WO2017203457A1 - Solid state forms of empagliflozin - Google Patents
Solid state forms of empagliflozin Download PDFInfo
- Publication number
- WO2017203457A1 WO2017203457A1 PCT/IB2017/053079 IB2017053079W WO2017203457A1 WO 2017203457 A1 WO2017203457 A1 WO 2017203457A1 IB 2017053079 W IB2017053079 W IB 2017053079W WO 2017203457 A1 WO2017203457 A1 WO 2017203457A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- empagliflozin
- mixture
- solution
- solvent
- amorphous
- Prior art date
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- OBWASQILIWPZMG-QZMOQZSNSA-N empagliflozin Chemical compound O[C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@H]1C1=CC=C(Cl)C(CC=2C=CC(O[C@@H]3COCC3)=CC=2)=C1 OBWASQILIWPZMG-QZMOQZSNSA-N 0.000 title claims abstract description 389
- 229960003345 empagliflozin Drugs 0.000 title claims abstract description 388
- 239000007787 solid Substances 0.000 title abstract description 61
- 238000000034 method Methods 0.000 claims abstract description 69
- 238000002360 preparation method Methods 0.000 claims abstract description 60
- 230000008569 process Effects 0.000 claims abstract description 40
- 238000000746 purification Methods 0.000 claims abstract description 12
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 156
- 239000000203 mixture Substances 0.000 claims description 135
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 84
- 239000002904 solvent Substances 0.000 claims description 81
- 239000007962 solid dispersion Substances 0.000 claims description 75
- 238000000634 powder X-ray diffraction Methods 0.000 claims description 65
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 58
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 54
- 229960002429 proline Drugs 0.000 claims description 51
- 229930182821 L-proline Natural products 0.000 claims description 50
- ONIBWKKTOPOVIA-BYPYZUCNSA-N L-Proline Chemical compound OC(=O)[C@@H]1CCCN1 ONIBWKKTOPOVIA-BYPYZUCNSA-N 0.000 claims description 49
- 230000009477 glass transition Effects 0.000 claims description 44
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 43
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 40
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 38
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 36
- 229940093499 ethyl acetate Drugs 0.000 claims description 28
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- 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 claims description 28
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- 239000012296 anti-solvent Substances 0.000 claims description 23
- 239000003937 drug carrier Substances 0.000 claims description 20
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 claims description 20
- 239000012044 organic layer Substances 0.000 claims description 19
- 239000003960 organic solvent Substances 0.000 claims description 18
- WWCNXHYRAKUQDB-SNVBAGLBSA-N [(3r)-oxolan-3-yl] 4-methylbenzenesulfonate Chemical compound C1=CC(C)=CC=C1S(=O)(=O)O[C@H]1COCC1 WWCNXHYRAKUQDB-SNVBAGLBSA-N 0.000 claims description 15
- 229920002153 Hydroxypropyl cellulose Polymers 0.000 claims description 14
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 14
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- 229920000609 methyl cellulose Polymers 0.000 claims description 14
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- -1 compound (R)-tetrahydrofuran-3-yl-4-methyl benzenesulfonate Chemical class 0.000 claims description 13
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- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 claims description 12
- 239000001863 hydroxypropyl cellulose Substances 0.000 claims description 12
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 claims description 11
- 238000010438 heat treatment Methods 0.000 claims description 11
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 10
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 claims description 10
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- YYROPELSRYBVMQ-UHFFFAOYSA-N 4-toluenesulfonyl chloride Chemical compound CC1=CC=C(S(Cl)(=O)=O)C=C1 YYROPELSRYBVMQ-UHFFFAOYSA-N 0.000 claims description 8
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- 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 claims description 8
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- 239000001856 Ethyl cellulose Substances 0.000 claims description 6
- ZZSNKZQZMQGXPY-UHFFFAOYSA-N Ethyl cellulose Chemical compound CCOCC1OC(OC)C(OCC)C(OCC)C1OC1C(O)C(O)C(OC)C(CO)O1 ZZSNKZQZMQGXPY-UHFFFAOYSA-N 0.000 claims description 6
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- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 6
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- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 5
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- DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 claims description 4
- 239000001506 calcium phosphate Substances 0.000 claims description 4
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- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 claims description 4
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- XDPCNPCKDGQBAN-SCSAIBSYSA-N (3r)-oxolan-3-ol Chemical compound O[C@@H]1CCOC1 XDPCNPCKDGQBAN-SCSAIBSYSA-N 0.000 claims description 3
- 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 claims description 3
- IZSANPWSFUSNMY-UHFFFAOYSA-N cyclohexane-1,2,3-triol Chemical compound OC1CCCC(O)C1O IZSANPWSFUSNMY-UHFFFAOYSA-N 0.000 claims description 3
- 238000002156 mixing Methods 0.000 claims description 3
- LNAZSHAWQACDHT-XIYTZBAFSA-N (2r,3r,4s,5r,6s)-4,5-dimethoxy-2-(methoxymethyl)-3-[(2s,3r,4s,5r,6r)-3,4,5-trimethoxy-6-(methoxymethyl)oxan-2-yl]oxy-6-[(2r,3r,4s,5r,6r)-4,5,6-trimethoxy-2-(methoxymethyl)oxan-3-yl]oxyoxane Chemical compound CO[C@@H]1[C@@H](OC)[C@H](OC)[C@@H](COC)O[C@H]1O[C@H]1[C@H](OC)[C@@H](OC)[C@H](O[C@H]2[C@@H]([C@@H](OC)[C@H](OC)O[C@@H]2COC)OC)O[C@@H]1COC LNAZSHAWQACDHT-XIYTZBAFSA-N 0.000 claims description 2
- GUBGYTABKSRVRQ-UHFFFAOYSA-N 2-(hydroxymethyl)-6-[4,5,6-trihydroxy-2-(hydroxymethyl)oxan-3-yl]oxyoxane-3,4,5-triol Chemical compound OCC1OC(OC2C(O)C(O)C(O)OC2CO)C(O)C(O)C1O GUBGYTABKSRVRQ-UHFFFAOYSA-N 0.000 claims description 2
- 241000416162 Astragalus gummifer Species 0.000 claims description 2
- 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 claims description 2
- 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 claims description 2
- 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 claims description 2
- 235000019739 Dicalciumphosphate Nutrition 0.000 claims description 2
- 108010010803 Gelatin Proteins 0.000 claims description 2
- 229920002907 Guar gum Polymers 0.000 claims description 2
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 2
- 240000007472 Leucaena leucocephala Species 0.000 claims description 2
- 235000010643 Leucaena leucocephala Nutrition 0.000 claims description 2
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- 229920001615 Tragacanth Polymers 0.000 claims description 2
- NEFBYIFKOOEVPA-UHFFFAOYSA-K dicalcium phosphate Chemical compound [Ca+2].[Ca+2].[O-]P([O-])([O-])=O NEFBYIFKOOEVPA-UHFFFAOYSA-K 0.000 claims description 2
- 229940038472 dicalcium phosphate Drugs 0.000 claims description 2
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- OQCDKBAXFALNLD-UHFFFAOYSA-N octadecanoic acid Natural products CCCCCCCC(C)CCCCCCCCC(O)=O OQCDKBAXFALNLD-UHFFFAOYSA-N 0.000 claims description 2
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- 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
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 description 1
- 239000002202 Polyethylene glycol Substances 0.000 description 1
- MTCFGRXMJLQNBG-UHFFFAOYSA-N Serine Natural products OCC(N)C(O)=O MTCFGRXMJLQNBG-UHFFFAOYSA-N 0.000 description 1
- 102000000070 Sodium-Glucose Transport Proteins Human genes 0.000 description 1
- 108010080361 Sodium-Glucose Transport Proteins Proteins 0.000 description 1
- 102100037202 Sodium/myo-inositol cotransporter 2 Human genes 0.000 description 1
- 101710090560 Sodium/myo-inositol cotransporter 2 Proteins 0.000 description 1
- AYFVYJQAPQTCCC-UHFFFAOYSA-N Threonine Natural products CC(O)C(N)C(O)=O AYFVYJQAPQTCCC-UHFFFAOYSA-N 0.000 description 1
- 239000004473 Threonine Substances 0.000 description 1
- RHQDFWAXVIIEBN-UHFFFAOYSA-N Trifluoroethanol Chemical compound OCC(F)(F)F RHQDFWAXVIIEBN-UHFFFAOYSA-N 0.000 description 1
- QIVBCDIJIAJPQS-UHFFFAOYSA-N Tryptophan Natural products C1=CC=C2C(CC(N)C(O)=O)=CNC2=C1 QIVBCDIJIAJPQS-UHFFFAOYSA-N 0.000 description 1
- KZSNJWFQEVHDMF-UHFFFAOYSA-N Valine Natural products CC(C)C(N)C(O)=O KZSNJWFQEVHDMF-UHFFFAOYSA-N 0.000 description 1
- GJWAPAVRQYYSTK-UHFFFAOYSA-N [(dimethyl-$l^{3}-silanyl)amino]-dimethylsilicon Chemical compound C[Si](C)N[Si](C)C GJWAPAVRQYYSTK-UHFFFAOYSA-N 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- KXKVLQRXCPHEJC-UHFFFAOYSA-N acetic acid trimethyl ester Natural products COC(C)=O KXKVLQRXCPHEJC-UHFFFAOYSA-N 0.000 description 1
- 239000004480 active ingredient Substances 0.000 description 1
- 235000004279 alanine Nutrition 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 150000001408 amides Chemical class 0.000 description 1
- 125000000129 anionic group Chemical group 0.000 description 1
- 239000003963 antioxidant agent Substances 0.000 description 1
- ODKSFYDXXFIFQN-UHFFFAOYSA-N arginine Natural products OC(=O)C(N)CCCNC(N)=N ODKSFYDXXFIFQN-UHFFFAOYSA-N 0.000 description 1
- 235000009697 arginine Nutrition 0.000 description 1
- 125000003118 aryl group Chemical group 0.000 description 1
- 229960001230 asparagine Drugs 0.000 description 1
- 235000009582 asparagine Nutrition 0.000 description 1
- 235000003704 aspartic acid Nutrition 0.000 description 1
- 230000006399 behavior Effects 0.000 description 1
- OQFSQFPPLPISGP-UHFFFAOYSA-N beta-carboxyaspartic acid Natural products OC(=O)C(N)C(C(O)=O)C(O)=O OQFSQFPPLPISGP-UHFFFAOYSA-N 0.000 description 1
- 239000011230 binding agent Substances 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- 210000004369 blood Anatomy 0.000 description 1
- 150000001721 carbon Chemical group 0.000 description 1
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 1
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 1
- 239000000969 carrier Substances 0.000 description 1
- 230000003197 catalytic effect Effects 0.000 description 1
- 125000002091 cationic group Chemical group 0.000 description 1
- 239000003610 charcoal Substances 0.000 description 1
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- 239000003086 colorant Substances 0.000 description 1
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- 230000001276 controlling effect Effects 0.000 description 1
- 239000012043 crude product Substances 0.000 description 1
- 125000004093 cyano group Chemical group *C#N 0.000 description 1
- 125000004122 cyclic group Chemical group 0.000 description 1
- 229940097362 cyclodextrins Drugs 0.000 description 1
- HPXRVTGHNJAIIH-UHFFFAOYSA-N cyclohexanol Chemical compound OC1CCCCC1 HPXRVTGHNJAIIH-UHFFFAOYSA-N 0.000 description 1
- XUJNEKJLAYXESH-UHFFFAOYSA-N cysteine Natural products SCC(N)C(O)=O XUJNEKJLAYXESH-UHFFFAOYSA-N 0.000 description 1
- 235000018417 cysteine Nutrition 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- XXJWXESWEXIICW-UHFFFAOYSA-N diethylene glycol monoethyl ether Chemical compound CCOCCOCCO XXJWXESWEXIICW-UHFFFAOYSA-N 0.000 description 1
- 229940075557 diethylene glycol monoethyl ether Drugs 0.000 description 1
- SBZXBUIDTXKZTM-UHFFFAOYSA-N diglyme Chemical compound COCCOCCOC SBZXBUIDTXKZTM-UHFFFAOYSA-N 0.000 description 1
- JVSWJIKNEAIKJW-UHFFFAOYSA-N dimethyl-hexane Natural products CCCCCC(C)C JVSWJIKNEAIKJW-UHFFFAOYSA-N 0.000 description 1
- 239000007884 disintegrant Substances 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 239000003759 ester based solvent Substances 0.000 description 1
- IDGUHHHQCWSQLU-UHFFFAOYSA-N ethanol;hydrate Chemical compound O.CCO IDGUHHHQCWSQLU-UHFFFAOYSA-N 0.000 description 1
- 239000004210 ether based solvent Substances 0.000 description 1
- 150000002170 ethers Chemical class 0.000 description 1
- JBTWLSYIZRCDFO-UHFFFAOYSA-N ethyl methyl carbonate Chemical compound CCOC(=O)OC JBTWLSYIZRCDFO-UHFFFAOYSA-N 0.000 description 1
- 229940093476 ethylene glycol Drugs 0.000 description 1
- 239000010408 film Substances 0.000 description 1
- 239000000796 flavoring agent Substances 0.000 description 1
- 235000013355 food flavoring agent Nutrition 0.000 description 1
- 235000003599 food sweetener Nutrition 0.000 description 1
- WBJINCZRORDGAQ-UHFFFAOYSA-N formic acid ethyl ester Natural products CCOC=O WBJINCZRORDGAQ-UHFFFAOYSA-N 0.000 description 1
- 239000008103 glucose Substances 0.000 description 1
- 230000014101 glucose homeostasis Effects 0.000 description 1
- 235000013922 glutamic acid Nutrition 0.000 description 1
- 239000004220 glutamic acid Substances 0.000 description 1
- ZDXPYRJPNDTMRX-UHFFFAOYSA-N glutamine Natural products OC(=O)C(N)CCC(N)=O ZDXPYRJPNDTMRX-UHFFFAOYSA-N 0.000 description 1
- 235000004554 glutamine Nutrition 0.000 description 1
- 238000000227 grinding Methods 0.000 description 1
- 229910052736 halogen Inorganic materials 0.000 description 1
- 125000005843 halogen group Chemical group 0.000 description 1
- FUZZWVXGSFPDMH-UHFFFAOYSA-N hexanoic acid Chemical compound CCCCCC(O)=O FUZZWVXGSFPDMH-UHFFFAOYSA-N 0.000 description 1
- HNDVDQJCIGZPNO-UHFFFAOYSA-N histidine Natural products OC(=O)C(N)CC1=CN=CN1 HNDVDQJCIGZPNO-UHFFFAOYSA-N 0.000 description 1
- 235000014304 histidine Nutrition 0.000 description 1
- 239000008240 homogeneous mixture Substances 0.000 description 1
- 150000004677 hydrates Chemical class 0.000 description 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 230000003993 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
- ZXEKIIBDNHEJCQ-UHFFFAOYSA-N isobutanol Chemical compound CC(C)CO ZXEKIIBDNHEJCQ-UHFFFAOYSA-N 0.000 description 1
- KQNPFQTWMSNSAP-UHFFFAOYSA-M isobutyrate Chemical compound CC(C)C([O-])=O KQNPFQTWMSNSAP-UHFFFAOYSA-M 0.000 description 1
- FGKJLKRYENPLQH-UHFFFAOYSA-M isocaproate Chemical compound CC(C)CCC([O-])=O FGKJLKRYENPLQH-UHFFFAOYSA-M 0.000 description 1
- 229960000310 isoleucine Drugs 0.000 description 1
- AGPKZVBTJJNPAG-UHFFFAOYSA-N isoleucine Natural products CCC(C)C(N)C(O)=O AGPKZVBTJJNPAG-UHFFFAOYSA-N 0.000 description 1
- JMMWKPVZQRWMSS-UHFFFAOYSA-N isopropanol acetate Natural products CC(C)OC(C)=O JMMWKPVZQRWMSS-UHFFFAOYSA-N 0.000 description 1
- 229940011051 isopropyl acetate Drugs 0.000 description 1
- GWYFCOCPABKNJV-UHFFFAOYSA-N isovaleric acid Chemical compound CC(C)CC(O)=O GWYFCOCPABKNJV-UHFFFAOYSA-N 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
- 239000005453 ketone based solvent Substances 0.000 description 1
- 238000004811 liquid chromatography Methods 0.000 description 1
- 239000000314 lubricant Substances 0.000 description 1
- 235000018977 lysine Nutrition 0.000 description 1
- 230000001404 mediated effect Effects 0.000 description 1
- 238000002844 melting Methods 0.000 description 1
- 230000008018 melting Effects 0.000 description 1
- 229930182817 methionine Natural products 0.000 description 1
- GYNNXHKOJHMOHS-UHFFFAOYSA-N methyl-cycloheptane Natural products CC1CCCCCC1 GYNNXHKOJHMOHS-UHFFFAOYSA-N 0.000 description 1
- 238000003801 milling Methods 0.000 description 1
- 239000002808 molecular sieve Substances 0.000 description 1
- PYLWMHQQBFSUBP-UHFFFAOYSA-N monofluorobenzene Chemical compound FC1=CC=CC=C1 PYLWMHQQBFSUBP-UHFFFAOYSA-N 0.000 description 1
- 229940124305 n-propanol Drugs 0.000 description 1
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 1
- GLKFBDCTMIJHDH-UHFFFAOYSA-N nitrobenzene;pyridine Chemical compound C1=CC=NC=C1.[O-][N+](=O)C1=CC=CC=C1 GLKFBDCTMIJHDH-UHFFFAOYSA-N 0.000 description 1
- MCSAJNNLRCFZED-UHFFFAOYSA-N nitroethane Chemical compound CC[N+]([O-])=O MCSAJNNLRCFZED-UHFFFAOYSA-N 0.000 description 1
- LYGJENNIWJXYER-UHFFFAOYSA-N nitromethane Chemical compound C[N+]([O-])=O LYGJENNIWJXYER-UHFFFAOYSA-N 0.000 description 1
- 238000010899 nucleation Methods 0.000 description 1
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 1
- 238000005457 optimization Methods 0.000 description 1
- 239000012074 organic phase Substances 0.000 description 1
- 125000004430 oxygen atom Chemical group O* 0.000 description 1
- JYVLIDXNZAXMDK-UHFFFAOYSA-N pentan-2-ol Chemical compound CCCC(C)O JYVLIDXNZAXMDK-UHFFFAOYSA-N 0.000 description 1
- 239000012071 phase Substances 0.000 description 1
- WVDDGKGOMKODPV-ZQBYOMGUSA-N phenyl(114C)methanol Chemical compound O[14CH2]C1=CC=CC=C1 WVDDGKGOMKODPV-ZQBYOMGUSA-N 0.000 description 1
- 230000000704 physical effect Effects 0.000 description 1
- 239000004014 plasticizer Substances 0.000 description 1
- 239000003880 polar aprotic solvent Substances 0.000 description 1
- 229920001223 polyethylene glycol Polymers 0.000 description 1
- 239000003755 preservative agent Substances 0.000 description 1
- 229940090181 propyl acetate Drugs 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- 229920005989 resin Polymers 0.000 description 1
- 239000011347 resin Substances 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 238000006748 scratching Methods 0.000 description 1
- 230000002393 scratching effect Effects 0.000 description 1
- 238000010898 silica gel chromatography Methods 0.000 description 1
- URGAHOPLAPQHLN-UHFFFAOYSA-N sodium aluminosilicate Chemical compound [Na+].[Al+3].[O-][Si]([O-])=O.[O-][Si]([O-])=O URGAHOPLAPQHLN-UHFFFAOYSA-N 0.000 description 1
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- MBDNRNMVTZADMQ-UHFFFAOYSA-N sulfolene Chemical compound O=S1(=O)CC=CC1 MBDNRNMVTZADMQ-UHFFFAOYSA-N 0.000 description 1
- 150000003457 sulfones Chemical class 0.000 description 1
- 150000003462 sulfoxides Chemical class 0.000 description 1
- 239000004094 surface-active agent Substances 0.000 description 1
- 239000003765 sweetening agent Substances 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
- BCNZYOJHNLTNEZ-UHFFFAOYSA-N tert-butyldimethylsilyl chloride Chemical compound CC(C)(C)[Si](C)(C)Cl BCNZYOJHNLTNEZ-UHFFFAOYSA-N 0.000 description 1
- 238000002411 thermogravimetry Methods 0.000 description 1
- JOXIMZWYDAKGHI-UHFFFAOYSA-M toluene-4-sulfonate Chemical compound CC1=CC=C(S([O-])(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-M 0.000 description 1
- OUYCCCASQSFEME-UHFFFAOYSA-N tyrosine Natural products OC(=O)C(N)CC1=CC=C(O)C=C1 OUYCCCASQSFEME-UHFFFAOYSA-N 0.000 description 1
- NQPDZGIKBAWPEJ-UHFFFAOYSA-N valeric acid Chemical compound CCCCC(O)=O NQPDZGIKBAWPEJ-UHFFFAOYSA-N 0.000 description 1
- 239000004474 valine Substances 0.000 description 1
- 239000001993 wax Substances 0.000 description 1
- 238000009736 wetting Methods 0.000 description 1
- 239000008096 xylene Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D407/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00
- C07D407/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 containing two hetero rings
- C07D407/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
- A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
- A61K31/7048—Compounds having saccharide radicals and heterocyclic rings having oxygen as a ring hetero atom, e.g. leucoglucosan, hesperidin, erythromycin, nystatin, digitoxin or digoxin
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
- C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
- C07D307/04—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
- C07D307/18—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D307/20—Oxygen atoms
Definitions
- the present application relates to solid state forms of empagliflozin and processes for preparation of empagliflozin and intermediates thereof
- the drug compound having the adopted name Empagliflozin has a chemical name 1 -chloro-4(beta-D-glucopyranos-1 -yl)-2-[4-((S)-tetrahydrofuran-3-yloxy)-benzyl)- benzene, and is represented by the structure of formula I.
- Empagliflozin is a sodium-dependent glucose cotransporter 2 (SGLT 2) inhibitor and is used for the treatment of patients with type 2 diabetes mellitus.
- SGLT 2 sodium-dependent glucose cotransporter 2
- US Patent No. 7,713,938 discloses a crystalline form of empagliflozin and a pharmaceutical composition comprising the crystalline form.
- the US '938 also discloses that "the method of manufacturing empagliflozin as described in product patent process does not yield a crystalline form".
- Polymorphism the occurrence of different crystal forms, is a phenomenon of some molecules and molecular complexes. A single molecule may give rise to a variety of polymorphs having distinct crystal structures and physical properties. Polymorphs in general will have different melting points, thermal behaviors (e.g. measured by thermogravimetric analysis - "TGA”, or differential scanning calorimetry - “DSC”), X-ray powder diffraction (XRPD or powder XRD) pattern, infrared absorption fingerprint, and solid state nuclear magnetic resonance (NMR) spectrum. One or more of these techniques may be used to distinguish different polymorphic forms of a compound.
- TGA thermogravimetric analysis -
- DSC differential scanning calorimetry -
- XRPD or powder XRD X-ray powder diffraction
- NMR solid state nuclear magnetic resonance
- Discovering new polymorphic forms, hydrates and solvates of a pharmaceutical product can provide materials having desirable processing properties, such as ease of handling, ease of processing, storage stability, and ease of purification or as desirable intermediate crystal forms that facilitate conversion to other polymorphic forms.
- New polymorphic forms and solvates of a pharmaceutically useful compound or salts thereof can also provide an opportunity to improve the performance characteristics of a pharmaceutical product. It enlarges the repertoire of materials that a formulation scientist has available for formulation optimization, for example by providing a product with different properties, e.g., better processing or handling characteristics, improved dissolution profile, or improved shelf-life. For at least these reasons, there is a need for additional solid forms of Empagliflozin.
- aspects of the present application relate to amorphous empagliflozin, amorphous solid dispersion of empagliflozin, and complexes of empagliflozin with amino acids, crystalline forms of empagliflozin, their preparative processes and pharmaceutical compositions thereof.
- the present application provides stable amorphous empagliflozin.
- the present application provides amorphous empagliflozin having a glass transition onset temperature of at least 60 °C or above.
- the present application provides a process for preparing amorphous empagliflozin having a glass transition onset temperature of at least 60 °C or above, comprising;
- the present application provides amorphous solid dispersion of empaglilflozin having a glass transition onset temperature of at least 55 °C or above comprising empagliflozin and one or more pharmaceutically acceptable carriers.
- the present application provides a process for preparing amorphous solid dispersion having a glass transition onset temperature of at least 55 °C or above comprising empagliflozin and one or more pharmaceutically acceptable carriers, comprising;
- the present application provides a process for preparing crystalline form of empagliflozin characterized by PXRD peaks at 18.84°, 20.36°, and 25.21 ° 2 theta, which comprises;
- the present application provides a process for purification of empagliflozin, comprising:
- step (b) optionally, heating the solution obtained in step (a);
- step (c) separating the organic layer from the mixture obtained in step (b); and d) isolating pure empagliflozin from the organic layer of step (c).
- the present application provides a crystalline Form N of Empagliflozin, characterized by a PXRD pattern comprising the peaks at about 4.13, 7.79, 1 1.55, 16.74, 23.20 and 27.87 ⁇ 0.2° 2 ⁇ .
- the present application provides a complex of empagliflozin with phenylalanine.
- the present application provides a process for the preparation of the complex of empagliflozin with phenylalanine, comprising
- the present application provides a crystalline Form-Alpha (Form a) of Empagliflozin, characterized by a PXRD pattern as shown in Figure 32.
- the present application provides a crystalline Form-Beta (Form ⁇ ) of Empagliflozin, characterized by a PXRD pattern comprising the peaks at about 3.44, 4.04, 9.35, 10.20 and 14.1 1 ⁇ 0.2° 2 ⁇ .
- the present application provides a crystalline Form- Gamma (Form Y) of Empagliflozin, characterized by a PXRD pattern comprising the peaks at about 4.82, 7.19, 10.17 and 1 1 .20 ⁇ 0.2° 2 ⁇ .
- the present application provides a process for preparation of (R)-tetrahydrofuran-3-yl-4-methylbenzenesulfonate having greater than about 99.8% of chiral purity, comprising
- the present application provides a process for preparation of empagliflozin having greater than about 99.8% of chiral purity, comprising:
- the present application provides use of the crystalline forms of empagliflozin of the present invention and the empagliflozin phenylalanine complex and empagliflozin L-proline complex of the present invention to improve the purity of empagliflozin.
- the present application provides a pharmaceutical composition comprising any of amorphous empagliflozin or empagliflozin solid dispersion or empagliflozin L-proline complex or empagliflozin phenylalanine complex of the present invention or any of the crystalline forms of empagliflozin of the present invention and at least one pharmaceutically acceptable carrier.
- Figure 1 is powder X-ray power diffraction pattern of an amorphous form of empagliflozin prepared according to Example 1 .
- Figure 2 is powder X-ray power diffraction pattern of an amorphous solid dispersion comprising empagliflozin and HPMC Phthalate prepared according to Example 6.
- Figure 3 is powder X-ray power diffraction pattern of an amorphous solid dispersion comprising empagliflozin and methyl cellulose prepared according to Example 7.
- Figure 4 is powder X-ray power diffraction pattern of crystalline form of empagliflozin prepared according to Example 8.
- Figure 5 is powder X-ray power diffraction pattern of empagliflozin L-proline complex prepared according to Example 13.
- Figure 6 is powder X-ray power diffraction pattern of an amorphous form of empagliflozin prepared according to Example 15.
- Figure 7 is powder X-ray power diffraction pattern of an amorphous solid dispersion comprising empagliflozin and L-HPC prepared according to Example 17.
- Figure 8 is powder X-ray power diffraction pattern of an amorphous solid dispersion comprising empagliflozin and ethyl cellulose prepared according to Example 18.
- Figure 9 is powder X-ray power diffraction pattern of an amorphous solid dispersion comprising empagliflozin and ethyl cellulose (at 40% RH) prepared according to Example 18.
- Figure 10 is powder X-ray power diffraction pattern of an amorphous solid dispersion comprising empagliflozin and Eudragit RLPO prepared according to Example 19.
- Figure 1 1 is powder X-ray power diffraction pattern of an amorphous solid dispersion comprising empagliflozin and Eudragit RLPO (at 40% RH) prepared according to Example 19.
- Figure 12 is powder X-ray power diffraction pattern of an amorphous solid dispersion comprising empagliflozin and hydroxypropyl methyl cellulose (HPMC) prepared according to Example 20.
- Figure 13 is powder X-ray power diffraction pattern of an amorphous solid dispersion comprising empagliflozin and hydroxypropyl methyl cellulose (at 40% RH) prepared according to Example 20.
- Figure 14 is powder X-ray power diffraction pattern of an amorphous solid dispersion comprising empagliflozin and hydroxypropyl methyl cellulose acetate succinate (HPMC- AS) prepared according to Example 21 .
- Figure 15 is powder X-ray power diffraction pattern of an amorphous solid dispersion comprising empagliflozin and hydroxypropyl methyl cellulose acetate succinate (HPMC- AS) (at 40% RH) prepared according to Example 21 .
- HPMC- AS hydroxypropyl methyl cellulose acetate succinate
- Figure 16 is powder X-ray power diffraction pattern of an amorphous solid dispersion comprising empagliflozin and Soluplus prepared according to Example 22.
- Figure 17 is powder X-ray power diffraction pattern of an amorphous solid dispersion comprising empagliflozin and Soluplus (at 40% RH) prepared according to Example 22.
- Figure 18 is powder X-ray power diffraction pattern of an amorphous solid dispersion comprising empagliflozin and Eudragit-E100 prepared according to Example 23.
- Figure 19 is powder X-ray power diffraction pattern of an amorphous solid dispersion comprising empagliflozin and Eudragit-E100 (at 40% RH) prepared according to Example 23.
- Figure 20 is powder X-ray power diffraction pattern of an amorphous solid dispersion comprising empagliflozin and hydroxypropyl methyl cellulose phthalate (HPMC- Phthalate) prepared according to Example 25.
- Figure 21 is powder X-ray power diffraction pattern of an amorphous solid dispersion comprising empagliflozin and hydroxypropyl methyl cellulose phthalate (HPMC- Phthalate) (at 40% RH) prepared according to Example 25.
- HPMC- Phthalate hydroxypropyl methyl cellulose phthalate
- Figure 22 is powder X-ray power diffraction pattern of an amorphous solid dispersion comprising empagliflozin and methyl cellulose prepared according to Example 26.
- Figure 23 is powder X-ray power diffraction pattern of an amorphous solid dispersion comprising empagliflozin and methyl cellulose (at 40% RH) prepared according to Example 26.
- Figure 24 is powder X-ray power diffraction pattern of an amorphous solid dispersion comprising empagliflozin, hydroxypropyl methyl cellulose (HPMC) and Syloid (1 :1 :0.5) prepared according to Example 27.
- Figure 25 is powder X-ray power diffraction pattern of an amorphous solid dispersion comprising empagliflozin, hydroxypropyl methyl cellulose (HPMC) and Lactose monohydrate (1 :1 :0.5) prepared according to Example 27.
- Figure 26 is powder X-ray power diffraction pattern of an amorphous solid dispersion comprising empagliflozin, hydroxypropyl methyl cellulose (HPMC) and croscarmellose sodium (1 :1 :0.5) prepared according to Example 27.
- Figure 27 is powder X-ray power diffraction pattern of an amorphous solid dispersion comprising empagliflozin, hydroxypropyl cellulose (HPC) and Syloid (1 :1 :0.5) prepared according to Example 28.
- Figure 28 is powder X-ray power diffraction pattern of an amorphous solid dispersion comprising empagliflozin, hydroxypropyl cellulose (HPC) and Lactose monohydrate (1 :1 :0.5) prepared according to Example 28.
- Figure 29 is powder X-ray power diffraction pattern of an amorphous solid dispersion comprising empagliflozin, hydroxypropyl cellulose (HPC) and croscarmellose sodium (1 :1 :0.5) prepared according to Example 28.
- Figure 30 is an illustrative X-ray powder diffraction pattern of crystalline Form N of Empagliflozin prepared by the method of Example No 31 .
- Figure 31 is an illustrative X-ray powder diffraction pattern of crystalline Form of the complex of Empagliflozin with L-phenylalanine prepared by the method of Example No 32.
- Figure 32 is an illustrative X-ray powder diffraction pattern of crystalline Form-Alpha (a) of Empagliflozin prepared by the method of Example No 33.
- Figure 33 is an illustrative X-ray powder diffraction pattern of crystalline Form-Beta ( ⁇ ) of Empagliflozin prepared by the method of Example No 34.
- Figure 34 is an illustrative X-ray powder diffraction pattern of crystalline Form-Gamma ( ⁇ ) of Empagliflozin prepared by the method of Example No 35.
- Figure 35 is DSC thermogram of amorphous Empagliflozin prepared by the method of Example No 15.
- Empagliflozin used as the input in the process for preparation of stable amorphous empagliflozin and amorphous solid dispersion of the present invention can be prepared by any process known in the art.
- the present application provides stable amorphous empagliflozin.
- the present application provides amorphous empagliflozin having a glass transition onset temperature of at least 60 °C or above.
- the present application provides a process for preparing amorphous empagliflozin having a glass transition onset temperature of at least 60 °C or above, comprising;
- Providing a solution in step (a) includes direct use of a reaction mixture containing empagliflozin that is obtained in the course of its synthesis or dissolving empagliflozin in a solvent or a mixture of solvents.
- Suitable solvents which can be used for dissolving empagliflozin include but are not limited to: alcohol solvents such as methanol, ethanol, isopropyl alcohol, n-propanol, isoamyl alcohol n-butanol, 2-butanol and the like; halogenated hydrocarbons such as dichloromethane, 1 ,2-dichloroethane, chloroform, carbon tetrachloride and the like; ketones such as acetone, ethyl methyl ketone, methyl isobutyl ketone and the like; dimethylformamide, dimethylacetamide and dimethylsulfoxide; and any mixtures of two or more thereof.
- alcohol solvents such as methanol, ethanol, isopropyl alcohol, n-propanol, isoamyl alcohol n-butanol, 2-butanol and the like
- halogenated hydrocarbons such as dichloromethane, 1 ,2-dich
- the obtained solution may be optionally filtered to remove any insoluble particles. Suitable techniques to remove insoluble particles are filtration, centrifugation, decantation, and any other known techniques in the art.
- the solution can be filtered by passing through paper, glass fiber, or other membrane material, or a clarifying agent such as Celite.
- the filtration apparatus may need to be preheated to avoid premature precipitation of solid.
- Step (b) involves removing solvent from the solution of empagliflozin.
- Suitable techniques which can be used for the removal of solvent include but not limited to evaporation, flash evaporation, simple evaporation, rotational drying, spray drying, agitated thin-film drying, agitated nutsche filter drying, pressure nutsche filter drying, freeze-drying or any other suitable technique known in the art.
- Step (c) involves recovering an amorphous form of empagliflozin.
- the said recovery can be achieved by using the processes known in the art.
- the resulting compound in step (c) may optionally be further dried. Drying can be carried out in a tray dryer, vacuum oven, air oven, cone vacuum dryer, rotary vacuum dryer, fluidized bed dryer, spin flash dryer, flash dryer, or the like. The drying can be carried out at temperatures of less than about 60°C, less than about 50°C, less than about 40°C, less than about 30°C, less than about 20°C, or any other suitable temperatures; at atmospheric pressure or under a reduced pressure; as long as the empagliflozin is not degraded in its quality. The drying can be carried out for any desired times until the required product quality is achieved. Suitable time for drying can vary from few minutes to several hours for example from about 30 minutes to about 24 or more hours.
- the present application provides amorphous Empagliflozin having a chemical purity of at least 99% by HPLC or at least 99.5% by HPLC or at least 99.9% by HPLC.
- the amorphous empagliflozin is stable for 3 months in ICH storage conditions i.e. (i) 25°C ⁇ 2°C and 60%RH ⁇ 5RH, (ii) 40°C ⁇ 2°C and 75%RH ⁇ 5RH, (iii) 30 °C ⁇ 2 °C and 75%RH ⁇ 5RH and (iv) 2°C - 8°C.
- Packing conditions used for amorphous empagliflozin are incorporated below.
- Packing method-1 Take the sample in a clear anti-static polyethylene bag and tie it with plastic strip by twisting after removing air.
- Packing method-2 Take the sample in a clear anti-static polyethylene bag and tie it with plastic strip by twisting after removing air. Keep the above in a black polythene bag fill it with nitrogen gas and tie it with plastic strip. Keep the bag in triple laminated bag and seal it with VNS Sealer, keep the above triple laminated bag in another triple laminated bag and seal it with VNS Sealer. Finally keep the packet in HDPE container and store in the stability chamber.
- Amorphous empagliflozin of the present application was found to be stable under mechanical stress such as grinding and milling and stable under hygroscopic conditions such as higher relative humidity conditions of more than 60% RH.
- the amorphous empagliflozin of the present invention is showing glass transition onset temperature of 66.29 °C, and glass transition temperature of 70.13 °C.
- the DSC thermogram is shown in Figure 35.
- the present application provides amorphous solid dispersion of empagliflozin having a glass transition onset temperature of at least 55 °C or above, comprising empagliflozin and one or more pharmaceutically acceptable carriers.
- the present application provides a process for preparing amorphous solid dispersion of empagliflozin having a glass transition onset temperature of at least 55 °C or above, comprising empagliflozin and one or more pharmaceutically acceptable carriers, comprising;
- step (a) recovering an amorphous solid dispersion having a glass transition onset temperature of at least 60 °C or above, comprising empagliflozin and one or more pharmaceutically acceptable carriers.
- Providing a solution in step (a) includes direct use of a reaction mixture containing empagliflozin that is obtained in the course of its synthesis or dissolving empagliflozin and pharmaceutically acceptable carrier in a solvent.
- empagliflozin Any physical form of empagliflozin may be utilized for providing the solution of empagliflozin in step (a).
- Suitable pharmaceutically acceptable carriers which can be used in step (a) include, but are not limited to: diluents such as starches, pregelatinized starches, lactose, powdered celluloses, microcrystalline celluloses, dicalcium phosphate, tricalcium phosphate, Polyethylene glycol, Copovidone, Soluplus, Silicified microcrystalline cellulose mannitol, sorbitol, sugar and the like; binders such as acacia, guar gum, tragacanth, gelatin, polyvinylpyrrolidones, hydroxypropyl celluloses, hydroxypropyl methylcelluloses such as HPMC-Phthalate, HPMC-AS, HPMC-15 CPS; pregelatinized starches and the like; disintegrants such as starches, sodium starch glycolate, pregelatinized starches, crospovidones, croscarmellose sodium, colloidal silicon dioxide and the like; lubricants such as stearic acid, magnesium ste
- the pharmaceutically acceptable carriers are hydroxypropyl methylcellulose phthalate (HPMC-Phthalate) and methyl cellulose.
- Suitable solvents which can be used for dissolving the empagliflozin include but are not limited to: alcohol solvents such as methanol, ethanol, isopropyl alcohol, n- propanol, isoamyl alcohol n-butanol, 2-butanol and the like; halogenated hydrocarbons such as dichloromethane, 1 ,2-dichloroethane, chloroform, carbon tetrachloride and the like; ketones such as acetone, ethyl methyl ketone and the like; esters such as ethyl acetate, n-propyl acetate, n-butyl acetate, t-butyl acetate and the like; nitriles such as acetonitrile, propionitrile and the like; dimethylformamide, dimethylacetamide and dimethylsulfoxide, and any mixtures of two or more thereof.
- alcohol solvents such as methanol, ethanol, iso
- step (a) After dissolution in step (a), optionally undissolved particles, if any, may be removed suitably by filtration, centrifugation, decantation, and any other known techniques.
- the solution can be filtered by passing through paper, glass fiber, or other membrane material, or a clarifying agent such as celite.
- the filtration apparatus may need to be preheated to avoid premature crystallization.
- Step (b) involves removing solvent from the solution obtained in step (a);
- Suitable techniques which can be used for the removal of solvent include but not limited to evaporation, flash evaporation, simple evaporation, rotational drying, spray drying, agitated thin-film drying, agitated nutsche filter drying, pressure nutsche filter drying, freeze-drying, filtration or any other technique known in the art.
- Step (c) involves recovering an amorphous solid dispersion comprising empagliflozin and one or more pharmaceutically acceptable carriers.
- the said recovery can be achieved by using the processes known in the art.
- the resulting compound obtained in step (c) may optionally be further dried. Drying can be carried out in a tray dryer, vacuum oven, air oven, cone vacuum dryer, rotary vacuum dryer, fluidized bed dryer, spin flash dryer, flash dryer, or the like. The drying can be carried out at temperatures of less than about 60°C, less than about 50°C, less than about 40°C, less than about 30°C, less than about 20°C, or any other suitable temperatures; at atmospheric pressure or under a reduced pressure; as long as the empagliflozin is not degraded in its quality. The drying can be carried out for any desired time until the required product quality is achieved. Suitable time for drying can vary from few minutes to several hours for example from about 30 minutes to about 24 or more hours.
- the active ingredient is hygroscopic or the formulation contains a hygroscopic ingredient
- a hygroscopic ingredient When the active ingredient is hygroscopic or the formulation contains a hygroscopic ingredient, and to increase the stability of the amorphous form or a solid dispersion comprising amorphous empagliflozin, addition of other carriers such as syloid, methyl cellulose, colloidal silicon dioxide, Eudragit, amorphous silica, micro crystalline cellulose, and the like, in the formulation has been found to be of particular value. Therefore these ingredients may be combined during the preparation of solid dispersion or after the preparation of amorphous empagliflozin or solid dispersion to control hygroscopicity and to improve stability.
- the present application provides a process for preparing crystalline form of empagliflozin characterized by PXRD peaks at 18.84°, 20.36°, and 25.21 ° 2 theta, which comprises;
- Providing a solution in step (a) includes direct use of a reaction mixture containing empagliflozin that is obtained in the course of its synthesis or dissolving empagliflozin in a solvent or a mixture of solvents.
- Suitable solvents which can be used for dissolving empagliflozin include but are not limited to: alcohol solvents such as methanol, ethanol, isopropyl alcohol, n-propanol, isoamyl alcohol n-butanol, 2-butanol and the like; ketones such as acetone, ethyl methyl ketone, methyl isobutyl ketone and the like and the like; halogenated hydrocarbons such as dichloromethane, 1 ,2-dichloroethane, chloroform, carbon tetrachloride and the like; dimethylformamide, dimethylacetamide and dimethylsulfoxide; and any mixtures of two or more thereof.
- alcohol solvents such as methanol, ethanol, isopropyl alcohol, n-propanol, isoamyl alcohol n-butanol, 2-butanol and the like
- ketones such as acetone, ethyl methyl ketone
- the mixture may be heated to get the complete dissolution.
- the obtained solution may optionally be filtered to remove any insoluble particles. Suitable techniques to remove insoluble particles are filtration, centrifugation, decantation, and any other known techniques in the art.
- the solution can be filtered by passing through paper, glass fiber, or other membrane material, or a clarifying agent such as Celite.
- the filtration apparatus may need to be preheated to avoid premature precipitation of solid.
- Step (b) involves heating the solution obtained in step (a) to a temperature higher than the temperature at which the solution is prepared.
- step (a) If the solution of step (a) is prepared at 30°C, the solution is heated to above 30°C, or If the solution of step (a) is prepared at 45°C, the solution is heated to above 45°C.
- Step (c) involves adding an anti-solvent to the hot solution obtained step (c).
- the suitable anti-solvents may include, but not limited to water, pentane, n-hexane, cyclohexane, cylcoheptane, n-heptane, diethyl ether, methyl ter. butyl ether, di isopropyl ether, cyclopentyi methyl ether, pet ether and the like.
- suitable anti- solvents are water, n-heptane and pet ether.
- the anti-solvent may be added to precipitate the crystalline form of empaglif!ozin or a reverse mode of addition may also be employed.
- the mixture may be stirred for sufficient time i.e. 1 5 minutes to 1 0 hours or more.
- anti-solvent addition may be carried out at suitable temperatures, such as at about 30°C to 100°C.
- suitable temperature may be at about 40 to 80°C.
- anti-solvent addition may be carried out for sufficient time to complete precipitation of crystalline form of empaglifiozin. in an aspect, anti-solvent addition may be carried out in sufficient volume to complete precipitation of crystalline form of empaglifiozin.
- Step (d) involves isolation of crystalline form of empaglifiozin. Isolation of crystalline form of empaglifiozin may be carried out by any known methods such as filtration of precipitated solid.
- the isolation of crystalline form of empaglifiozin is carried out at a temperature at which the precipitation is formed.
- the crystalline form of empaglifiozin obtained in step (d) may optionally be washed with the anti-solvent with sufficient volume to remove traces solvent from wet solid.
- the crystalline form of empaglifiozin obtained as above may be dried, if desired, at suitable temperatures at about 50°C, or above. The drying may be performed at atmospheric or reduced pressures, for about 1 - 20 hours, or longer by using the drying equipment known in the art.
- the crystalline form of empagliflozin characterized by PXRD peaks at 18.84°, 20.36°, and 25.21 ° ⁇ 0.2 degrees 2 theta can be prepared by slurrying amorphous empagliflozin in water or on a similar solvent and isolating the crystalline form of empagliflozin by the known methods.
- the present application provides the crystalline form of empagliflozin characterized by PXRD peaks at 18.84°, 20.36°, and 25.21 ° ⁇ 0.2 degrees 2 theta prepared by the process described above having a chemical purity of at least 99% by HPLC or at least 99.5% by HPLC or at least 99.9% by HPLC.
- the present application provides an empagliflozin L-proline complex characterized by PXRD peaks at about 4.36 ⁇ 0.2, 12.97 ⁇ 0.2, 15.67 ⁇ 0.2 and 18.80 ⁇ 0.2 degrees 2-theta.
- the present application provides a process for preparation of the empagliflozin L-proline complex characterized by PXRD peaks at about 4.36 ⁇ 0.2, 12.97 ⁇ 0.2, 15.67 ⁇ 0.2 and 18.80 ⁇ 0.2 degrees 2-theta, comprising:
- step (b) optionally, heating the mixture obtained in step (a);
- Step (a) of the process involves mixing empagliflozin and L-proline in a solvent or a mixture of solvents.
- Preferred solvents are alcoholic solvents such as methanol, ethanol, isopropyl alcohol, n-propanol, isoamyl alcohol and the like; ketones such as acetone, ethyl methyl ketone, methyl isobutyl ketone and the like; esters such as ethyl acetate, n-propyl acetate, n-butyl acetate, t-butyl acetate and the like. Any physical form of empagliflozin can be used as the starting material of the present invention.
- the mixture of empagliflozin and L-proline is prepared in any method such as first the L-proline is added to the solvent and then empagliflozin is added or first empagliflozin is added to a solvent and then L-proline is added.
- empagliflozin and L-proline are added at a time.
- about 1 equivalent of L-proline is used to prepare empagliflozin L-proline complex.
- about 2 equivalents of L-proline is used to prepare empagliflozin L-proline complex.
- greater than 2 equivalents of L-proline is used to prepare empagliflozin L-proline complex.
- L-proline in still other aspects, about 0.9 to about 1 .1 equivalents of L-proline is used to prepare empagliflozin L-proline complex. In further aspects, about 1.8 to about 2.2 equivalents, such as about 1 .98 to 2.02 equivalents, of L-proline is used to prepare empagliflozin L-proline complex.
- Step (b) involves optionally heating the mixture obtained in step (a).
- the mixture obtained step (a) may be heated to a temperature of about 40°C to about 150°C.
- Preferably the mixture is heated to a temperature of about 60°C to about 80°C.
- the mixture may be stirred for about 10 minutes to about 10 hours or longer.
- Step (c) involves isolation of empagliflozin L-proline complex from the mixture of step (b).
- the isolation of empagliflozin L-proline complex may be carried out by any known methods such as filtration of precipitated solid.
- the empagliflozin L-proline complex obtained as above may be dried, if desired, at suitable temperatures at about 50°C, or above.
- the drying may be performed at atmospheric or reduced pressures, for about 1 - 20 hours, or longer by using the drying equipment known in the art.
- Powder X-ray diffraction pattern (PXRD) the empagliflozin L-proline complex obtained by the process of the present application is depicted in Figure 5.
- amino acids which can be used to produce empagliflozin complexes include, but not limited to, glycine, alanine, serine, threonine, cysteine, valine, leucine, isoleucine, methionine, phenylalanine, tyrosine, tryptophan, aspartic acid, glutamic acid, asparagine, glutamine, histidine, lysine, arginine.
- the amino acid complexes of empagliflozin may be useful as intermediate.
- the empagliflozin crude may get purified as the impurities are removed during the complex formation.
- This intermediate can sufficiently be purified to produce the final empagliflozin in the desired form.
- the purification involves slurrying, recrystallization, crystallization etc.
- the present application provides a process for purification of empagliflozin, comprising:
- step (b) optionally, heating the solution obtained in step (a);
- step (c) separating the organic layer from the mixture obtained in step (b);
- step (d) isolating pure empagliflozin from the organic layer of step (c).
- Step (a) of the process involves providing a solution of empagliflozin L-proline complex in a mixture of an organic solvent and water.
- organic solvent Any type of organic solvent can be used in this process.
- Preferred solvents are esters such as ethyl acetate, n-propyl acetate, n-butyl acetate, t-butyl acetate and the like; alcoholic solvents such as methanol, ethanol, isopropyl alcohol, n-propanol, isoamyl alcohol and the like; ketones such as acetone, ethyl methyl ketone, methyl isobutyl ketone and the like; halogenated hydrocarbon solvents such as dichloromethane, dichloroethane, chloroform, carbon tetrachloride and the like.
- the organic solvent is ethylacetate.
- the step (a) solution is prepared by any means such as first the complex is added to an organic solvent and then water is added or first the complex is added to water and then an organic solvent is added. The organic solvent and water are taken in a ratio of about 1 :0.2 to about 1 :5.
- the solution obtained in step (a) may be heated to about 50°C and the solution may be stirred for about 10 minutes to about 5 hours.
- Step (c) of the process involves separating the organic layer form the mixture.
- the organic layer containing empagliflozin is separated from the mixture and the organic layer may be washed with water.
- Step (d) involves isolation of pure empagliflozin from the organic layer.
- Empagliflozin can be isolated by removal of the solvent.
- the solvent can be removed using a rotational distillation device such as a Buchi rotavapor, spray drying, agitated thin film drying, freeze drying (lyophilization), and the like, or other techniques specific to the equipment used.
- Small quantity of solvent or anti solvent may be added to the reaction flask or the reactor to make the slurry or suspension when the solvent is completely removed, which will be useful for easy filtration.
- the solvent may be removed, optionally under reduced pressures, at temperatures less than reflux temperature of the solvent, less than about 100°C, less than about 60°C, less than about 40°C, less than about 20°C, or any other suitable temperatures.
- the product thus isolated may be optionally further dried to afford pure empagliflozin. Drying may suitably be carried out in a tray dryer, vacuum oven, Buchi rotavapor, air oven, fluidized bed dryer, spin flash dryer, flash dryer, or the like. The drying may be carried out at atmospheric pressure or under reduced pressures at temperatures of less than about 100°C, less than about 60°C, less than about 40°C or any other suitable temperatures. The drying may be carried out for any time period required for obtaining a desired quality, such as from about 15 minutes to several hours.
- the present application provides empagliflozin prepared by the purification process described above is having a chemical purity of at least 99% by HPLC or at least 99.5% by HPLC or at least 99.9% by HPLC.
- the present application provides a crystalline Form N of Empagliflozin, characterized by a PXRD pattern comprising the peaks at about 4.13, 7.79, 1 1.55, 16.74, 23.20 and 27.87 ⁇ 0.2° 2 ⁇ .
- the present application provides a crystalline Form N of Empagliflozin, characterized by a PXRD pattern having one or more additional peaks at about 7.16, 15.51 , 15.86, 16.36, 22.08, 23.65, 24.47 and 26.65 ⁇ 0.2° 2 ⁇ .
- the application provides crystalline Form N of Empagliflozin, characterized by a PXRD pattern of figure 30.
- the present application provides a process for the preparation of crystalline Form N of Empagliflozin, comprising the step of treating Empagliflozin with N- methyl pyrrolidine or a mixture thereof.
- crystalline Form N of Empagliflozin may be obtained by treating Empagliflozin with N-methyl pyrrolidine.
- crystalline Form N of Empagliflozin may be obtained by treating Empagliflozin with a mixture of N-methyl pyrrolidine and atleast one additional solvent.
- additional solvent may be selected from the group comprising of diethyl ether, di isopropyl ether, methyl tert. butyl ether, methanol, ethanol, 2- propanol, acetone, methyl isobutyl ketone, water or mixtures thereof.
- treating Empagliflozin with N-methyl pyrrolidine or a mixture thereof may be carried out by combining Empagliflozin and N-methyl pyrrolidine or a mixture thereof.
- the mixture of Empagliflozin and N-methyl pyrrolidine or a mixture thereof may form a homogeneous mixture in the form of a solution.
- the mixture of Empagliflozin and N-methyl pyrrolidine or a mixture thereof is a heterogeneous mixture in the form a suspension.
- combining Empagliflozin with N-methyl pyrrolidine or a mixture thereof may be carried out optionally by heating a mixture of Empagliflozin and N- methyl pyrrolidine or a mixture thereof at about 0°C to reflux temperature.
- the mixture of Empagliflozin and N-methyl pyrrolidine or a mixture may be filtered to make it particle free and optionally treated with decolorizing agents such as charcoal, prior to filtration.
- seeds of crystalline Form N of Empagliflozin may be added to the mixture of Empagliflozin and N-methyl pyrrolidine or a mixture thereof, when the mixture forms a homogenous solution.
- seeds may be added at a suitable temperature and sufficient quantity such that the seeds are not dissolved.
- the mixture of Empagliflozin and N-methyl pyrrolidine or a mixture thereof may be contacted with an anti-solvent, when the mixture forms a homogenous solution.
- the anti-solvent may be a solvent in which Empagliflozin has low solubility or is insoluble.
- Anti-solvent may include, but not limited to water, diethyl ether, di isopropyl ether, methyl tert. butyl ether, n-propanol, 2-propanol, ethyl acetate, toluene, acetonitrile or mixtures thereof.
- anti-solvent may be contacted at a temperature and duration, suitable for the formation of crystalline form I II of Empagliflozin.
- anti- solvent may be contacted either by adding the anti-solvent to the mixture of Empagliflozin and N-methyl pyrrolidine or by adding the mixture to anti-solvent.
- anti-solvent may be contacted in single lot or multiple lots.
- the mixture of Empagliflozin and N-methyl pyrrolidine or a mixture thereof may be stirred for sufficient time to complete the formation of Form N and at suitable temperature where crystalline Form N is stable and do not convert to any other form of Empagliflozin.
- the mixture of Empagliflozin and N-methyl pyrrolidine or a mixture thereof may be stirred for at least 1 hour or more. In an aspect, the mixture of Empagliflozin and N-methyl pyrrolidine or a mixture thereof may be stirred at a temperature of about 0°C to reflux temperature.
- the mixture of Empagliflozin and N-methyl pyrrolidine or a mixture thereof may be cooled to a relatively lower temperature.
- the mixture may be cooled to a suitable temperature before or after addition of seeds and / or contacting with anti-solvent.
- the mixture comprising Empagliflozin and N-methyl pyrrolidine or a mixture thereof may be further stirred at the same temperature for time sufficient, after cooling, to obtain crystalline Form N of Empagliflozin.
- crystalline Form N of Empagliflozin may be carried out by any methods known in the art or procedures described in the present application.
- crystalline Form N may be isolated by employing any of the techniques, but not limited to: decantation, filtration by gravity or suction, centrifugation, adding solvent to make slurry followed by filtration, or other techniques specific to the equipment used and the like, and optionally washing with a solvent.
- the crystalline Form N of Empagliflozin may be optionally dried under suitable drying conditions, at which the Form N is stable.
- the crystalline Form N of Empagliflozin may be directly converted to any other solid form of Empagliflozin, without drying.
- the present application provides a pharmaceutical composition comprising the crystalline Form N of Empagliflozin and at least pharmaceutically acceptable carrier.
- the present application provides crystalline Form N of Empagliflozin or their pharmaceutical compositions comprising Empagliflozin having a chemical purity of at least 99% by HPLC or at least 99.5% by HPLC or at least 99.9% by HPLC.
- the present application provides crystalline Form N of Empagliflozin or their pharmaceutical composition, wherein particle size (D90) of Empagliflozin may be less than 100 microns or less than 50 microns or less than 20 microns.
- the present application provides a complex of empagliflozin with phenylalanine.
- the empagliflozin phenylalanine complex can be prepared by the following process. The process comprising:
- the step (a) involves dissolving empagliflozin and phenylalanine in a suitable solvent to form a solution.
- the solution containing empagliflozin and phenylalanine may prepared by adding phenylalanine into a solution containing empagliflozin.
- the solvent may be selected form the group comprising methanol, ethanol, isopropanol, tetrahydrofuran, acetone, acetonitrile and water or a mixture thereof. Preferably a mixture of ethanol and water is used.
- the mixture containing empagliflozin, phenylalanine and the solvent may be heated to elevated temperatures.
- the step (b) involves storing the solution to precipitate empagliflozin phenylalanine complex.
- Storing the solution means keeping the solution or stirring the solution at below the temperature at which the solution is formed. Storing may be carried till the precipitation occurs. Storing may be continued for additional time to precipitate maximum product. Storing may be carried out at about 35 °C to about -10 °C. A precipitate will be formed upon storing the solution.
- the step (c) involves isolation of empagliflozin phenylalanine complex.
- the suspension formed in the step (b) may be isolated by known techniques such as decantation, filtration by gravity or suction, centrifugation, adding solvent to make slurry followed by filtration, or other techniques specific to the equipment used and the like, and optionally washing with a solvent.
- the empagliflozin Phenylalanine complex may optionally be dried under suitable drying conditions, at which the complex is stable.
- the empagliflozin Phenylalanine complex may be directly converted to any other solid form of empagliflozin, without drying.
- the empagliflozin Phenylalanine complex is confirmed with the use of X-ray powder diffraction (XRPD), differential scanning calorimetry.
- XRPD X-ray powder diffraction
- the XRPD pattern is shown in Figure 31 .
- the empagliflozin phenylalanine complex exhibits a crystalline character.
- the characteristic diffraction peaks are 8.28 and 16.45 ⁇ 0.2 °2 ⁇ .
- Other characteristic diffraction peaks are 4.24, 24.67 and 25.32 ⁇ 0.2 °2 ⁇ .
- the present application provides a crystalline Form-Alpha (a) of Empagliflozin, characterized by a PXRD pattern as shown in Figure 32.
- the crystalline Form-Alpha of Empagliflozin may be directly converted to any other solid form of Empagliflozin, without drying.
- the present application provides a crystalline Form-Beta (Form ⁇ ) of Empagliflozin, characterized by a PXRD pattern comprising the peaks at about 3.44, 4.04, 9.35, 10.20 and 14.1 1 ⁇ 0.2° 2 ⁇ .
- the XRPD pattern of crystalline Form-Beta of Empagliflozin is shown in Figure 33.
- the characteristic diffraction peaks are 3.44, 4.04, 9.35, 10.20 and 14.1 1 ⁇ 0.2 °2 ⁇ .
- Other characteristic diffraction peaks are 18.21 , 19.13 and 24.20 ⁇ 0.2 °2 ⁇ .
- the present application provides a crystalline Form- Gamma (Form Y) of Empagliflozin, characterized by a PXRD pattern comprising the peaks at about 4.82, 7.19, 10.17 and 1 1.20 ⁇ 0.2° 2 ⁇ .
- the XRPD pattern of crystalline Form-Gamma of Empagliflozin is shown in Figure 34.
- the characteristic diffraction peaks are 4.82, 7.19, 10.17 and 1 1 .20 ⁇ 0.2 °2 ⁇ .
- Other characteristic diffraction peaks are 4.18, 18.15, 23.55 and 23.90 ⁇ 0.2 °2 ⁇ .
- the crystalline Form-Alpha, Form-Beta and Form-Gamma of empagliflozin can be prepared by the processes described in this application or by the processes described in the art.
- the present application provides crystalline forms of Empagliflozin described in this application having a chemical purity of at least 99% by HPLC or at least 99.5% by H PLC.
- the present application provides crystalline forms of Empagliflozin described in this application or their pharmaceutical composition, wherein particle size (D90) of Empagliflozin may be less than 200 microns or less than 100 microns or less than 50 microns or less than 20 microns.
- the present application provides a pharmaceutical composition
- a pharmaceutical composition comprising any of amorphous empagliflozin or empagliflozin solid dispersion or empagliflozin L-proline complex or empagliflozin phenylalanine complex of the present invention or any of the crystalline forms of empagliflozin of the present invention and at least pharmaceutically acceptable carrier.
- the present application provides a process for preparation of (R)-tetrahydrofuran-3-yl-4-methylbenzenesulfonate having greater than about 99.8% of chiral purity, comprising
- the step (a) is carried out using a suitable solvent such as dichloromethane, chlorobenzene or acetonitrile and the like.
- a suitable solvent such as dichloromethane, chlorobenzene or acetonitrile and the like.
- the crude product is slurried in a solvent or a mixture of solvents such as a mixture of ethylacetate and cyclohexane or a mixture of ethylacetate and n-hexane.
- a solvent or a mixture of solvents such as a mixture of ethylacetate and cyclohexane or a mixture of ethylacetate and n-hexane.
- the present application provides a method of treating or preventing type 2 diabetes, comprising administering to a subject in need thereof an effective amount of any of amorphous empagliflozin or empagliflozin solid dispersion or empagliflozin L-proline complex or empagliflozin phenylalanine complex of the present invention or any of the crystalline forms of empagliflozin of the present invention or a pharmaceutical composition thereof.
- amorphous refers to a solid lacking any long-range translational orientation symmetry that characterizes crystalline structures although; it may have short range molecular order similar to a crystalline solid.
- the term "complex” refers to a molecular entity formed by association involving two or more component molecular entities (ionic or uncharged), or by association involving two or more chemical species.
- the bonding between the components is non-covalent and is normally weaker than covalent bonding.
- the empagliflozin L-proline complex described herein is a molecular entity formed by the association between empagliflozin and L-proline.
- the empagliflozin- L- proline complex may in some aspects exist as a solid state form that is referred to herein as a co crystal form of an empagliflozin-L-proline complex, or as an empalgiflozin L-proline co-crystal, or as a crystalline empagliflozin- L-proline complex.
- anti-solvent refers to a liquid that, when combined with a solution of empagliflozin, reduces solubility of the empagliflozin in the solution, causing crystallization or precipitation in some instances spontaneously, and in other instances with additional steps, such as seeding, cooling, scratching and/or concentrating.
- Celite is flux-calcined diatomaceous earth.
- Hyflo is flux-calcined diatomaceous earth treated with sodium carbonate.
- Alcohol solvent is an organic solvent containing a carbon bound to a hydroxyl group.
- Alcohol solvents include, but are not limited to, methanol, ethanol, 2- nitroethanol, 2-fluoroethanol, 2,2,2-trifluoroethanol, hexafluoroisopropyl alcohol, ethylene glycol, 1 -propanol, 2-propanol (isopropyl alcohol), 2- methoxyethanol, 1 - butanol, 2-butanol, i-butyl alcohol, t-butyl alcohol, 2- ethoxyethanol, diethylene glycol, 1 - , 2-, or 3-pentanol, neo-pentyl alcohol, t-pentyl alcohol, diethylene glycol monomethyl ether, diethylene glycol monoethyl ether, cyclohexanol, benzyl alcohol, phenol, glycerol, or the like.
- hydrocarbon solvent refers to a liquid, non-aromatic, hydrocarbon, which may be linear, branched, or cyclic. It is capable of dissolving a solute to form a uniformly dispersed solution.
- hydrocarbon solvent include, but are not limited to, n- pentane, isopentane, neopentane, n-hexane, isohexane, 3-methylpentane, 2,3- dimethylbutane, neohexane, n-heptane, isoheptane, 3-methylhexane, neoheptane, 2,3- dimethylpentane, 2,4-dimethylpentane, 3,3-dimethylpentane, 3-ethylpentane, 2,2,3- trimethylbutane, n-octane, isooctane, 3-methylheptane, neooctane, cycl
- “Ester solvents” include, but are not limited to, ethyl acetate, n-propyl acetate, isopropyl acetate, n-butyl acetate, isobutyl acetate, t-butyl acetate, ethyl formate, methyl acetate, methyl propanoate, ethyl propanoate, methyl butanoate, ethyl butanoate, C3-6 esters, or the like.
- halogenated hydrocarbon solvent is an organic solvent containing a carbon bound to a halogen.
- Halogenated hydrocarbon solvents include, but are not limited to, dichloromethane, 1 ,2-dichloroethane, trichloroethylene, perchloroethylene, 1 ,1 ,1 - trichloroethane, 1 ,1 ,2-trichloroethane, chloroform, carbon tetrachloride, or the like.
- “Ketone solvents” include, but are not limited to, acetone, ethyl methyl ketone, diethyl ketone, methyl isopropyl ketone, methyl isobutyl ketone, C3-6ketones, 4- methyl-pentane-2-one or the like.
- a “nitrile solvent” is an organic solvent containing a cyano -(C ⁇ N) bonded to another carbon atom.
- “Nitrile solvents” include, but are not limited to, acetonitrile, propionitrile, C2-6nitriles, or the like.
- a "polar aprotic solvent” has a dielectric constant greater than 15 and is at least one selected from the group consisting of amide-based organic solvents, such as N,N- dimethylformamide (DMF), ⁇ , ⁇ -dimethylacetamide (DMA), Nmethylpyrrolidone (NMP), formamide, acetamide, propanamide, hexamethyl phosphoramide (HMPA), and hexamethyl phosphorus triamide (HMPT); nitro-based organic solvents, such as nitromethane, nitroethane, nitropropane, and nitrobenzene; pyridine-based organic solvents, such as pyridine and picoline; sulfone-based solvents, such as dimethylsulfone, diethylsulfone, diisopropylsulfone, 2-methylsulfolane, 3- methylsulfolane, 2,4-dimethylsulfolane, 3,4-dimethy sulfolane,
- ether solvent is an organic solvent containing an oxygen atom -O bonded to two other carbon atoms.
- “Ether solvents” include, but are not limited to, diethyl ether, diisopropyl ether, methyl t-butyl ether, glyme, diglyme, tetrahydrofuran (THF), 2- methyltetrahydrofuran, 1 ,4-dioxane, dibutyl ether, dimethylfuran, 2-methoxyethanol, 2- ethoxyethanol, anisole, C2-6 ethers, or the like.
- the term “co-crystal” refers to a crystal complex composed of at least two neutral molecules bound together in a crystal lattice by non-covalent interactions.
- the term “co-crystal” also can be referred as adduct.
- a therapeutically effective amount refers to an amount of an agent which is effective, upon single or multiple dose administration to the subject in providing a therapeutic benefit to the subject. In one aspect, the therapeutic benefit is maintaining glucose homeostasis, or regulating blood glucose levels.
- the empagliflozin amino acid complex of the present invention is used for the preparation of a medicament for treating conditions mediated by SLGT2, preferably type 2 diabetes.
- Example 1 Preparation of amorphous form of empagliflozin.
- Example 2 Preparation of amorphous form of empagliflozin.
- Example 3 Preparation of amorphous form of empagliflozin.
- Example 4 Preparation of amorphous form of empagliflozin.
- Example 5 Preparation of amorphous form of empagliflozin.
- Example 6 Preparation of amorphous solid dispersion of empagliflozin and hydroxy propyl methyl cellulose phthalate (Hypromellose Phthalate; HPMC- Phthalate).
- Example 7 Preparation of amorphous solid dispersion of empagliflozin and Methyl cellulose.
- Example 8 Preparation of crystalline form of empagliflozin.
- Example 9 Preparation of crystalline form of empagliflozin.
- Example 10 Preparation of crystalline form of empagliflozin.
- Example 11 Preparation of crystalline form of empagliflozin.
- Example 14 Preparation of amorphous form of empagliflozin.
- Empagliflozin (40 g) and methanol (800 ml_) were charged into a 2000 ml_ round bottom flask at 30 °C.
- the mixture was heated to 50 °C and stirred for 15 min.
- the solution was filtered to remove the un-dissolved particles and the filtrate was evaporated by spray drying, using a Buchi® MINI Spray Dryer B-290 with Buchi® Inert Loop B-295 at 75°C to afford 26 g of amorphous empagliflozin.
- the solid was dried for 4 hours at 30 °C under reduced pressure to get 22 grams of amorphous empagliflozin. Purity by HPLC: 99.85%. Methanol content by GC: 1919 ppm
- Example 15 Preparation of amorphous form of empagliflozin.
- Example 16 Preparation of amorphous form of empagliflozin.
- Example 17 Preparation of amorphous solid dispersion of empagliflozin and Low-Substituted Hydroxypropyl Cellulose (L-HPC).
- L-HPC Low-Substituted Hydroxypropyl Cellulose (2 g) and methanol (50 mL) were charged into a Buchi rotavapor flask at 25 °C and the mixture was heated to 55 °C.
- PXRD pattern Fig. 7.
- the solid amorphous material (1 g) was humidified at 30 °C and 40% RH for 10 hours. Flowable solid lumps obtained.
- Example 18 Preparation of amorphous solid dispersion of empagliflozin and Ethyl Cellulose.
- Example 19 Preparation of amorphous solid dispersion of empagliflozin and Eudragit RLPO.
- the solid amorphous material (1 g) was humidified at 30 °C and 40% RH for 10 hours. Amorphous solid (flowable upon disturbing) obtained. PXRD pattern: Fig. 1 1 .
- Example 20 Preparation of amorphous solid dispersion of empagliflozin and HPMC.
- the solid amorphous material (1 g) was humidified at 30 °C and 40% RH for 10 hours. Amorphous solid (flowable upon disturbing) obtained. PXRD pattern: Fig. 13.
- Example 21 Preparation of amorphous solid dispersion of empagliflozin and HPMC-AS.
- the solid amorphous material (1 g) was humidified at 30 °C and 40% RH for 10 hours. Amorphous solid (flowable) obtained. PXRD pattern: Fig.15.
- Example 22 Preparation of amorphous solid dispersion of empagliflozin and Soluplus.
- Empagliflozin (2 g) and methanol (50 ml_) were charged into a Buchi rotavapor flask at 25 °C and stirred for 15 minutes and heated to 55 °C to get clear solution.
- hydroxy propyl methyl cellulose acetate succinate (HPMC-AS MG) (2 g) and methanol (50 ml_) were charged at 25 °C and stirred for 15 minutes.
- the solid amorphous material (1 g) was humidified at 30 °C and 40% RH for 10 hours. Amorphous solid (sticky solid lumps) obtained. PXRD pattern: Fig.17.
- Example 23 Preparation of amorphous solid dispersion of empagliflozin and Eudragit-E100.
- Example 24 Preparation of amorphous solid dispersion of empagliflozin and Microcrystalline Cellulose.
- Hypromellose Phthalate (2 g) and methanol (60 mL) were charged into a round bottom flask at 27°C.
- Empagliflozin (2 g) and methanol (50 mL) were charged into another flask and heated to 55 °C.
- the resulted mixture was heated to 55°C and stirred for 15 min. at 55°C.
- Both the clear solutions were combined and the solution was charged into a rotavapor and completely evaporated under reduced pressure at 60 °C to get 3 g of amorphous solid dispersion of empagliflozin HPMC-Phthalate.
- the solid amorphous material (1 g) was humidified at 30 °C and 40% RH for 10 hours.
- PXRD pattern Fig.21 .
- Example 26 Preparation of amorphous solid dispersion of empagliflozin and Methyl cellulose.
- Methyl cellulose (2 g) and methanol (60 mL) were charged into a round bottom flask at 27°C.
- Empagliflozin (2 g) and methanol (50 mL) were charged at 27°C.
- Both the API and excipient solutions were combined and the solution was charged into a rotavapor and completely evaporated under reduced pressure at 62 °C to get 3.1 g of amorphous solid dispersion of empagliflozin Methyl Cellulose.
- PXRD pattern Fig. 22.
- the solid amorphous material (1 g) was humidified at 30 °C and 40% RH for 10 hours. Amorphous solid obtained.
- Example 27 Preparation of amorphous solid dispersion of empagliflozin, HPMC and adsorbent.
- Glass transition temperature is 73.92 °C
- P1 , P2 and P3 3 parts
- P1 PXRD pattern Fig 24; P2 PXRD pattern: Fig 25; P3 PXRD pattern: Fig 26.
- P2 Glass transition onset temperature is 71 .36 °C; Glass transition temperature is 76.08 °C.
- Example 28 Preparation of amorphous solid dispersion of empagliflozin, HPC and adsorbent.
- Glass transition temperature is 84.59 °C.
- P1 PXRD pattern Fig 27; P2 PXRD pattern: Fig 28; P3 PXRD pattern: Fig 29.
- P1 Glass transition onset temperature is 76.67 °C; Glass transition temperature is 90.64 °C
- Example 29 Preparation of crystalline Form N of Empagliflozin.
- Example 30 Preparation of crystalline Form N of Empagliflozin.
- Example 31 Preparation of crystalline Form N of Empagliflozin.
- Example 32 Preparation of Empagliflozin L-phenylalanine complex.
- Example 33 Preparation of crystalline Form-Alpha of Empagliflozin.
- Example 34 Preparation of crystalline Form-Beta of Empagliflozin.
- Empagliflozin (500 mg) and ethanol (20 mL) were charged into a round bottom flask and the mixture was heated to 70 °C to get clear solution and the clears solution was filtered for particle free.
- Butyl acetate (50 mL) was added to the test tube at 25°C and the mixture was kept at -20 °C for 22 days and the solid was filtered and dried in a vacuum tray drier to obtain the title compound.
- PXRD pattern Figure 33.
- Example 35 Preparation of crystalline Form-Gamma of Empagliflozin.
- n-Butyl Lithium in hexane (1 .6M, 2.8 Kg) was added slowly over a period of 3 hours at -80 °C.
- the reaction mixture was maintained for 1 hour at -80 °C.
- a solution of methanesulfonic acid (1 .46 Kg of methanesulfonic acid in 9.0 L of methanol) was added to the reaction mass at -70 °C.
- the reaction mass was heated to -10 °C and stirred for 30 minutes and heated to 30 °C and stirred for 12 hours at 30 °C.
- the reaction mass was cooled to 5 °C and sodium bicarbonate solution (2.0 Kg of sodium bicarbonate in 23 L of water) was added slowly.
- the reaction mass was stirred for 30 minutes at 30 °C.
- the reaction mass was washed with Toluene (6.0 L x 3) and the reaction mass was concentrated under vacuum until 20 volumes remains in the flask.
- the reaction mass was extracted with ethylacetate (10.0 L x 5) and the ethylacetate layer was washed with water (3.0 L).
- the ethylacetate layer was charged into a 100 L reactor and concentrated under vacuum to 3 volumes remained in the reactor.
- the concentrated ethylacetate layer was stripped off with acetonitrile (3.0 L x 3) then dichloromethane (7.0 L) and acetonitrile (1 .2 L) were charged into the reactor and the reaction mass was cooled to -30 °C.
- Triethylsilane (0.57 Kg) and Borontrifluoride etherate solution (1 .307 Kg) were charged into the reactor and the reaction mass was stirred for 3 hours at -30 °C. Temperature was raised to -5 °C and stirred for 6 hours. A solution of sodium carbonate (2.0 Kg of sodium carbonate in 20.0 L of water) was added to the reaction mass over a period of 30 minutes at 5 °C. The reaction mass was heated to 30 °C and stirred for 30 minutes. The reaction mass was concentrated under vacuum until 25 volumes remained in the reactor.
- Cesium carbonate lot 2 (0.57 Kg) was added to the reaction mass and the reaction mass was stirred for 2 hours.
- Cesium carbonate lot 3 (0.57 Kg) was added to the reaction mass the reaction mass was stirred for 20 hours at 45 °C.
- the reaction mass was cooled to 30 °C and water (4.0 L) was added to the mass and stirred for 30 minutes. Layers were separated and the aqueous layer was washed with toluene (4.0 L). The aqueous layer was concentrated at 70 °C under vacuum until 1 .0 volume remained in the reactor.
- the concentrated mass was cooled to 30 °C and water (10.0 L) and acetonitrile 1 .0 L) were charged into the reactor at 30 °C and the resulted mixture was heated to 45 °C and the mixture was stirred for 6 hours at 45 °C.
- the suspension was cooled to 25 °C and stirred for 7 hours at 25 °C.
- the precipitation was filtered and the wet solid was washed with water (3.0L) and the solid was suck dried.
- the wet compound and DMF (1 .0 L) were charged into another reactor and the solution was heated to 45 °C.
- Acetonitrile (1 .0 L) charged followed by water (10.0 L) into the reactor at 45 °C and stirred for 6 hours.
- the suspension was cooled to 25 °C and stirred for 6 hours.
- the precipitation was fileted and the wet cake was washed with water.
- the wet material was suck dried.
- the wet material was dried under vacuum at 60 °C for 6 hours to yield 0.55 Kg of crystalline empagliflozin. Purity by HPLC 99%.
- the wet compound was dried under vacuum at 65 °C for 4 hours.
- the dry compound was charged into a round bottom flask and acetonitrile (337 mL) and water (225 mL) were added to the flask and stirred for 20 minutes to get clear solution.
- the reaction mass was heated to 45 °C and stirred for 1 hour.
- Water (900 mL) was charged into the flask slowly over a period of 30 minutes.
- the reaction mass was cooled to 25 °C and stirred for 10 hours.
- the precipitation was filtered and the wet material suck dried for 30 minutes.
- the wet material was washed with water (225 mL x 2) and suck dried for 30 minutes.
- the wet material was charged into a round bottom flask.
- the wet compound was dried under vacuum at 65 °C for 4 hours.
- the dry compound was charged into a round bottom flask and DMF (200 mL) and water (200 mL) were added to the flask and stirred for 20 minutes to get clear solution.
- the clear solution was filtered through a micron filter to get a particle free clear solution.
- the reaction mass was heated to 55 °C and stirred for 1 hour.
- Water (600 mL) was charged into the flask slowly over a period of 30 minutes.
- the reaction mass was cooled to 25 °C and stirred for 3 hours.
- the precipitation was filtered and the wet material suck dried for 30 minutes.
- the wet material was washed with water (500 mL) and suck dried for 30 minutes.
- the wet material was charged into a round bottom flask. Methanol (300 ml) and water (45 mL) was added and the mass was heated to 50 °C to form clear solution. Water (1200 mL) was added to the clear solution and stirred the mass at 60 °C for 3 hours. Solid was isolated. The precipitation was cooled to 25 °C and stirred for 8 hours. The precipitation was filtered and suck dried for 30 minutes. The wet material was washed with water (225 mL) and suck dried for 30 minutes. The wet material was dried under vacuum at 65 °C for 6 hours to get 65 g of crystalline empagliflozin. Purity by HPLC: 99.8%.
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Abstract
The present invention provides solid state forms of empagliflozin, complexes of empagliflozin with amino acids, processes for their preparation and their use in purification of empagliflozin and also provided pharmaceutical compositions comprising them and their use in therapy (Formula I).
Description
SOLID STATE FORMS OF EMPAGLIFLOZIN
CROSS-REFERENCE TO RELATED APPLICATIONS
This application claims the benefit of Indian provisional patent application No. 201641018135 filed on 26 May 2016; Indian provisional patent application No. 201641038303 filed on 9 Nov 2016; Indian provisional patent application No. 201741001520 filed on 13 Jan 2017; and Indian provisional patent application No. 201741009875 filed on 21 Mar 2017 which are hereby incorporated by reference in its entirety.
FIELD OF THE INVENTION
The present application relates to solid state forms of empagliflozin and processes for preparation of empagliflozin and intermediates thereof
BACKGROUND OF THE INVENTION
The drug compound having the adopted name Empagliflozin, has a chemical name 1 -chloro-4(beta-D-glucopyranos-1 -yl)-2-[4-((S)-tetrahydrofuran-3-yloxy)-benzyl)- benzene, and is represented by the structure of formula I.
Formula I
Empagliflozin is a sodium-dependent glucose cotransporter 2 (SGLT 2) inhibitor and is used for the treatment of patients with type 2 diabetes mellitus.
Empagliflozin and its synthetic methods are described in US Patent No. 7,579,449 (US '449). Example 3 of US '449 describes isolation of empagliflozin as "the organic phase (ethylacetate phase) is dried over sodium sulphate, the solvent is removed and the residue is purified using silica gel column chromatography (dichloromethane/ methanol 1 :0→5: 1 ).
US Patent No. 7,713,938 (US '938) discloses a crystalline form of empagliflozin and a pharmaceutical composition comprising the crystalline form. The US '938 also
discloses that "the method of manufacturing empagliflozin as described in product patent process does not yield a crystalline form".
Indian patent application (IN1985MUM2013A), PCT applications (WO2016051368A1 , WO2016131431 A1 , WO2016169534A1 and WO2017046730A1 ), and Chinese patent applications (CN104788438A, CN105384730A1 , CN105481843A, CN105496966A, CN106188021 A and CN106317035A) describe various solid state forms and co-crystals of empagliflozin and processes for preparation thereof.
Polymorphism, the occurrence of different crystal forms, is a phenomenon of some molecules and molecular complexes. A single molecule may give rise to a variety of polymorphs having distinct crystal structures and physical properties. Polymorphs in general will have different melting points, thermal behaviors (e.g. measured by thermogravimetric analysis - "TGA", or differential scanning calorimetry - "DSC"), X-ray powder diffraction (XRPD or powder XRD) pattern, infrared absorption fingerprint, and solid state nuclear magnetic resonance (NMR) spectrum. One or more of these techniques may be used to distinguish different polymorphic forms of a compound.
Discovering new polymorphic forms, hydrates and solvates of a pharmaceutical product can provide materials having desirable processing properties, such as ease of handling, ease of processing, storage stability, and ease of purification or as desirable intermediate crystal forms that facilitate conversion to other polymorphic forms. New polymorphic forms and solvates of a pharmaceutically useful compound or salts thereof can also provide an opportunity to improve the performance characteristics of a pharmaceutical product. It enlarges the repertoire of materials that a formulation scientist has available for formulation optimization, for example by providing a product with different properties, e.g., better processing or handling characteristics, improved dissolution profile, or improved shelf-life. For at least these reasons, there is a need for additional solid forms of Empagliflozin.
SUMMARY OF THE INVENTION
Aspects of the present application relate to amorphous empagliflozin, amorphous solid dispersion of empagliflozin, and complexes of empagliflozin with amino acids,
crystalline forms of empagliflozin, their preparative processes and pharmaceutical compositions thereof.
In the first aspect, the present application provides stable amorphous empagliflozin.
In the second aspect, the present application provides amorphous empagliflozin having a glass transition onset temperature of at least 60 °C or above.
In the third aspect, the present application provides a process for preparing amorphous empagliflozin having a glass transition onset temperature of at least 60 °C or above, comprising;
a) providing a solution of empagliflozin in a solvent or a mixture solvents;
b) removing solvent from the solution obtained in step (a); and
c) recovering amorphous form of empagliflozin.
In the fourth aspect, the present application provides amorphous solid dispersion of empaglilflozin having a glass transition onset temperature of at least 55 °C or above comprising empagliflozin and one or more pharmaceutically acceptable carriers.
In the fifth aspect, the present application provides a process for preparing amorphous solid dispersion having a glass transition onset temperature of at least 55 °C or above comprising empagliflozin and one or more pharmaceutically acceptable carriers, comprising;
a) providing a solution comprising empagliflozin and one or more pharmaceutically acceptable carriers,
b) removing solvent from the solution obtained in step (a), and
c) recovering an amorphous solid dispersion comprising empagliflozin and one or more pharmaceutically acceptable carriers.
In the sixth aspect, the present application provides a process for preparing crystalline form of empagliflozin characterized by PXRD peaks at 18.84°, 20.36°, and 25.21 ° 2 theta, which comprises;
a) providing a solution of empagliflozin in a solvent or a mixture of solvents; b) heating the solution to a temperature higher than the temperature at which the solution is prepared;
c) adding an anti-solvent to the hot solution; and
d) isolating crystalline form of empagliflozin characterized by PXRD peaks at
18.84°, 20.36°, and 25.21 ° 2 theta.
In the seventh aspect, the present application provides a process for purification of empagliflozin, comprising:
a) providing a solution of empagliflozin L-proline complex characterized, by an X-Ray Powder Diffraction (XRPD) pattern having peaks at about 4.36 ± 0.2, 12.97 ± 0.2, 15.67 ± 0.2 and 18.80 ± 0.2 °2Θ, in a mixture of an organic solvent and water;
b) optionally, heating the solution obtained in step (a);
c) separating the organic layer from the mixture obtained in step (b); and d) isolating pure empagliflozin from the organic layer of step (c).
In the ninth aspect, the present application provides a crystalline Form N of Empagliflozin, characterized by a PXRD pattern comprising the peaks at about 4.13, 7.79, 1 1.55, 16.74, 23.20 and 27.87 ± 0.2° 2Θ.
In the tenth aspect, the present application provides a complex of empagliflozin with phenylalanine.
In the eleventh aspect, the present application provides a process for the preparation of the complex of empagliflozin with phenylalanine, comprising
(a) dissolving empagliflozin and phenylalanine in a solvent,
(b) storing the solution to precipitate the empagliflozin phenylalanine complex, and
(c) isolating the empagliflozin phenylalanine complex.
In the twelfth aspect, the present application provides a crystalline Form-Alpha (Form a) of Empagliflozin, characterized by a PXRD pattern as shown in Figure 32.
In the thirteenth aspect, the present application provides a crystalline Form-Beta (Form β) of Empagliflozin, characterized by a PXRD pattern comprising the peaks at about 3.44, 4.04, 9.35, 10.20 and 14.1 1 ± 0.2° 2Θ.
In the fourteenth aspect, the present application provides a crystalline Form- Gamma (Form Y) of Empagliflozin, characterized by a PXRD pattern comprising the peaks at about 4.82, 7.19, 10.17 and 1 1 .20 ± 0.2° 2Θ.
In the fifteenth aspect, the present application provides a process for preparation of (R)-tetrahydrofuran-3-yl-4-methylbenzenesulfonate having greater than about 99.8% of chiral purity, comprising
(a) reacting (R)-tetrahydrofuran-3-ol with 4-methylbenzene-1 -sulfonyl chloride in presence of pyridine
(b) slurrying the crude compound (R)-tetrahydrofuran-3-yl-4- methylbenzenesulfonate with a mixture of ethylacetate and cyclohexane, and
(c) isolating the (R)-tetrahydrofuran-3-yl-4-methylbenzenesulfonate having chiral purity of greater than about 99.8%.
In the sixteenth aspect, the present application provides a process for preparation of empagliflozin having greater than about 99.8% of chiral purity, comprising:
(a) slurrying the crude (R)-tetrahydrofuran-3-yl-4-methylbenzenesulfonate with a mixture of ethylacetate and cyclohexane to get (R)-tetrahydrofuran-3-yl-4- methylbenzenesulfonate having chiral purity of greater than about 99.8%. and
(b) reacting (R)-tetrahydrofuran-3-yl-4-methylbenzenesulfonate having greater than about 99.8% of chiral purity with (1 R,2R,3S,6R)-4-(4-chloro-3-(4- hydroxybenzyl)phenyl)-6-(hydroxymethyl)cyclohexane-1 ,2,3-triol in presence f a base.
In the seventeenth aspect, the present application provides use of the crystalline forms of empagliflozin of the present invention and the empagliflozin phenylalanine complex and empagliflozin L-proline complex of the present invention to improve the purity of empagliflozin.
In the eighteenth aspect, the present application provides a pharmaceutical composition comprising any of amorphous empagliflozin or empagliflozin solid dispersion or empagliflozin L-proline complex or empagliflozin phenylalanine complex of the present invention or any of the crystalline forms of empagliflozin of the present invention and at least one pharmaceutically acceptable carrier.
BRIEF DESCRIPTION OF THE DRAWINGS
Figure 1 is powder X-ray power diffraction pattern of an amorphous form of empagliflozin prepared according to Example 1 .
Figure 2 is powder X-ray power diffraction pattern of an amorphous solid dispersion comprising empagliflozin and HPMC Phthalate prepared according to Example 6.
Figure 3 is powder X-ray power diffraction pattern of an amorphous solid dispersion comprising empagliflozin and methyl cellulose prepared according to Example 7.
Figure 4 is powder X-ray power diffraction pattern of crystalline form of empagliflozin prepared according to Example 8.
Figure 5 is powder X-ray power diffraction pattern of empagliflozin L-proline complex prepared according to Example 13.
Figure 6 is powder X-ray power diffraction pattern of an amorphous form of empagliflozin prepared according to Example 15.
Figure 7 is powder X-ray power diffraction pattern of an amorphous solid dispersion comprising empagliflozin and L-HPC prepared according to Example 17.
Figure 8 is powder X-ray power diffraction pattern of an amorphous solid dispersion comprising empagliflozin and ethyl cellulose prepared according to Example 18.
Figure 9 is powder X-ray power diffraction pattern of an amorphous solid dispersion comprising empagliflozin and ethyl cellulose (at 40% RH) prepared according to Example 18.
Figure 10 is powder X-ray power diffraction pattern of an amorphous solid dispersion comprising empagliflozin and Eudragit RLPO prepared according to Example 19.
Figure 1 1 is powder X-ray power diffraction pattern of an amorphous solid dispersion comprising empagliflozin and Eudragit RLPO (at 40% RH) prepared according to Example 19.
Figure 12 is powder X-ray power diffraction pattern of an amorphous solid dispersion comprising empagliflozin and hydroxypropyl methyl cellulose (HPMC) prepared according to Example 20.
Figure 13 is powder X-ray power diffraction pattern of an amorphous solid dispersion comprising empagliflozin and hydroxypropyl methyl cellulose (at 40% RH) prepared according to Example 20.
Figure 14 is powder X-ray power diffraction pattern of an amorphous solid dispersion comprising empagliflozin and hydroxypropyl methyl cellulose acetate succinate (HPMC- AS) prepared according to Example 21 .
Figure 15 is powder X-ray power diffraction pattern of an amorphous solid dispersion comprising empagliflozin and hydroxypropyl methyl cellulose acetate succinate (HPMC- AS) (at 40% RH) prepared according to Example 21 .
Figure 16 is powder X-ray power diffraction pattern of an amorphous solid dispersion comprising empagliflozin and Soluplus prepared according to Example 22.
Figure 17 is powder X-ray power diffraction pattern of an amorphous solid dispersion comprising empagliflozin and Soluplus (at 40% RH) prepared according to Example 22. Figure 18 is powder X-ray power diffraction pattern of an amorphous solid dispersion comprising empagliflozin and Eudragit-E100 prepared according to Example 23.
Figure 19 is powder X-ray power diffraction pattern of an amorphous solid dispersion comprising empagliflozin and Eudragit-E100 (at 40% RH) prepared according to Example 23.
Figure 20 is powder X-ray power diffraction pattern of an amorphous solid dispersion comprising empagliflozin and hydroxypropyl methyl cellulose phthalate (HPMC- Phthalate) prepared according to Example 25.
Figure 21 is powder X-ray power diffraction pattern of an amorphous solid dispersion comprising empagliflozin and hydroxypropyl methyl cellulose phthalate (HPMC- Phthalate) (at 40% RH) prepared according to Example 25.
Figure 22 is powder X-ray power diffraction pattern of an amorphous solid dispersion comprising empagliflozin and methyl cellulose prepared according to Example 26.
Figure 23 is powder X-ray power diffraction pattern of an amorphous solid dispersion comprising empagliflozin and methyl cellulose (at 40% RH) prepared according to Example 26.
Figure 24 is powder X-ray power diffraction pattern of an amorphous solid dispersion comprising empagliflozin, hydroxypropyl methyl cellulose (HPMC) and Syloid (1 :1 :0.5) prepared according to Example 27.
Figure 25 is powder X-ray power diffraction pattern of an amorphous solid dispersion comprising empagliflozin, hydroxypropyl methyl cellulose (HPMC) and Lactose monohydrate (1 :1 :0.5) prepared according to Example 27.
Figure 26 is powder X-ray power diffraction pattern of an amorphous solid dispersion comprising empagliflozin, hydroxypropyl methyl cellulose (HPMC) and croscarmellose sodium (1 :1 :0.5) prepared according to Example 27.
Figure 27 is powder X-ray power diffraction pattern of an amorphous solid dispersion comprising empagliflozin, hydroxypropyl cellulose (HPC) and Syloid (1 :1 :0.5) prepared according to Example 28.
Figure 28 is powder X-ray power diffraction pattern of an amorphous solid dispersion comprising empagliflozin, hydroxypropyl cellulose (HPC) and Lactose monohydrate (1 :1 :0.5) prepared according to Example 28.
Figure 29 is powder X-ray power diffraction pattern of an amorphous solid dispersion comprising empagliflozin, hydroxypropyl cellulose (HPC) and croscarmellose sodium (1 :1 :0.5) prepared according to Example 28.
Figure 30 is an illustrative X-ray powder diffraction pattern of crystalline Form N of Empagliflozin prepared by the method of Example No 31 .
Figure 31 is an illustrative X-ray powder diffraction pattern of crystalline Form of the complex of Empagliflozin with L-phenylalanine prepared by the method of Example No 32.
Figure 32 is an illustrative X-ray powder diffraction pattern of crystalline Form-Alpha (a) of Empagliflozin prepared by the method of Example No 33.
Figure 33 is an illustrative X-ray powder diffraction pattern of crystalline Form-Beta (β) of Empagliflozin prepared by the method of Example No 34.
Figure 34 is an illustrative X-ray powder diffraction pattern of crystalline Form-Gamma (γ) of Empagliflozin prepared by the method of Example No 35.
Figure 35 is DSC thermogram of amorphous Empagliflozin prepared by the method of Example No 15.
DETAILED DESCRIPTION
Empagliflozin used as the input in the process for preparation of stable amorphous empagliflozin and amorphous solid dispersion of the present invention can be prepared by any process known in the art.
In the first aspect, the present application provides stable amorphous empagliflozin.
In the second aspect, the present application provides amorphous empagliflozin having a glass transition onset temperature of at least 60 °C or above.
In the third aspect, the present application provides a process for preparing amorphous empagliflozin having a glass transition onset temperature of at least 60 °C or above, comprising;
a) providing a solution of empagliflozin in a solvent or a mixture solvents;
b) removing solvent from the solution obtained in step (a); and
c) recovering amorphous empagliflozin having a glass transition onset temperature of at least 60 °C or above.
Providing a solution in step (a) includes direct use of a reaction mixture containing empagliflozin that is obtained in the course of its synthesis or dissolving empagliflozin in a solvent or a mixture of solvents.
Any physical form of empagliflozin may be utilized for providing the solution of empagliflozin in step (a). Suitable solvents which can be used for dissolving empagliflozin include but are not limited to: alcohol solvents such as methanol, ethanol, isopropyl alcohol, n-propanol, isoamyl alcohol n-butanol, 2-butanol and the like; halogenated hydrocarbons such as dichloromethane, 1 ,2-dichloroethane, chloroform, carbon tetrachloride and the like; ketones such as acetone, ethyl methyl ketone, methyl isobutyl ketone and the like; dimethylformamide, dimethylacetamide and dimethylsulfoxide; and any mixtures of two or more thereof.
After dissolution in step (a), the obtained solution may be optionally filtered to remove any insoluble particles. Suitable techniques to remove insoluble particles are filtration, centrifugation, decantation, and any other known techniques in the art. The solution can be filtered by passing through paper, glass fiber, or other membrane material, or a clarifying agent such as Celite. Depending upon the equipment used and the concentration and temperature of the solution, the filtration apparatus may need to be preheated to avoid premature precipitation of solid.
Step (b) involves removing solvent from the solution of empagliflozin. Suitable techniques which can be used for the removal of solvent include but not limited to evaporation, flash evaporation, simple evaporation, rotational drying, spray drying, agitated thin-film drying, agitated nutsche filter drying, pressure nutsche filter drying, freeze-drying or any other suitable technique known in the art.
Step (c) involves recovering an amorphous form of empagliflozin. The said recovery can be achieved by using the processes known in the art.
The resulting compound in step (c) may optionally be further dried. Drying can be carried out in a tray dryer, vacuum oven, air oven, cone vacuum dryer, rotary vacuum dryer, fluidized bed dryer, spin flash dryer, flash dryer, or the like. The drying can be carried out at temperatures of less than about 60°C, less than about 50°C, less than about 40°C, less than about 30°C, less than about 20°C, or any other suitable temperatures; at atmospheric pressure or under a reduced pressure; as long as the empagliflozin is not degraded in its quality. The drying can be carried out for any desired times until the required product quality is achieved. Suitable time for drying can vary from few minutes to several hours for example from about 30 minutes to about 24 or more hours.
In another aspect, the present application provides amorphous Empagliflozin having a chemical purity of at least 99% by HPLC or at least 99.5% by HPLC or at least 99.9% by HPLC.
The amorphous empagliflozin is stable for 3 months in ICH storage conditions i.e. (i) 25°C ± 2°C and 60%RH ± 5RH, (ii) 40°C±2°C and 75%RH ± 5RH, (iii) 30 °C ± 2 °C and 75%RH ± 5RH and (iv) 2°C - 8°C. Packing conditions used for amorphous empagliflozin are incorporated below.
Packing method-1 : Take the sample in a clear anti-static polyethylene bag and tie it with plastic strip by twisting after removing air. Keep the above in a black polythene bag along with Molecular sieve pouch, fill it with nitrogen gas and tie it with plastic strip. Keep the bag in triple laminated bag and seal it with VNS Sealer, keep the above triple laminated bag in another triple laminated bag and seal it with VNS Sealer. Finally keep the packet in HDPE container and store in the stability chamber.
Packing method-2: Take the sample in a clear anti-static polyethylene bag and tie it with plastic strip by twisting after removing air. Keep the above in a black polythene bag fill it with nitrogen gas and tie it with plastic strip. Keep the bag in triple laminated bag and seal it with VNS Sealer, keep the above triple laminated bag in another triple laminated bag and seal it with VNS Sealer. Finally keep the packet in HDPE container and store in the stability chamber.
Amorphous empagliflozin of the present application was found to be stable under mechanical stress such as grinding and milling and stable under hygroscopic conditions such as higher relative humidity conditions of more than 60% RH.
In another aspect, the amorphous empagliflozin of the present invention is showing glass transition onset temperature of 66.29 °C, and glass transition temperature of 70.13 °C. The DSC thermogram is shown in Figure 35.
In the fourth aspect, the present application provides amorphous solid dispersion of empagliflozin having a glass transition onset temperature of at least 55 °C or above, comprising empagliflozin and one or more pharmaceutically acceptable carriers.
In the fifth aspect, the present application provides a process for preparing amorphous solid dispersion of empagliflozin having a glass transition onset temperature of at least 55 °C or above, comprising empagliflozin and one or more pharmaceutically acceptable carriers, comprising;
a) providing a solution comprising empagliflozin and one or more pharmaceutically acceptable carriers,
b) removing solvent from the solution obtained in step (a), and
c) recovering an amorphous solid dispersion having a glass transition onset temperature of at least 60 °C or above, comprising empagliflozin and one or more pharmaceutically acceptable carriers.
Providing a solution in step (a) includes direct use of a reaction mixture containing empagliflozin that is obtained in the course of its synthesis or dissolving empagliflozin and pharmaceutically acceptable carrier in a solvent.
Any physical form of empagliflozin may be utilized for providing the solution of empagliflozin in step (a).
Suitable pharmaceutically acceptable carriers which can be used in step (a) include, but are not limited to: diluents such as starches, pregelatinized starches, lactose, powdered celluloses, microcrystalline celluloses, dicalcium phosphate, tricalcium phosphate, Polyethylene glycol, Copovidone, Soluplus, Silicified microcrystalline cellulose mannitol, sorbitol, sugar and the like; binders such as acacia, guar gum, tragacanth, gelatin, polyvinylpyrrolidones, hydroxypropyl celluloses, hydroxypropyl methylcelluloses such as HPMC-Phthalate, HPMC-AS, HPMC-15 CPS; pregelatinized starches and the like; disintegrants such as starches, sodium starch glycolate, pregelatinized starches, crospovidones, croscarmellose sodium, colloidal silicon dioxide and the like; lubricants such as stearic acid, magnesium stearate, zinc stearate and the like; glidants such as colloidal silicon dioxide and the like; solubility or wetting enhancers such as anionic or cationic or neutral surfactants; complex forming agents such as various grades of cyclodextrins and resins; release rate controlling agents such as hydroxypropyl celluloses, hydroxymethyl celluloses, hydroxypropyl methylcelluloses, ethylcelluloses, methylcelluloses, various grades of methyl methacrylates, waxes and the like. Other pharmaceutically acceptable excipients that are of use include but are not limited to film formers, plasticizers, colorants, flavoring agents, sweeteners, viscosity enhancers, preservatives, antioxidants, and the like.
In a preferred aspect, the pharmaceutically acceptable carriers are hydroxypropyl methylcellulose phthalate (HPMC-Phthalate) and methyl cellulose.
Suitable solvents which can be used for dissolving the empagliflozin include but are not limited to: alcohol solvents such as methanol, ethanol, isopropyl alcohol, n- propanol, isoamyl alcohol n-butanol, 2-butanol and the like; halogenated hydrocarbons such as dichloromethane, 1 ,2-dichloroethane, chloroform, carbon tetrachloride and the like; ketones such as acetone, ethyl methyl ketone and the like; esters such as ethyl acetate, n-propyl acetate, n-butyl acetate, t-butyl acetate and the like; nitriles such as
acetonitrile, propionitrile and the like; dimethylformamide, dimethylacetamide and dimethylsulfoxide, and any mixtures of two or more thereof.
After dissolution in step (a), optionally undissolved particles, if any, may be removed suitably by filtration, centrifugation, decantation, and any other known techniques. The solution can be filtered by passing through paper, glass fiber, or other membrane material, or a clarifying agent such as celite. Depending upon the equipment used and the concentration and temperature of the solution, the filtration apparatus may need to be preheated to avoid premature crystallization.
Step (b) involves removing solvent from the solution obtained in step (a);
Suitable techniques which can be used for the removal of solvent include but not limited to evaporation, flash evaporation, simple evaporation, rotational drying, spray drying, agitated thin-film drying, agitated nutsche filter drying, pressure nutsche filter drying, freeze-drying, filtration or any other technique known in the art.
Step (c) involves recovering an amorphous solid dispersion comprising empagliflozin and one or more pharmaceutically acceptable carriers. The said recovery can be achieved by using the processes known in the art.
The resulting compound obtained in step (c) may optionally be further dried. Drying can be carried out in a tray dryer, vacuum oven, air oven, cone vacuum dryer, rotary vacuum dryer, fluidized bed dryer, spin flash dryer, flash dryer, or the like. The drying can be carried out at temperatures of less than about 60°C, less than about 50°C, less than about 40°C, less than about 30°C, less than about 20°C, or any other suitable temperatures; at atmospheric pressure or under a reduced pressure; as long as the empagliflozin is not degraded in its quality. The drying can be carried out for any desired time until the required product quality is achieved. Suitable time for drying can vary from few minutes to several hours for example from about 30 minutes to about 24 or more hours.
When the active ingredient is hygroscopic or the formulation contains a hygroscopic ingredient, and to increase the stability of the amorphous form or a solid dispersion comprising amorphous empagliflozin, addition of other carriers such as syloid, methyl cellulose, colloidal silicon dioxide, Eudragit, amorphous silica, micro crystalline cellulose, and the like, in the formulation has been found to be of particular
value. Therefore these ingredients may be combined during the preparation of solid dispersion or after the preparation of amorphous empagliflozin or solid dispersion to control hygroscopicity and to improve stability.
In the sixth aspect, the present application provides a process for preparing crystalline form of empagliflozin characterized by PXRD peaks at 18.84°, 20.36°, and 25.21 ° 2 theta, which comprises;
a) providing a solution of empagliflozin in a solvent or a mixture of solvents; b) heating the solution to a temperature higher than the temperature at which the solution is prepared;
c) adding an anti-solvent to the hot solution; and
d) isolating crystalline form of empagliflozin characterized by PXRD peaks at 18.84°, 20.36°, and 25.21 ° 2 theta.
Providing a solution in step (a) includes direct use of a reaction mixture containing empagliflozin that is obtained in the course of its synthesis or dissolving empagliflozin in a solvent or a mixture of solvents.
Any physical form of empagliflozin may be utilized for providing the solution of empagliflozin in step (a). Suitable solvents which can be used for dissolving empagliflozin include but are not limited to: alcohol solvents such as methanol, ethanol, isopropyl alcohol, n-propanol, isoamyl alcohol n-butanol, 2-butanol and the like; ketones such as acetone, ethyl methyl ketone, methyl isobutyl ketone and the like and the like; halogenated hydrocarbons such as dichloromethane, 1 ,2-dichloroethane, chloroform, carbon tetrachloride and the like; dimethylformamide, dimethylacetamide and dimethylsulfoxide; and any mixtures of two or more thereof.
If the empagliflozin is not dissolved in the solvent the mixture may be heated to get the complete dissolution.
After dissolution in step (a), the obtained solution may optionally be filtered to remove any insoluble particles. Suitable techniques to remove insoluble particles are filtration, centrifugation, decantation, and any other known techniques in the art. The solution can be filtered by passing through paper, glass fiber, or other membrane material, or a clarifying agent such as Celite. Depending upon the equipment used and
the concentration and temperature of the solution, the filtration apparatus may need to be preheated to avoid premature precipitation of solid.
Step (b) involves heating the solution obtained in step (a) to a temperature higher than the temperature at which the solution is prepared.
If the solution of step (a) is prepared at 30°C, the solution is heated to above 30°C, or If the solution of step (a) is prepared at 45°C, the solution is heated to above 45°C.
Step (c) involves adding an anti-solvent to the hot solution obtained step (c). The suitable anti-solvents may include, but not limited to water, pentane, n-hexane, cyclohexane, cylcoheptane, n-heptane, diethyl ether, methyl ter. butyl ether, di isopropyl ether, cyclopentyi methyl ether, pet ether and the like. Preferably suitable anti- solvents are water, n-heptane and pet ether.
The anti-solvent may be added to precipitate the crystalline form of empaglif!ozin or a reverse mode of addition may also be employed.
In an aspect, the mixture may be stirred for sufficient time i.e. 1 5 minutes to 1 0 hours or more.
In an aspect, anti-solvent addition may be carried out at suitable temperatures, such as at about 30°C to 100°C. Preferably suitable temperature may be at about 40 to 80°C.
In an aspect, anti-solvent addition may be carried out for sufficient time to complete precipitation of crystalline form of empaglifiozin. in an aspect, anti-solvent addition may be carried out in sufficient volume to complete precipitation of crystalline form of empaglifiozin.
Step (d) involves isolation of crystalline form of empaglifiozin. Isolation of crystalline form of empaglifiozin may be carried out by any known methods such as filtration of precipitated solid.
In one aspect, the isolation of crystalline form of empaglifiozin is carried out at a temperature at which the precipitation is formed.
The crystalline form of empaglifiozin obtained in step (d) may optionally be washed with the anti-solvent with sufficient volume to remove traces solvent from wet solid. The crystalline form of empaglifiozin obtained as above may be dried, if desired,
at suitable temperatures at about 50°C, or above. The drying may be performed at atmospheric or reduced pressures, for about 1 - 20 hours, or longer by using the drying equipment known in the art.
In another aspect, the crystalline form of empagliflozin characterized by PXRD peaks at 18.84°, 20.36°, and 25.21 ° ± 0.2 degrees 2 theta can be prepared by slurrying amorphous empagliflozin in water or on a similar solvent and isolating the crystalline form of empagliflozin by the known methods.
In another aspect, the present application provides the crystalline form of empagliflozin characterized by PXRD peaks at 18.84°, 20.36°, and 25.21 ° ± 0.2 degrees 2 theta prepared by the process described above having a chemical purity of at least 99% by HPLC or at least 99.5% by HPLC or at least 99.9% by HPLC.
In the seventh aspect, the present application provides an empagliflozin L-proline complex characterized by PXRD peaks at about 4.36 ± 0.2, 12.97 ± 0.2, 15.67 ± 0.2 and 18.80 ± 0.2 degrees 2-theta.
In the eighth aspect, the present application provides a process for preparation of the empagliflozin L-proline complex characterized by PXRD peaks at about 4.36 ± 0.2, 12.97 ± 0.2, 15.67 ± 0.2 and 18.80 ± 0.2 degrees 2-theta, comprising:
(a) mixing empagliflozin and L-proline in a solvent or a mixture of solvents;
(b) optionally, heating the mixture obtained in step (a);
(c) isolating the empagliflozin L-proline complex.
Step (a) of the process involves mixing empagliflozin and L-proline in a solvent or a mixture of solvents.
Preferred solvents are alcoholic solvents such as methanol, ethanol, isopropyl alcohol, n-propanol, isoamyl alcohol and the like; ketones such as acetone, ethyl methyl ketone, methyl isobutyl ketone and the like; esters such as ethyl acetate, n-propyl acetate, n-butyl acetate, t-butyl acetate and the like. Any physical form of empagliflozin can be used as the starting material of the present invention.
The mixture of empagliflozin and L-proline is prepared in any method such as first the L-proline is added to the solvent and then empagliflozin is added or first empagliflozin is added to a solvent and then L-proline is added. In a specific aspect empagliflozin and L-proline are added at a time.
In certain aspects, about 1 equivalent of L-proline is used to prepare empagliflozin L-proline complex. In other aspects, about 2 equivalents of L-proline is used to prepare empagliflozin L-proline complex. In yet other aspects, greater than 2 equivalents of L-proline is used to prepare empagliflozin L-proline complex. In still other aspects, about 0.9 to about 1 .1 equivalents of L-proline is used to prepare empagliflozin L-proline complex. In further aspects, about 1.8 to about 2.2 equivalents, such as about 1 .98 to 2.02 equivalents, of L-proline is used to prepare empagliflozin L-proline complex.
Step (b) involves optionally heating the mixture obtained in step (a). The mixture obtained step (a) may be heated to a temperature of about 40°C to about 150°C. Preferably the mixture is heated to a temperature of about 60°C to about 80°C. The mixture may be stirred for about 10 minutes to about 10 hours or longer.
Step (c) involves isolation of empagliflozin L-proline complex from the mixture of step (b). The isolation of empagliflozin L-proline complex may be carried out by any known methods such as filtration of precipitated solid.
The empagliflozin L-proline complex obtained as above may be dried, if desired, at suitable temperatures at about 50°C, or above. The drying may be performed at atmospheric or reduced pressures, for about 1 - 20 hours, or longer by using the drying equipment known in the art.
Powder X-ray diffraction pattern (PXRD) the empagliflozin L-proline complex obtained by the process of the present application is depicted in Figure 5.
Similar process can be adopted to produce other amino acid complexes of empagliflozin. The amino acids which can be used to produce empagliflozin complexes include, but not limited to, glycine, alanine, serine, threonine, cysteine, valine, leucine, isoleucine, methionine, phenylalanine, tyrosine, tryptophan, aspartic acid, glutamic acid, asparagine, glutamine, histidine, lysine, arginine.
The amino acid complexes of empagliflozin may be useful as intermediate. During the formation of the complex, the empagliflozin crude may get purified as the impurities are removed during the complex formation. This intermediate can sufficiently be purified to produce the final empagliflozin in the desired form. The purification involves slurrying, recrystallization, crystallization etc.
In the eighth aspect, the present application provides a process for purification of empagliflozin, comprising:
(a) providing a solution of empagliflozin L-proline complex characterized by PXRD peaks at about 4.36 ± 0.2, 12.97 ± 0.2, 15.67 ± 0.2 and 18.80 ± 0.2 ° 2Θ in a mixture of an organic solvent and water;
(b) optionally, heating the solution obtained in step (a);
(c) separating the organic layer from the mixture obtained in step (b); and
(d) isolating pure empagliflozin from the organic layer of step (c).
Step (a) of the process involves providing a solution of empagliflozin L-proline complex in a mixture of an organic solvent and water. Any type of organic solvent can be used in this process. Preferred solvents are esters such as ethyl acetate, n-propyl acetate, n-butyl acetate, t-butyl acetate and the like; alcoholic solvents such as methanol, ethanol, isopropyl alcohol, n-propanol, isoamyl alcohol and the like; ketones such as acetone, ethyl methyl ketone, methyl isobutyl ketone and the like; halogenated hydrocarbon solvents such as dichloromethane, dichloroethane, chloroform, carbon tetrachloride and the like. Most preferably the organic solvent is ethylacetate. The step (a) solution is prepared by any means such as first the complex is added to an organic solvent and then water is added or first the complex is added to water and then an organic solvent is added. The organic solvent and water are taken in a ratio of about 1 :0.2 to about 1 :5.
The solution obtained in step (a) may be heated to about 50°C and the solution may be stirred for about 10 minutes to about 5 hours.
Step (c) of the process involves separating the organic layer form the mixture. The organic layer containing empagliflozin is separated from the mixture and the organic layer may be washed with water.
Step (d) involves isolation of pure empagliflozin from the organic layer. Empagliflozin can be isolated by removal of the solvent. The solvent can be removed using a rotational distillation device such as a Buchi rotavapor, spray drying, agitated thin film drying, freeze drying (lyophilization), and the like, or other techniques specific to the equipment used. Small quantity of solvent or anti solvent may be added to the
reaction flask or the reactor to make the slurry or suspension when the solvent is completely removed, which will be useful for easy filtration.
The solvent may be removed, optionally under reduced pressures, at temperatures less than reflux temperature of the solvent, less than about 100°C, less than about 60°C, less than about 40°C, less than about 20°C, or any other suitable temperatures.
The product thus isolated may be optionally further dried to afford pure empagliflozin. Drying may suitably be carried out in a tray dryer, vacuum oven, Buchi rotavapor, air oven, fluidized bed dryer, spin flash dryer, flash dryer, or the like. The drying may be carried out at atmospheric pressure or under reduced pressures at temperatures of less than about 100°C, less than about 60°C, less than about 40°C or any other suitable temperatures. The drying may be carried out for any time period required for obtaining a desired quality, such as from about 15 minutes to several hours.
In one aspect, the present application provides empagliflozin prepared by the purification process described above is having a chemical purity of at least 99% by HPLC or at least 99.5% by HPLC or at least 99.9% by HPLC.
In the ninth aspect, the present application provides a crystalline Form N of Empagliflozin, characterized by a PXRD pattern comprising the peaks at about 4.13, 7.79, 1 1.55, 16.74, 23.20 and 27.87 ± 0.2° 2Θ. In an aspect, the present application provides a crystalline Form N of Empagliflozin, characterized by a PXRD pattern having one or more additional peaks at about 7.16, 15.51 , 15.86, 16.36, 22.08, 23.65, 24.47 and 26.65 ±0.2° 2Θ. In an aspect, the application provides crystalline Form N of Empagliflozin, characterized by a PXRD pattern of figure 30.
In one aspect, the present application provides a process for the preparation of crystalline Form N of Empagliflozin, comprising the step of treating Empagliflozin with N- methyl pyrrolidine or a mixture thereof.
In an aspect, crystalline Form N of Empagliflozin may be obtained by treating Empagliflozin with N-methyl pyrrolidine.
In an aspect, crystalline Form N of Empagliflozin may be obtained by treating Empagliflozin with a mixture of N-methyl pyrrolidine and atleast one additional solvent. In an aspect, additional solvent may be selected from the group comprising
of diethyl ether, di isopropyl ether, methyl tert. butyl ether, methanol, ethanol, 2- propanol, acetone, methyl isobutyl ketone, water or mixtures thereof.
In an aspect, treating Empagliflozin with N-methyl pyrrolidine or a mixture thereof may be carried out by combining Empagliflozin and N-methyl pyrrolidine or a mixture thereof.
In an aspect, the mixture of Empagliflozin and N-methyl pyrrolidine or a mixture thereof may form a homogeneous mixture in the form of a solution.
In an aspect, the mixture of Empagliflozin and N-methyl pyrrolidine or a mixture thereof is a heterogeneous mixture in the form a suspension.
In an aspect, combining Empagliflozin with N-methyl pyrrolidine or a mixture thereof may be carried out optionally by heating a mixture of Empagliflozin and N- methyl pyrrolidine or a mixture thereof at about 0°C to reflux temperature.
In an aspect, when the mixture of Empagliflozin and N-methyl pyrrolidine or a mixture forms a homogenous solution, it may be filtered to make it particle free and optionally treated with decolorizing agents such as charcoal, prior to filtration.
In an aspect, optionally seeds of crystalline Form N of Empagliflozin may be added to the mixture of Empagliflozin and N-methyl pyrrolidine or a mixture thereof, when the mixture forms a homogenous solution. In an aspect, seeds may be added at a suitable temperature and sufficient quantity such that the seeds are not dissolved.
In an aspect, optionally the mixture of Empagliflozin and N-methyl pyrrolidine or a mixture thereof may be contacted with an anti-solvent, when the mixture forms a homogenous solution. The anti-solvent may be a solvent in which Empagliflozin has low solubility or is insoluble. Anti-solvent may include, but not limited to water, diethyl ether, di isopropyl ether, methyl tert. butyl ether, n-propanol, 2-propanol, ethyl acetate, toluene, acetonitrile or mixtures thereof.
In an aspect, anti-solvent may be contacted at a temperature and duration, suitable for the formation of crystalline form I II of Empagliflozin. In an aspect, anti- solvent may be contacted either by adding the anti-solvent to the mixture of Empagliflozin and N-methyl pyrrolidine or by adding the mixture to anti-solvent. In an aspect, anti-solvent may be contacted in single lot or multiple lots.
In an aspect, the mixture of Empagliflozin and N-methyl pyrrolidine or a mixture thereof may be stirred for sufficient time to complete the formation of Form N and at suitable temperature where crystalline Form N is stable and do not convert to any other form of Empagliflozin.
In an aspect, the mixture of Empagliflozin and N-methyl pyrrolidine or a mixture thereof may be stirred for at least 1 hour or more. In an aspect, the mixture of Empagliflozin and N-methyl pyrrolidine or a mixture thereof may be stirred at a temperature of about 0°C to reflux temperature.
In an optional aspect, the mixture of Empagliflozin and N-methyl pyrrolidine or a mixture thereof may be cooled to a relatively lower temperature. In an aspect, the mixture may be cooled to a suitable temperature before or after addition of seeds and / or contacting with anti-solvent. In an aspect, the mixture comprising Empagliflozin and N-methyl pyrrolidine or a mixture thereof may be further stirred at the same temperature for time sufficient, after cooling, to obtain crystalline Form N of Empagliflozin.
Isolation of crystalline Form N of Empagliflozin may be carried out by any methods known in the art or procedures described in the present application. In an aspect, crystalline Form N may be isolated by employing any of the techniques, but not limited to: decantation, filtration by gravity or suction, centrifugation, adding solvent to make slurry followed by filtration, or other techniques specific to the equipment used and the like, and optionally washing with a solvent.
In an aspect, the crystalline Form N of Empagliflozin may be optionally dried under suitable drying conditions, at which the Form N is stable. In an alternate aspect, the crystalline Form N of Empagliflozin may be directly converted to any other solid form of Empagliflozin, without drying.
In one aspect, the present application provides a pharmaceutical composition comprising the crystalline Form N of Empagliflozin and at least pharmaceutically acceptable carrier.
In another aspect, the present application provides crystalline Form N of Empagliflozin or their pharmaceutical compositions comprising Empagliflozin having a
chemical purity of at least 99% by HPLC or at least 99.5% by HPLC or at least 99.9% by HPLC.
In another aspect, the present application provides crystalline Form N of Empagliflozin or their pharmaceutical composition, wherein particle size (D90) of Empagliflozin may be less than 100 microns or less than 50 microns or less than 20 microns.
In the tenth aspect, the present application provides a complex of empagliflozin with phenylalanine.
Empagliflozin forms a stable complex with L-phenylalanine. The empagliflozin phenylalanine complex can be prepared by the following process. The process comprising:
(a) dissolving empagliflozin and phenylalanine in a solvent,
(b) storing the solution to precipitate the empagliflozin phenylalanine complex, and
(c) isolating the empagliflozin phenylalanine complex.
The step (a) involves dissolving empagliflozin and phenylalanine in a suitable solvent to form a solution. The solution containing empagliflozin and phenylalanine may prepared by adding phenylalanine into a solution containing empagliflozin.
The solvent may be selected form the group comprising methanol, ethanol, isopropanol, tetrahydrofuran, acetone, acetonitrile and water or a mixture thereof. Preferably a mixture of ethanol and water is used.
To get the complete dissolution the mixture containing empagliflozin, phenylalanine and the solvent may be heated to elevated temperatures.
The step (b) involves storing the solution to precipitate empagliflozin phenylalanine complex. Storing the solution means keeping the solution or stirring the solution at below the temperature at which the solution is formed. Storing may be carried till the precipitation occurs. Storing may be continued for additional time to precipitate maximum product. Storing may be carried out at about 35 °C to about -10 °C. A precipitate will be formed upon storing the solution.
The step (c) involves isolation of empagliflozin phenylalanine complex. The suspension formed in the step (b) may be isolated by known techniques such as decantation, filtration by gravity or suction, centrifugation, adding solvent to make slurry
followed by filtration, or other techniques specific to the equipment used and the like, and optionally washing with a solvent.
In an aspect, the empagliflozin Phenylalanine complex may optionally be dried under suitable drying conditions, at which the complex is stable.
In another aspect, the empagliflozin Phenylalanine complex may be directly converted to any other solid form of empagliflozin, without drying.
The empagliflozin Phenylalanine complex is confirmed with the use of X-ray powder diffraction (XRPD), differential scanning calorimetry. The XRPD pattern is shown in Figure 31 . The empagliflozin phenylalanine complex exhibits a crystalline character. The characteristic diffraction peaks are 8.28 and 16.45 ±0.2 °2Θ. Other characteristic diffraction peaks are 4.24, 24.67 and 25.32 ±0.2 °2Θ.
In the eleventh aspect, the present application provides a crystalline Form-Alpha (a) of Empagliflozin, characterized by a PXRD pattern as shown in Figure 32.
In an alternate aspect, the crystalline Form-Alpha of Empagliflozin may be directly converted to any other solid form of Empagliflozin, without drying.
In the twelfth aspect, the present application provides a crystalline Form-Beta (Form β) of Empagliflozin, characterized by a PXRD pattern comprising the peaks at about 3.44, 4.04, 9.35, 10.20 and 14.1 1 ± 0.2° 2Θ.
The XRPD pattern of crystalline Form-Beta of Empagliflozin is shown in Figure 33. The characteristic diffraction peaks are 3.44, 4.04, 9.35, 10.20 and 14.1 1 ±0.2 °2Θ. Other characteristic diffraction peaks are 18.21 , 19.13 and 24.20 ±0.2 °2Θ.
In the thirteenth aspect, the present application provides a crystalline Form- Gamma (Form Y) of Empagliflozin, characterized by a PXRD pattern comprising the peaks at about 4.82, 7.19, 10.17 and 1 1.20 ± 0.2° 2Θ.
The XRPD pattern of crystalline Form-Gamma of Empagliflozin is shown in Figure 34. The characteristic diffraction peaks are 4.82, 7.19, 10.17 and 1 1 .20 ±0.2 °2Θ. Other characteristic diffraction peaks are 4.18, 18.15, 23.55 and 23.90 ±0.2 °2Θ.
The crystalline Form-Alpha, Form-Beta and Form-Gamma of empagliflozin can be prepared by the processes described in this application or by the processes described in the art.
In another aspect, the present application provides crystalline forms of Empagliflozin described in this application having a chemical purity of at least 99% by HPLC or at least 99.5% by H PLC.
In another aspect, the present application provides crystalline forms of Empagliflozin described in this application or their pharmaceutical composition, wherein particle size (D90) of Empagliflozin may be less than 200 microns or less than 100 microns or less than 50 microns or less than 20 microns.
In the fourteenth aspect, the present application provides a pharmaceutical composition comprising any of amorphous empagliflozin or empagliflozin solid dispersion or empagliflozin L-proline complex or empagliflozin phenylalanine complex of the present invention or any of the crystalline forms of empagliflozin of the present invention and at least pharmaceutically acceptable carrier.
In the fifteenth aspect, the present application provides a process for preparation of (R)-tetrahydrofuran-3-yl-4-methylbenzenesulfonate having greater than about 99.8% of chiral purity, comprising
(a) reacting (R)-tetrahydrofuran-3-ol with 4-methylbenzene-1 -sulfonyl chloride in presence of pyridine
(b) slurrying the crude compound (R)-tetrahydrofuran-3-yl-4- methylbenzenesulfonate with a mixture of ethylacetate and cyclohexane, and
(c) isolating the (R)-tetrahydrofuran-3-yl-4-methylbenzenesulfonate having chiral purity of greater than about 99.8%.
The step (a) is carried out using a suitable solvent such as dichloromethane, chlorobenzene or acetonitrile and the like. After completion of the reaction the crude product is slurried in a solvent or a mixture of solvents such as a mixture of ethylacetate and cyclohexane or a mixture of ethylacetate and n-hexane. The specific process of the reaction and purification are described in the examples section.
In the sixteenth aspect, the present application provides a process for preparation of empagliflozin having greater than about 99.8% of chiral purity, comprising:
(a) slurrying crude (R)-tetrahydrofuran-3-yl-4-methylbenzenesulfonate with a mixture of ethylacetate and cyclohexane to get (R)-tetrahydrofuran-3-yl-4- methylbenzenesulfonate having chiral purity of greater than about 99.8%, and
(b) reacting the (R)-tetrahydrofuran-3-yl-4-methylbenzenesulfonate having greater than about 99.8% of chiral purity with (1 R,2R,3S,6R)-4-(4-chloro-3- (4-hydroxybenzyl)phenyl)-6-(hydroxymethyl)cyclohexane-1 ,2,3-triol in resence of a base.
The specific process of the reaction and purification are described in the examples section.
In the seventeenth aspect, the present application provides a method of treating or preventing type 2 diabetes, comprising administering to a subject in need thereof an effective amount of any of amorphous empagliflozin or empagliflozin solid dispersion or empagliflozin L-proline complex or empagliflozin phenylalanine complex of the present invention or any of the crystalline forms of empagliflozin of the present invention or a pharmaceutical composition thereof.
Empagliflozin and its impurities can be analyzed using HPLC, such as with a liquid chromatography equipped with a UV detector and the parameters described below:
temp
Detection 225nm
Diluent Methanol: Water 800: 200 v/v
Preparation of Mix separately MQ water: Methanol: Acetonitrile: Ortho
Mobile phase-A phosphoric acid in the ratio of 650: 140: 210: 0.1 v/v/v/v.
Preparation of Mix separately Acetonitrile: Water in the ratio of 900: 100 v/v.
Mobile phase-B
Gradient Time (min) 0 35 70 78 80 90 programme % M.P-A 100 85 20 20 100 100
% M.P-B 0 15 80 80 0 0
Certain specific aspects and aspects of the present application will be explained in greater detail with reference to the following examples, which are provided only for purposes of illustration and should not be construed as limiting the scope of the application in any manner. Variations of the described procedures, as will be apparent to those skilled in the art, are intended to be within the scope of the present application.
DEFINITIONS
The following definitions are used in connection with the present invention unless the context indicates otherwise. The term "amorphous" refers to a solid lacking any long-range translational orientation symmetry that characterizes crystalline structures although; it may have short range molecular order similar to a crystalline solid.
As used herein, the term "complex" refers to a molecular entity formed by association involving two or more component molecular entities (ionic or uncharged), or by association involving two or more chemical species. The bonding between the components is non-covalent and is normally weaker than covalent bonding. Accordingly, the empagliflozin L-proline complex described herein is a molecular entity formed by the association between empagliflozin and L-proline. The empagliflozin- L- proline complex may in some aspects exist as a solid state form that is referred to
herein as a co crystal form of an empagliflozin-L-proline complex, or as an empalgiflozin L-proline co-crystal, or as a crystalline empagliflozin- L-proline complex.
The term "anti-solvent" refers to a liquid that, when combined with a solution of empagliflozin, reduces solubility of the empagliflozin in the solution, causing crystallization or precipitation in some instances spontaneously, and in other instances with additional steps, such as seeding, cooling, scratching and/or concentrating.
Celite is flux-calcined diatomaceous earth. Hyflo is flux-calcined diatomaceous earth treated with sodium carbonate.
An "alcohol solvent" is an organic solvent containing a carbon bound to a hydroxyl group. "Alcoholic solvents" include, but are not limited to, methanol, ethanol, 2- nitroethanol, 2-fluoroethanol, 2,2,2-trifluoroethanol, hexafluoroisopropyl alcohol, ethylene glycol, 1 -propanol, 2-propanol (isopropyl alcohol), 2- methoxyethanol, 1 - butanol, 2-butanol, i-butyl alcohol, t-butyl alcohol, 2- ethoxyethanol, diethylene glycol, 1 - , 2-, or 3-pentanol, neo-pentyl alcohol, t-pentyl alcohol, diethylene glycol monomethyl ether, diethylene glycol monoethyl ether, cyclohexanol, benzyl alcohol, phenol, glycerol, or the like.
A "hydrocarbon solvent" refers to a liquid, non-aromatic, hydrocarbon, which may be linear, branched, or cyclic. It is capable of dissolving a solute to form a uniformly dispersed solution. Examples of a hydrocarbon solvent include, but are not limited to, n- pentane, isopentane, neopentane, n-hexane, isohexane, 3-methylpentane, 2,3- dimethylbutane, neohexane, n-heptane, isoheptane, 3-methylhexane, neoheptane, 2,3- dimethylpentane, 2,4-dimethylpentane, 3,3-dimethylpentane, 3-ethylpentane, 2,2,3- trimethylbutane, n-octane, isooctane, 3-methylheptane, neooctane, cyclohexane, methylcyclohexane, cycloheptane, Examples of aromatic hydrocarbon solvents include, but are not limited to benzene, toluene, ethylbenzene, m-xylene, o xylene, p-xylene, indane, naphthalene, tetralin, trimethylbenzene, chlorobenzene, fluorobenzene, trifluorotoluene, anisole, C6-C10 aromatic hydrocarbons, or mixtures thereof.
An "ester solvent" is an organic solvent containing a carboxyl group -(C=0)-0 bonded to two other carbon atoms. "Ester solvents" include, but are not limited to, ethyl acetate, n-propyl acetate, isopropyl acetate, n-butyl acetate, isobutyl acetate, t-butyl
acetate, ethyl formate, methyl acetate, methyl propanoate, ethyl propanoate, methyl butanoate, ethyl butanoate, C3-6 esters, or the like.
A "halogenated hydrocarbon solvent" is an organic solvent containing a carbon bound to a halogen. "Halogenated hydrocarbon solvents" include, but are not limited to, dichloromethane, 1 ,2-dichloroethane, trichloroethylene, perchloroethylene, 1 ,1 ,1 - trichloroethane, 1 ,1 ,2-trichloroethane, chloroform, carbon tetrachloride, or the like.
A "ketone solvent" is an organic solvent containing a carbonyl group -(C=0)- bonded to two other carbon atoms. "Ketone solvents" include, but are not limited to, acetone, ethyl methyl ketone, diethyl ketone, methyl isopropyl ketone, methyl isobutyl ketone, C3-6ketones, 4- methyl-pentane-2-one or the like.
A "nitrile solvent" is an organic solvent containing a cyano -(C≡N) bonded to another carbon atom. "Nitrile solvents" include, but are not limited to, acetonitrile, propionitrile, C2-6nitriles, or the like.
A "polar aprotic solvent" has a dielectric constant greater than 15 and is at least one selected from the group consisting of amide-based organic solvents, such as N,N- dimethylformamide (DMF), Ν,Ν-dimethylacetamide (DMA), Nmethylpyrrolidone (NMP), formamide, acetamide, propanamide, hexamethyl phosphoramide (HMPA), and hexamethyl phosphorus triamide (HMPT); nitro-based organic solvents, such as nitromethane, nitroethane, nitropropane, and nitrobenzene; pyridine-based organic solvents, such as pyridine and picoline; sulfone-based solvents, such as dimethylsulfone, diethylsulfone, diisopropylsulfone, 2-methylsulfolane, 3- methylsulfolane, 2,4-dimethylsulfolane, 3,4-dimethy sulfolane, 3-sulfolene, and sulfolane; and sulfoxide-based solvents such as dimethylsulfoxide (DMSO).
An "ether solvent" is an organic solvent containing an oxygen atom -O bonded to two other carbon atoms. "Ether solvents" include, but are not limited to, diethyl ether, diisopropyl ether, methyl t-butyl ether, glyme, diglyme, tetrahydrofuran (THF), 2- methyltetrahydrofuran, 1 ,4-dioxane, dibutyl ether, dimethylfuran, 2-methoxyethanol, 2- ethoxyethanol, anisole, C2-6 ethers, or the like.
As used herein, the term "co-crystal" refers to a crystal complex composed of at least two neutral molecules bound together in a crystal lattice by non-covalent interactions. The term "co-crystal" also can be referred as adduct.
"A therapeutically effective amount" as used herein refers to an amount of an agent which is effective, upon single or multiple dose administration to the subject in providing a therapeutic benefit to the subject. In one aspect, the therapeutic benefit is maintaining glucose homeostasis, or regulating blood glucose levels. In additional aspects, the empagliflozin amino acid complex of the present invention is used for the preparation of a medicament for treating conditions mediated by SLGT2, preferably type 2 diabetes.
Certain specific aspects and aspects of the present invention will be explained in more detail with reference to the following examples, which are provided for purposes of illustration only and should not be construed as limiting the scope of the present invention in any manner.
EXAMPLES
Example 1 : Preparation of amorphous form of empagliflozin.
Empagliflozin (2 gm) and n-Propanol (120 ml_) were charged into a 250 ml_ round bottom flask at 27°C. The mixture was heated to 70°C and stirred for 15 min. The solution was filtered to remove the un-dissolved particles and the filtrate was evaporated by spray drying, using a Buchi® MINI Spray Dryer B-290 with Buchi® Inert Loop B-295 at 95°C to afford 880 mg of amorphous empagliflozin.
PXRD pattern: Fig. 1 .
Parameters for the spray drier of the above experiment: Aspirator: 70 %; Feed rate: 20 ml_/ min; Inlet temperature: 95°C; Outlet temperature: 60°C.
Example 2: Preparation of amorphous form of empagliflozin.
Empagliflozin (500 mg) and methanol (35 ml_) were charged into a Buchi flask at 27°C.
The mixture was heated to 55°C and stirred for 10 min. The solution was filtered to remove the un-dissolved particles and the filtrate was distilled under reduced pressure at 60°C. After distillation the solid was dried under vacuum at 25°C to get 260 mg of amorphous empagliflozin. PXRD pattern: amorphous
Example 3: Preparation of amorphous form of empagliflozin.
Empagliflozin (500 mg), dichloromethane (10 ml_) and n-Propanol (10 ml_) were added to a test tube at 27°C. The mixture was heated to 65°C and stirred for 15 min. The
solution was filtered to remove the un-dissolved particles and the filtrate was distilled under reduced pressure at 60°C to get 180 mg of amorphous empagliflozin. PXRD pattern: amorphous.
Example 4: Preparation of amorphous form of empagliflozin.
Empagliflozin (500 mg) and acetone (40 ml_) were charged into a round bottom flask at 27°C. The mixture was heated to 60°C and stirred for 15 min. The solution was filtered to remove the un-dissolved particles and the filtrate was distilled under reduced pressure at 60°C to get amorphous empagliflozin. PXRD pattern: amorphous.
Example 5: Preparation of amorphous form of empagliflozin.
Empagliflozin (2 gm) and 2-Butanol (170 ml_) were charged into a 250 ml_ round bottom flask at 27°C. The mixture was heated to 75°C and stirred for 15 min. The solution was filtered to remove the un-dissolved particles and the filtrate was evaporated by spray drying, using a Buchi® MINI Spray Dryer B-290 with Buchi® Inert Loop B-295 at 95°C to afford 830 mg of amorphous empagliflozin. PXRD pattern: amorphous.
Parameters for the spray drier of the above experiment: Aspirator: 70%; Feed rate: 20 imL/min; Inlet temperature: 95°C; Outlet temperature: 60°C.
Example 6: Preparation of amorphous solid dispersion of empagliflozin and hydroxy propyl methyl cellulose phthalate (Hypromellose Phthalate; HPMC- Phthalate).
Empagliflozin (250 mg), Hypromellose Phthalate (250 mg) and methanol (30 ml_) were charged into a round bottom flask at 27°C. The resulted mixture was heated to 60°C and stirred for 15 min. at 60°C. The clear solution was filtered to remove the undissolved particles and the filtrate was completely evaporated under reduced pressure at 60°C to get 180 mg of amorphous solid dispersion of empagliflozin and Hypromellose Phthalate. PXRD pattern: Fig. 2.
Glass transition onset temperature is 75.99 °C
Glass transition temperature is 81 .61 °C
Example 7: Preparation of amorphous solid dispersion of empagliflozin and Methyl cellulose.
Empagliflozin (250 mg), Methyl cellulose (250 mg), methanol (25 ml_) and water (25 ml_) were charged into a round bottom flask at 27°C. The resulted mixture was heated to
50°C and stirred for 15 min. at 50°C. The clear solution was filtered to remove the undissolved particles and the filtrate was completely evaporated under reduced pressure at 70°C to get 432 mg of amorphous solid dispersion of empagliflozin and Methyl cellulose. PXRD pattern: Fig. 3.
Glass transition onset temperature is 90.87 °C
Glass transition temperature is 92.40.13 °C
Example 8: Preparation of crystalline form of empagliflozin.
Empagliflozin (500 mg) and methanol (10 mL) were charged into a round bottom flask at 27°C. The mixture was heated to 40°C and stirred for 10 min. The solution was filtered to remove the un-dissolved particles and the hot filtrate was taken into another round bottom flask. Water (30 mL) was added to the flask at 50°C and the mixture was stirred at 50°C for 2 hours. The precipitate was filtered at 50°C and the solid was dried under vacuum at 50°C to get 254 mg of crystalline empagliflozin. PXRD pattern: Fig. 4.
Example 9: Preparation of crystalline form of empagliflozin.
Empagliflozin (500 mg) and methanol (10 mL) were charged into a round bottom flask at 27°C. The mixture was heated to 40°C and stirred for 10 min. The solution was filtered to remove the un-dissolved particles and the hot filtrate was added to water (25 mL) at 60°C. The mixture was stirred at 50°C for 2 hours. The precipitate was filtered at 60°C to get 320 mg of crystalline empagliflozin. PXRD pattern matches with Fig. 4.
Example 10: Preparation of crystalline form of empagliflozin.
Empagliflozin (500 mg) and DMSO (2 mL) were charged into a test tube at 27°C and stirred for 10 min. The solution was filtered to remove the un-dissolved particles. The clear solution was added to water (10 mL) at 50°C and the mixture was stirred at 50°C for 2 hours. The precipitate was filtered at 50°C to get 340 mg of crystalline empagliflozin. PXRD pattern matches with Fig. 4.
Example 11 : Preparation of crystalline form of empagliflozin.
Empagliflozin (500 mg) and acetone (15 mL) were charged into an easymax reactor at 27°C. The mixture was heated to 55°C and stirred for 10 min. The solution was filtered to remove the un-dissolved particles and the hot filtrate was taken into another round bottom flask. The clear solution was added to Heptane (25 mL) at 70°C and stirred for 1 hour at 70°C. Pet ether (25 mL) was added the mixture at 70°C and the mixture was
stirred at 70°C for 2 hours. The precipitate was filtered at 70°C to get 374 mg of crystalline empagliflozin. PXRD pattern matches with Fig. 4.
Example 12: Purification of empagliflozin
(a) Preparation of empagliflozin and L-proline complex
Isopropanol (4 mL) and L-proline (0.459 g) were charged into 50 mL 2 neck round bottom flask. Water (0.5 mL) was added to the mass at 26°C. The mixture was heated to 80°C and stirred for 30 minutes at 80°C. A solution of empagliflozin (purity: 91 .6%) (1 g of empagliflozin in 4 mL of isopropanol) was added to the reaction mixture at 80°C and resulted mixture was stirred for 1 hour at 80°C. Reaction mixture was cooled to 27°C and MTBE (16 mL) was added to the mixture and the reaction mixture was stirred for 2 hours at 27°C. The precipitation was filtered and the wet cake was washed with MTBE (4 mL) and suck dried for 1 hour to get the title complex.
(b) Conversion of empagliflozin L-proline complex to empagliflozin
Empagliflozin and L-proline complex prepared in example 12 was dissolved in water (10 mL) and ethylacetate (10 mL) and the resulted solution was stirred for 20 minutes at 27°C. Separated the layers and the aqueous layer was extracted with ethylacetate (10 mL). The ethylacetate layers were combined and washed with saturated NaCI solution (5 mL). The organic layer was dried over sodium sulphate and was concentrated under vacuum at 40°C to yield 0.470 g of empagliflozin. Purity: 98.15 by HPLC.
Example 13: Preparation of empagliflozin L-proline complex
Isopropanol (4 mL) and L-proline (0.459 g) were charged into 50 mL 2 neck round bottom flask. Water (0.5 mL) was added to the mass at 30°C. The mixture was heated to 82°C and stirred for 30 minutes at 82°C. A solution of empagliflozin (purity: 95%) (1 g of empagliflozin in 4 mL of isopropanol) was added to the reaction mixture at 82°C and resulted mixture was stirred for 1 hour at 82°C. Reaction mixture was cooled to 30°C and MTBE (16 mL) was added to the mixture and the reaction mixture was stirred for 2 hours at 33°C. The precipitation was filtered and the wet cake was washed with MTBE (4 mL) and suck dried under vacuum for 1 hour to get the 1 .12 gm of title complex as white solid. Purity: 98.57% by HPLC.
PXRD pattern: Fig. 5.
Example 14: Preparation of amorphous form of empagliflozin.
Empagliflozin (40 g) and methanol (800 ml_) were charged into a 2000 ml_ round bottom flask at 30 °C. The mixture was heated to 50 °C and stirred for 15 min. The solution was filtered to remove the un-dissolved particles and the filtrate was evaporated by spray drying, using a Buchi® MINI Spray Dryer B-290 with Buchi® Inert Loop B-295 at 75°C to afford 26 g of amorphous empagliflozin. The solid was dried for 4 hours at 30 °C under reduced pressure to get 22 grams of amorphous empagliflozin. Purity by HPLC: 99.85%. Methanol content by GC: 1919 ppm
Parameters for the spray drier of the above experiment: Aspirator: 70 %; Feed rate: 9 ml_/ min; Inlet temperature: 75°C; Outlet temperature: 60°C.
Example 15: Preparation of amorphous form of empagliflozin.
Empagliflozin (45 g) and methanol (900 ml_) were charged into a 2000 ml_ round bottom flask at 30 °C. The mixture was heated to 50 °C and stirred for 10 min. The solution was filtered to remove the un-dissolved particles and the filtrate was evaporated by spray drying, using a Buchi® MINI Spray Dryer B-290 with Buchi® Inert Loop B-295 at 75°C to afford 28 g of amorphous empagliflozin. The solid was dried for 4 hours at 30 °C under reduced pressure to get 28 grams of amorphous empagliflozin. Purity by HPLC: 99.9%. Methanol content by GC: 1 189 ppm.
Glass transition onset temperature is 66.29 °C
Glass transition temperature is 70.13 °C
PXRD pattern: Fig. 6.
DSC thermogram: Fig. 35.
Parameters for the spray drier of the above experiment: Aspirator: 75 %; Feed rate: 9 mL/ min; Inlet temperature: 75°C; Outlet temperature: 60°C.
Example 16: Preparation of amorphous form of empagliflozin.
Empagliflozin (60 g) and methanol (1200 mL) were charged into a 2000 mL round bottom flask at 25 °C. The mixture was heated to 50 °C and stirred for 10 min. The solution was cooled to 30 °C and filtered to remove the un-dissolved particles and the filtrate was evaporated by spray drying, using a Buchi® MINI Spray Dryer B-290 with Buchi® Inert Loop B-295 at 70 °C to afford 37 g of amorphous empagliflozin. The solid was dried for 4 hours at 30 °C under reduced pressure to get 31 grams of amorphous empagliflozin. Purity by HPLC: 99.81 %. PXRD pattern: Fig. 1 .
Parameters for the spray drier of the above experiment: Aspirator: 70 %; Feed rate: 9 ml_/ min; Inlet temperature: 75°C; Outlet temperature: 60°C.
Example 17: Preparation of amorphous solid dispersion of empagliflozin and Low-Substituted Hydroxypropyl Cellulose (L-HPC).
Low-Substituted Hydroxypropyl Cellulose (L-HPC) (2 g) and methanol (50 mL) were charged into a Buchi rotavapor flask at 25 °C and the mixture was heated to 55 °C. In another flask Empagliflozin (2 g) and methanol (50 mL) were charged at 25 °C and stirred for 15 min. Both the clear solutions were combined and the solution was charged into a rotavapor and completely evaporated under reduced pressure at 55 °C to get 3 g of amorphous solid dispersion of empagliflozin and L-HPC. PXRD pattern: Fig. 7.
The solid amorphous material (1 g) was humidified at 30 °C and 40% RH for 10 hours. Flowable solid lumps obtained.
Example 18: Preparation of amorphous solid dispersion of empagliflozin and Ethyl Cellulose.
Empagliflozin (2 g) and methanol (50 mL) were charged into a Buchi rotavapor flask at 25 °C and stirred for 15 minutes. In another flask Ethyl Cellulose (2 g) and methanol (60 mL) were charged at 25 °C and heated to 58 °C to get clear solution. Both the clear solutions were combined and the solution was charged into a rotavapor and completely evaporated under reduced pressure at 60 °C to get 2.8 g of amorphous solid dispersion of empagliflozin and Ethyl Cellulose. PXRD pattern: Fig. 8.
The solid amorphous material (1 g) was humidified at 30 °C and 40% RH for 10 hours. Freely flowable amorphous solid obtained. PXRD pattern: 9
Glass transition onset temperature is 66.79 °C
Glass transition temperature is 70.48 °C
Example 19: Preparation of amorphous solid dispersion of empagliflozin and Eudragit RLPO.
Empagliflozin (2 g) and methanol (50 mL) were charged into a Buchi rotavapor flask at 25 °C and stirred for 15 minutes. In another flask Eudragit RLPO (2 g) and methanol (36 mL) were charged at 25 °C and heated to 55 °C to get clear solution. Both the clear solutions were combined and the solution was charged into a rotavapor and completely
evaporated under reduced pressure at 60 °C to get 3.2 g of amorphous solid dispersion of empagliflozin and Eudragit RLPO. PXRD pattern: Fig. 10.
The solid amorphous material (1 g) was humidified at 30 °C and 40% RH for 10 hours. Amorphous solid (flowable upon disturbing) obtained. PXRD pattern: Fig. 1 1 .
Glass transition onset temperature is 67.17 °C
Glass transition temperature is 70.87 °C
Example 20: Preparation of amorphous solid dispersion of empagliflozin and HPMC.
Empagliflozin (2 g) and methanol (50 mL) were charged into a Buchi rotavapor flask at 25 °C and stirred for 15 minutes and heated to 55 °C to get clear solution. In another flask hydroxy propyl methyl cellulose (HPMC) (2 g) and methanol (50 mL) were charged at 25 °C and stirred for 15 minutes. Both the clear solutions were combined and the solution was charged into a rotavapor and completely evaporated under reduced pressure at 60 °C to get 2.4 g of amorphous solid dispersion of empagliflozin and HPMC. PXRD pattern: Fig. 12.
The solid amorphous material (1 g) was humidified at 30 °C and 40% RH for 10 hours. Amorphous solid (flowable upon disturbing) obtained. PXRD pattern: Fig. 13.
Example 21 : Preparation of amorphous solid dispersion of empagliflozin and HPMC-AS.
Empagliflozin (2 g) and methanol (50 mL) were charged into a Buchi rotavapor flask at 25 °C and stirred for 15 minutes and heated to 55 °C to get clear solution. In another flask hydroxy propyl methyl cellulose acetate succinate (HPMC-AS MG) (2 g) and methanol (50 mL) were charged at 25 °C and stirred for 15 minutes. Both the clear solutions were combined and the solution was charged into a rotavapor and completely evaporated under reduced pressure at 60 °C to get 2.8 g of amorphous solid dispersion of empagliflozin and HPMC-AS. PXRD pattern: Fig. 14.
The solid amorphous material (1 g) was humidified at 30 °C and 40% RH for 10 hours. Amorphous solid (flowable) obtained. PXRD pattern: Fig.15.
Example 22: Preparation of amorphous solid dispersion of empagliflozin and Soluplus.
Empagliflozin (2 g) and methanol (50 ml_) were charged into a Buchi rotavapor flask at 25 °C and stirred for 15 minutes and heated to 55 °C to get clear solution. In another flask hydroxy propyl methyl cellulose acetate succinate (HPMC-AS MG) (2 g) and methanol (50 ml_) were charged at 25 °C and stirred for 15 minutes. Both the clear solutions were combined and the solution was charged into a rotavapor and completely evaporated under reduced pressure at 60 °C to get 3.4 g of amorphous solid dispersion of empagliflozin and Soluplus. PXRD pattern: Fig. 16.
The solid amorphous material (1 g) was humidified at 30 °C and 40% RH for 10 hours. Amorphous solid (sticky solid lumps) obtained. PXRD pattern: Fig.17.
Glass transition onset temperature is 74.42 °C
Glass transition temperature is 76.30 °C
Example 23: Preparation of amorphous solid dispersion of empagliflozin and Eudragit-E100.
Eudragit-E100 (2 g) and methanol (80 ml_) were charged into a Buchi rotavapor flask at 25 °C and stirred for 15 minutes and heated to 65 °C to get clear solution. In another flask Empagliflozin (2 g) and methanol (50 ml_) were charged at 25 °C and stirred for 15 minutes. Both the clear solutions were combined and the solution was charged into a rotavapor and completely evaporated under reduced pressure at 60 °C to get 3 g of amorphous solid dispersion of empagliflozin and Eudragit-E100. PXRD pattern: Fig. 18. The solid amorphous material (1 g) was humidified at 30 °C and 40% RH for 10 hours. Amorphous solid (sticky solid lumps) obtained. PXRD pattern: Fig.19.
Glass transition onset temperature is 96.08 °C
Glass transition temperature is 99.22 °C
Example 24: Preparation of amorphous solid dispersion of empagliflozin and Microcrystalline Cellulose.
Empagliflozin (2 g) and methanol (80 ml_) were charged into a Buchi rotavapor flask at 25 °C and stirred for 15 minutes and heated to 55 °C to get clear solution. Microcrystalline Cellulose (MCC; 2 g) was charged at 55 °C and stirred for 15 minutes. The solution was charged into a rotavapor and completely evaporated under reduced pressure at 65 °C. 2.7 g of crystalline sticky solid dispersion of empagliflozin and MCC was obtained.
Example 25: Preparation of amorphous solid dispersion of empagliflozin and hydroxy propyl methyl cellulose phthalate (Hypromellose Phthalate; HPMC- Phthalate).
Hypromellose Phthalate (2 g) and methanol (60 mL) were charged into a round bottom flask at 27°C. Empagliflozin (2 g) and methanol (50 mL) were charged into another flask and heated to 55 °C. The resulted mixture was heated to 55°C and stirred for 15 min. at 55°C. Both the clear solutions were combined and the solution was charged into a rotavapor and completely evaporated under reduced pressure at 60 °C to get 3 g of amorphous solid dispersion of empagliflozin HPMC-Phthalate. PXRD pattern: Fig. 20. The solid amorphous material (1 g) was humidified at 30 °C and 40% RH for 10 hours. Amorphous solid obtained. PXRD pattern: Fig.21 .
Example 26: Preparation of amorphous solid dispersion of empagliflozin and Methyl cellulose.
Methyl cellulose (2 g) and methanol (60 mL) were charged into a round bottom flask at 27°C. In another flask Empagliflozin (2 g) and methanol (50 mL) were charged at 27°C. Both the API and excipient solutions were combined and the solution was charged into a rotavapor and completely evaporated under reduced pressure at 62 °C to get 3.1 g of amorphous solid dispersion of empagliflozin Methyl Cellulose. PXRD pattern: Fig. 22. The solid amorphous material (1 g) was humidified at 30 °C and 40% RH for 10 hours. Amorphous solid obtained. PXRD pattern: Fig.23.
Example 27: Preparation of amorphous solid dispersion of empagliflozin, HPMC and adsorbent.
Empagliflozin (5 g) and methanol (175 mL) were charged into a Buchi rotavapor flask at 25 °C and stirred for 15 minutes and heated to 55 °C to get clear solution. In another flask hydroxy propyl methyl cellulose (HPMC) (5 g) and methanol (125 mL) were charged at 25 °C and stirred for 15 minutes and heated to 55 °C to get clear solution. Both the clear solutions were combined and the solution was charged into a rotavapor and completely evaporated under reduced pressure at 60 °C to get 6.2 g of amorphous solid dispersion of empagliflozin and HPMC. PXRD pattern: Fig. 12.
Glass transition onset temperature is 58.77 °C
Glass transition temperature is 73.92 °C
Taken 3 g of the above amorphous solid dispersion and divided into 3 parts (P1 , P2 and P3) 1 g each part. Added 500 mg of Syloid to P1 , 500 mg of Lactose to P2 and 500 mg of Croscarmellose sodium and kept all the three samples in humidification chamber at 40 % RH and 30 °C for 10 hours.
Good improvement in flowability and stability is found by addition of adsorbents syloid, lactose, and croscarmellose sodium (API : HPMC : Adsorbent = 1 :1 :0.5) when exposed even for one day at 40% RH and 30 °C remained amorphous.
P1 PXRD pattern: Fig 24; P2 PXRD pattern: Fig 25; P3 PXRD pattern: Fig 26.
P1 : Glass transition onset temperature is 54.18 °C; Glass transition temperature is
63.71 °C
P2: Glass transition onset temperature is 71 .36 °C; Glass transition temperature is 76.08 °C.
Example 28: Preparation of amorphous solid dispersion of empagliflozin, HPC and adsorbent.
Empagliflozin (5 g) and methanol (175 mL) were charged into a Buchi rotavapor flask at 25 °C and stirred for 15 minutes and heated to 55 °C to get clear solution. In another flask hydroxy propyl cellulose (HPC) (5 g) and methanol (125 mL) were charged at 25 °C and stirred for 15 minutes and heated to 55 °C to get clear solution. Both the clear solutions were combined and the solution was charged into a rotavapor and completely evaporated under reduced pressure at 60 °C to get 6.8 g of amorphous solid dispersion of empagliflozin and HPC. PXRD pattern: Fig. 7.
Glass transition onset temperature is 73.32 °C
Glass transition temperature is 84.59 °C.
Taken 3 g of the above amorphous solid dispersion and divided into 3 parts (P1 , P2 and P3) 1 g each part. Added 5oo mg of Syloid to P1 , 500 mg of Lactose monohydrate to P2 and 500 mg of Croscarmellose sodium and kept all the three samples in humidification chamber at 40 % RH and 30 °C for 10 hours.
Good improvement in flowability and stability is found by addition of adsorbents syloid, lactose, and croscarmellose sodium (API : HPC : Adsorbent = 1 :1 :0.5) when exposed even for one day at 40% RH and 30 °C remained amorphous.
P1 PXRD pattern: Fig 27; P2 PXRD pattern: Fig 28; P3 PXRD pattern: Fig 29.
P1 : Glass transition onset temperature is 76.67 °C; Glass transition temperature is 90.64 °C
P2: Glass transition onset temperature is 70.89 °C; Glass transition temperature is 82.46 °C
P3: Glass transition onset temperature is 82.62 °C; Glass transition temperature is 84.88 °C
Example 29: Preparation of crystalline Form N of Empagliflozin.
Empagliflozin (0.5 g) was dissolved in N-methyl pyrrolidine (0.5 mL) at 25°C and methyl tert. butyl ether (7.5 mL) was added slowly at the same temperature. Stirred the mixture for 15.5 hours at 25°C and the solid was filtered to obtain the title compound.
Example 30: Preparation of crystalline Form N of Empagliflozin.
Empagliflozin (0.5 g) was dissolved in N-methyl pyrrolidine (0.5 mL) at 22°C and methyl tert. butyl ether (7.5 mL) was added slowly at the same temperature. Stirred the mixture for 15 hours at 22°C and the solid was filtered to obtain the title compound.
Example 31 : Preparation of crystalline Form N of Empagliflozin.
Empagliflozin (5 g) was dissolved in N-methyl pyrrolidine (5 mL) at 23°C and methyl tert. butyl ether (75 mL) was added slowly in 8 minutes at the same temperature. Stirred the mixture for 15 hours at 23°C and the solid was filtered to obtain 4.9 g of the title compound. PXRD pattern: Figure 30.
Example 32: Preparation of Empagliflozin L-phenylalanine complex.
Empagliflozin (300 mg) and L-phenylalanine (143 mg) were added to water ethanol mixture (1 :1 , 14 mL) at 25°C and the mixture was heated to 50 °C using a hot air gun to form clear solution. The solution was kept idle for 14 days at 5 ° C. The precipitation was filtered to obtain the title compound. PXRD pattern: Figure 31 .
Example 33: Preparation of crystalline Form-Alpha of Empagliflozin.
Empagliflozin (100 mg) and ethanol (4 mL) were charged into a test tube and the mixture was heated to 70 °C to get clear solution and the clears solution was filtered for particle free. Propyl acetate (10 mL) was added to the test tube at 25°C and the mixture was kept at -20 °C for 4 days and the solid was filtered to obtain the title compound. PXRD pattern: Figure 32.
Example 34: Preparation of crystalline Form-Beta of Empagliflozin.
Empagliflozin (500 mg) and ethanol (20 mL) were charged into a round bottom flask and the mixture was heated to 70 °C to get clear solution and the clears solution was filtered for particle free. Butyl acetate (50 mL) was added to the test tube at 25°C and the mixture was kept at -20 °C for 22 days and the solid was filtered and dried in a vacuum tray drier to obtain the title compound. PXRD pattern: Figure 33.
Example 35: Preparation of crystalline Form-Gamma of Empagliflozin.
Empagliflozin (1000 mg) and dimethylacetamide (2 mL) were charged into a round bottom flask. The solid dissolved and isolated immediately. N-Hexane (20 mL) was added to the mixture at 25°C, thick mass was formed. The suspension was filtered and the solid was washed with diethyl ether (10 mL) and the solid was dried in an air tray drier obtain the title compound. PXRD pattern: Figure 34.
Example 36: Preparation of Empagliflozin
(a) Preparation of R)-tetrah drofuran-3-yl 4-methylbenzenesulfonate
(R)-Hydroxy-THF (20 g), dichloromethane (300 mL) and Pyridine (71 .8 g) were charged into a 1000 mL round bottom flask and the mixture was cooled to 5 °C. 4- methylbenzene-1 -sulfonyl chloride (47.6 gm) was charged into the flask at 5 °C and the mixture was stirred for 10 hours at 28 °C. Water (500 mL) was charged to the flask and stirred for 15 minutes. Layers separated and the organic layer was washed with dilute hydrochloric acid (50 mL of HCI in 150 mL of water). The organic layer was washed with aqueous sodium bicarbonate solution (200 mL) and water (200 mL). The organic layer was concentrated under vacuum to yield 48 gm of (R)-tetrahydrofuran-3-yl-4- methylbenzenesulfonate.
The crude compound was taken into another round bottom flask and ethylacetate (30 mL) was added and stirred for 10 minutes. The clear solution was cooled to 15 °C and 50 mg seed compound was added. Cyclohexane (300 mL) was added slowly over a period of 30 minutes at 15 °C. The obtained suspension was stirred for 1 hour at 15 °C. The precipitation was filtered and wet material was washed with chilled cyclohexane (80
mL). The wet compound was dried under vacuum for 2 hours at 30 °C to yield 42 gm of title compound. Purity by HPLC: 99.87%.
(b) Preparation of 4-(2-chloro-5-iodobenzyl)phenol
In a clean and dried round bottom flask, 2-chloro-5-iodobenzoic acid (30 g), chlorobenzene (300 mL), and catalytic amount of N,N-dimethylformamide (1 .5 mL) were charged. The reaction mixture was cooled to 10 °C and oxalyl chloride (17.52 g) was added drop wise over 15 minutes. At the end of the addition, reaction mixture was warmed to 25 °C and stirred for 3 hours. The reaction mixture was concentrated under vacuum and to this crude material, 300 mL of chlorobenzene was added under nitrogen atmosphere and the mixture was cooled to 5 °C. To this, AICI3 (15.58 g) was charged. To the reaction mixture, anisole (12.06 g) was added drop wise at 5 °C. The reaction mixture was stirred for 1 .5 h at 5 °C. Fresh AICI3 (28.3 g) was charged at 5 °C and the reaction mixture heated to 60 °C. The reaction mixture was cooled to 5 °C. At this temperature, TMDS (49.9 g) was added drop wise over a period of 0.5 h. The reaction mixture was then warmed to 25 °C and stirred for 5 hours. The reaction mixture was quenched by pouring the RM into 450 mL ice cold water. Ethyl acetate (600 mL) was added to this RM and stirred for 10 minutes at 20 °C. Layers were separated and aqueous layer extracted with ethyl acetate (90 mL). The combined organic layers were washed with 5% aqueous NaHC03 (600 mL) and saturated brine solution (300 mL). The organic layer was concentrated under vacuum at 50 °C. n-Hexane (150 mL) was added to the crude and stirred for 1 h at 60 °C. The heterogeneous mixture was cooled to 10 °C and stirred for further 1 h. The solid was filtered and washed with n-Hexane (50 mL). The white solid obtained was dried under vacuum at 40 °C (White solid, 28.8 g, Yield: 78.69 %, HPLC purity 97.7 %.
(c) Preparation of tert-butyl(4-(2-chloro-5-iodobenzyl)phenoxy)dimethylsilane
TBDMSCI
CI -OH CI -OTBDMS
TEA, DMAP
4-(2-chloro-5-iodobenzyl)phenol (30 g), dichloromethane (300 mL) were charged into a 1000 mL round bottom flask and the clear solution was cooled to 5 °C. A solution of tert- butylchlorodimethylsilane (14.43 g of TBDMSCI in 150 mL of DCM) was added to the flask at 5 °C. N,N-dimethylpyridin-4-amine (1 .064 g) and triethylamine (13.21 g) were added to the reaction mass at 5 °C. The reaction mass was stirred at 28 °C for 3 hours. Water (150 mL) was charged to the reaction mass and the mixture was stirred for 30 minutes. Layers separated and the organic layer was washed with 1 % aqueous HCI (150 mL) and with saturated sodium bicarbonate solution (150 mL), and with water (150 mL). The organic layer was concentrated under vacuum to yield 40 g crude material. The crude material and methanol (120 mL) were charged into a round bottom flask and 0.5 g of seed material was added. The solution was cooled to 10 °C and stirred for 2 hours. The suspension was filtered and was with 20 mL of methanol and the wet cake was dried under vacuum to yield 30 g of the title compound. Purity 98% by HPLC.
(d) Preparation of Empagliflozin
Tert-butyl(4-(2-chloro-5-iodobenzyl)phenoxy)dimethylsilane (1 .0 Kg), tetrahydrofuran (6.0 L) and (3R,4S,5R,6R)-3,4,5-tris((trimethylsilyl)oxy)-6-(((trimethylsilyl)oxy)methyl)
tetrahydro-2H-pyran-2-one (1 .221 Kg) were charged into a 20 L flask under Nitrogen atmosphere. Toluene (6.0 L) was charged into the flask and the resulted mixture was cooled to -80 °C. n-Butyl Lithium in hexane (1 .6M, 2.8 Kg) was added slowly over a period of 3 hours at -80 °C. The reaction mixture was maintained for 1 hour at -80 °C. A solution of methanesulfonic acid (1 .46 Kg of methanesulfonic acid in 9.0 L of methanol) was added to the reaction mass at -70 °C. The reaction mass was heated to -10 °C and stirred for 30 minutes and heated to 30 °C and stirred for 12 hours at 30 °C. The reaction mass was cooled to 5 °C and sodium bicarbonate solution (2.0 Kg of sodium bicarbonate in 23 L of water) was added slowly. The reaction mass was stirred for 30 minutes at 30 °C. The reaction mass was washed with Toluene (6.0 Lx 3) and the reaction mass was concentrated under vacuum until 20 volumes remains in the flask. The reaction mass was extracted with ethylacetate (10.0 Lx5) and the ethylacetate layer was washed with water (3.0 L). The ethylacetate layer was charged into a 100 L reactor and concentrated under vacuum to 3 volumes remained in the reactor. The concentrated ethylacetate layer was stripped off with acetonitrile (3.0 Lx 3) then dichloromethane (7.0 L) and acetonitrile (1 .2 L) were charged into the reactor and the reaction mass was cooled to -30 °C. Triethylsilane (0.57 Kg) and Borontrifluoride etherate solution (1 .307 Kg) were charged into the reactor and the reaction mass was stirred for 3 hours at -30 °C. Temperature was raised to -5 °C and stirred for 6 hours. A solution of sodium carbonate (2.0 Kg of sodium carbonate in 20.0 L of water) was added to the reaction mass over a period of 30 minutes at 5 °C. The reaction mass was heated to 30 °C and stirred for 30 minutes. The reaction mass was concentrated under vacuum until 25 volumes remained in the reactor. The mass was washed with toluene (4.0 L) and extracted with ethylacetate (8.0 Lx2 and 4.0 Lx4) and the ethylacetate layer washed with water (2.0 Lx2) The organic layer was concentrated under vacuum until 2 volumes remained in the reactor then the crude mass was stripped off with ethylacetate (3.0 l_x2) and with DMF (1 .4 L). Tosyl-THF (0.634 Kg) and DMF (0.20 L) were charged into the reactor and the resulted mass was stirred for 30 minutes at 30 °C. Cesium carbonate lot 1 (0.57 Kg) was added to the reaction mass. Reaction mass was heated to 45 °C and stirred for 2 hours at 45 °C. Cesium carbonate lot 2 (0.57 Kg) was added to the reaction mass and the reaction mass was stirred for 2 hours. Cesium carbonate
lot 3 (0.57 Kg) was added to the reaction mass the reaction mass was stirred for 20 hours at 45 °C. The reaction mass was cooled to 30 °C and water (4.0 L) was added to the mass and stirred for 30 minutes. Layers were separated and the aqueous layer was washed with toluene (4.0 L). The aqueous layer was concentrated at 70 °C under vacuum until 1 .0 volume remained in the reactor. The concentrated mass was cooled to 30 °C and water (10.0 L) and acetonitrile 1 .0 L) were charged into the reactor at 30 °C and the resulted mixture was heated to 45 °C and the mixture was stirred for 6 hours at 45 °C. The suspension was cooled to 25 °C and stirred for 7 hours at 25 °C. The precipitation was filtered and the wet solid was washed with water (3.0L) and the solid was suck dried. The wet compound and DMF (1 .0 L) were charged into another reactor and the solution was heated to 45 °C. Acetonitrile (1 .0 L) charged followed by water (10.0 L) into the reactor at 45 °C and stirred for 6 hours. The suspension was cooled to 25 °C and stirred for 6 hours. The precipitation was fileted and the wet cake was washed with water. The wet material was suck dried. The wet material was dried under vacuum at 60 °C for 6 hours to yield 0.55 Kg of crystalline empagliflozin. Purity by HPLC 99%.
Ex mple 37: Purification of Empagliflozin
Empagliflozin (crude)
Empaglilfozin (pure)
Empagliflozin (75 g), acetonitrile (1500 ml_) and water (15 ml_) were charged into a round bottom flask and the resulted mixture was heated to 75 °C and stirred for 30 minutes to form clear solution. L-proline lot 1 (19.2 g) was charged into the flask and stirred for 2 hours at 75 °C. L-proline lot 2 (19.2 g) was charged into the flask and stirred
for 6 hours at 75 °C. Reaction mass was cooled to 25 °C and stirred for 6 hours. The precipitation was filtered and suck dried for 30 minutes. The wet solid was washed with acetonitrile (375 mL) and suck dried for 2 hours. The wet compound was dried under vacuum at 65 °C for 4 hours. The dry compound was charged into a round bottom flask and acetonitrile (337 mL) and water (225 mL) were added to the flask and stirred for 20 minutes to get clear solution. The reaction mass was heated to 45 °C and stirred for 1 hour. Water (900 mL) was charged into the flask slowly over a period of 30 minutes. The reaction mass was cooled to 25 °C and stirred for 10 hours. The precipitation was filtered and the wet material suck dried for 30 minutes. The wet material was washed with water (225 mLx 2) and suck dried for 30 minutes. The wet material was charged into a round bottom flask. Methanol (300 ml) and water (45 mL) was added and the mass was heated to 50 °C to form clear solution. Water (1200 mL) was added to the clear solution and stirred the mass at 60 °C for 3 hours. Solid was isolated. The precipitation was cooled to 25 °C and stirred for 8 hours. The precipitation was filtered and suck dried for 30 minutes. The wet material was washed with water (225 mL) and suck dried for 30 minutes. The wet material was dried under vacuum at 65 °C for 6 hours to get 64 g of crystalline empagliflozin. Purity by HPLC: 99.8%.
Ex mple 38: Purification of Empagliflozin
Empagl oz n crude
Empaglilfozin (pure)
Empagliflozin (75 g), acetonitrile (1500 mL) and water (15 mL) were charged into a round bottom flask and the resulted mixture was heated to 75 °C and stirred for 30 minutes to form clear solution. L-proline lot 1 (19.2 g) was charged into the flask and
stirred for 2 hours at 75 °C. L-proline lot 2 (19.2 g) was charged into the flask and stirred for 6 hours at 75 °C. Reaction mass was cooled to 25 °C and stirred for 6 hours. The precipitation was filtered and suck dried for 30 minutes. The wet solid was washed with acetonitrile (375 mL) and suck dried for 2 hours. The wet compound was dried under vacuum at 65 °C for 4 hours. The dry compound was charged into a round bottom flask and DMF (200 mL) and water (200 mL) were added to the flask and stirred for 20 minutes to get clear solution. The clear solution was filtered through a micron filter to get a particle free clear solution. The reaction mass was heated to 55 °C and stirred for 1 hour. Water (600 mL) was charged into the flask slowly over a period of 30 minutes. The reaction mass was cooled to 25 °C and stirred for 3 hours. The precipitation was filtered and the wet material suck dried for 30 minutes. The wet material was washed with water (500 mL) and suck dried for 30 minutes. The wet material was charged into a round bottom flask. Methanol (300 ml) and water (45 mL) was added and the mass was heated to 50 °C to form clear solution. Water (1200 mL) was added to the clear solution and stirred the mass at 60 °C for 3 hours. Solid was isolated. The precipitation was cooled to 25 °C and stirred for 8 hours. The precipitation was filtered and suck dried for 30 minutes. The wet material was washed with water (225 mL) and suck dried for 30 minutes. The wet material was dried under vacuum at 65 °C for 6 hours to get 65 g of crystalline empagliflozin. Purity by HPLC: 99.8%.
Claims
1 . A process for preparing crystalline form of empagliflozin characterized by PXRD peaks at about 18.84°, 20.36°, and 25.21 ° 2 theta, comprising;
a) providing a solution of empagliflozin in a solvent or a mixture of solvents; b) heating the solution to a temperature higher than the temperature at which the solution is prepared;
c) adding an anti-solvent to the hot solution of step (b); and
d) isolating crystalline form of empagliflozin characterized by PXRD peaks at 18.84°, 20.36°, and 25.21 ° 2 theta.
2. The process of claim 1 , wherein the solvent is selected from the group comprising methanol, ethanol, isopropanol, tetrahydrofuran, acetone, acetonitrile, water and mixtures thereof.
3. The process of claim 1 , wherein the solvent is methanol.
4. The process of claim 1 , wherein the anti-solvent is water.
5. A complex of empagliflozin with L-proline, characterized by an X-Ray Powder Diffraction (XRPD) pattern having peaks at about 4.36 ± 0.2, 12.97 ± 0.2, 15.67 ± 0.2 and 18.80 ± 0.2 °2Θ.
6. A process for preparation of empagliflozin L-proline complex, characterized by an X- Ray Powder Diffraction (XRPD) pattern having peaks at about 4.36 ± 0.2, 12.97 ± 0.2, 15.67 ± 0.2 and 18.80 ± 0.2 °2Θ, comprising:
(a) mixing empagliflozin, L-proline and a mixture of isopropanol and water;
(b) optionally, heating the mixture obtained in step (a);
(c) adding methyl tertiary butyl ether (MTBE) to the mixture; and
(d) isolating the empagliflozin L-proline complex characterized by an X-Ray Powder Diffraction (XRPD) pattern having peaks at about 4.36 ± 0.2, 12.97 ± 0.2, 15.67 ± 0.2 and 18.80 ± 0.2 °2Θ.
7. A process for purification of empagliflozin, comprising:
(a) providing a solution of empagliflozin L-proline complex, characterized by an X-Ray Powder Diffraction (XRPD) pattern having peaks at about 4.36 ± 0.2, 12.97 ± 0.2, 15.67 ± 0.2 and 18.80 ± 0.2 °2Θ in a mixture of organic solvent and water;
(b) optionally heating the solution obtained in step (a);
(c) separating the organic layer from the mixture obtained in step (b); and
(d) isolating pure empagliflozin from the organic layer of step (c).
8. Amorphous empagliflozin having a glass transition onset temperature of at least 60 °C or above.
9. A process for preparation of amorphous empagliflozin having a glass transition onset temperature of at least 60 °C or above, comprising:
a) providing a solution of empagliflozin in a solvent or a mixture of solvents; b) removing solvent from the solution obtained in step (a); and
c) recovering amorphous empagliflozin having a glass transition onset temperature of at least 60 °C or above.
10. The process of claim 9, wherein the solvent is selected from the group comprising methanol, ethanol, isopropanol, n-propanol, tert-butanol, tetrahydrofuran, acetone, acetonitrile, dichloromethane, water and mixtures thereof.
1 1 . Amorphous solid dispersion of empagliflozin, having a glass transition onset temperature of at least 55 °C or above, comprising empagliflozin and one or more pharmaceutically acceptable carriers.
12. The amorphous solid dispersion of empagliflozin of claim 1 1 , wherein the pharmaceutically acceptable carrier is selected from the group comprising pregelatinized starch, lactose, powdered cellulose, microcrystalline cellulose, dicalcium phosphate, tricalcium phosphate, Copovidone, Soluplus, Silicified microcrystalline cellulose, mannitol, sorbitol, acacia, guar gum, tragacanth, gelatin, polyvinylpyrrolidone, hydroxymethyl celluloses, ethylcellulose, methylcellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, HPMC-Phthalate, HPMC-AS, HPMC-15 CPS, sodium starch glycolate, crospovidone, croscarmellose sodium, colloidal silicon dioxide stearic acid, magnesium stearate, zinc stearate, colloidal silicon dioxide and mixtures thereof.
13. The amorphous solid dispersion of empagliflozin of claim 1 1 , wherein the pharmaceutically acceptable carrier is selected from the group comprising hydroxypropyl methylcellulose, hydroxypropyl methylcellulose phthalate (HPMC- Phthalate), methyl cellulose and Copovidone.
14. The amorphous solid dispersion of empagliflozin of claim 1 1 , wherein the pharmaceutically acceptable carrier is Copovidone.
15. The amorphous solid dispersion of empagliflozin of claim 1 1 , wherein the pharmaceutically acceptable carrier is hydroxypropyl methylcellulose phthalate (HPMC- Phthalate).
16. A process for preparation of (R)-tetrahydrofuran-3-yl-4-methylbenzenesulfonate having greater than about 99.8% of chiral purity, comprising
(a) reacting (R)-tetrahydrofuran-3-ol with 4-methylbenzene-1 -sulfonyl chloride in presence of pyridine
(b) slurrying the crude compound (R)-tetrahydrofuran-3-yl-4-methyl benzenesulfonate with a mixture of ethylacetate and cyclohexane, and
(c) isolating the (R)-tetrahydrofuran-3-yl-4-methylbenzenesulfonate having chiral purity of greater than about 99.8%.
17. A process for preparation of empagliflozin having greater than about 99.8% of chiral purity, comprising:
(a) slurrying the crude compound (R)-tetrahydrofuran-3-yl-4-methyl benzenesulfonate with a mixture of ethylacetate and cyclohexane to get (R)- tetrahydrofuran-3-yl-4-methylbenzenesulfonate having chiral purity of greater than about 99.8%, and
(b) reacting the (R)-tetrahydrofuran-3-yl-4-methylbenzenesulfonate having greater than about 99.8% of chiral purity with (1 R,2R,3S,6R)-4-(4-chloro-3-(4- hydroxybenzyl)phenyl)-6-(hydroxymethyl)cyclohexane-1 ,2,3-triol in presence of a base.
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KR102207319B1 (en) * | 2020-03-23 | 2021-01-25 | 유니셀랩 주식회사 | New Empagliflozin cocrystal |
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WO2021123165A1 (en) | 2019-12-19 | 2021-06-24 | Krka, D.D., Novo Mesto | Dosage form comprising amorphous solid solution of empagliflozin with polymer |
WO2022065895A1 (en) * | 2020-09-24 | 2022-03-31 | 동아에스티 주식회사 | Novel salt of empagliflozin derivative, which is sglt-2 inhibitor, and hydrate of salt |
WO2024062310A1 (en) * | 2022-09-22 | 2024-03-28 | Savoi Guilherme | Co-crystals derived from empagliflozin and dapagliflozin with l-proline |
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