °C for 1 h. After cooling and stirring at 20 - 25 °C overnight, the mixture was filtered, the product crystals were washed with 2-propanol and dried to afford white to off-white crystalline Form X of vismodegib (93.8 g, 91.2%, 99.64% HPLC purity).
Example 4
HBTU (13.89 g, 36.6 mmol, 1.5 equiv.) and triethylamine (10.2 mL, 73.2 mmol, 3.0 equiv.) were added into a dichloromethane (50 mL) mixture of 2-chloro-4-(methylsulfonyl)benzoic acid (7.45 g, 31.7 mmol, 1.3 equiv.), then, 4-chloro-3-(pyridin-2-yl)aniline (5.0 g, 24.4 mmol, 1.0 equiv.) was added to the reaction mixture and stirred at 20 - 25 °C for 24 h. After completion of the reaction, water (20 mL) was added and the solvent was evaporated in vacuo. Methanol (10 mL) was added onto the residue and the mixture was heated and stirred at 70 °C for 1 h. After cooling and stirring for 1 h at 20 - 25 °C, the mixture was filtered and product crystals were washed with 2-propanol. Ethanol (15 mL) mixture of crude product was heated to 70 °C and stirred at this temperature for 1 h. After cooling and stirring overnight at 20 - 25 °C, the mixture was filtered, the product crystals were washed with 2-propanol and dried to afford white to off-white crystalline Form X of vismodegib (7.32 g, 71.1%, 96.91% HPLC purity).
Example 5
HBTU (13.89 g, 36.6 mmol, 1.5 equiv.) and triethylamine (10.2 mL, 73.2 mmol, 3.0 equiv.) were added into a dichloromethane (100 mL) mixture of 2-chloro-4-(methylsulfonyl)benzoic acid (7.45 g, 31.7 mmol, 1.3 equiv.) and stirred at 20 - 25 °C for 1 h. Then, 4-chloro-3- (pyridin-2-yl)aniline (5.0 g, 24.4 mmol, 1.0 equiv.) was added and the reaction mixture was stirred at 20 - 25 °C for overnight. After completion of the reaction, water (20 mL) was added and the solvent was evaporated in vacuo. Methanol (10 mL) was added onto the residue and the mixture was heated and stirred at 70 °C for 1 h. After cooling and stirring for 30 min at 20 - 25 °C, and then stirring for 2 h at 0 °C, the mixture was filtered and product crystals were washed with 2-propanol. 1-Propanol (15 mL) mixture of crude product was heated to 70 °C and stirred at this temperature for 1 h. After cooling and stirring at 20 - 25 °C overnight, the mixture was filtered, the product crystals were washed with 2-propanol and dried to afford white to off-white crystalline Form X of vismodegib (7.05 g, 68.5%, 96.25% HPFC purity).
Example 6
HBTU (13.89 g, 36.6 mmol, 1.5 equiv.) and triethylamine (10.2 mF, 73.2 mmol, 3.0 equiv.) were added into a dichloromethane (100 mF) mixture of 2-chloro-4-(methylsulfonyl)benzoic acid (7.45 g, 31.7 mmol, 1.3 equiv.) and stirred at 0 °C for 1 h. Then, 4-chloro-3-(pyridin-2- yl)aniline (5.0 g, 24.4 mmol, 1.0 equiv.) was added and the reaction mixture was stirred at 0 °C for 1 h then at 20 - 25 °C overnight. After completion of the reaction, water (20 mL) was
added and the solvent was evaporated in vacuo. Methanol (10 mL) was added onto the residue and the mixture was heated and stirred at 70 °C for 1 h. After cooling and stirring at 20 - 25 °C for 33 min, and then stirring at 0 °C for 2 h, the mixture was filtered and product crystals were washed with 2-propanol. 2-Propanol (15 mL) mixture of crude product was heated to 70 °C and stirred at this temperature for 1 h. After cooling and stirring for 30 min at 20 - 25 °C and then for 2 h at 0 °C, the mixture was filtered, the product crystals were washed with 2- propanol and dried to afford white to off-white crystalline Form X of vismodegib (7.30 g, 70.9%, 97.48% HPLC purity).
Example 7
HBTU (13.89 g, 36.6 mmol, 1.5 equiv.) and triethylamine (10.2 mL, 73.2 mmol, 3.0 equiv.) were added into a dichloromethane (100 mL) mixture of 2-chloro-4-(methylsulfonyl)benzoic acid (7.45 g, 31.7 mmol, 1.3 equiv.) and stirred at 0 °C for 30 min. Then, 4-chloro-3-(pyridin- 2-yl)aniline (5.0 g, 24.4 mmol, 1.0 equiv.) was added and the reaction mixture was stirred at 0 °C overnight. After completion of the reaction, water (20 mL) was added and the solvent was evaporated in vacuo. Methanol (10 mL) was added onto the residue and the mixture was heated and stirred at 70 °C for 1 h. After cooling and stirring for 33 min at 20 - 25 °C, and then stirring for 2 h at 0 °C, the mixture was filtered and product crystals were washed with 2- propanol. 1-Butanol (15 mL) mixture of crude product was heated to 70 °C and stirred at this temperature for 1 h. After cooling and stirring at 20 - 25 °C overnight, the mixture was filtered, the product crystals were washed with 2-propanol and dried to afford white to off- white crystalline Form X of vismodegib (4.23 g, 41.1%, 99.09% HPLC purity).
Example 8
HBTU (13.89 g, 36.6 mmol, 1.5 equiv.) and triethylamine (10.2 mL, 73.2 mmol, 3.0 equiv.) were added into a dichloromethane (100 mL) mixture of 2-chloro-4-(methylsulfonyl)benzoic acid (7.45 g, 31.7 mmol, 1.3 equiv.) and stirred at 0 °C for 30 min. Then, 4-chloro-3-(pyridin- 2-yl)aniline (5.0 g, 24.4 mmol, 1.0 equiv.) was added and the reaction mixture was stirred at 0 °C for 1 h. After completion of the reaction, water (20 mL) was added and the solvent was evaporated in vacuo. Methanol (10 mL) was added onto the residue and the mixture was heated and stirred at 70 °C for 1 h. After cooling and stirring at 20 - 25 °C overnight, the mixture was filtered and product crystals were washed with 2-propanol. 1-Hexanol (15 mL) mixture of crude product was heated to 70 °C and stirred at this temperature for 1 h. After cooling and stirring for 1 h at 20 - 25 °C, the mixture was filtered, the product crystals were
washed with 2-propanol and dried to afford white to off-white crystalline Form X of vismodegib (6.48 g, 66.5%, 99.86% HPLC purity).
Example 9
The mixture of vismodegib (5 g) in dichloromethane (10 mL) was stirred at reflux temperature for 1 - 2 h and then stirred at 20 - 25 °C for 1 - 2 h. Product was isolated by filtration, washed with 2-propanol and dried to afford white to off-white crystalline Form X of vismodegib (4.4 g, 88.0%, 99.90% HPLC purity).
Example 10
The mixture of vismodegib (5 g) in ethyl acetate (10 mL) was stirred at 70 °C for 1 h and then stirred at 20 - 25 °C for 1 h. Product was isolated by filtration, washed with 2-propanol and dried to afford white to off-white crystalline Form X of vismodegib (4.6 g, 92.0%, 99.90% HPLC purity).
Example 11
The mixture of vismodegib (5 g) in acetonitrile (10 mL) was stirred at 70 °C for 1 h and then stirred at 20 - 25 °C for 1 h. Product was isolated by filtration, washed with 2-propanol and dried to afford white to off-white crystalline Form X of vismodegib (4.6 g, 98.0%, 99.92% HPLC purity).
Example 12
The mixture of vismodegib (5 g) in acetone (10 mL) was stirred at 55 °C for 1 h and then stirred at 20 - 25 °C for 1 h. Product was isolated by filtration, washed with 2-propanol and dried to afford white to off-white crystalline Form X of vismodegib (4.0 g, 80.0%, 99.94% HPLC purity).
Example 13
The mixture of vismodegib (5 g) in n-hexane (15 mL) was stirred at 70 °C for 1 h and then stirred at 20 - 25 °C for 1 h. Product was isolated by filtration, washed with 2-propanol and dried to afford white to off-white crystalline Form X of vismodegib (4.6 g, 92.0%, 99.69% HPLC purity).
Example 14
The mixture of vismodegib (5 g) in n-hexane (20 mL) was stirred at 75 °C for 2 h and then stirred at 20 - 25 °C for 2 h. Product was isolated by filtration, washed with 2-propanol and
dried to afford white to off-white crystalline Form X of vismodegib (4.8 g, 96.0%, 99.76% HPLC purity).
Example 15
The mixture of vismodegib (5 g) in toluene (15 mL) was stirred at 110 °C for 1 h and then stirred at 20 - 25 °C for 1 h. Product was isolated by filtration, washed with 2-propanol and dried to afford white to off-white crystalline Form X of vismodegib (4.6 g, 92.0%, 99.83% HPLC purity).
Example 16
The mixture of vismodegib (5 g) in chloroform (15 mL) was stirred at 70 °C for 1 h and then stirred at 20 - 25 °C for 1 h. Product was isolated by filtration, washed with 2-propanol and dried to afford white to off-white crystalline Form X of vismodegib (4.0 g, 80.0%, 99.89% HPLC purity).
Example 17
The mixture of vismodegib (5 g) in tetrahydrofuran (15 mL) was stirred at 70 °C for 1 h and then stirred overnight at 20 - 25 °C. Product was isolated by filtration, washed with 2- propanol and dried to afford white to off-white crystalline Form X of vismodegib (2.6 g, 52.0%, 99.96% HPLC purity).
Example 18
The mixture of vismodegib (5 g) in isobutanol (15 mL) was stirred at 110 °C for 1 h and then stirred overnight at 20 - 25 °C. Product was isolated by filtration, washed with 2-propanol and dried to afford white to off-white crystalline Form X of vismodegib (4.6 g, 92.0%, 96.76% HPLC purity).
Example 19
The mixture of vismodegib (5 g) in 1,2-propanediol (15 mL) was stirred at 100 °C for 1 h and then stirred overnight at 20 - 25 °C. Product was isolated by filtration, washed with 2- propanol and dried to afford white to off-white crystalline Form X of vismodegib (4.5 g, 90.0%, 98.42% HPLC purity).
Example 20
The mixture of vismodegib (5 g) in methanol / N,N-dimethylformamide (15 mL / 3 mL) was stirred at 80 °C for 2 h and then stirred at 20 - 25 °C for 2 h. Product was isolated by
filtration, washed with 2-propanol and dried to afford white to off-white crystalline Form X of vismodegib (4.2 g, 84.0%, 99.62% HPLC purity).
Example 21
The mixture of vismodegib (5 g) in methanol / dimethyl sulfoxide (15 mL / 3 mL) was stirred at 80 °C for 2 h and then stirred at 20 - 25 °C for 2 h. Product was isolated by filtration, washed with 2-propanol and dried to afford white to off-white crystalline Form X of vismodegib (4.1 g, 82.0%, 99.58% HPLC purity).
Claims
1. Crystalline Form X of vismodegib.
2. The crystalline Form X of vismodegib of claim 1, characterized by an XRPD pattern having characteristic peaks at 9.37 ± 0.2, 11.49 ± 0.2, 15.70 ± 0.2, 16.56 ± 0.2, 18.84 ± 0.2, 18.95 ± 0.2 and 23.85 ± 0.2 degree 2-theta; and further characterized by having peaks at 10.61 ± 0.2, 12.10 ± 0.2, 15.94 ± 0.2, 17.27 ± 0.2, 21.36 ± 0.2, 23.56 ± 0.2, 25.85 ± 0.2 and 28.42 ± 0.2 degree 2-theta.
3. The crystalline Form X of vismodegib of claim 1, characterized by a XPRD pattern having 2-theta values as shown in Fig. 1.
4. The crystalline Form X of vismodegib of claim 1, characterized by an IR spectrum as shown in Fig. 3.
5. The crystalline Form X of vismodegib of claim 1, characterized by a DSC thermogram as shown in Fig. 4.
6. A pharmaceutical composition comprising crystalline Form X of vismodegib and optionally at least one pharmaceutically acceptable excipient.
7. A method of treating basal cell carcinoma comprising administering a therapeutically effective amount of crystalline Form X of vismodegib.
8. The method of claim 7, comprising administering therapeutically effective amount of crystalline Form X of vismodegib according to any one of the claims 1 to 7.
9. A method of treating basal cell carcinoma comprising administering therapeutically effective amount of crystalline Form X of vismodegib, wherein the crystalline Form X of vismodegib is characterized by an XPRD pattern having 2-theta values as shown in Fig. 1.
10. The use of crystalline Form X of vismodegib according to any one of the claims 1 to 9 in the manufacture of a medicament for the treatment of basal cell carcinoma.
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WO2014147504A2 (en) * | 2013-03-22 | 2014-09-25 | Shilpa Medicare Limited | Process for preparation of 2-chloro-n-(4-chloro-3-pyridin-2-ylphenyl)-4-methylsulfonylbenzamide solid forms |
WO2014195977A2 (en) * | 2013-06-05 | 2014-12-11 | Hetero Research Foundation | Novel polymorphs of vismodegib |
WO2016020324A1 (en) * | 2014-08-07 | 2016-02-11 | Basf Se | Multi-component crystals of vismodegib and selected co-crystal formers or solvents |
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WO2014147504A2 (en) * | 2013-03-22 | 2014-09-25 | Shilpa Medicare Limited | Process for preparation of 2-chloro-n-(4-chloro-3-pyridin-2-ylphenyl)-4-methylsulfonylbenzamide solid forms |
WO2014195977A2 (en) * | 2013-06-05 | 2014-12-11 | Hetero Research Foundation | Novel polymorphs of vismodegib |
WO2016020324A1 (en) * | 2014-08-07 | 2016-02-11 | Basf Se | Multi-component crystals of vismodegib and selected co-crystal formers or solvents |
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