WO2017036884A1 - A lesinurad, free form / lesinurad ethyl ester co-crystal - Google Patents
A lesinurad, free form / lesinurad ethyl ester co-crystal Download PDFInfo
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- WO2017036884A1 WO2017036884A1 PCT/EP2016/069998 EP2016069998W WO2017036884A1 WO 2017036884 A1 WO2017036884 A1 WO 2017036884A1 EP 2016069998 W EP2016069998 W EP 2016069998W WO 2017036884 A1 WO2017036884 A1 WO 2017036884A1
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- WO
- WIPO (PCT)
- Prior art keywords
- lesinurad
- ethyl ester
- free form
- crystal
- crystal according
- Prior art date
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- 229960003838 lesinurad Drugs 0.000 title claims abstract description 286
- FGQFOYHRJSUHMR-UHFFFAOYSA-N lesinurad Chemical compound OC(=O)CSC1=NN=C(Br)N1C(C1=CC=CC=C11)=CC=C1C1CC1 FGQFOYHRJSUHMR-UHFFFAOYSA-N 0.000 title claims abstract description 172
- 239000013078 crystal Substances 0.000 title claims abstract description 122
- 238000002360 preparation method Methods 0.000 claims abstract description 26
- 238000000634 powder X-ray diffraction Methods 0.000 claims description 56
- 238000000034 method Methods 0.000 claims description 37
- 239000002904 solvent Substances 0.000 claims description 31
- 230000008569 process Effects 0.000 claims description 26
- 238000004455 differential thermal analysis Methods 0.000 claims description 24
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 22
- 239000000203 mixture Substances 0.000 claims description 17
- 238000001228 spectrum Methods 0.000 claims description 15
- 238000002441 X-ray diffraction Methods 0.000 claims description 14
- 238000001757 thermogravimetry curve Methods 0.000 claims description 11
- 230000005855 radiation Effects 0.000 claims description 7
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 claims description 6
- 229910002483 Cu Ka Inorganic materials 0.000 claims description 6
- 238000002329 infrared spectrum Methods 0.000 claims description 4
- 238000010521 absorption reaction Methods 0.000 claims description 3
- 238000007127 saponification reaction Methods 0.000 claims description 2
- IOUDSMHEYZSUQF-UHFFFAOYSA-N ethyl 2-[[5-bromo-4-(4-cyclopropylnaphthalen-1-yl)-1,2,4-triazol-3-yl]sulfanyl]acetate Chemical compound CCOC(=O)CSC1=NN=C(Br)N1C(C1=CC=CC=C11)=CC=C1C1CC1 IOUDSMHEYZSUQF-UHFFFAOYSA-N 0.000 abstract 1
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 27
- 238000002411 thermogravimetry Methods 0.000 description 18
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 15
- 239000000243 solution Substances 0.000 description 15
- 238000004458 analytical method Methods 0.000 description 13
- 238000002425 crystallisation Methods 0.000 description 13
- 230000008025 crystallization Effects 0.000 description 12
- FVYMVLTWIBGEMC-UHFFFAOYSA-M sodium;2-[[5-bromo-4-(4-cyclopropylnaphthalen-1-yl)-1,2,4-triazol-3-yl]sulfanyl]acetate Chemical compound [Na+].[O-]C(=O)CSC1=NN=C(Br)N1C(C1=CC=CC=C11)=CC=C1C1CC1 FVYMVLTWIBGEMC-UHFFFAOYSA-M 0.000 description 12
- 239000007787 solid Substances 0.000 description 12
- 238000000113 differential scanning calorimetry Methods 0.000 description 9
- 238000005259 measurement Methods 0.000 description 9
- 239000000463 material Substances 0.000 description 8
- 239000012453 solvate Substances 0.000 description 8
- 238000005481 NMR spectroscopy Methods 0.000 description 7
- 150000001875 compounds Chemical class 0.000 description 7
- 239000008194 pharmaceutical composition Substances 0.000 description 7
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 7
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 6
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 6
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 6
- 229910016523 CuKa Inorganic materials 0.000 description 6
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
- 238000006243 chemical reaction Methods 0.000 description 6
- 238000004128 high performance liquid chromatography Methods 0.000 description 6
- 150000003839 salts Chemical group 0.000 description 6
- 230000015572 biosynthetic process Effects 0.000 description 5
- 230000008859 change Effects 0.000 description 5
- 239000011877 solvent mixture Substances 0.000 description 5
- 230000004580 weight loss Effects 0.000 description 5
- 239000007864 aqueous solution Substances 0.000 description 4
- 239000002585 base Substances 0.000 description 4
- 239000003814 drug Substances 0.000 description 4
- 239000000945 filler Substances 0.000 description 4
- 239000012535 impurity Substances 0.000 description 4
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 4
- 238000001953 recrystallisation Methods 0.000 description 4
- 201000005569 Gout Diseases 0.000 description 3
- 239000004411 aluminium Substances 0.000 description 3
- 229910052782 aluminium Inorganic materials 0.000 description 3
- XAGFODPZIPBFFR-UHFFFAOYSA-N aluminium Chemical compound [Al] XAGFODPZIPBFFR-UHFFFAOYSA-N 0.000 description 3
- 239000012296 anti-solvent Substances 0.000 description 3
- -1 di-hydrate Chemical class 0.000 description 3
- 229940079593 drug Drugs 0.000 description 3
- 239000007789 gas Substances 0.000 description 3
- 150000002500 ions Chemical class 0.000 description 3
- 239000010410 layer Substances 0.000 description 3
- 229910052757 nitrogen Inorganic materials 0.000 description 3
- 238000010926 purge Methods 0.000 description 3
- 230000004044 response Effects 0.000 description 3
- 238000000859 sublimation Methods 0.000 description 3
- 230000008022 sublimation Effects 0.000 description 3
- 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 2
- AEMRFAOFKBGASW-UHFFFAOYSA-N Glycolic acid Chemical compound OCC(O)=O AEMRFAOFKBGASW-UHFFFAOYSA-N 0.000 description 2
- 101000821902 Homo sapiens Solute carrier family 22 member 11 Proteins 0.000 description 2
- 238000004566 IR spectroscopy Methods 0.000 description 2
- 229920000881 Modified starch Polymers 0.000 description 2
- ONIBWKKTOPOVIA-UHFFFAOYSA-N Proline Natural products OC(=O)C1CCCN1 ONIBWKKTOPOVIA-UHFFFAOYSA-N 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- 102100021493 Solute carrier family 22 member 11 Human genes 0.000 description 2
- 229920002472 Starch Polymers 0.000 description 2
- 229930006000 Sucrose Natural products 0.000 description 2
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 description 2
- ATJFFYVFTNAWJD-UHFFFAOYSA-N Tin Chemical compound [Sn] ATJFFYVFTNAWJD-UHFFFAOYSA-N 0.000 description 2
- 108010093894 Xanthine oxidase Proteins 0.000 description 2
- 102100033220 Xanthine oxidase Human genes 0.000 description 2
- 230000009102 absorption Effects 0.000 description 2
- 239000002253 acid Substances 0.000 description 2
- 239000011230 binding agent Substances 0.000 description 2
- 238000012512 characterization method Methods 0.000 description 2
- 238000002288 cocrystallisation Methods 0.000 description 2
- 230000001419 dependent effect Effects 0.000 description 2
- 239000003085 diluting agent Substances 0.000 description 2
- 238000004090 dissolution Methods 0.000 description 2
- 238000001704 evaporation Methods 0.000 description 2
- 230000008020 evaporation Effects 0.000 description 2
- 238000002474 experimental method Methods 0.000 description 2
- 235000019253 formic acid Nutrition 0.000 description 2
- 238000010438 heat treatment Methods 0.000 description 2
- 229910052738 indium Inorganic materials 0.000 description 2
- APFVFJFRJDLVQX-UHFFFAOYSA-N indium atom Chemical compound [In] APFVFJFRJDLVQX-UHFFFAOYSA-N 0.000 description 2
- 239000003112 inhibitor Substances 0.000 description 2
- 239000000314 lubricant Substances 0.000 description 2
- 230000014759 maintenance of location Effects 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- 238000002844 melting Methods 0.000 description 2
- 230000008018 melting Effects 0.000 description 2
- 229910052751 metal Inorganic materials 0.000 description 2
- 239000002184 metal Substances 0.000 description 2
- 229910000000 metal hydroxide Inorganic materials 0.000 description 2
- 150000004692 metal hydroxides Chemical class 0.000 description 2
- 238000003801 milling Methods 0.000 description 2
- 238000010899 nucleation Methods 0.000 description 2
- 239000003921 oil Substances 0.000 description 2
- 235000019198 oils Nutrition 0.000 description 2
- 239000012044 organic layer Substances 0.000 description 2
- 239000002245 particle Substances 0.000 description 2
- 159000000000 sodium salts Chemical class 0.000 description 2
- 239000011343 solid material Substances 0.000 description 2
- 238000001179 sorption measurement Methods 0.000 description 2
- 238000012430 stability testing Methods 0.000 description 2
- 239000008107 starch Substances 0.000 description 2
- 235000019698 starch Nutrition 0.000 description 2
- 238000003860 storage Methods 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 239000005720 sucrose Substances 0.000 description 2
- 238000003786 synthesis reaction Methods 0.000 description 2
- 230000009466 transformation Effects 0.000 description 2
- SCYULBFZEHDVBN-UHFFFAOYSA-N 1,1-Dichloroethane Chemical compound CC(Cl)Cl SCYULBFZEHDVBN-UHFFFAOYSA-N 0.000 description 1
- OKMWKBLSFKFYGZ-UHFFFAOYSA-N 1-behenoylglycerol Chemical compound CCCCCCCCCCCCCCCCCCCCCC(=O)OCC(O)CO OKMWKBLSFKFYGZ-UHFFFAOYSA-N 0.000 description 1
- IXPNQXFRVYWDDI-UHFFFAOYSA-N 1-methyl-2,4-dioxo-1,3-diazinane-5-carboximidamide Chemical compound CN1CC(C(N)=N)C(=O)NC1=O IXPNQXFRVYWDDI-UHFFFAOYSA-N 0.000 description 1
- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 description 1
- WSVLPVUVIUVCRA-KPKNDVKVSA-N Alpha-lactose monohydrate Chemical compound O.O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O WSVLPVUVIUVCRA-KPKNDVKVSA-N 0.000 description 1
- 241001415342 Ardea Species 0.000 description 1
- 229920002799 BoPET Polymers 0.000 description 1
- FBPFZTCFMRRESA-FSIIMWSLSA-N D-Glucitol Natural products OC[C@H](O)[C@H](O)[C@@H](O)[C@H](O)CO FBPFZTCFMRRESA-FSIIMWSLSA-N 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
- FBPFZTCFMRRESA-JGWLITMVSA-N D-glucitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-JGWLITMVSA-N 0.000 description 1
- 108010010803 Gelatin Proteins 0.000 description 1
- SQUHHTBVTRBESD-UHFFFAOYSA-N Hexa-Ac-myo-Inositol Natural products CC(=O)OC1C(OC(C)=O)C(OC(C)=O)C(OC(C)=O)C(OC(C)=O)C1OC(C)=O SQUHHTBVTRBESD-UHFFFAOYSA-N 0.000 description 1
- 229920002153 Hydroxypropyl cellulose Polymers 0.000 description 1
- 201000001431 Hyperuricemia Diseases 0.000 description 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- ONIBWKKTOPOVIA-BYPYZUCNSA-N L-Proline Chemical compound OC(=O)[C@@H]1CCCN1 ONIBWKKTOPOVIA-BYPYZUCNSA-N 0.000 description 1
- 229930195725 Mannitol Natural products 0.000 description 1
- 229920000168 Microcrystalline cellulose Polymers 0.000 description 1
- 239000005041 Mylar™ Substances 0.000 description 1
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 1
- 102100030935 Solute carrier family 2, facilitated glucose transporter member 9 Human genes 0.000 description 1
- LEHOTFFKMJEONL-UHFFFAOYSA-N Uric Acid Chemical compound N1C(=O)NC(=O)C2=C1NC(=O)N2 LEHOTFFKMJEONL-UHFFFAOYSA-N 0.000 description 1
- TVWHNULVHGKJHS-UHFFFAOYSA-N Uric acid Natural products N1C(=O)NC(=O)C2NC(=O)NC21 TVWHNULVHGKJHS-UHFFFAOYSA-N 0.000 description 1
- 240000008042 Zea mays Species 0.000 description 1
- 235000005824 Zea mays ssp. parviglumis Nutrition 0.000 description 1
- 235000002017 Zea mays subsp mays Nutrition 0.000 description 1
- 238000002835 absorbance 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
- 229910052783 alkali metal Inorganic materials 0.000 description 1
- 150000008044 alkali metal hydroxides Chemical class 0.000 description 1
- 150000001340 alkali metals Chemical class 0.000 description 1
- 229910052784 alkaline earth metal Inorganic materials 0.000 description 1
- 229910001860 alkaline earth metal hydroxide Inorganic materials 0.000 description 1
- 229960003459 allopurinol Drugs 0.000 description 1
- OFCNXPDARWKPPY-UHFFFAOYSA-N allopurinol Chemical compound OC1=NC=NC2=C1C=NN2 OFCNXPDARWKPPY-UHFFFAOYSA-N 0.000 description 1
- 229960004977 anhydrous lactose Drugs 0.000 description 1
- 239000010405 anode material Substances 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 230000005540 biological transmission Effects 0.000 description 1
- 239000001506 calcium phosphate Substances 0.000 description 1
- 229910000389 calcium phosphate Inorganic materials 0.000 description 1
- 235000011010 calcium phosphates Nutrition 0.000 description 1
- CJZGTCYPCWQAJB-UHFFFAOYSA-L calcium stearate Chemical compound [Ca+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O CJZGTCYPCWQAJB-UHFFFAOYSA-L 0.000 description 1
- 235000013539 calcium stearate Nutrition 0.000 description 1
- 239000008116 calcium stearate Substances 0.000 description 1
- 238000004364 calculation method Methods 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 239000001768 carboxy methyl cellulose Substances 0.000 description 1
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- 235000005822 corn Nutrition 0.000 description 1
- 238000005443 coulometric titration Methods 0.000 description 1
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- 150000002148 esters Chemical class 0.000 description 1
- 150000002170 ethers Chemical class 0.000 description 1
- 125000001301 ethoxy group Chemical group [H]C([H])([H])C([H])([H])O* 0.000 description 1
- 125000004494 ethyl ester group Chemical group 0.000 description 1
- 230000029142 excretion Effects 0.000 description 1
- BQSJTQLCZDPROO-UHFFFAOYSA-N febuxostat Chemical compound C1=C(C#N)C(OCC(C)C)=CC=C1C1=NC(C)=C(C(O)=O)S1 BQSJTQLCZDPROO-UHFFFAOYSA-N 0.000 description 1
- 229960005101 febuxostat Drugs 0.000 description 1
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- 229930195733 hydrocarbon Natural products 0.000 description 1
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- 239000001866 hydroxypropyl methyl cellulose Substances 0.000 description 1
- 235000010979 hydroxypropyl methyl cellulose Nutrition 0.000 description 1
- 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 description 1
- UFVKGYZPFZQRLF-UHFFFAOYSA-N hydroxypropyl methyl cellulose Chemical compound OC1C(O)C(OC)OC(CO)C1OC1C(O)C(O)C(OC2C(C(O)C(OC3C(C(O)C(O)C(CO)O3)O)C(CO)O2)O)C(CO)O1 UFVKGYZPFZQRLF-UHFFFAOYSA-N 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- CDAISMWEOUEBRE-GPIVLXJGSA-N inositol Chemical compound O[C@H]1[C@H](O)[C@@H](O)[C@H](O)[C@H](O)[C@@H]1O CDAISMWEOUEBRE-GPIVLXJGSA-N 0.000 description 1
- 229960000367 inositol Drugs 0.000 description 1
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- 150000002576 ketones Chemical class 0.000 description 1
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- 239000008184 oral solid dosage form Substances 0.000 description 1
- 230000020477 pH reduction Effects 0.000 description 1
- 238000009522 phase III clinical trial Methods 0.000 description 1
- 229920001223 polyethylene glycol Polymers 0.000 description 1
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 1
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 1
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- 239000000843 powder Substances 0.000 description 1
- 230000000191 radiation effect Effects 0.000 description 1
- CDAISMWEOUEBRE-UHFFFAOYSA-N scyllo-inosotol Natural products OC1C(O)C(O)C(O)C(O)C1O CDAISMWEOUEBRE-UHFFFAOYSA-N 0.000 description 1
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- 150000003384 small molecules Chemical class 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 235000010413 sodium alginate Nutrition 0.000 description 1
- 239000000661 sodium alginate Substances 0.000 description 1
- 229940005550 sodium alginate Drugs 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 235000019812 sodium carboxymethyl cellulose Nutrition 0.000 description 1
- 229920001027 sodium carboxymethylcellulose Polymers 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 229960002668 sodium chloride Drugs 0.000 description 1
- 229910052938 sodium sulfate Inorganic materials 0.000 description 1
- 235000011152 sodium sulphate Nutrition 0.000 description 1
- 238000000371 solid-state nuclear magnetic resonance spectroscopy Methods 0.000 description 1
- 239000000600 sorbitol Substances 0.000 description 1
- 238000012306 spectroscopic technique Methods 0.000 description 1
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- 235000020357 syrup Nutrition 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- 238000004448 titration Methods 0.000 description 1
- 238000000844 transformation Methods 0.000 description 1
- 230000007704 transition Effects 0.000 description 1
- 238000002834 transmittance Methods 0.000 description 1
- QORWJWZARLRLPR-UHFFFAOYSA-H tricalcium bis(phosphate) Chemical compound [Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O QORWJWZARLRLPR-UHFFFAOYSA-H 0.000 description 1
- 150000004684 trihydrates Chemical class 0.000 description 1
- 238000000825 ultraviolet detection Methods 0.000 description 1
- 108010078530 urate transporter Proteins 0.000 description 1
- 229940116269 uric acid Drugs 0.000 description 1
- 238000009834 vaporization Methods 0.000 description 1
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D249/00—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms
- C07D249/02—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms not condensed with other rings
- C07D249/08—1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles
- C07D249/10—1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D249/12—Oxygen or sulfur atoms
Definitions
- the present disclosure relates to a co-crystal comprising 2-[5-bromo-4-(4- cyclopropylnaphthalen-l-yl)-4H-l,2,4-triazol-3-ylsulfanyl]acetic acid (lesinurad, free form) and ethyl-2-[5-bromo-4-(4-cyclopropylnaphthalen-l-yl)-4H-l,2,4-triazol-3- ylsulfanyl] acetate (lesinurad ethyl ester).
- the present disclosure also generally relates to the use of a lesinurad, free form/ lesinurad ethyl ester co-crystal for the preparation of amorphous lesinurad.
- Lesinurad is a small-molecule, oral inhibitor of the urate transporter 1 [URAT1] and organic anion transporter 4 [OAT4]. It is being developed by Ardea Biosciences and AstraZeneca for the treatment of gout by normalizing/increasing the excretion of uric acid. Its sodium salt, lesinurad sodium, has been approved by the EMA and is awaiting approval in the U.S. for chronic management of hyperuricaemia in combination with xanthine oxidase (XO) inhibitors in gout patients. Phase III clinical trials are ongoing as a monotherapy treatment in patients intolerant to allopurinol or febuxostat.
- WO2009/070740 discloses lesinurad, free form and lesinurad ethyl ester. Several crystalline forms of lesinurad, free form and lesinurad sodium have been reported.
- WO2012/092395 discloses different polymorphs of lesinurad, free form.
- WO2011/085009 discloses different forms of lesinurad sodium.
- WO2015/075561 discloses crystalline forms of lesinurad, free form, as well as crystalline forms of lesinurad sodium.
- WO2014/008295 discloses lesinurad ethyl ester.
- WO2015/095703 discloses salt forms of lesinurad and co-crystals of lesinurad, free form with proline and glycolic acid. The co-crystals of WO2015/095703 are described to be used in the preparation of a medicament.
- Example 15 assesses the stability of a lesinurad, free form / proline co-crystal under pharmaceutical storage test conditions.
- amorphous lesinurad sodium During attempts to develop amorphous lesinurad sodium the present inventors have identified difficulties in the preparation of amorphous lesinurad sodium from known crystalline forms of lesinurad.
- the present disclosure provides a co-crystal comprising 2-[5-bromo-4-(4- cyclopropylnaphthalen-l-yl)-4H-l,2,4-triazol-3-ylsulfanyl]acetic acid (lesinurad, free form) and ethyl-2-[5-bromo-4-(4-cyclopropylnaphthalen-l-yl)-4H-l,2,4-triazol-3- ylsulfanyl] acetate (lesinurad ethyl ester).
- the present disclosure also provides a process for the preparation of a lesinurad, free form / lesinurad ethyl ester co-crystal.
- a lesinurad, free form / lesinurad ethyl ester co-crystal is a useful intermediate. It generally relates to the use of a lesinurad, free form / lesinurad ethyl ester co-crystal for the preparation of amorphous lesinurad which can then be used further for the preparation of pharmaceutical compositions.
- FIG. 1. illustrates the x-ray powder diffraction pattern (XRPD) [powder x-ray diffraction
- FIG. 2. illustrates the differential scanning calorimetry (DSC) thermogram of a lesinurad, free form / lesinurad ethyl ester co-crystal crystal Form B.
- FIG. 3. illustrates the infrared (IR) spectrum of a lesinurad, free form / lesinurad ethyl ester co-crystal crystal Form B.
- FIG. 4. illustrates the x-ray powder diffraction pattern (XRPD) [powder x-ray diffraction
- lesinurad refers to lesinurad, free form as well as salt forms of lesinurad such as lesinurad sodium.
- polymorph refers to crystalline forms having the same chemical composition but different spatial arrangements of the molecules, atoms, and/or ions forming the crystal.
- solvate refers to a crystalline form of a molecule, atom, and/or ions that further comprises molecules of a solvent or solvents incorporated into the crystalline lattice structure.
- the solvent molecules in the solvate may be present in a regular arrangement and/or a non-ordered arrangement.
- the solvate may comprise either a stoichiometric or nonstoichiometric amount of the solvent molecules.
- a solvate with a nonstoichiometric amount of solvent molecules may result from partial loss of solvent from the solvate.
- the solvent is water, the solvate is often referred to as a "hydrate".
- the solvate When the solvent is present in stoichiometric amount, the solvate may be referred to by adding greek numeral prefixes.
- a hydrate may be referred to as monohydrate, di-hydrate, tri- hydrate etc., depending on the water / lesinurad stoichiometry.
- the solvent content can be measured, for example, by GC, ⁇ -NMR or Karl-Fischer (KF) titration.
- amorphous refers to a solid form of a molecule, atom, and/or ions that is not crystalline. An amorphous solid does not display a definitive X-ray diffraction pattern [Bragg peak].
- the term "substantially pure" with reference to a particular polymorphic form means that the polymorphic form includes less than 10%, preferably less than 5%, more preferably less than 3%, most preferably less than 1% by weight of any other physical forms of the compound.
- free form refers to the compound per se without salt formation or association with a solvent (e.g., solvate).
- peak used herein corresponds to its typical meaning in the art of XRPD. It may generally mean peaks clearly visible in XRPD patterns. Further, a “peak” may, in a corresponding XRPD pattern, resemble a single peak at a given specified position, or it may represent a double-peak or multiple peaks around a given specified (central) position of the denoted "peak”.
- X-ray powder diffraction peak positions means that typical peak position and intensity variability are taken into account.
- peak positions (2 ⁇ ) will show some inter-apparatus variability, typically as much as 0.2°.
- relative peak intensities will show inter-apparatus variability as well as variability due to degree of crystallinity, preferred orientation, prepared sample surface, and other factors known to those skilled in the art, and should be taken as qualitative measure only.
- a lesinurad free form / lesinurad ethyl ester co-crystal may be referred to herein as being characterized by graphical data "as shown in" a Figure.
- Such data include, for example, powder X-ray difractograms (XRPD), differential scanning calorimetry (DSC) thermograms and thermogravimetric analysis (TGA).
- XRPD powder X-ray difractograms
- DSC differential scanning calorimetry
- TGA thermogravimetric analysis
- the person skilled in the art understands that factors such as variations in instrument type, response and variations in sample directionality, sample concentration and sample purity may lead to small variations for such data when presented in graphical form, for example variations relating to the exact peak positions and intensities.
- a comparison of the graphical data in the Figures herein with the graphical data generated for an unknown solid form and the confirmation that two sets of graphical data relate to the same crystal form is well within the knowledge of a person skilled in the art.
- Anhydrous refers to a solid form which contains not more than 1% (w/w) of water, the water content being determined according to Karl Fischer coulometric titration.
- Root temperature as used herein means a temperature of from 18°C to 25°C, such as 22°C.
- Reduced pressure as used herein means a pressure of from 10 mbar to 100 mbar.
- suitable water-soluble fillers can include, for example, anhydrous lactose, lactose monohydrate, mannitol, sodium chloride, powdered sugar, sorbitol, sucrose, inositol and pregelatinized starch.
- suitable water-insoluble fillers can include, for example, microcrystalline cellulose, calcium phosphate and starch.
- suitable binders can include, for example, pre-gelatinized starch, sodium carboxymethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, polyvinyl pyrrolidone, copolyvidone, gelatin, natural gums, starch paste, sucrose, corn syrup, polyethylene glycols and sodium alginate.
- suitable lubricants can include, for example, hydrogenated vegetable oil, calcium stearate, and glyceryl behenate. Analytical methods used for characterization
- an X-ray diffraction pattern may be obtained with a measurement error that is dependent upon the measurement conditions employed.
- intensities in an X-ray diffraction pattern may fluctuate depending upon measurement conditions employed.
- relative intensities may also vary depending upon experimental conditions and, accordingly, the exact order of intensity should not be taken into account.
- a measurement error of diffraction angle for a conventional X-ray diffraction pattern is typically about 5% or less, and such degree of measurement error should be taken into account as pertaining to the aforementioned diffraction angles.
- crystal forms of the instant invention are not limited to the crystal forms that provide X-ray diffraction patterns completely identical to the X-ray diffraction patterns depicted in the accompanying Figures disclosed herein. Any crystal forms that provide X- ray diffraction patterns substantially identical to those disclosed in the accompanying Figures fall within the scope of the present invention.
- the ability to ascertain substantial identities of X-ray diffraction patterns is within the purview of one of ordinary skill in the art.
- TG-DTA generally refers to the simultaneous application of thermogravimetry (TG) and differential thermal analysis (DTA) to one and the same sample in a single instrument.
- the measurement conditions are perfectly identical for the TG and DTA signals (same atmosphere, gas flow rate, vapor pressure of the sample, heating rate, thermal contact to the sample crucible and sensor, radiation effect, etc.).
- TG can provide information about physical phenomena, such as second-order phase transitions, including vaporization, sublimation, absorption, adsorption, and desorption
- DTA can provide information on the transformations that have occurred, such as glass transitions, crystallization, melting and sublimation.
- the present disclosure relates to a lesinurad, free form / lesinurad ethyl ester co-crystal.
- a lesinurad, free form / lesinurad ethyl ester co-crystal can form from a solvent comprising lesinurad, free form and lesinurad ethyl ester.
- the lesinurad, free form / lesinurad ethyl ester co-crystal has the beneficial property of enabling the removal of impurities derived from lesinurad synthesis, which impurities are not removed in a satisfactory manner by crystallization of lesinurad, free form alone.
- WO2012092395 describes two forms of lesinurad, free form, Form 1 and Form 2.
- Method 2 of WO2012092395 describes the crystallization of lesinurad, free form, Form 2 from t-butanol with a purity of 94%.
- Lesinurad, free form when prepared according to WO2009070740 is consistent with Form 2 described in WO2012092395.
- the present disclosure relates to a co-crystal comprising 2-[5-bromo-4-(4- cyclopropylnaphthalen-l-yl)-4H-l,2,4-triazol-3-ylsulfanyl]acetic acid (lesinurad, free form) and ethyl-2-[5-bromo-4-(4-cyclopropylnaphthalen-l-yl)-4H-l,2,4-triazol-3- ylsulfanyl] acetate (lesinurad ethyl ester).
- This co-crystal can be obtained from lesinurad, free form, Form 2.
- the lesinurad, free form/ lesinurad ethyl ester co-crystal is therefore a valuable intermediate for the production of amorphous lesinurad.
- Lesinurad, free form, Form 2 is slightly hygroscopic with a mass increase of 2% during the first sorption cycle from 40-90% relative humidity, whereas no change in the pattern of the lesinurad, free form / lesinurad ethyl ester co-crystal is observed after 1 week stability testing at 40°C / 75% relative humidity, indicating that the lesinurad, free form/ lesinurad ethyl ester co-crystal is an intermediate which is suitable for storage.
- the lesinurad, free form / lesinurad ethyl ester co-crystal is described and characterized herein.
- the present disclosure provides a co-crystal comprising 2-[5-bromo-4-(4- cyclopropylnaphthalen-l-yl)-4H-l,2,4-triazol-3-ylsulfanyl]acetic acid (lesinurad, free form) and ethyl-2-[5-bromo-4-(4-cyclopropylnaphthalen-l-yl)-4H-l,2,4-triazol-3- ylsulfanyl] acetate (lesinurad ethyl ester) that has advantageous chemical purity over other solid state forms of lesinurad and over the lesinurad, free form, Form 2 described in WO2012092395 as intermediate for the preparation of amorphous lesinurad.
- the lesinurad, free form / lesinurad ethyl ester co-crystal can be characterized as an anhydrate form.
- the molar ratio of lesinurad, free form and lesinurad ethyl ester can be typically in a range of about 1.0 : 0.7 to 1.3, more preferably in a range of about 1.0 : 0.8 to 1.2 , and in particular in a ratio of about 1.0 : 1.0.
- XRPD x-ray powder diffraction pattern
- XRPD x-ray powder diffraction pattern
- the lesinurad, free form / lesinurad ethyl ester co- crystal is provided in substantially pure form.
- the lesinurad, free form / lesinurad ethyl ester co-crystal has substantially pure phase homogeneity as indicated by less than 10%, preferably less than 5 %, and more preferably less than 2 % of the total peak area in the experimentally measured XRPD pattern arising from the extra peaks that are absent from the simulated XRPD pattern.
- a crystalline form having substantially pure phase homogeneity with less than 1% of the total peak area in the experimentally measured XRPD pattern arising from the extra peaks that are absent from the simulated XRPD pattern.
- a composition consisting essentially of the lesinurad, free form / lesinurad ethyl ester co-crystal of the present invention.
- the composition of this embodiment may comprise at least 90 weight % of the lesinurad, free form / lesinurad ethyl ester co-crystal of the present invention, based on the combined weight of lesinurad, free form and lesinurad ethyl ester in the composition.
- the presence of more than one polymorph in a sample may be determined by techniques such as x-ray powder diffraction (XRPD) or solid state nuclear magnetic resonance spectroscopy.
- the presence of extra peaks in the comparison of an experimentally measured XRPD pattern with a simulated XRPD pattern may indicate more than one polymorph in the sample.
- the simulated XRPD may be calculated from single crystal x-ray data, see Smith, D.K., "A FORTRAN Program for Calculating X-Ray Powder Diffraction Patterns," Lawrence Radiation Laboratory, Livermore, California, UCRL-7196 (April 1963) or TOP AS program (Total Pattern Analysis Solution, available through Brucker AXS Inc.).
- the present invention also provides a lesinurad, free form / lesinurad ethyl ester co- crystal having a X-ray diffraction spectrum substantially the same as the X-ray powder diffraction spectrum shown in FIG. 1.
- the present invention also provides a lesinurad, free form / lesinurad ethyl ester co- crystal having a thermogravimetric differential thermal analysis (TG-DTA) thermogram shown in FIG. 2.
- TG-DTA thermogravimetric differential thermal analysis
- the present invention also provides a lesinurad, free form / lesinurad ethyl ester co- crystal having a X-ray diffraction spectrum substantially the same as the X-ray powder diffraction spectrum shown in FIG. 3.
- the present invention also provides a lesinurad, free form / lesinurad ethyl ester co- crystal having a thermogravimetric differential thermal analysis (TG-DTA) thermogram shown in FIG. 4.
- TG-DTA thermogravimetric differential thermal analysis
- Crystalline forms may be prepared by a variety of methods, including for example, crystallization or recrystallization from a suitable solvent, sublimation, growth from a melt, solid state transformation from another phase, crystallization from a supercritical fluid, and jet spraying.
- Techniques for crystallization or recrystallization of crystalline forms from a solvent mixture include, for example, evaporation of the solvent, decreasing the temperature of the solvent mixture, crystal seeding a supersaturated solvent mixture of the molecule and/or salt, freeze drying the solvent mixture, and addition of antisolvents (countersolvents) to the solvent mixture.
- Crystals of drugs including polymorphs, methods of preparation, and characterization of drug crystals are discussed in Solid-State Chemistry of Drugs, S.R. Byrn, R.R. Pfeiffer, and J.G. Stowell, 2 nd Edition, SSCI, West Lafayette, Indiana (1999).
- solvent for crystallization techniques that employ solvent, the choice of solvent or solvents is typically dependent upon one or more factors, such as solubility of the compound, crystallization technique, and vapor pressure of the solvent.
- Combinations of solvents may be employed, for example, the compound may be solubilized into a first solvent to afford a solution, followed by the addition of an antisolvent to decrease the solubility of the compound in the solution and to afford the formation of crystals.
- An antisolvent is a solvent in which the compound has low solubility.
- Seed crystals may be added to any crystallization mixture to promote crystallization. Seeding may be employed to control growth of a particular polymorph or to control the particle size distribution of the crystalline product. Accordingly, calculation of the amount of seeds needed depends on the size of the seed available and the desired size of an average product particle as described, for example, in "Programmed Cooling of Batch Crystallizers," J.W. Mullin and J. Nyvlt, Chemical Engineering Science, 1971,26, 369- 377. In general, seeds of small size are needed to control effectively the growth of crystals in the batch. Seed of small size may be generated by sieving, milling, or micronizing of large crystals, or by micro-crystallization of solutions. Care should be taken that milling or micronizing of crystals does not result in any change in crystallinity form the desired crystal form (i.e., change to amorphous or to another polymorph).
- a cooled crystallization mixture may be filtered under vacuum, and the isolated solids may be washed with a suitable solvent, such as cold recrystallization solvent, and dried under a nitrogen purge to afford the desired crystalline form.
- the isolated solids may be analyzed by a suitable spectroscopic or analytical technique, such as solid state nuclear magnetic resonance, differential scanning calorimetry, x-ray powder diffraction, or the like, to assure formation of the preferred crystalline form of the product.
- the resulting crystalline form is typically produced in an amount of greater than about 70 weight % isolated yield, preferably greater than 90 weight % isolated yield, based on the weight of the compound originally employed in the crystallization procedure.
- the product may be comilled or passed through a mesh screen to delump the product, if necessary.
- a co-crystal comprising 2-[5-bromo-4-(4-cyclopropylnaphthalen-l-yl)-4H- 1,2,4- triazol-3-ylsulfanyl]acetic acid (lesinurad, free form) and ethyl-2-[5-bromo-4-(4- cyclopropylnaphthalen-l-yl)-4H-l,2,4-triazol-3-ylsulfanyl]acetate (lesinurad ethyl ester).
- the lesinurad, free form / lesinurad ethyl ester co-crystal according to item 5 having a molar ratio of lesinurad: lesinurad ethyl ester of about 1.0 : 1.0.
- the lesinurad, free form / lesinurad ethyl ester co-crystal according to any one of items 1 to 11 characterized by having a differential thermal analysis (DTA) thermogram comprising an endothermic peak between 75°C and 95°C.
- DTA differential thermal analysis
- the lesinurad, free form / lesinurad ethyl ester co-crystal according to item 12 having a differential thermal analysis thermogram substantially the same as the differential thermal analysis thermogram shown in FIG. 2.
- the lesinurad, free form / lesinurad ethyl ester co-crystal according to any one of items 1 to 13 further characterized by showing a weight loss of from 0.5% to 1.5% between 30°C and 85°C when analyzed by thermogravimetric analysis (TGA).
- TGA thermogravimetric analysis
- the lesinurad, free form / lesinurad ethyl ester co-crystal according to any one of items 1 to 14 characterized by an infrared spectrum comprising absorption peaks at between 2505cm "1 and 2520cm "1 and at between 1722cm "1 and 1732cm "1 .
- the lesinurad, free form / lesinurad ethyl ester co-crystal according to any one of items 1 to 6 characterized by a x-ray powder diffraction pattern comprising four or more 2 ⁇ values selected from the group consisting of 3.6 ⁇ 0.2°, 10.8 ⁇ 0.2°, 16.5 ⁇ 0.2°, 21.0 ⁇ 0.2° and 23.7 ⁇ 0.2° when measured at a temperature of about 25°C using Cu Ka radiation.
- the lesinurad, free form / lesinurad ethyl ester co-crystal according to item 16 having a X-ray diffraction spectrum substantially the same as the X-ray powder diffraction spectrum shown in FIG. 4. 18.
- a composition comprising at least 90 weight % of lesinurad, free form / lesinurad ethyl ester co-crystal according to any one of items 1 to 17, based the weight of the composition.
- composition of item 18 consisting essentially of the crystalline form of any one of items 7 to 13 or 15 to 16.
- amorphous lesinurad is an amorphous lesinurad metal salt.
- the metal salt is a pharmaceutically acceptable alkali metal or alkaline earth metal salt.
- amorphous lesinurad is amorphous lesinurad sodium salt.
- a process of preparing a lesinurad, free form / lesinurad ethyl ester co-crystal comprising the step of allowing a lesinurad, free form / lesinurad ethyl ester co-crystal to crystallize from a solvent comprising lesinurad, free form and lesinurad ethyl ester.
- aqueous solution of a metal hydroxide is an aqueous solution of an alkali metal hydroxide or an aqueous solution of an alkaline earth metal hydroxide.
- the process of item 35 comprising the step of contacting sodium lesinurad in a solvent selected from the group consisting ofalcohols, ketones, esters, ethers, dichloromethane or dichloro ethane, hydrocarbons and mixtures thereof.
- any one of items 38 to 40, wherein the pharmaceutical composition further comprises at least one water-soluble filler; at least one water-insoluble filler; at least one binder; and at least one lubricant.
- the pharmaceutical composition further comprises at least one water-soluble filler; at least one water-insoluble filler; at least one binder; and at least one lubricant.
- Thermogravimetric analyses were carried out on a Seiko Exstar SII 6200 TG/DTA.
- the calibration standards were indium and tin.
- Samples were accurately weighed and placed in an open aluminium sample pan, inserted into the instrument and held at room temperature. The sample was then heated at a rate of 10°C/min from 20°C to 300°C during which time the change in sample weight was recorded along with any differential thermal events (DTA). Nitrogen was used as the purge gas, at a flow rate of 300 cm 3 /min.
- DTA differential thermal events
- DSC Differential Scanning Calorimetry
- Infrared spectroscopy was carried out on a Bruker ALPHA P spectrometer. Sufficient material was placed onto the center of the plate of the spectrometer and the spectra were obtained using the following parameters:
- ⁇ -NMR spectroscopic experiments were performed on a Bruker AV500 (frequency: 500 MHz). Experiments were performed in d6-dimethylsulfoxide and each sample was prepared to ca. 10 mM concentration.
- the aqueous layer was then extracted with dichloromethane (2x1 OmL) and the washings were combined with the organic layer and dried over sodium sulfate. Evaporation of the dichloromethane yielded an oil (-100% th. yield). The oil was analyzed by HPLC which indicated the presence of 95.4%) lesinurad ethyl ester and 1.8% lesinurad, free form.
- the lesinurad ethyl ester can be prepared according to other methods, e.g. such as described in WO2009/070740 or WO 2014/008295.
- Example 1 Co-crystallisation of Lesinurad, free form and Lesinurad ethyl ester (Form A)
- XRPD analysis was performed on lesinurad, free form / lesinurad ethyl ester co-crystal, Form A.
- the x-ray powder diffraction pattern (XRPD) is displayed in Figure 4.
- TGA of free form / lesinurad ethyl ester co-crystal, Form B showed a weight loss of ca. 1.0% from the outset up to ca. 100°C, followed by a second weight loss of ca. 0.5% between 100°C and ca. 145°C, prior to the onset of decomposition.
- DTA of free form / lesinurad ethyl ester co-crystal, Form B showed an endothermic event at onset ca. 76.8°C (peak at ca. 85.6°C) corresponding to the initial weight loss.
- DSC analysis of free form / lesinurad ethyl ester co-crystal, Form B showed an endotherm at onset ca. 85.7°C (peak at ca. 90.3°C).
- the differential scanning calorimetry (DSC) thermogram of lesinurad, free form / lesinurad ethyl ester co-crystal, Form B is displayed in Figure 2.
- TG analysis up to 130°C was also carried out for free form / lesinurad ethyl ester co- crystal, Form B, where the TGA showed a weight loss of ca. 0.8%> from the outset up to ca. 85°C and the DTA showed an endothermic event at onset ca. 83.2°C (peak at ca. 89.9°C), likely due to melting of the material.
- Wavenumber (cm-1) 2978, 2927, 2512, 1727, 1597. 1581, 1462, 1449, 1417, 1401, 1379, 1336, 1293, 1265, 1199, 1176, 1108, 1023, 1008, 992, 975, 928, 894, 861, 836, 765, 690, 662, 543, 501, 428.
- Example 3 amorphous lesinurad sodium from lesinurad, free form / lesinurad ethyl ester co-crystal
- Example 2 The material from Example 2 is dissolved in ethanol. To this solution is added 0.5 equivalent of NaOH (aq) and the reaction is stirred at ambient temperature or with gentle warming until completion (2 to 5 h). The resulting solution is then freeze dried or spray dried to give amorphous lesinurad sodium.
- Example 4 preparation of amorphous lesinurad, free form.
- This solid material obtained is dissolved in 1 : 1 mixture of dichloromethane and acetone. The solvent is removed to yield a glass-like 'bubbly' solid.
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Abstract
The present disclosure relates to a co-crystal comprising 2-[5-bromo-4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazol-3-ylsulfanyl]acetic acid (lesinurad, free form) and ethyl-2-[5-bromo-4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazol-3-ylsulfanyl]acetate (lesinurad ethyl ester). The present disclosure also generally relates to the use of a lesinurad, free form / lesinurad ethyl ester co-crystal for the preparation of amorphous lesinurad.
Description
A Lesinurad, free form / Lesinurad ethyl ester co-crystal
FIELD OF INDUSTRIAL APPLICABILITY
The present disclosure relates to a co-crystal comprising 2-[5-bromo-4-(4- cyclopropylnaphthalen-l-yl)-4H-l,2,4-triazol-3-ylsulfanyl]acetic acid (lesinurad, free form) and ethyl-2-[5-bromo-4-(4-cyclopropylnaphthalen-l-yl)-4H-l,2,4-triazol-3- ylsulfanyl] acetate (lesinurad ethyl ester). The present disclosure also generally relates to the use of a lesinurad, free form/ lesinurad ethyl ester co-crystal for the preparation of amorphous lesinurad. BACKGROUND OF THE DISCLOSURE
Lesinurad is a small-molecule, oral inhibitor of the urate transporter 1 [URAT1] and organic anion transporter 4 [OAT4]. It is being developed by Ardea Biosciences and AstraZeneca for the treatment of gout by normalizing/increasing the excretion of uric acid. Its sodium salt, lesinurad sodium, has been approved by the EMA and is awaiting approval in the U.S. for chronic management of hyperuricaemia in combination with xanthine oxidase (XO) inhibitors in gout patients. Phase III clinical trials are ongoing as a monotherapy treatment in patients intolerant to allopurinol or febuxostat.
Lesinurad, free form is known as 2-[5-bromo-4-(4-cyclopropylnaphthalen-l-yl)-4H-l,2,4- triazol-3-ylsulfanyl]acetic acid or as 2-((5-bromo-4-(4-cyclopropylnaphthalen-l-yl)-4H- 1 ,2,4-triazol-3-yl)thio)acetic acid. It can be produced according to the processes described in WO2006/026356 or WO2014/008295. The structure of its sodium salt is shown below:
WO2009/070740 discloses lesinurad, free form and lesinurad ethyl ester. Several crystalline forms of lesinurad, free form and lesinurad sodium have been reported.
WO2012/092395 discloses different polymorphs of lesinurad, free form.
WO2011/085009 discloses different forms of lesinurad sodium. WO2015/075561 discloses crystalline forms of lesinurad, free form, as well as crystalline forms of lesinurad sodium. WO2014/008295 discloses lesinurad ethyl ester. WO2015/095703 discloses salt forms of lesinurad and co-crystals of lesinurad, free form with proline and glycolic acid. The co-crystals of WO2015/095703 are described to be used in the preparation of a medicament. Example 15 assesses the stability of a lesinurad, free form /
proline co-crystal under pharmaceutical storage test conditions.
During attempts to develop amorphous lesinurad sodium the present inventors have identified difficulties in the preparation of amorphous lesinurad sodium from known crystalline forms of lesinurad. A co-crystal of lesinurad, free form and lesinurad ethyl ester was identified as a useful tool to remove impurities from lesinurad synthesis which were not sufficiently removed by known crystalline forms of lesinurad, thus enabling preparation of highly pure amorphous lesinurad salts, such as lesinurad sodium.
SUMMARY OF THE DISCLOSURE The present disclosure provides a co-crystal comprising 2-[5-bromo-4-(4- cyclopropylnaphthalen-l-yl)-4H-l,2,4-triazol-3-ylsulfanyl]acetic acid (lesinurad, free form) and ethyl-2-[5-bromo-4-(4-cyclopropylnaphthalen-l-yl)-4H-l,2,4-triazol-3- ylsulfanyl] acetate (lesinurad ethyl ester).
The present disclosure also provides a process for the preparation of a lesinurad, free form / lesinurad ethyl ester co-crystal.
It further provides a process for the preparation of amorphous lesinurad, wherein a lesinurad, free form / lesinurad ethyl ester co-crystal is a useful intermediate. It generally relates to the use of a lesinurad, free form / lesinurad ethyl ester co-crystal for the preparation of amorphous lesinurad which can then be used further for the preparation of pharmaceutical compositions.
BRIEF DESCRIPTION OF THE DRAWINGS
FIG. 1. illustrates the x-ray powder diffraction pattern (XRPD) [powder x-ray diffraction
- PXRD] of a lesinurad, free form / lesinurad ethyl ester co-crystal, Form B when measured at 25°C and using Cu Ka radiation.
FIG. 2. illustrates the differential scanning calorimetry (DSC) thermogram of a lesinurad, free form / lesinurad ethyl ester co-crystal crystal Form B.
FIG. 3. illustrates the infrared (IR) spectrum of a lesinurad, free form / lesinurad ethyl ester co-crystal crystal Form B. FIG. 4. illustrates the x-ray powder diffraction pattern (XRPD) [powder x-ray diffraction
- PXRD] of a lesinurad, free form / lesinurad ethyl ester co-crystal, Form A when measured at 25°C and using Cu Ka radiation.
DETAILED DESCRIPTION OF THE DISCLOSURE
Definitions
As used herein "lesinurad" refers to lesinurad, free form as well as salt forms of lesinurad such as lesinurad sodium.
As used herein "polymorph" refers to crystalline forms having the same chemical composition but different spatial arrangements of the molecules, atoms, and/or ions forming the crystal.
As used herein "solvate" refers to a crystalline form of a molecule, atom, and/or ions that further comprises molecules of a solvent or solvents incorporated into the crystalline lattice structure. The solvent molecules in the solvate may be present in a regular arrangement and/or a non-ordered arrangement. The solvate may comprise either a stoichiometric or nonstoichiometric amount of the solvent molecules. For example, a solvate with a nonstoichiometric amount of solvent molecules may result from partial loss of solvent from the solvate. When the solvent is water, the solvate is often referred to as a "hydrate". When the solvent is present in stoichiometric amount, the solvate may be referred to by adding greek numeral prefixes. For example, a hydrate may be referred to as monohydrate, di-hydrate, tri- hydrate etc., depending on the water / lesinurad stoichiometry. The solvent content can be measured, for example, by GC, Ή-NMR or Karl-Fischer (KF) titration.
As used herein "amorphous" refers to a solid form of a molecule, atom, and/or ions that is not crystalline. An amorphous solid does not display a definitive X-ray diffraction pattern [Bragg peak].
As used herein, the term "substantially pure" with reference to a particular polymorphic form means that the polymorphic form includes less than 10%, preferably less than 5%, more preferably less than 3%, most preferably less than 1% by weight of any other physical forms of the compound.
The term "free form" refers to the compound per se without salt formation or association with a solvent (e.g., solvate). The term "peak" used herein corresponds to its typical meaning in the art of XRPD. It may generally mean peaks clearly visible in XRPD patterns. Further, a "peak" may, in a corresponding XRPD pattern, resemble a single peak at a given specified position, or it may represent a double-peak or multiple peaks around a given specified (central) position of the denoted "peak".
The term "essentially the same" with reference to X-ray powder diffraction peak positions means that typical peak position and intensity variability are taken into account. For
example, one skilled in the art will appreciate that the peak positions (2Θ) will show some inter-apparatus variability, typically as much as 0.2°. Further, one skilled in the art will appreciate that relative peak intensities will show inter-apparatus variability as well as variability due to degree of crystallinity, preferred orientation, prepared sample surface, and other factors known to those skilled in the art, and should be taken as qualitative measure only.
A lesinurad free form / lesinurad ethyl ester co-crystal may be referred to herein as being characterized by graphical data "as shown in" a Figure. Such data include, for example, powder X-ray difractograms (XRPD), differential scanning calorimetry (DSC) thermograms and thermogravimetric analysis (TGA). The person skilled in the art understands that factors such as variations in instrument type, response and variations in sample directionality, sample concentration and sample purity may lead to small variations for such data when presented in graphical form, for example variations relating to the exact peak positions and intensities. However, a comparison of the graphical data in the Figures herein with the graphical data generated for an unknown solid form and the confirmation that two sets of graphical data relate to the same crystal form is well within the knowledge of a person skilled in the art.
"Anhydrous" as used herein refers to a solid form which contains not more than 1% (w/w) of water, the water content being determined according to Karl Fischer coulometric titration.
"Room temperature" as used herein means a temperature of from 18°C to 25°C, such as 22°C.
"Reduced pressure" as used herein means a pressure of from 10 mbar to 100 mbar.
As used herein, suitable water-soluble fillers can include, for example, anhydrous lactose, lactose monohydrate, mannitol, sodium chloride, powdered sugar, sorbitol, sucrose, inositol and pregelatinized starch.
As used herein, suitable water-insoluble fillers can include, for example, microcrystalline cellulose, calcium phosphate and starch.
As used herein, suitable binders can include, for example, pre-gelatinized starch, sodium carboxymethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, polyvinyl pyrrolidone, copolyvidone, gelatin, natural gums, starch paste, sucrose, corn syrup, polyethylene glycols and sodium alginate.
As used herein, suitable lubricants can include, for example, hydrogenated vegetable oil, calcium stearate, and glyceryl behenate.
Analytical methods used for characterization
/. X-ray Powder Diffraction Measurements (XRPD)
One of ordinary skill in the art will appreciate that an X-ray diffraction pattern may be obtained with a measurement error that is dependent upon the measurement conditions employed. In particular, it is generally known that intensities in an X-ray diffraction pattern may fluctuate depending upon measurement conditions employed. It should be further understood that relative intensities may also vary depending upon experimental conditions and, accordingly, the exact order of intensity should not be taken into account. Additionally, a measurement error of diffraction angle for a conventional X-ray diffraction pattern is typically about 5% or less, and such degree of measurement error should be taken into account as pertaining to the aforementioned diffraction angles. Consequently, it is to be understood that the crystal forms of the instant invention are not limited to the crystal forms that provide X-ray diffraction patterns completely identical to the X-ray diffraction patterns depicted in the accompanying Figures disclosed herein. Any crystal forms that provide X- ray diffraction patterns substantially identical to those disclosed in the accompanying Figures fall within the scope of the present invention. The ability to ascertain substantial identities of X-ray diffraction patterns is within the purview of one of ordinary skill in the art.
II. Simultaneous application of thermogravimetry (TG) and differential thermal analysis (DTA) or "Thermogravimetric Differential Thermal Analysis " (TG/DTA)
TG-DTA generally refers to the simultaneous application of thermogravimetry (TG) and differential thermal analysis (DTA) to one and the same sample in a single instrument. The measurement conditions are perfectly identical for the TG and DTA signals (same atmosphere, gas flow rate, vapor pressure of the sample, heating rate, thermal contact to the sample crucible and sensor, radiation effect, etc.). TG can provide information about physical phenomena, such as second-order phase transitions, including vaporization, sublimation, absorption, adsorption, and desorption, while DTA can provide information on the transformations that have occurred, such as glass transitions, crystallization, melting and sublimation.
Analytical methods are specified in the Example section.
The present disclosure relates to a lesinurad, free form / lesinurad ethyl ester co-crystal. Surprisingly it has been found that a lesinurad, free form / lesinurad ethyl ester co-crystal can form from a solvent comprising lesinurad, free form and lesinurad ethyl ester. The lesinurad, free form / lesinurad ethyl ester co-crystal has the beneficial property of enabling the removal of impurities derived from lesinurad synthesis, which impurities are not removed in a satisfactory manner by crystallization of lesinurad, free form alone.
Lesinurate and crystalline forms of lesinurad as well as methods for the preparation of
amorphous lesinurad are known. WO2012092395 describes two forms of lesinurad, free form, Form 1 and Form 2. Method 2 of WO2012092395 describes the crystallization of lesinurad, free form, Form 2 from t-butanol with a purity of 94%. Lesinurad, free form when prepared according to WO2009070740 is consistent with Form 2 described in WO2012092395.
However there is still a need for new and improved processes for the production of amorphous lesinurad with a high degree of purity. The recrystallization of lesinurad, free form, Form 2 from most solvents does not afford a purity uplift, and the conversion of lesinurad, free form, Form 2 into amorphous lesinurad sodium does not afford a purity uplift.
The present disclosure relates to a co-crystal comprising 2-[5-bromo-4-(4- cyclopropylnaphthalen-l-yl)-4H-l,2,4-triazol-3-ylsulfanyl]acetic acid (lesinurad, free form) and ethyl-2-[5-bromo-4-(4-cyclopropylnaphthalen-l-yl)-4H-l,2,4-triazol-3- ylsulfanyl] acetate (lesinurad ethyl ester). This co-crystal can be obtained from lesinurad, free form, Form 2. The lesinurad, free form/ lesinurad ethyl ester co-crystal is therefore a valuable intermediate for the production of amorphous lesinurad.
Lesinurad, free form, Form 2 is slightly hygroscopic with a mass increase of 2% during the first sorption cycle from 40-90% relative humidity, whereas no change in the pattern of the lesinurad, free form / lesinurad ethyl ester co-crystal is observed after 1 week stability testing at 40°C / 75% relative humidity, indicating that the lesinurad, free form/ lesinurad ethyl ester co-crystal is an intermediate which is suitable for storage.
The lesinurad, free form / lesinurad ethyl ester co-crystal is described and characterized herein.
The present disclosure provides a co-crystal comprising 2-[5-bromo-4-(4- cyclopropylnaphthalen-l-yl)-4H-l,2,4-triazol-3-ylsulfanyl]acetic acid (lesinurad, free form) and ethyl-2-[5-bromo-4-(4-cyclopropylnaphthalen-l-yl)-4H-l,2,4-triazol-3- ylsulfanyl] acetate (lesinurad ethyl ester) that has advantageous chemical purity over other solid state forms of lesinurad and over the lesinurad, free form, Form 2 described in WO2012092395 as intermediate for the preparation of amorphous lesinurad. The lesinurad, free form / lesinurad ethyl ester co-crystal can be characterized as an anhydrate form. In the lesinurad, free form / lesinurad ethyl ester co-crystal the molar ratio of lesinurad, free form and lesinurad ethyl ester can be typically in a range of about 1.0 : 0.7 to 1.3, more preferably in a range of about 1.0 : 0.8 to 1.2 , and in particular in a ratio of about 1.0 : 1.0. In one aspect the lesinurad, free form / lesinurad ethyl ester co-crystal of the present invention may be characterized by a x-ray powder diffraction pattern (XRPD) comprising four or more peaks at 2Θ values (CuKa λ=1.5419 A) selected from the group consisting of 9.9±0.2°, 11.1±0.2°, 13.3±0.2°, 20.9±0.2°, 23.6±0.2° and 25.3±0.2°, measured at a
temperature of about 25 °C. Preferably, the lesinurad, free form / lesinurad ethyl ester co- crystal may be characterized by a x-ray powder diffraction pattern comprising five or more peaks at 2Θ values (CuKa λ= 1.5419 A) selected from the group consisting of 9.9±0.2°, 11.1±0.2°, 13.3±0.2°, 20.9±0.2°, 23.6±0.2° and 25.3±0.2° at a temperature of about 25 °C.
Preferably, the lesinurad, free form / lesinurad ethyl ester co-crystal is characterized by a XRPD comprising characteristic peaks at 2Θ values (CuKa λ=1.5419 A) of 9.9±0.2°, 11.1±0.2°, 20.9±0.2° and 23.6±0.2° at a temperature of about 25°C. The lesinurad, free form / lesinurad ethyl ester co-crystal may be further characterized by a XRPD further comprising one or more additional characteristic peaks at 2Θ values (CuKa λ=1.5419 A) of 13.3±0.2° and 25.3±0.2°at a temperature of about 25°C.
In another aspect the lesinurad, free form / lesinurad ethyl ester co-crystal of the present invention may be characterized by a x-ray powder diffraction pattern (XRPD) comprising four or more 2Θ values (CuKa λ=1.5419 A) selected from the group consisting of 3.6±0.2°, 10.8±0.2°, 16.5±0.2°, 21.0±0.2° and 23.7±0.2°, measured at a temperature of about 25°C and an x-ray wavelength, λ, of 1.5419 A. Preferably, the lesinurad, free form / lesinurad ethyl ester co-crystal may be characterized by a x-ray powder diffraction pattern comprising five or more 2Θ values (CuKa λ=1.5419 A) selected from the group consisting of 3.6±0.2°, 10.8±0.2°, 16.5±0.2°, 21.0±0.2° and 23.7±0.2°, at a temperature of about 25 °C.
In one embodiment of the disclosure, the lesinurad, free form / lesinurad ethyl ester co- crystal is provided in substantially pure form.
Preferably, the lesinurad, free form / lesinurad ethyl ester co-crystal has substantially pure phase homogeneity as indicated by less than 10%, preferably less than 5 %, and more preferably less than 2 % of the total peak area in the experimentally measured XRPD pattern arising from the extra peaks that are absent from the simulated XRPD pattern. Most preferred is a crystalline form having substantially pure phase homogeneity with less than 1% of the total peak area in the experimentally measured XRPD pattern arising from the extra peaks that are absent from the simulated XRPD pattern. In one embodiment, a composition is provided consisting essentially of the lesinurad, free form / lesinurad ethyl ester co-crystal of the present invention. The composition of this embodiment may comprise at least 90 weight % of the lesinurad, free form / lesinurad ethyl ester co-crystal of the present invention, based on the combined weight of lesinurad, free form and lesinurad ethyl ester in the composition. The presence of more than one polymorph in a sample may be determined by techniques such as x-ray powder diffraction (XRPD) or solid state nuclear magnetic resonance spectroscopy. For example, the presence of extra peaks in the comparison of an experimentally measured XRPD pattern with a simulated XRPD pattern may indicate more than one polymorph in the sample. The simulated XRPD may be calculated from
single crystal x-ray data, see Smith, D.K., "A FORTRAN Program for Calculating X-Ray Powder Diffraction Patterns," Lawrence Radiation Laboratory, Livermore, California, UCRL-7196 (April 1963) or TOP AS program (Total Pattern Analysis Solution, available through Brucker AXS Inc.). The present invention also provides a lesinurad, free form / lesinurad ethyl ester co- crystal having a X-ray diffraction spectrum substantially the same as the X-ray powder diffraction spectrum shown in FIG. 1.
The present invention also provides a lesinurad, free form / lesinurad ethyl ester co- crystal having a thermogravimetric differential thermal analysis (TG-DTA) thermogram shown in FIG. 2.
The present invention also provides a lesinurad, free form / lesinurad ethyl ester co- crystal having a X-ray diffraction spectrum substantially the same as the X-ray powder diffraction spectrum shown in FIG. 3.
The present invention also provides a lesinurad, free form / lesinurad ethyl ester co- crystal having a thermogravimetric differential thermal analysis (TG-DTA) thermogram shown in FIG. 4.
Preparation of Crystalline Materials:
Crystalline forms may be prepared by a variety of methods, including for example, crystallization or recrystallization from a suitable solvent, sublimation, growth from a melt, solid state transformation from another phase, crystallization from a supercritical fluid, and jet spraying. Techniques for crystallization or recrystallization of crystalline forms from a solvent mixture include, for example, evaporation of the solvent, decreasing the temperature of the solvent mixture, crystal seeding a supersaturated solvent mixture of the molecule and/or salt, freeze drying the solvent mixture, and addition of antisolvents (countersolvents) to the solvent mixture.
Crystals of drugs, including polymorphs, methods of preparation, and characterization of drug crystals are discussed in Solid-State Chemistry of Drugs, S.R. Byrn, R.R. Pfeiffer, and J.G. Stowell, 2nd Edition, SSCI, West Lafayette, Indiana (1999). For crystallization techniques that employ solvent, the choice of solvent or solvents is typically dependent upon one or more factors, such as solubility of the compound, crystallization technique, and vapor pressure of the solvent. Combinations of solvents may be employed, for example, the compound may be solubilized into a first solvent to afford a solution, followed by the addition of an antisolvent to decrease the solubility of the compound in the solution and to afford the formation of crystals. An antisolvent is a solvent in which the compound has low solubility.
Seed crystals may be added to any crystallization mixture to promote crystallization. Seeding may be employed to control growth of a particular polymorph or to control the particle size distribution of the crystalline product. Accordingly, calculation of the amount of seeds needed depends on the size of the seed available and the desired size of an average product particle as described, for example, in "Programmed Cooling of Batch Crystallizers," J.W. Mullin and J. Nyvlt, Chemical Engineering Science, 1971,26, 369- 377. In general, seeds of small size are needed to control effectively the growth of crystals in the batch. Seed of small size may be generated by sieving, milling, or micronizing of large crystals, or by micro-crystallization of solutions. Care should be taken that milling or micronizing of crystals does not result in any change in crystallinity form the desired crystal form (i.e., change to amorphous or to another polymorph).
A cooled crystallization mixture may be filtered under vacuum, and the isolated solids may be washed with a suitable solvent, such as cold recrystallization solvent, and dried under a nitrogen purge to afford the desired crystalline form. The isolated solids may be analyzed by a suitable spectroscopic or analytical technique, such as solid state nuclear magnetic resonance, differential scanning calorimetry, x-ray powder diffraction, or the like, to assure formation of the preferred crystalline form of the product. The resulting crystalline form is typically produced in an amount of greater than about 70 weight % isolated yield, preferably greater than 90 weight % isolated yield, based on the weight of the compound originally employed in the crystallization procedure. The product may be comilled or passed through a mesh screen to delump the product, if necessary.
Preferred processes for the preparation of the lesinurad, free form / lesinurad ethyl ester co-crystal of the invention are provided in the examples and in the embodiment section.
Enumerated Embodiment section
Aspects, advantageous features and preferred embodiments of the present invention are summarized in the following items:
1. A co-crystal comprising 2-[5-bromo-4-(4-cyclopropylnaphthalen-l-yl)-4H- 1,2,4- triazol-3-ylsulfanyl]acetic acid (lesinurad, free form) and ethyl-2-[5-bromo-4-(4- cyclopropylnaphthalen-l-yl)-4H-l,2,4-triazol-3-ylsulfanyl]acetate (lesinurad ethyl ester).
2. The lesinurad, free form / lesinurad ethyl ester co-crystal according to item 1, which is an anhydrate.
3. The lesinurad, free form / lesinurad ethyl ester co-crystal according to any one of items 1 or 2 in substantially pure form.
4. The lesinurad, free form / lesinurad ethyl ester co-crystal according to any one of items 1 to 3 having a molar ratio of lesinurad: lesinurad ethyl ester in a range of from 1.0 : 0.7 to 1.0 : 1.3
5. The lesinurad, free form / lesinurad ethyl ester co-crystal according to item 4, having a molar ratio of lesinurad: lesinurad ethyl ester in a range of from 1.0 : 0.8 to 1.0 : 1.2.
6. The lesinurad, free form / lesinurad ethyl ester co-crystal according to item 5 having a molar ratio of lesinurad: lesinurad ethyl ester of about 1.0 : 1.0. 7. The lesinurad, free form / lesinurad ethyl ester co-crystal according to any one of items 1 to 6 characterized by a x-ray powder diffraction pattern comprising four or more peaks at 2Θ values selected from the group consisting of 9.9±0.2°, 11.1±0.2°, 13.3±0.2°, 20.9±0.2°, 23.6±0.2° and 25.3±0.2° when measured at a temperature of about 25 °C using Cu Ka radiation. 8. The lesinurad, free form / lesinurad ethyl ester co-crystal according to item 7, characterized by a XRPD comprising characteristic peaks at 2-Theta angles of 9.9±0.2°, 11.1±0.2°, 20.9±0.2° and 23.6±0.2°.
9. The lesinurad, free form / lesinurad ethyl ester co-crystal according to any one of items 7 or 8, wherein the XRPD further comprises at least one additional peak at 2-Theta angles of 13.3±0.2° and 25.3±0.2°0.2, 18.5 ± 0.2° and 24.0± 0.2°,
10. The lesinurad, free form / lesinurad ethyl ester co-crystal according to any one of items 7 or 8, wherein the XRPD comprises peaks at all positions identified in list 1.
11. The lesinurad, free form / lesinurad ethyl ester co-crystal according to item 10, having a X-ray diffraction spectrum substantially the same as the X-ray powder diffraction spectrum shown in FIG. 1.
12. The lesinurad, free form / lesinurad ethyl ester co-crystal according to any one of items 1 to 11 characterized by having a differential thermal analysis (DTA) thermogram comprising an endothermic peak between 75°C and 95°C.
13. The lesinurad, free form / lesinurad ethyl ester co-crystal according to item 12 having a differential thermal analysis thermogram substantially the same as the differential thermal analysis thermogram shown in FIG. 2.
14. The lesinurad, free form / lesinurad ethyl ester co-crystal according to any one of items 1 to 13 further characterized by showing a weight loss of from 0.5% to 1.5% between 30°C and 85°C when analyzed by thermogravimetric analysis (TGA). 15. The lesinurad, free form / lesinurad ethyl ester co-crystal according to any one of items 1 to 14 characterized by an infrared spectrum comprising absorption peaks at between 2505cm"1 and 2520cm"1 and at between 1722cm"1 and 1732cm"1.
16. The lesinurad, free form / lesinurad ethyl ester co-crystal according to any one of items 1 to 6 characterized by a x-ray powder diffraction pattern comprising four or more 2Θ values selected from the group consisting of 3.6±0.2°, 10.8±0.2°, 16.5±0.2°, 21.0±0.2°
and 23.7±0.2° when measured at a temperature of about 25°C using Cu Ka radiation.
17. The lesinurad, free form / lesinurad ethyl ester co-crystal according to item 16, having a X-ray diffraction spectrum substantially the same as the X-ray powder diffraction spectrum shown in FIG. 4. 18. A composition comprising at least 90 weight % of lesinurad, free form / lesinurad ethyl ester co-crystal according to any one of items 1 to 17, based the weight of the composition.
19. The composition of item 18 consisting essentially of the crystalline form of any one of items 7 to 13 or 15 to 16. 20. Use of the lesinurad, free form / lesinurad ethyl ester co-crystal according to any one of items 1 to 6, 7 to 14 or 15 to 17 or of the composition according to any one of items 18 to 19 for the preparation of amorphous lesinurad for use in a pharmaceutical composition.
21. Use according to item 20, wherein the amorphous lesinurad is an amorphous lesinurad metal salt. 22. Use according to item 21, wherein the metal salt is a pharmaceutically acceptable alkali metal or alkaline earth metal salt.
23. Use according to any one of items 20 to 22, wherein the amorphous lesinurad is amorphous lesinurad sodium salt.
24. Use of the amorphous lesinurad prepared from the lesinurad, free form / lesinurad ethyl ester co-crystal according to any one of items 1 to 6, 7 to 14 or 15 to 17 or from the composition according to any one of items 18 to 19 for the preparation of a
pharmaceutical composition for the treatment of gout.
25. A process of preparing a lesinurad, free form / lesinurad ethyl ester co-crystal comprising the step of allowing a lesinurad, free form / lesinurad ethyl ester co-crystal to crystallize from a solvent comprising lesinurad, free form and lesinurad ethyl ester.
26. The process of item 25, wherein the solvent comprises, preferably is, ethanol.
27. The process of any one of items 25 to 26, wherein the lesinurad, free form / lesinurad ethyl ester co-crystal is allowed to crystallize at a temperature of from -30°C to -15°C. 28. A process for the preparation of amorphous lesinurad from a lesinurad, free form / lesinurad ethyl ester co-crystal comprising a saponification reaction.
29. The process of item 28, wherein lesinurad ethyl ester is brought into contact with an aqueous base.
30. The process of item 29, wherein the aqueous base is an aqueous solution of a metal hydroxide.
31. The process of item 30, wherein the aqueous solution of a metal hydroxide is an aqueous solution of an alkali metal hydroxide or an aqueous solution of an alkaline earth metal hydroxide.
32. The process of any one of items 29 to 31, wherein the aqueous base is a sodium hydroxide solution.
33. The process of any one of items 28 to 32, comprising the further step of reducing the amount of residual ethanol in amorphous lesinurad.
34. The process of any one of items 28 to 33, wherein the obtained amorphous lesinurad is amorphous lesinurad, free form..
35. The process of item 34 comprising an acidification reaction..
36. The process of item 35 comprising the step of contacting sodium lesinurad in a solvent selected from the group consisting ofalcohols, ketones, esters, ethers, dichloromethane or dichloro ethane, hydrocarbons and mixtures thereof.
37. The process of item 36, wherein the solvent is selected from the group consisting of acetone, dichloromethane and mixtures thereof.
38. The process of any one of items 28 to 37, wherein the obtained amorphous lesinurad is further mixed with a pharmaceutically acceptable carrier or diluent for the preparation of a pharmaceutical composition.
39. The process of item 38, wherein the pharmaceutical composition is an oral solid dosage form.
40. The process of item 39, wherein the pharmaceutical composition is a capsule.
41. The process of any one of items 38 to 40, wherein the pharmaceutical composition further comprises at least one water-soluble filler; at least one water-insoluble filler; at least one binder; and at least one lubricant.
The following non-limiting examples are illustrative of the disclosure and are not to be construed to be limiting to the scope of the claims.
EXAMPLES
Instrumentation, and Methods of Analysis
High Performance Liquid Chromatography-Ultraviolet Detection (HPLC-UV)
Column: Waters Symmetry CI 8 150 x 3.9 mm, 5 μιη
Mobile Phase A: 0.1% Formic acid
Mobile Phase B: 0.1% Formic acid in acetonitrile
Diluent: 20% Acetonitrile
Flow Rate: 1.2 mL/min
Runtime: 30 minutes
Column Temperature: 25°C
Autosampler Temperature Ambient
Injection Volume: 10
Detection: 235 nm
Sample Concentration: 0.5 mg/mL
Gradient program:
XRPD analysis was carried out on a PANalytical X'Pert Pro X-ray Diffractometer, scanning the samples between 3 and 35 °2-theta. The material was loaded into a 96-well plate with mylar film as the base. The samples were then loaded into the plate holder of a PANalytical X'Pert Pro X-ray Diffractometer running in transmission mode and analyzed, using the following experimental conditions:
Raw Data Origin: XRD measurement (*.XRDML)
Scan Axis: Gonio
Start Position [°2Θ]: 3.0066
End Position [°2Θ]: 34.9866
Step Size [°2Θ]: 0.0130
Scan Step Time [s]: 18.8700
Scan Type: Continuous
PSD Mode: Scanning
PSD Length [°2Θ]: 3.35
Offset [°2Θ]: 0.0000
Divergence Slit Type: Fixed
Divergence Slit Size [°]: 1.0000
Specimen Length [mm] : 10.00
Measurement Temperature 25.00
Anode Material: Cu
K-Alphal,2 [A]: 1.5419
K-Beta [A]: 1.39225
K-A2 / K-A1 Ratio: 0.50000
Generator Settings: 40 niA, 40 kV
Diffractometer Type: 0000000011154173
Diffractometer Number: 0
Goniometer Radius [mm] : 240.00
Dist. Focus-Diverg. Slit [mm]: 91.00
Incident Beam Monochromator: No
Spinning: No
Thermo gravimetric Differential Thermal Analysis (TG-DTA)
Thermogravimetric analyses were carried out on a Seiko Exstar SII 6200 TG/DTA. The calibration standards were indium and tin. Samples were accurately weighed and placed in an open aluminium sample pan, inserted into the instrument and held at room temperature. The sample was then heated at a rate of 10°C/min from 20°C to 300°C during which time the change in sample weight was recorded along with any differential thermal events (DTA). Nitrogen was used as the purge gas, at a flow rate of 300 cm3/min. The skilled person will appreciate that the TG trace is the trace starting at about 100% at 0 min in the TG/DTA.
Differential Scanning Calorimetry (DSC)
Differential Scanning Calorimetry (DSC) analyses were carried out on a Seiko Exstar SII 6200 DSC. The calibration standards were indium and tin. Approximately 5 mg of material was weighed into an aluminium DSC pan and sealed non-hermetically with a pierced aluminium lid. The sample pan was then loaded into the instrument (equipped with a cooler) and held at 20°C. Once a stable heat-flow response was obtained, the sample and reference were heated at a scan rate of 10°C/min and the resulting heat flow response monitored. Nitrogen was used as the purge gas, at a flow rate of 50 cm3/min.
Infrared Spectroscopy (IR)
Infrared spectroscopy was carried out on a Bruker ALPHA P spectrometer. Sufficient material was placed onto the center of the plate of the spectrometer and the spectra were obtained using the following parameters:
Resolution: 4 cm"1
Background Scan Time: 16 scans
Sample Scan Time: 16 scans
Data Collection: 4000 to 400 cm 1
Result Spectrum: Transmittance
Software: OPUS version 6
¾ Nuclear Magnetic Resonance Spectroscopy (lH NMR)
^-NMR spectroscopic experiments were performed on a Bruker AV500 (frequency: 500 MHz). Experiments were performed in d6-dimethylsulfoxide and each sample was prepared to ca. 10 mM concentration.
Preparation 1 : Preparation of Lesinurad, ethyl ester
Lesinurad, free form (0.25g), prepared according to WO2009070740, purity 97.01% by HPLC analysis, was suspended in ethanol (1.25mL) at 20°C and the resulting slurry treated with sulfuric acid (75uL). The resulting solution was stirred for lh at 20°C and then temperature cycled between 5°C and 25°C for 144h. The solution was then concentrated on a rotary evaporator and the residue re-dissolved in dichloromethane (lOmL) and washed with sodium bicarbonate solution (lOmL). The layers were separated and the organic layer was washed with water (2xl0mL). The aqueous layer was then extracted with dichloromethane (2x1 OmL) and the washings were combined with the organic layer and dried over sodium sulfate. Evaporation of the dichloromethane yielded an oil (-100% th. yield). The oil was analyzed by HPLC which indicated the presence of 95.4%) lesinurad ethyl ester and 1.8% lesinurad, free form.
Alternatively the lesinurad ethyl ester can be prepared according to other methods, e.g. such as described in WO2009/070740 or WO 2014/008295. Example 1 : Co-crystallisation of Lesinurad, free form and Lesinurad ethyl ester (Form A)
Lesinurad, free form (0.025g), prepared according to WO2009070740, purity 97.01%) by HPLC analysis, was dissolved in ethanol (0.35mL) at 50°C. The resulting solution was added to lesinurad ethyl ester from Preparation 1 (1 : 1 molar ration with lesinurad, free form) until complete dissolution was observed. Heptane (0.35mL) was added and the solution was cooled to 5°C and held at that temperature for 18h.
XRPD analysis was performed on lesinurad, free form / lesinurad ethyl ester co-crystal, Form A. The x-ray powder diffraction pattern (XRPD) is displayed in Figure 4.
Significant peaks were observed at the following positions [± 0.2 °2Th.] (list 2):
3.6; 9.8; 10.8; 13.3; 16.5; 21.0; 23.6; 23.7; 25.5; 26.2. Further drying of the lesinurad, free form / lesinurad ethyl ester co-crystal, Form A resulted in conversion to lesinurad, free form / lesinurad ethyl ester co-crystal, Form B and presents an alternative to Example 2 for the preparation of lesinurad, free form / lesinurad ethyl ester co-crystal, Form B.
Example 2: Co-crystallisation of Lesinurad free form and Lesinurad ethyl ester (Form B)
Lesinurad free form (0.025g) prepared according to WO2009070740, purity 97.01%) by HPLC analysis, was dissolved in ethanol (0.35mL) at 50°C. The resulting solution was added to lesinurad ethyl ester from Preparation 1 until complete dissolution was observed. Heptane (0.35mL) was added and the solution was warmed to 50°C and held at that temperature for 72h. After this time an additional 0.2mL of heptane were added and the resulting solid isolated by filtration and dried at 35°C under vacuum for 23h.
XRPD analysis was performed on lesinurad, free form / lesinurad ethyl ester co-crystal, Form B. The x-ray powder diffraction pattern (XRPD) is displayed in Figure 1.
Significant peaks were observed at the following positions [± 0.2 °2Th.] (list 1):
3.7; 9.9; 11.1; 13.3; 17.0; 20.4; 20.6; 20.9; 23.6; 23.8; 25.3; 26.8. TGA of free form / lesinurad ethyl ester co-crystal, Form B showed a weight loss of ca. 1.0% from the outset up to ca. 100°C, followed by a second weight loss of ca. 0.5% between 100°C and ca. 145°C, prior to the onset of decomposition.
DTA of free form / lesinurad ethyl ester co-crystal, Form B showed an endothermic event at onset ca. 76.8°C (peak at ca. 85.6°C) corresponding to the initial weight loss. DSC analysis of free form / lesinurad ethyl ester co-crystal, Form B showed an endotherm at onset ca. 85.7°C (peak at ca. 90.3°C). The differential scanning calorimetry (DSC) thermogram of lesinurad, free form / lesinurad ethyl ester co-crystal, Form B is displayed in Figure 2.
TG analysis up to 130°C was also carried out for free form / lesinurad ethyl ester co- crystal, Form B, where the TGA showed a weight loss of ca. 0.8%> from the outset up to ca. 85°C and the DTA showed an endothermic event at onset ca. 83.2°C (peak at ca. 89.9°C), likely due to melting of the material.
Post-TGA XRPD analysis of free form / lesinurad ethyl ester co-crystal, Form B indicated that lesinurad, free form / lesinurad ethyl ester co-crystal from example 2 converted to amorphous material after heating to 130°C.
Lesinurad, free form / lesinurad ethyl ester co-crystal, Form B was assessed by ¾ NMR. The analysis indicates a 1 : 1 mixture of lesinurad, free form / lesinurad ethyl ester.. The reduced integration obtained for the acid proton at δ 13.0 ppm and signals consistent with a ethoxy group present at δ 4.09 ppm (quartett) and 1.16 ppm (triplet). Two signals (doublets) observed for the SCFh group, in approximately 1 :1 ratio.
The IR spectrum of lesinurad, free form / lesinurad ethyl ester co-crystal, Form B was consistent with the lH NMR assessment as a broad signal at ca. 2512 cm"1 was observed (corresponding to the OH of the acid group) and a 10 cm"1 shift in the vc=o to ca.1727 cm" 1 was observed.
Detected absorbances; Wavenumber (cm-1): 2978, 2927, 2512, 1727, 1597. 1581, 1462, 1449, 1417, 1401, 1379, 1336, 1293, 1265, 1199, 1176, 1108, 1023, 1008, 992, 975, 928, 894, 861, 836, 765, 690, 662, 543, 501, 428.
The IR spectrum of lesinurad, free form / lesinurad ethyl ester co-crystal, Form B is displayed in Figure 3. The HPLC analysis of lesinurad, free form / lesinurad ethyl ester co-crystal, Form B showed two peaks with a ratio of ca. 1 : 1 separated by about 2 min.
No change in the lesinurad, free form / lesinurad ethyl ester co-crystal, Form B was
observed after 1 week stability testing at 40°C / 75% relative humidity.
Example 3 : amorphous lesinurad sodium from lesinurad, free form / lesinurad ethyl ester co-crystal
The material from Example 2 is dissolved in ethanol. To this solution is added 0.5 equivalent of NaOH (aq) and the reaction is stirred at ambient temperature or with gentle warming until completion (2 to 5 h).The resulting solution is then freeze dried or spray dried to give amorphous lesinurad sodium.
Example 4: preparation of amorphous lesinurad, free form.
The material from example 3 is dissolved in dichloromethane. To this solution is added 1 equivalent of HC1 (aqueous) and the reaction is stirred at ambient temperature for one hour. Water is then added to the reaction mass. The dichloromethane layer is separated and washed with water. The solvent dichloromethane is evaporated to yield solid material.
This solid material obtained is dissolved in 1 : 1 mixture of dichloromethane and acetone. The solvent is removed to yield a glass-like 'bubbly' solid.
XRPD analysis of solid is performed to confirm amorphous nature of the material.
HPLC purity analysis of lesinurad, free form. Form 2 vs. lesinurad, free form / lesinurad ethyl ester co-crystal. Form B
Approximate Relative Lesinurad, free Lesinurad, free form / Retention Time Retention Time form, Form 2 Lesinurad ethyl ester (min) (min) (%) co-crystal, Form B (%)
5.27 0.56 0.21 -
7.10 0.75 1.08 0.45
8.68 0.92 0.10 -
9.46 1 96.80 52.51
10.38 1.10 0.13 0.06
10.97 1.16 0.45 0.15
11.11 1.17 0.52 0.18
12.00 1.27 0.71 45.95
12.23 1.29 - 0.54
13.25 1.40 - 0.16
Many of the impurities are reduced in lesinurad, free form / lesinurad ethyl ester co- crystal, Form B compared with lesinurad, free form, Form 2.
Claims
1. A co-crystal comprising 2-[5-bromo-4-(4-cyclopropylnaphthalen-l-yl)-4H- 1,2,4- triazol-3-ylsulfanyl]acetic acid (lesinurad, free form) and ethyl-2-[5-bromo-4-(4- cyclopropylnaphthalen-l-yl)-4H-l,2,4-triazol-3-ylsulfanyl]acetate (lesinurad ethyl ester).
2. The lesinurad, free form / lesinurad ethyl ester co-crystal according to claim 1, in substantially pure form.
3. The lesinurad / lesinurad ethyl ester co-crystal according to any one of claims 1 to 2 characterized by a x-ray powder diffraction pattern comprising four or more peaks at 2Θ values selected from the group consisting of 9.9±0.2°, 11.1±0.2°, 13.3±0.2°, 20.9±0.2°, 23.6±0.2° and 25.3±0.2° when measured at a temperature of about 25°C using Cu Ka radiation.
4. The lesinurad, free form / lesinurad ethyl ester co-crystal according to claim 3, having a X-ray diffraction spectrum substantially the same as the X-ray powder diffraction spectrum shown in FIG. 1.
5. The lesinurad, free form / lesinurad ethyl ester co-crystal according to any one of claims 1 to 4 characterized by having a differential thermal analysis (DTA) thermogram comprising an endothermic peak between 75°C and 95°C.
6. The lesinurad, free form / lesinurad ethyl ester co-crystal according to claim 5 having a differential thermal analysis thermogram substantially the same as the differential thermal analysis thermogram shown in FIG. 2.
7. The lesinurad, free form / lesinurad ethyl ester co-crystal according to any one of claims 1 to 6 characterized by an infrared spectrum comprising absorption peaks at between 2505cm"1 and 2520cm"1 and at between 1722cm"1 and 1732cm"1.
8. The lesinurad, free form / lesinurad ethyl ester co-crystal according to any one of claims 1 to 2 characterized by a x-ray powder diffraction pattern comprising four or more
2Θ values selected from the group consisting of 3.6±0.2°, 10.8±0.2°, 16.5±0.2°, 21.0±0.2° and 23.7±0.2° when measured at a temperature of about 25°C using Cu Ka radiation.
9. The lesinurad, free form / lesinurad ethyl ester co-crystal according to claim 8, having a X-ray diffraction spectrum substantially the same as the X-ray powder diffraction spectrum shown in FIG. 4.
10. A composition comprising at least 90 weight % of lesinurad, free form / lesinurad ethyl ester co-crystal according to any one of claims 1 to 9, based the weight of the composition.
11. Use of a lesinurad, free form / lesinurad ethyl ester co-crystal according to any one of claims 1 to 9 for the preparation of amorphous lesinurad.
12. A process of making a lesinurad, free form / lesinurad ethyl ester co-crystal according to any one of claims 1 to 9 comprising the step of
allowing a lesinurad, free form / lesinurad ethyl ester co-crystal to crystallize from a solvent comprising lesinurad, free form and lesinurad ethyl ester.
13. The process of claim 12, wherein the solvent comprises, preferably is, ethanol.
14. A process for the preparation of amorphous lesinurad from a lesinurad, free form / lesinurad ethyl ester co-crystal according to any one of claims 1 to 9 comprising a saponification reaction.
15. The process of claim 14, comprising the further step of reducing the amount of residual ethanol in amorphous lesinurad.
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