WO2022144926A1 - Process for the preparation of amorphous n-{(2s)-1-[3-(3-chloro-4-cyanophenyl)-1h-pyrazol-1-yl]propan-2-yl}-5-(1-hydroxyethyl)-1h-pyrazole-3-carboxamide - Google Patents
Process for the preparation of amorphous n-{(2s)-1-[3-(3-chloro-4-cyanophenyl)-1h-pyrazol-1-yl]propan-2-yl}-5-(1-hydroxyethyl)-1h-pyrazole-3-carboxamide Download PDFInfo
- Publication number
- WO2022144926A1 WO2022144926A1 PCT/IN2021/051220 IN2021051220W WO2022144926A1 WO 2022144926 A1 WO2022144926 A1 WO 2022144926A1 IN 2021051220 W IN2021051220 W IN 2021051220W WO 2022144926 A1 WO2022144926 A1 WO 2022144926A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- darolutamide
- mixture
- formula
- ssa
- surface area
- Prior art date
Links
- BLIJXOOIHRSQRB-PXYINDEMSA-N n-[(2s)-1-[3-(3-chloro-4-cyanophenyl)pyrazol-1-yl]propan-2-yl]-5-(1-hydroxyethyl)-1h-pyrazole-3-carboxamide Chemical compound C([C@H](C)NC(=O)C=1NN=C(C=1)C(C)O)N(N=1)C=CC=1C1=CC=C(C#N)C(Cl)=C1 BLIJXOOIHRSQRB-PXYINDEMSA-N 0.000 title claims abstract description 88
- 238000000034 method Methods 0.000 title claims abstract description 44
- 230000008569 process Effects 0.000 title claims abstract description 33
- 238000002360 preparation method Methods 0.000 title claims abstract description 22
- 229950001379 darolutamide Drugs 0.000 claims description 82
- 239000000203 mixture Substances 0.000 claims description 54
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 51
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 24
- 239000002904 solvent Substances 0.000 claims description 22
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 13
- 239000008194 pharmaceutical composition Substances 0.000 claims description 6
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 5
- 239000003759 ester based solvent Substances 0.000 claims description 2
- 239000005456 alcohol based solvent Substances 0.000 claims 1
- 239000003937 drug carrier Substances 0.000 claims 1
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 39
- 239000002245 particle Substances 0.000 description 20
- 239000007787 solid Substances 0.000 description 20
- 150000001875 compounds Chemical class 0.000 description 18
- 229940093499 ethyl acetate Drugs 0.000 description 13
- 235000019439 ethyl acetate Nutrition 0.000 description 13
- 239000000243 solution Substances 0.000 description 12
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 10
- 238000001035 drying Methods 0.000 description 8
- 239000007921 spray Substances 0.000 description 8
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 6
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 6
- MTHSVFCYNBDYFN-UHFFFAOYSA-N diethylene glycol Chemical compound OCCOCCO MTHSVFCYNBDYFN-UHFFFAOYSA-N 0.000 description 6
- 239000003814 drug Substances 0.000 description 6
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 5
- 238000004458 analytical method Methods 0.000 description 5
- 238000004090 dissolution Methods 0.000 description 5
- 229940079593 drug Drugs 0.000 description 5
- 238000001914 filtration Methods 0.000 description 5
- 238000004128 high performance liquid chromatography Methods 0.000 description 5
- 229910052757 nitrogen Inorganic materials 0.000 description 5
- 238000000634 powder X-ray diffraction Methods 0.000 description 5
- 238000001144 powder X-ray diffraction data Methods 0.000 description 5
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 4
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 4
- 238000003801 milling Methods 0.000 description 4
- ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-Butanone Chemical compound CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 description 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 3
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- WVDDGKGOMKODPV-UHFFFAOYSA-N Benzyl alcohol Chemical compound OCC1=CC=CC=C1 WVDDGKGOMKODPV-UHFFFAOYSA-N 0.000 description 3
- XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 description 3
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 3
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 3
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- 239000008186 active pharmaceutical agent Substances 0.000 description 3
- 229910052799 carbon Inorganic materials 0.000 description 3
- 229940088679 drug related substance Drugs 0.000 description 3
- GMBPVBVTPBWIKC-NSHDSACASA-N 3-acetyl-n-[(2s)-1-[3-(3-chloro-4-cyanophenyl)pyrazol-1-yl]propan-2-yl]-1h-pyrazole-5-carboxamide Chemical compound C([C@H](C)NC(=O)C=1NN=C(C=1)C(C)=O)N(N=1)C=CC=1C1=CC=C(C#N)C(Cl)=C1 GMBPVBVTPBWIKC-NSHDSACASA-N 0.000 description 2
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 2
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 description 2
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 description 2
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 description 2
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 description 2
- URLKBWYHVLBVBO-UHFFFAOYSA-N Para-Xylene Chemical group CC1=CC=C(C)C=C1 URLKBWYHVLBVBO-UHFFFAOYSA-N 0.000 description 2
- OFBQJSOFQDEBGM-UHFFFAOYSA-N Pentane Chemical compound CCCCC OFBQJSOFQDEBGM-UHFFFAOYSA-N 0.000 description 2
- 206010060862 Prostate cancer Diseases 0.000 description 2
- 208000000236 Prostatic Neoplasms Diseases 0.000 description 2
- DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 description 2
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 2
- 238000002441 X-ray diffraction Methods 0.000 description 2
- RDOXTESZEPMUJZ-UHFFFAOYSA-N anisole Chemical compound COC1=CC=CC=C1 RDOXTESZEPMUJZ-UHFFFAOYSA-N 0.000 description 2
- 238000000498 ball milling Methods 0.000 description 2
- DKPFZGUDAPQIHT-UHFFFAOYSA-N butyl acetate Chemical compound CCCCOC(C)=O DKPFZGUDAPQIHT-UHFFFAOYSA-N 0.000 description 2
- 238000005119 centrifugation Methods 0.000 description 2
- 125000001309 chloro group Chemical group Cl* 0.000 description 2
- DMEGYFMYUHOHGS-UHFFFAOYSA-N cycloheptane Chemical compound C1CCCCCC1 DMEGYFMYUHOHGS-UHFFFAOYSA-N 0.000 description 2
- 238000010908 decantation Methods 0.000 description 2
- 229940126534 drug product Drugs 0.000 description 2
- 230000005484 gravity Effects 0.000 description 2
- 238000003621 hammer milling Methods 0.000 description 2
- 238000010438 heat treatment Methods 0.000 description 2
- ZXEKIIBDNHEJCQ-UHFFFAOYSA-N isobutanol Chemical compound CC(C)CO ZXEKIIBDNHEJCQ-UHFFFAOYSA-N 0.000 description 2
- IVSZLXZYQVIEFR-UHFFFAOYSA-N m-xylene Chemical compound CC1=CC=CC(C)=C1 IVSZLXZYQVIEFR-UHFFFAOYSA-N 0.000 description 2
- UAEPNZWRGJTJPN-UHFFFAOYSA-N methylcyclohexane Chemical compound CC1CCCCC1 UAEPNZWRGJTJPN-UHFFFAOYSA-N 0.000 description 2
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 2
- KPSSIOMAKSHJJG-UHFFFAOYSA-N neopentyl alcohol Chemical compound CC(C)(C)CO KPSSIOMAKSHJJG-UHFFFAOYSA-N 0.000 description 2
- AQIXEPGDORPWBJ-UHFFFAOYSA-N pentan-3-ol Chemical compound CCC(O)CC AQIXEPGDORPWBJ-UHFFFAOYSA-N 0.000 description 2
- 239000000825 pharmaceutical preparation Substances 0.000 description 2
- 230000000704 physical effect Effects 0.000 description 2
- 239000000843 powder Substances 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 description 2
- 238000010992 reflux Methods 0.000 description 2
- 239000002002 slurry Substances 0.000 description 2
- 229910000033 sodium borohydride Inorganic materials 0.000 description 2
- 239000012279 sodium borohydride Substances 0.000 description 2
- 238000001179 sorption measurement Methods 0.000 description 2
- VZGDMQKNWNREIO-UHFFFAOYSA-N tetrachloromethane Chemical compound ClC(Cl)(Cl)Cl VZGDMQKNWNREIO-UHFFFAOYSA-N 0.000 description 2
- 238000005406 washing Methods 0.000 description 2
- QIVUCLWGARAQIO-OLIXTKCUSA-N (3s)-n-[(3s,5s,6r)-6-methyl-2-oxo-1-(2,2,2-trifluoroethyl)-5-(2,3,6-trifluorophenyl)piperidin-3-yl]-2-oxospiro[1h-pyrrolo[2,3-b]pyridine-3,6'-5,7-dihydrocyclopenta[b]pyridine]-3'-carboxamide Chemical compound C1([C@H]2[C@H](N(C(=O)[C@@H](NC(=O)C=3C=C4C[C@]5(CC4=NC=3)C3=CC=CN=C3NC5=O)C2)CC(F)(F)F)C)=C(F)C=CC(F)=C1F QIVUCLWGARAQIO-OLIXTKCUSA-N 0.000 description 1
- LZDKZFUFMNSQCJ-UHFFFAOYSA-N 1,2-diethoxyethane Chemical compound CCOCCOCC LZDKZFUFMNSQCJ-UHFFFAOYSA-N 0.000 description 1
- VDFVNEFVBPFDSB-UHFFFAOYSA-N 1,3-dioxane Chemical compound C1COCOC1 VDFVNEFVBPFDSB-UHFFFAOYSA-N 0.000 description 1
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 1
- RRQYJINTUHWNHW-UHFFFAOYSA-N 1-ethoxy-2-(2-ethoxyethoxy)ethane Chemical compound CCOCCOCCOCC RRQYJINTUHWNHW-UHFFFAOYSA-N 0.000 description 1
- XNWFRZJHXBZDAG-UHFFFAOYSA-N 2-METHOXYETHANOL Chemical compound COCCO XNWFRZJHXBZDAG-UHFFFAOYSA-N 0.000 description 1
- OFUMROLKEGKJMS-UHFFFAOYSA-N 2-[2-(1,3-benzodioxol-5-yl)-3-[2-(cyclohexylamino)pyrimidin-4-yl]imidazol-4-yl]acetonitrile Chemical compound O1COC2=C1C=CC(=C2)C=1N(C(=CN=1)CC#N)C1=NC(=NC=C1)NC1CCCCC1 OFUMROLKEGKJMS-UHFFFAOYSA-N 0.000 description 1
- ZNQVEEAIQZEUHB-UHFFFAOYSA-N 2-ethoxyethanol Chemical compound CCOCCO ZNQVEEAIQZEUHB-UHFFFAOYSA-N 0.000 description 1
- 229940093475 2-ethoxyethanol Drugs 0.000 description 1
- GGDYAKVUZMZKRV-UHFFFAOYSA-N 2-fluoroethanol Chemical compound OCCF GGDYAKVUZMZKRV-UHFFFAOYSA-N 0.000 description 1
- MSXVEPNJUHWQHW-UHFFFAOYSA-N 2-methylbutan-2-ol Chemical compound CCC(C)(C)O MSXVEPNJUHWQHW-UHFFFAOYSA-N 0.000 description 1
- KIPMDPDAFINLIV-UHFFFAOYSA-N 2-nitroethanol Chemical compound OCC[N+]([O-])=O KIPMDPDAFINLIV-UHFFFAOYSA-N 0.000 description 1
- SJVGFKBLUYAEOK-SFHVURJKSA-N 6-[4-[(3S)-3-(3,5-difluorophenyl)-3,4-dihydropyrazole-2-carbonyl]piperidin-1-yl]pyrimidine-4-carbonitrile Chemical compound FC=1C=C(C=C(C=1)F)[C@@H]1CC=NN1C(=O)C1CCN(CC1)C1=CC(=NC=N1)C#N SJVGFKBLUYAEOK-SFHVURJKSA-N 0.000 description 1
- 239000004215 Carbon black (E152) Substances 0.000 description 1
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 description 1
- -1 Darolutamide compound Chemical class 0.000 description 1
- 238000004566 IR spectroscopy Methods 0.000 description 1
- NTIZESTWPVYFNL-UHFFFAOYSA-N Methyl isobutyl ketone Chemical compound CC(C)CC(C)=O NTIZESTWPVYFNL-UHFFFAOYSA-N 0.000 description 1
- UIHCLUNTQKBZGK-UHFFFAOYSA-N Methyl isobutyl ketone Natural products CCC(C)C(C)=O UIHCLUNTQKBZGK-UHFFFAOYSA-N 0.000 description 1
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 1
- AMQJEAYHLZJPGS-UHFFFAOYSA-N N-Pentanol Chemical compound CCCCCO AMQJEAYHLZJPGS-UHFFFAOYSA-N 0.000 description 1
- XBDQKXXYIPTUBI-UHFFFAOYSA-M Propionate Chemical compound CCC([O-])=O XBDQKXXYIPTUBI-UHFFFAOYSA-M 0.000 description 1
- RHQDFWAXVIIEBN-UHFFFAOYSA-N Trifluoroethanol Chemical compound OCC(F)(F)F RHQDFWAXVIIEBN-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
- 230000001476 alcoholic effect Effects 0.000 description 1
- 230000002280 anti-androgenic effect Effects 0.000 description 1
- 239000000051 antiandrogen Substances 0.000 description 1
- 230000008901 benefit Effects 0.000 description 1
- 235000019445 benzyl alcohol Nutrition 0.000 description 1
- 229960000074 biopharmaceutical Drugs 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 230000015556 catabolic process Effects 0.000 description 1
- HRYZWHHZPQKTII-UHFFFAOYSA-N chloroethane Chemical compound CCCl HRYZWHHZPQKTII-UHFFFAOYSA-N 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- HPXRVTGHNJAIIH-UHFFFAOYSA-N cyclohexanol Chemical compound OC1CCCCC1 HPXRVTGHNJAIIH-UHFFFAOYSA-N 0.000 description 1
- 238000006731 degradation reaction Methods 0.000 description 1
- 229940019778 diethylene glycol diethyl ether Drugs 0.000 description 1
- SBZXBUIDTXKZTM-UHFFFAOYSA-N diglyme Chemical compound COCCOCCOC SBZXBUIDTXKZTM-UHFFFAOYSA-N 0.000 description 1
- NKDDWNXOKDWJAK-UHFFFAOYSA-N dimethoxymethane Chemical compound COCOC NKDDWNXOKDWJAK-UHFFFAOYSA-N 0.000 description 1
- 239000006185 dispersion Substances 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- 238000012377 drug delivery Methods 0.000 description 1
- 239000000839 emulsion Substances 0.000 description 1
- 239000004210 ether based solvent Substances 0.000 description 1
- 229960003750 ethyl chloride Drugs 0.000 description 1
- JBTWLSYIZRCDFO-UHFFFAOYSA-N ethyl methyl carbonate Chemical compound CCOC(=O)OC JBTWLSYIZRCDFO-UHFFFAOYSA-N 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 239000007789 gas Substances 0.000 description 1
- 239000008187 granular material Substances 0.000 description 1
- 230000036541 health Effects 0.000 description 1
- 229930195733 hydrocarbon Natural products 0.000 description 1
- 150000002430 hydrocarbons Chemical class 0.000 description 1
- 239000012535 impurity Substances 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- LRDFRRGEGBBSRN-UHFFFAOYSA-N isobutyronitrile Chemical compound CC(C)C#N LRDFRRGEGBBSRN-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
- 239000005453 ketone based solvent Substances 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 238000002844 melting Methods 0.000 description 1
- 230000008018 melting Effects 0.000 description 1
- GBMDVOWEEQVZKZ-UHFFFAOYSA-N methanol;hydrate Chemical compound O.OC GBMDVOWEEQVZKZ-UHFFFAOYSA-N 0.000 description 1
- UZKWTJUDCOPSNM-UHFFFAOYSA-N methoxybenzene Substances CCCCOC=C UZKWTJUDCOPSNM-UHFFFAOYSA-N 0.000 description 1
- 229940043265 methyl isobutyl ketone Drugs 0.000 description 1
- GYNNXHKOJHMOHS-UHFFFAOYSA-N methyl-cycloheptane Natural products CC1CCCCCC1 GYNNXHKOJHMOHS-UHFFFAOYSA-N 0.000 description 1
- VOVZXURTCKPRDQ-CQSZACIVSA-N n-[4-[chloro(difluoro)methoxy]phenyl]-6-[(3r)-3-hydroxypyrrolidin-1-yl]-5-(1h-pyrazol-5-yl)pyridine-3-carboxamide Chemical compound C1[C@H](O)CCN1C1=NC=C(C(=O)NC=2C=CC(OC(F)(F)Cl)=CC=2)C=C1C1=CC=NN1 VOVZXURTCKPRDQ-CQSZACIVSA-N 0.000 description 1
- 150000002825 nitriles Chemical class 0.000 description 1
- 230000000683 nonmetastatic effect Effects 0.000 description 1
- XULSCZPZVQIMFM-IPZQJPLYSA-N odevixibat Chemical compound C12=CC(SC)=C(OCC(=O)N[C@@H](C(=O)N[C@@H](CC)C(O)=O)C=3C=CC(O)=CC=3)C=C2S(=O)(=O)NC(CCCC)(CCCC)CN1C1=CC=CC=C1 XULSCZPZVQIMFM-IPZQJPLYSA-N 0.000 description 1
- 238000007415 particle size distribution analysis Methods 0.000 description 1
- 238000010951 particle size reduction Methods 0.000 description 1
- JYVLIDXNZAXMDK-UHFFFAOYSA-N pentan-2-ol Chemical compound CCCC(C)O JYVLIDXNZAXMDK-UHFFFAOYSA-N 0.000 description 1
- 230000035699 permeability Effects 0.000 description 1
- 239000006187 pill Substances 0.000 description 1
- 239000003880 polar aprotic solvent Substances 0.000 description 1
- 239000002798 polar solvent Substances 0.000 description 1
- FVSKHRXBFJPNKK-UHFFFAOYSA-N propionitrile Chemical compound CCC#N FVSKHRXBFJPNKK-UHFFFAOYSA-N 0.000 description 1
- 230000005855 radiation Effects 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 238000004611 spectroscopical analysis Methods 0.000 description 1
- 238000001694 spray drying Methods 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
- ZSDSQXJSNMTJDA-UHFFFAOYSA-N trifluralin Chemical compound CCCN(CCC)C1=C([N+]([O-])=O)C=C(C(F)(F)F)C=C1[N+]([O-])=O ZSDSQXJSNMTJDA-UHFFFAOYSA-N 0.000 description 1
- YFNKIDBQEZZDLK-UHFFFAOYSA-N triglyme Chemical compound COCCOCCOCCOC YFNKIDBQEZZDLK-UHFFFAOYSA-N 0.000 description 1
- KMIOJWCYOHBUJS-HAKPAVFJSA-N vorolanib Chemical compound C1N(C(=O)N(C)C)CC[C@@H]1NC(=O)C1=C(C)NC(\C=C/2C3=CC(F)=CC=C3NC\2=O)=C1C KMIOJWCYOHBUJS-HAKPAVFJSA-N 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
- C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
- C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D231/14—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three 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
Definitions
- the present invention relates to amorphous form of N- ⁇ (2S)-l-[3-(3-chloro-4- cyanophenyl)-lH-pyrazol-l-yl]propan-2-yl ⁇ -5-(l-hydroxyethyl)-lH-pyrazole-3-carboxamide of formula- 1, having specific surface area (SSA) in a range from about 0.1 to 10 m 2 /g and process for preparation of amorphous form of formula- 1.
- SSA specific surface area
- Darolutamide is chemically known as N- ⁇ (2S)-l-[3-(3-chloro-4-cyanophenyl)-lH- pyrazol-l-yl]propan-2-yl ⁇ -5-(l-hydroxyethyl)-lH-pyrazole-3-carboxamide of formula- 1.
- Darolutamide was developed by Orion Corporation and Bayer Health Care. It is an anti-androgen medication which is used in the treatment of prostate cancer in men. It was approved by USFDA in July 2019, approved to treat non-metastatic castration-resistant prostate cancer (nmCRPC) in conjunction with surgical or medical castration.
- nmCRPC non-metastatic castration-resistant prostate cancer
- US8975254 B2 discloses N- ⁇ (2S)-l-[3-(3-chloro-4-cyanophenyl)-lH-pyrazol-l-yl] propan-2-yl ⁇ -5-(l-hydroxyethyl)-lH-pyrazole-3-carboxamide and process for its preparation.
- US 11168058 B2 discloses crystalline particles of N- ⁇ (2S)-l-[3-(3-chloro-4- cyanophenyl)-lH-pyrazol-l-yl]propan-2-yl ⁇ -5-(l-hydroxyethyl)-lH-pyrazole-3-carboxamide having a specific surface area (SSA) in a range from about 8 to 16 m 2 /g.
- SSA specific surface area
- Polymorphism is the occurrence of different crystalline forms of a single compound and it is a property of some compounds and complexes. Thus, polymorphs are distinct solids sharing the same molecular formula, yet each polymorph may have distinct physical properties. Therefore, a single compound may give rise to a variety of polymorphic forms where each form has different and distinct physical properties, such as different solubility profiles, different melting point temperatures and/or different x-ray diffraction peaks. Since the solubility of each polymorph may vary, identifying the existence of pharmaceutical polymorphs is essential for providing pharmaceuticals with predicable solubility profiles. It is desirable to investigate all solid state forms of a drug, including all polymorphic forms, and to determine the stability, dissolution and flow properties of each polymorphic form.
- Polymorphic forms of a compound can be distinguished in a laboratory by X-ray diffraction spectroscopy and by other methods such as, infrared spectrometry. Additionally, polymorphic forms of the same drug substance or active pharmaceutical ingredient, can be administered by itself or formulated as a drug product (also known as the final or finished dosage form), and are well known in the pharmaceutical art to affect, for example, the solubility, stability, flowability, tractability and compressibility of drug substances and the safety and efficacy of drug products.
- Darolutamide Due to its low solubility and high permeability, Darolutamide can be put into class II of the Biopharmaceutical Classification System (BCS).
- BCS Biopharmaceutical Classification System
- the dissolution rate is the limiting factor during drug absorption. Enhancement of bioavailability of poorly soluble drugs is routinely attempted by micronization. Micronization, i.e. reduction of particle size to the range of only few micrometers, typically increases the dissolution rate of the poorly soluble drug through increased specific surface area (SSA).
- SSA specific surface area
- the object of the present invention is to provide amorphous Darolutamide which is having powder properties allowing straightforward pharmaceutical processing, high dissolution rate and consequently improved bioavailability.
- Another object of the present invention is to provide particles of Darolutamide with lower sticking tendency during processing and better flow properties.
- the present invention provides amorphous form of Darolutamide of formula- 1, having specific surface area (SSA) in a range from about 0.1 to about 10 m 2 /g and process for the preparation of such form.
- SSA specific surface area
- the present invention also provides crystalline form of Darolutamide of formula- 1, having specific surface area (SSA) in a range from about 17 to about 40 m 2 /g and process for the preparation of such form.
- SSA specific surface area
- Figure-1 Illustrates the PXRD pattern of amorphous Darolutamide.
- Figure-2 Illustrates the PXRD pattern of crystalline Darolutamide.
- suitable solvent refers to “hydrocarbon solvents” such as n-hexane, n-heptane, cyclohexane, pet ether, toluene, pentane, cycloheptane, methyl cyclohexane, m-, o-, or p-xylene, and the like; “ether solvents” such as dimethoxy methane, tetrahydrofuran, 1,3-dioxane, 1,4-dioxane, diethyl ether, ethylene glycol dimethyl ether, ethylene glycol diethyl ether, diethylene glycol dimethyl ether, diethylene glycol diethyl ether, triethylene glycol dimethyl ether, anisole, t-butyl methyl ether, dimethoxy ethane and the like; “ester solvents” such as methyl acetate, ethyl acetate, is
- enantiopure as used herein means that a compound has an enantiomeric excess of at least 80%, preferably at least 90%, more preferably at least 95%, even more preferably at least 99%.
- the present invention provides a process for the preparation of amorphous form of Darolutamide of formula- 1, which comprises: a) providing a solution of Darolutamide in a solvent, b) isolating amorphous form of Darolutamide of formula- 1.
- the solvent used in step-a) is selected from alcohol solvent, chloro solvent and /or mixture thereof.
- providing a solution of Darolutamide is carried out by suspending or dissolving Darolutamide in a solvent.
- providing a solution of Darolutamide is optionally by heating the mixture to a suitable temperature ranging from ambient temperature to reflux temperature of the solvent used.
- the solution is filtered to make it particle free.
- isolating amorphous form of Darolutamide is carried out by employing any of the techniques, but not limited to decantation, spray drying, 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 resulting amorphous form of Darolutamide can be dried by techniques such as tray dryer, vacuum oven, rotatory cone dryer, air oven, fluidized bed dryer, spin flash dryer, flash dryer, or the like.
- the drying is 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 is carried out for any time period required for obtaining a desired quality, such as from about 15 minutes to 10 hours or longer.
- the present invention provides amorphous form of Darolutamide having specific surface area (SSA) of about 0.1 to about 10 m 2 /g.
- SSA specific surface area
- the present invention provides amorphous form of Darolutamide, which is characterized by its X-ray powder diffraction (XRD) pattern as illustrated in Figure- 1.
- XRD X-ray powder diffraction
- the present invention provides amorphous form of Darolutamide prepared according to the present invention is having purity of about 99.9%; preferably about 99.95%; more preferably about 99.97% as measured by HPLC.
- the present invention provides amorphous form of Darolutamide having specific surface area (SSA) in the range from about 0.1 to about 100 m 2 /g or from about 0.1 to about 50 m 2 /g or from about 0.1 to about 10 m 2 /g or from about 0.1 to about 5 m 2 /g or from about 0.1 to about 4 m 2 /g or from about 0.1 to about 3 m 2 /g.
- SSA specific surface area
- the present invention provides amorphous form of Darolutamide having specific surface area (SSA) in the range from about 0.5 to about 100 m 2 /g or from about 0.5 to about 50 m 2 /g or from about 0.5 to about 10 m 2 /g or from about 0.5 to about 5 m 2 /g or from about 0.5 to about 4 m 2 /g or from about 0.5 to about 3 m 2 /g.
- SSA specific surface area
- the present invention provides amorphous form of Darolutamide having volume median diameter (Dv50) between 0.1-1000 pm, preferably between 0.1-100 pm, more preferably between 0.1-50 pm, in particular between 0.5-25 pm.
- Dv90 is between 0.1-1000 pm, preferably between 0.1-100 pm, more preferably between 0.1- 50 pm, in particular between 1-50 pm.
- the present invention provides Darolutamide having specific surface area (SSA) in the range from about 0.5 to about 100 m 2 /g or from about 0.5 to about 50 m 2 /g or from about 0.5 to about 10 m 2 /g or from about 0.5 to about 5 m 2 /g or from about 0.5 to about 4 m 2 /g or from about 0.5 to about 3 m 2 /g.
- SSA specific surface area
- the present invention provides Darolutamide having volume median diameter (Dv50) between 0.1-1000 pm, preferably between 0.1-100 pm, more preferably between 0.1-50 pm, in particular between 0.5-25 pm.
- Dv90 is between 0.1-1000 pm, preferably between 0.1-100 pm, more preferably between 0.1-50 pm, in particular between 1-50 pm.
- the present invention provides a pharmaceutical composition comprising amorphous form of Darolutamide compound of formula- 1 and one or more pharmaceutically acceptable excipients.
- the present invention provides a process for the preparation of Crystalline form of Darolutamide of formula- 1, which comprises: a) providing a solution of Darolutamide in a solvent, b) isolating crystalline form of Darolutamide of formula- 1.
- the solvent used in step-a) is selected from alcohol solvent, ester solvent, water and /or mixture thereof.
- providing a solution of Darolutamide is carried out by suspending or dissolving Darolutamide in a solvent.
- providing a solution of Darolutamide is optionally by heating the mixture to a suitable temperature ranging from ambient temperature to reflux temperature of the solvent used.
- the solution is filtered to make it particle free.
- isolating Crystalline form of Darolutamide is carried out 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, cooling the mixture to solidify followed by filtration, or other techniques specific to the equipment used and the like, and optionally washing with a solvent.
- the resulting Crystalline form of Darolutamide can be dried by techniques such as tray dryer, vacuum oven, rotatory cone dryer, air oven, fluidized bed dryer, spin flash dryer, flash dryer, or the like.
- the drying is 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 is carried out for any time period required for obtaining a desired quality, such as from about 15 minutes to 10 hours or longer.
- the present invention provides Crystalline form of Darolutamide having specific surface area (SSA) of about 17 to about 40 m 2 /g, which is characterized by its Specific surface area (SSA) Method of Analysis.
- SSA specific surface area
- the present invention provides Crystalline form of Darolutamide having specific surface area (SSA) of about 0.5 to about 7 m 2 /g, which is obtained by micronization techniques such as ball milling, roller milling and hammer milling, and jet mills. Milling or micronization may be performed before drying, or after the completion of drying of the product.
- SSA specific surface area
- the present invention provides Crystalline form of Darolutamide, which is characterized by its X-ray powder diffraction (XRD) pattern as illustrated in Figure-2.
- XRD X-ray powder diffraction
- the present invention provides Crystalline form of Darolutamide prepared according to the present invention is having purity of about 99.9%; preferably about 99.95%; more preferably about 99.97% as measured by HPLC.
- the present invention provides Crystalline form of Darolutamide having specific surface area (SSA) of about 0.5 m 2 /g or 1 m 2 /g or 2 m 2 /g or 3 m 2 /g or 4 m 2 /g or 5 m 2 /g or 6 m 2 /g or 7 m 2 /g or in the range from about 17 to about 100 m 2 /g or from about 17 to about 50 m 2 /g or from about 17 to about 40 m 2 /g or from about 17 to about 30 m 2 /g or from about 25 to about 35 m 2 /g.
- the present invention provides crystalline form of Darolutamide having volume median diameter (Dv50) between 0.1-100 pm, preferably between 0.1-75 pm, more preferably between 0.1-50 pm, in particular between 1-25 pm.
- Dv50 volume median diameter
- the present invention provides Crystalline form of Darolutamide having volume median diameter Dv90 is between 0.1-1000 pm, preferably between 0.1-100 pm, more preferably between 0.1-50 pm, in particular between 50-100 pm.
- the present invention provides a pharmaceutical composition comprising Crystalline form of Darolutamide prepared according to the present invention and one or more pharmaceutically acceptable excipients and/or earners.
- the excipient can be selected from one or more described in Excipient Development for Pharmaceutical, Biotechnology, and Drug Delivery Systems 2006.
- compositions include tablets, pills, powders, liquids, suspensions, emulsions, granules, capsules, suppositories, or injection preparations.
- the starting material of Darolutamide used in the present invention can be prepared from any of the processes known in the art.
- Darolutamide produced by the present invention can be micronized or milled using conventional techniques to get the desired particle size and surface area to achieve desired solubility profile to suit to pharmaceutical composition requirements.
- Techniques that may be used for particle size reduction include, but not limited to ball milling, roller milling and hammer milling, and jet mills. Milling or micronization may be performed before drying, or after the completion of drying of the product.
- SSA Specific surface area
- Particle size distribution (PSD) analysis was performed using Malvern Mastersizer 2000 instrument.
- Example-2 Preparation of crystalline form-I of Darolutamide.
- the obtained solid was collected from the spray dryer and dried under vacuum to get the title compound.
- Particle size distribution (Dv50): 10.38 pm; (Dv90): 19.26 pm
- the obtained solid was collected from the spray dryer and dried under vacuum to get the title compound.
- Particle size distribution (Dv50): 12.27 pm; (Dv90): 23.80 pm
- Particle size distribution (Dv50): 8.06 pm; (Dv90): 15.11 pm
- Particle size distribution (PSD): (Dv50): 11.63 pm; (Dv90): 76.18 pm
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The present invention relates to amorphous form of N-{(2S)-1-[3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl]propan-2-yl}-5-(1-hydroxyethyl)-1H-pyrazole-3-carboxamide of formula-1, having specific surface area (SSA) in the range from about 0.1 to about 10 m2/g, and process for the preparation of amorphous form of formula-1. Formula-1 The present invention also provides crystalline form of N-{(2S)-1-[3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl]propan-2-yl}-5-(1-hydroxyethyl)-1H-pyrazole-3-carboxamide of formula-1, having specific surface area (SSA) in the range from about 18 to about 40 m2/g, and process for the preparation of crystalline form of formula-1.
Description
Process for the preparation of amorphous N-l(2S)-l-[3-(3-chloro-4-cvanoDhenyl)-lH- pyrazol-l-yl]propan-2-yn-5-(l-hydroxyethyl)-lH-pyrazole-3-carboxamide
Related Application:
This application claims the benefit of priority of our Indian patent applications number 202041057493 filed on 31st December 2020 and 202141000396 filed on 05th January 2021 which are incorporated herein by reference.
Field of the invention:
The present invention relates to amorphous form of N-{(2S)-l-[3-(3-chloro-4- cyanophenyl)-lH-pyrazol-l-yl]propan-2-yl}-5-(l-hydroxyethyl)-lH-pyrazole-3-carboxamide of formula- 1, having specific surface area (SSA) in a range from about 0.1 to 10 m2/g and process for preparation of amorphous form of formula- 1.
Background of the invention:
Darolutamide is chemically known as N-{(2S)-l-[3-(3-chloro-4-cyanophenyl)-lH- pyrazol-l-yl]propan-2-yl}-5-(l-hydroxyethyl)-lH-pyrazole-3-carboxamide of formula- 1.
Darolutamide was developed by Orion Corporation and Bayer Health Care. It is an anti-androgen medication which is used in the treatment of prostate cancer in men. It was approved by USFDA in July 2019, approved to treat non-metastatic castration-resistant prostate cancer (nmCRPC) in conjunction with surgical or medical castration.
US8975254 B2 discloses N-{(2S)-l-[3-(3-chloro-4-cyanophenyl)-lH-pyrazol-l-yl] propan-2-yl}-5-(l-hydroxyethyl)-lH-pyrazole-3-carboxamide and process for its preparation.
US 11168058 B2 discloses crystalline particles of N-{(2S)-l-[3-(3-chloro-4- cyanophenyl)-lH-pyrazol-l-yl]propan-2-yl}-5-(l-hydroxyethyl)-lH-pyrazole-3-carboxamide having a specific surface area (SSA) in a range from about 8 to 16 m2/g.
Polymorphism is the occurrence of different crystalline forms of a single compound and it is a property of some compounds and complexes. Thus, polymorphs are distinct solids
sharing the same molecular formula, yet each polymorph may have distinct physical properties. Therefore, a single compound may give rise to a variety of polymorphic forms where each form has different and distinct physical properties, such as different solubility profiles, different melting point temperatures and/or different x-ray diffraction peaks. Since the solubility of each polymorph may vary, identifying the existence of pharmaceutical polymorphs is essential for providing pharmaceuticals with predicable solubility profiles. It is desirable to investigate all solid state forms of a drug, including all polymorphic forms, and to determine the stability, dissolution and flow properties of each polymorphic form.
Polymorphic forms of a compound can be distinguished in a laboratory by X-ray diffraction spectroscopy and by other methods such as, infrared spectrometry. Additionally, polymorphic forms of the same drug substance or active pharmaceutical ingredient, can be administered by itself or formulated as a drug product (also known as the final or finished dosage form), and are well known in the pharmaceutical art to affect, for example, the solubility, stability, flowability, tractability and compressibility of drug substances and the safety and efficacy of drug products.
Due to its low solubility and high permeability, Darolutamide can be put into class II of the Biopharmaceutical Classification System (BCS). When administering such low soluble substances orally, the dissolution rate is the limiting factor during drug absorption. Enhancement of bioavailability of poorly soluble drugs is routinely attempted by micronization. Micronization, i.e. reduction of particle size to the range of only few micrometers, typically increases the dissolution rate of the poorly soluble drug through increased specific surface area (SSA).
Micronized particles, however, often suffer from poor flow and dispersion properties causing drawbacks in subsequent pharmaceutical processing. Micronization of crystalline forms could introduce impurities in to drug substance and can induce polymorphic changes, cause degradation, and impact bulk density. Hence, there is still a need for improving its dissolution rate and bioavailability. Hence, the object of the present invention is to provide amorphous Darolutamide which is having powder properties allowing straightforward pharmaceutical processing, high dissolution rate and consequently improved bioavailability. Another object of the present invention is to provide particles of Darolutamide with lower sticking tendency during processing and better flow properties.
Brief description of the invention:
The present invention provides amorphous form of Darolutamide of formula- 1,
having specific surface area (SSA) in a range from about 0.1 to about 10 m2/g and process for the preparation of such form.
The present invention also provides crystalline form of Darolutamide of formula- 1, having specific surface area (SSA) in a range from about 17 to about 40 m2/g and process for the preparation of such form.
Brief description of the Drawings:
Figure-1: Illustrates the PXRD pattern of amorphous Darolutamide. Figure-2: Illustrates the PXRD pattern of crystalline Darolutamide.
Detailed description of the Invention:
As used herein the term “suitable solvent” used in the present invention refers to “hydrocarbon solvents” such as n-hexane, n-heptane, cyclohexane, pet ether, toluene, pentane, cycloheptane, methyl cyclohexane, m-, o-, or p-xylene, and the like; “ether solvents” such as dimethoxy methane, tetrahydrofuran, 1,3-dioxane, 1,4-dioxane, diethyl ether, ethylene glycol dimethyl ether, ethylene glycol diethyl ether, diethylene glycol dimethyl ether, diethylene glycol diethyl ether, triethylene glycol dimethyl ether, anisole, t-butyl methyl ether, dimethoxy ethane and the like; “ester solvents” such as methyl acetate, ethyl acetate, isopropyl acetate, n-butyl acetate and the like; “polar-aprotic solvents such as dimethylacetamide (DMA), dimethylformamide (DMF), dimethylsulfoxide (DMSO), N- methylpyrrolidone (NMP) and the like; “chloro solvents” such as dichloromethane, di chloroethane, chloroform, carbon tetrachloride and the like; “ketone solvents” such as acetone, methyl ethyl ketone, methyl isobutylketone and the like; “nitrile solvents” such as acetonitrile, propionitrile, isobutyronitrile and the like; “alcoholic solvents” such as methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, t-butanol, 2-nitroethanol, 2- fluoroethanol, 2,2,2-trifluoroethanol, ethylene glycol, 2 -methoxyethanol, 1,2-ethoxy ethanol, diethylene glycol, 1,2, or 3-pentanol, neo-pentyl alcohol, t-pentyl alcohol, diethylene glycol, monoethyl ether, cyclohexanol, benzyl alcohol or glycerol and the like; “polar solvents” such as water or mixtures thereof.
The term “enantiopure” as used herein means that a compound has an enantiomeric excess of at least 80%, preferably at least 90%, more preferably at least 95%, even more preferably at least 99%.
The term “enantiopure” as used herein means that an enantiomer is present in a purity of at least 99% enantiomeric excess, preferably in a purity of 99.5-100% enantiomeric excess.
In the first embodiment, the present invention provides a process for the preparation of amorphous form of Darolutamide of formula- 1, which comprises: a) providing a solution of Darolutamide in a solvent, b) isolating amorphous form of Darolutamide of formula- 1.
In the process of first embodiment, the solvent used in step-a) is selected from alcohol solvent, chloro solvent and /or mixture thereof.
In the process of first embodiment, providing a solution of Darolutamide is carried out by suspending or dissolving Darolutamide in a solvent.
In the process of first embodiment, providing a solution of Darolutamide is optionally by heating the mixture to a suitable temperature ranging from ambient temperature to reflux temperature of the solvent used. Optionally, the solution is filtered to make it particle free.
In the process of first embodiment, isolating amorphous form of Darolutamide is carried out by employing any of the techniques, but not limited to decantation, spray drying, 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 the process of first embodiment, the resulting amorphous form of Darolutamide can be dried by techniques such as tray dryer, vacuum oven, rotatory cone dryer, air oven, fluidized bed dryer, spin flash dryer, flash dryer, or the like. The drying is 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 is carried out for any time period required for obtaining a desired quality, such as from about 15 minutes to 10 hours or longer.
In the process of first embodiment, the present invention provides amorphous form of Darolutamide having specific surface area (SSA) of about 0.1 to about 10 m2/g.
In the process of first embodiment, the present invention provides amorphous form of Darolutamide, which is characterized by its X-ray powder diffraction (XRD) pattern as illustrated in Figure- 1.
In the process of first embodiment, the present invention provides amorphous form of Darolutamide prepared according to the present invention is having purity of about 99.9%; preferably about 99.95%; more preferably about 99.97% as measured by HPLC.
In the second embodiment, the present invention provides amorphous form of Darolutamide having specific surface area (SSA) in the range from about 0.1 to about 100
m2/g or from about 0.1 to about 50 m2/g or from about 0.1 to about 10 m2/g or from about 0.1 to about 5 m2/g or from about 0.1 to about 4 m2/g or from about 0.1 to about 3 m2/g.
In the third embodiment, the present invention provides amorphous form of Darolutamide having specific surface area (SSA) in the range from about 0.5 to about 100 m2/g or from about 0.5 to about 50 m2/g or from about 0.5 to about 10 m2/g or from about 0.5 to about 5 m2/g or from about 0.5 to about 4 m2/g or from about 0.5 to about 3 m2/g.
In the fourth embodiment, the present invention provides amorphous form of Darolutamide having volume median diameter (Dv50) between 0.1-1000 pm, preferably between 0.1-100 pm, more preferably between 0.1-50 pm, in particular between 0.5-25 pm. Dv90 is between 0.1-1000 pm, preferably between 0.1-100 pm, more preferably between 0.1- 50 pm, in particular between 1-50 pm.
In the fifth embodiment, the present invention provides Darolutamide having specific surface area (SSA) in the range from about 0.5 to about 100 m2/g or from about 0.5 to about 50 m2/g or from about 0.5 to about 10 m2/g or from about 0.5 to about 5 m2/g or from about 0.5 to about 4 m2/g or from about 0.5 to about 3 m2/g.
In the sixth embodiment, the present invention provides Darolutamide having volume median diameter (Dv50) between 0.1-1000 pm, preferably between 0.1-100 pm, more preferably between 0.1-50 pm, in particular between 0.5-25 pm. Dv90 is between 0.1-1000 pm, preferably between 0.1-100 pm, more preferably between 0.1-50 pm, in particular between 1-50 pm.
In the seventh embodiment, the present invention provides a pharmaceutical composition comprising amorphous form of Darolutamide compound of formula- 1 and one or more pharmaceutically acceptable excipients.
In the eighth embodiment, the present invention provides a process for the preparation of Crystalline form of Darolutamide of formula- 1, which comprises: a) providing a solution of Darolutamide in a solvent, b) isolating crystalline form of Darolutamide of formula- 1.
In the process of eighth embodiment, the solvent used in step-a) is selected from alcohol solvent, ester solvent, water and /or mixture thereof.
In the process of eighth embodiment, providing a solution of Darolutamide is carried out by suspending or dissolving Darolutamide in a solvent.
In the process of eighth embodiment, providing a solution of Darolutamide is optionally by heating the mixture to a suitable temperature ranging from ambient temperature
to reflux temperature of the solvent used. Optionally, the solution is filtered to make it particle free.
In the process of eighth embodiment, isolating Crystalline form of Darolutamide is carried out 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, cooling the mixture to solidify followed by filtration, or other techniques specific to the equipment used and the like, and optionally washing with a solvent.
In the process of eighth embodiment, the resulting Crystalline form of Darolutamide can be dried by techniques such as tray dryer, vacuum oven, rotatory cone dryer, air oven, fluidized bed dryer, spin flash dryer, flash dryer, or the like. The drying is 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 is carried out for any time period required for obtaining a desired quality, such as from about 15 minutes to 10 hours or longer.
In the process of eighth embodiment, the present invention provides Crystalline form of Darolutamide having specific surface area (SSA) of about 17 to about 40 m2/g, which is characterized by its Specific surface area (SSA) Method of Analysis.
In the process of eighth embodiment, the present invention provides Crystalline form of Darolutamide having specific surface area (SSA) of about 0.5 to about 7 m2/g, which is obtained by micronization techniques such as ball milling, roller milling and hammer milling, and jet mills. Milling or micronization may be performed before drying, or after the completion of drying of the product.
In the process of eighth embodiment, the present invention provides Crystalline form of Darolutamide, which is characterized by its X-ray powder diffraction (XRD) pattern as illustrated in Figure-2.
In the process of eighth embodiment, the present invention provides Crystalline form of Darolutamide prepared according to the present invention is having purity of about 99.9%; preferably about 99.95%; more preferably about 99.97% as measured by HPLC.
In the ninth embodiment, the present invention provides Crystalline form of Darolutamide having specific surface area (SSA) of about 0.5 m2/g or 1 m2/g or 2 m2/g or 3 m2/g or 4 m2/g or 5 m2/g or 6 m2/g or 7 m2/g or in the range from about 17 to about 100 m2/g or from about 17 to about 50 m2/g or from about 17 to about 40 m2/g or from about 17 to about 30 m2/g or from about 25 to about 35 m2/g.
In the tenth embodiment, the present invention provides crystalline form of Darolutamide having volume median diameter (Dv50) between 0.1-100 pm, preferably between 0.1-75 pm, more preferably between 0.1-50 pm, in particular between 1-25 pm.
In the eleventh embodiment, the present invention provides Crystalline form of Darolutamide having volume median diameter Dv90 is between 0.1-1000 pm, preferably between 0.1-100 pm, more preferably between 0.1-50 pm, in particular between 50-100 pm.
In the twelfth embodiment, the present invention provides a pharmaceutical composition comprising Crystalline form of Darolutamide prepared according to the present invention and one or more pharmaceutically acceptable excipients and/or earners.
The excipient can be selected from one or more described in Excipient Development for Pharmaceutical, Biotechnology, and Drug Delivery Systems 2006.
As used herein, the term "pharmaceutical compositions" include tablets, pills, powders, liquids, suspensions, emulsions, granules, capsules, suppositories, or injection preparations.
The starting material of Darolutamide used in the present invention can be prepared from any of the processes known in the art.
Darolutamide produced by the present invention can be micronized or milled using conventional techniques to get the desired particle size and surface area to achieve desired solubility profile to suit to pharmaceutical composition requirements. Techniques that may be used for particle size reduction include, but not limited to ball milling, roller milling and hammer milling, and jet mills. Milling or micronization may be performed before drying, or after the completion of drying of the product.
Specific surface area (SSA) Method of Analysis:
Specific surface area (SSA) of Crystalline form of Darolutamide can be analyzed using three -point nitrogen adsorption technique based on the Brunauer, Emmett and Teller (BET) theory using TriStar 3000 automated gas adsorption analyzer, (Micromeritics, Inc.). The samples were dried for 16 hours in 25°C. The volumetric method was applied at the relative pressure range 0.05 to 0.3 P/Po.
P-XRD Method of Analysis:
PXRD analysis of compound of formula- 1 was carried out by using BRUKER/D8 ADVANCE diffractometer using Cu Kα radiation of wavelength 1.5406 A° and continuous scan speed of 0.03°/min.
PSD method of Analysis:
Particle size distribution (PSD) analysis was performed using Malvern Mastersizer 2000 instrument.
The process described in the present invention was demonstrated in examples illustrated below. These examples are provided as illustration only and therefore should not be construed as limitation of the scope of the invention.
Examples:
Example- 1: Preparation of Darolutamide.
Methanol (500 ml) was added to (S)-5-acetyl-N-(l-(3-(3-chloro-4-cyanophenyl)-lH- pyrazol-l-yl)propan-2-yl)-lH-pyrazole-3 -carboxamide (100 g) at 25-30°C. Cooled the mixture to 15-20°C. Sodium borohydride (9.51 g) was added to the mixture at 15-20°C and stirred for 45 minutes. Raised the temperature of the mixture to 25-30°C and stirred for 90 minutes. Water (1000 ml) was slowly added to the mixture at 25-30°C and stirred for 6 hours. Filtered the solid, washed with water and dried to get the title compound. Yield: 90.0 g; Purity by HPLC: 98.58% and MR: 178-183°C.
Example-2: Preparation of crystalline form-I of Darolutamide.
A mixture of ethyl acetate (18 Lt) and water (3 Lt) were added to Darolutamide (1.5 kg) at 25-30°C and stirred for 10 minutes. Raised the temperature of the mixture to 75-80°C and stirred for 1 hour. Cooled the mixture to 65-70°C. The mixture was treated with carbon in ethyl acetate. Filtered the mixture through hyflow bed and washed with ethyl acetate. Observed solid filtered and dried. To the obtained solid, ethyl acetate (18 Lt) and water (3.0 Lt) were added at 25-30°C. Raised the temperature of the mixture to 75-80°C and stirred for 1 hour. Cooled the mixture to 25-30°C and stirred for 10 hours. Filtered the solid, washed with ethyl acetate and dried to get the title compound. Yield: 1.2 kg.
Example-3: Preparation of amorphous Darolutamide
A mixture of methanol (32.5 Lt) and dichloromethane (32.5 Lt) were added to crystalline form-I of Darolutamide (2.60 kg) at 25-30°C and stirred for 30 minutes. Filtered the mixture for particle free and washed with methanol and dichloromethane. The obtained particle free solution was spray dried at below mentioned parameters Inlet temperature: 70-75°C; Outlet temperature: 65-70°C; Feed rate: 10 ml/min; Atomizer Nozzle tip diameter: 1.2 mm; Aspirator flow rate: 80%; Nitrogen pressure: 2.5 kg The obtained solid was collected from the spray dryer and dried under vacuum to get the title compound.
Yield: 2.05 kg; Specific surface area (SSA): 1.43 m2/g.
The PXRD pattern of the obtained compound was shown in figure- 1.
Example-4: Preparation of Darolutamide
Methanol (1000 ml) was added to (S)-5-acetyl-N-(l-(3-(3-chloro-4-cyanophenyl)-lH- pyrazol-l-yl)propan-2-yl)-lH-pyrazole-3-carboxamide (100 g) at 25-30°C. Cooled the mixture to 15-20°C. Sodium borohydride (11.41 g) was slowly added to the mixture at 15- 20°C and stirred for 45 minutes. Raised the temperature of the mixture to 25-30°C and stirred for 90 minutes. Cooled the mixture to 10-15°C and slowly added the mixture to water (2500 ml) at 25-30°C. Treated with aqueous acetic acid at 25-30°C and stirred for 3 hours. Filtered the solid, washed with water and dried. Obtained solid added to water (1500 ml) at 25-30°C. Heated the mixture at 50-55°C and stirred for 60 minutes. Cooled the mixture to 25-30°C and stirred for 2 hours. Filtered the solid and dried. Obtained solid was added to the mixture of methanol (720 ml) and ethyl acetate (360 ml) at 25-30°C. Heated the mixture to 60-65°C and treated with carbon powder. Cooled the mixture to 25-30°C and water (1200 ml) was added to the mixture. Stirred the mixture for 4 hours at 25-30°C. Filtered the solid and washed with methanol water mixture. Dried to get the title compound.
Yield: 71.0 g; Purity by HPLC: 99.85%
Example-5: Preparation of amorphous Darolutamide
A mixture of methanol (1875 ml) and dichloro methane (1875 ml) were added to Darolutamide (150 g) at 25-30°C and stirred for 30 minutes. Filtered the mixture for particle free and washed with methanol and dichloromethane. The obtained particle free solution was spray dried at below mentioned parameters
Inlet temperature: 65-70°C; Outlet temperature: 50-55°C; Feed rate: 10 ml/min; Atomizer Nozzle tip diameter: 1.0 mm; Aspirator flow rate: 70%; Nitrogen pressure: 2.0 kg
The obtained solid was collected from the spray dryer and dried under vacuum to get the title compound.
Yield: 108g; Purity by HPLC: 99.88%
Specific surface area (SSA): 0.939 m2/g.
Particle size distribution (PSD): (Dv50): 10.38 pm; (Dv90): 19.26 pm
Example-6: Preparation of amorphous Darolutamide
Methanol (875 ml) was added to Darolutamide (25 g) at 25-30°C. Heated the mixture to 45-50°C and stirred for 10 minutes. Filtered the mixture for particle free and washed with methanol. The obtained particle free solution was spray dried at below mentioned parameters.
Inlet temperature: 70-75°C; Outlet temperature: 50-55°C; Feed rate: 10 ml/min; Atomizer Nozzle tip diameter: 1.0 mm; Aspirator flow rate: 70%; Nitrogen pressure: 2.0 kg
The obtained solid was collected from the spray dryer and dried under vacuum to get the title compound.
Yield: 15g; Specific surface area (SSA): 0.988 m2/g.
Particle size distribution (PSD): (Dv50): 12.27 pm; (Dv90): 23.80 pm
Example-7: Preparation of amorphous Darolutamide
A mixture of methanol (875 ml) and dichloromethane (12.5 ml) were added to Darolutamide (25 g) at 25-30°C. Heated the mixture to 45-50°C and stirred for 10 minutes. Filtered the mixture for particle free and washed with methanol. The obtained particle free solution was spray dried at below mentioned parameters.
Inlet temperature: 70-75°C; Outlet temperature: 50-55°C; Feed rate: 10 ml/min; Atomizer Nozzle tip diameter: 1.0 mm; Aspirator flow rate: 70%; Nitrogen pressure: 2.0 kg
The obtained solid was collected from the spray dryer and dried under vacuum to get the title compound. Yield: 15g;
Particle size distribution (PSD): (Dv50): 8.06 pm; (Dv90): 15.11 pm
Example-8: Preparation of crystalline Darolutamide
A mixture of ethyl acetate (18 liter) and water (3 liter) were added to Darolutamide (1.5 kg) at 25-30°C and stirred for 10 minutes. Raised the temperature of the mixture to 75- 80°C and stirred for 1 hour. Cooled the mixture to 65-70°C. The mixture was treated with carbon in ethyl acetate. Filtered the mixture through hyflow bed and washed with ethyl acetate. Mixture/filterate stirred for 10 hours at 25-30°C. Filtered the solid, washed with ethylacetate and dried to get solid. To the obtained solid, ethyl acetate (18 liter) and water (3.0 liter) were added at 25-30°C. Raised the temperature of the mixture to 75-80°C and stirred for 1 hour. Cooled the mixture to 25-30°C and stirred for 10 hours. Filtered the solid, washed with ethyl acetate and dried to get the title compound. Yield: 1.2 kg.
Specific surface area (SSA): 29.56 m2/g.
Particle size distribution (PSD): (Dv50): 11.63 pm; (Dv90): 76.18 pm
The PXRD pattern of the obtained compound was shown in figure-2.
Example-9: Preparation of crystalline Darolutamide
Methanol (6.6 litre) was added to Darolutamide (550 gm) at 25-30°C and stirred for 10 minutes. Raised the temperature of the mixture to 65-70°C and stirred for 1 hour. The mixture was treated with carbon at 65-70°C. Filtered the mixture through hyflow bed and washed with methanol. Mixture/filtrate cooled to 25-30°C and seeded with crystalline
Darolutamide, stirred for 3 hours at 25-30°C. Mixture cooled to 0-5°C and stirred for 6 hours.
Filtered the solid, washed with methanol and dried to get the title compound.
Yield: 502 gm.
Specific surface area (SSA): 20.11 m2/g. Particle size distribution (PSD): (Dv50): 15.01 pm; (Dv90): 62.65 pm
Claims
2. Amorphous form of Darolutamide as claimed in claim 1, having a specific surface area (SSA) in a range from about 0.1 to about 5 m2/g.
3. Amorphous form of Darolutamide as claimed in claim 1, having a specific surface area (SSA) in a range from about 0.1 to about 3 m2/g.
4. Amorphous form of Darolutamide of formula- 1 having a volume median diameter (Dv50) in a range from about 1 pm to about 20 pm.
5. Amorphous form of Darolutamide as claimed in claim 4, having a volume median diameter (Dv50) in a range from about 5 pm to about 15 pm.
6. A process for the preparation of amorphous Darolutamide as claimed in claim 1, comprising; a) providing a solution of Darolutamide of formula- 1 in a solvent, b) isolating amorphous form of Darolutamide of formula- 1.
7. The process as claimed in claim 6, wherein a solution of Darolutamide in step a) is provided by dissolving Darolutamide in dichloromethane, methanol or a mixture of dichloromethane and methanol.
8. Crystalline form of Darolutamide of formula- 1 having a specific surface area (SSA) in a range from about 17 to about 40m2/g.
9. Crystalline form of Darolutamide of formula- 1 , having a specific surface area (SSA) in a range from about 0.5 to about 7 m2/g.
10. Crystalline form of Darolutamide of formula- 1 having a volume median diameter (Dv50) in a range from about 1pm to about 10pm.
11. A process for the preparation of crystalline form of Darolutamide as claimed in claim 8, comprising; c) providing a solution of Darolutamide of formula- 1 in a solvent, d) isolating crystalline form of Darolutamide of formula- 1.
The process as claimed in claim 10, wherein a solution of Darolutamide in step a) is provided by dissolving Darolutamide in alcohol solvents, ester solvents, water and /or mixture thereof. The pharmaceutical composition comprising Darolutamide obtained according to any of preceding claims and a pharmaceutically acceptable carrier. The pharmaceutical composition comprising Darolutamide obtained according to any of preceding claims and its pharmaceutically acceptable excipients.
Applications Claiming Priority (4)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
IN202041057493 | 2020-12-31 | ||
IN202041057493 | 2020-12-31 | ||
IN202141000396 | 2021-01-05 | ||
IN202141000396 | 2021-01-05 |
Publications (1)
Publication Number | Publication Date |
---|---|
WO2022144926A1 true WO2022144926A1 (en) | 2022-07-07 |
Family
ID=82260302
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/IN2021/051220 WO2022144926A1 (en) | 2020-12-31 | 2021-12-31 | Process for the preparation of amorphous n-{(2s)-1-[3-(3-chloro-4-cyanophenyl)-1h-pyrazol-1-yl]propan-2-yl}-5-(1-hydroxyethyl)-1h-pyrazole-3-carboxamide |
Country Status (1)
Country | Link |
---|---|
WO (1) | WO2022144926A1 (en) |
Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2016120530A1 (en) * | 2015-01-30 | 2016-08-04 | Orion Corporation | A carboxamide derivative and its diastereomers in stable crystalline form |
WO2018162793A1 (en) * | 2017-03-07 | 2018-09-13 | Orion Corporation | Manufacture of a crystalline pharmaceutical product |
-
2021
- 2021-12-31 WO PCT/IN2021/051220 patent/WO2022144926A1/en active Application Filing
Patent Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2016120530A1 (en) * | 2015-01-30 | 2016-08-04 | Orion Corporation | A carboxamide derivative and its diastereomers in stable crystalline form |
WO2018162793A1 (en) * | 2017-03-07 | 2018-09-13 | Orion Corporation | Manufacture of a crystalline pharmaceutical product |
Non-Patent Citations (2)
Title |
---|
LIAN YU: "Amorphous pharmaceutical solids: preparation, characterization and stabilization", ADVANCED DRUG DELIVERY REVIEWS, vol. 48, 2001, pages 27 - 42, XP009065056, DOI: 10.1016/S0169-409X(01)00098-9 * |
VIPPAGUNTA S R, BRITTAIN H G, GRANT D J W: "CRYSTALLINE SOLIDS", ADVANCED DRUG DELIVERY REVIEWS, ELSEVIER, AMSTERDAM , NL, vol. 48, no. 01, 1 January 2001 (2001-01-01), Amsterdam , NL , pages 03 - 26, XP001181963, ISSN: 0169-409X, DOI: 10.1016/S0169-409X(01)00097-7 * |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
CA2717326C (en) | Preparation of lenalidomide | |
KR101251726B1 (en) | NILOTINIB HCl CRYSTALLINE FORMS | |
US20060111417A1 (en) | Amorphous telmisartan | |
WO2012066565A2 (en) | Asenapine maleate amorphous and crystalline form and process for preparation thereof | |
WO2016027243A1 (en) | Novel solid state forms of afatinib dimaleate | |
EP3229791A2 (en) | Novel polymorphs of ivacaftor, process for its preparation and pharmaceutical composition thereof | |
WO2012123858A1 (en) | Amorphous lurasidone hydrochloride | |
WO2013171756A1 (en) | Amorphous form of linagliptin and process for preparation thereof | |
WO2017208169A1 (en) | Polymorphs of betrixaban & its maleate salt | |
EP3253741A1 (en) | Process for preparation of polymorphic form of mirabegron | |
WO2004069277A1 (en) | Stable dispersion of solid particles comprising a water-insoluble pyrazine compound | |
WO2022144926A1 (en) | Process for the preparation of amorphous n-{(2s)-1-[3-(3-chloro-4-cyanophenyl)-1h-pyrazol-1-yl]propan-2-yl}-5-(1-hydroxyethyl)-1h-pyrazole-3-carboxamide | |
WO2020141562A1 (en) | Novel crystalline forms and process for the preparation of 4-{8-amino-3-[(2s)-1-(but-2-ynoyl)pyrrolidin-2-yl]imidazo[1,5-a]pyrazin-1-yl)}-n-(pyridine-2-yl)benzamide | |
CN109574975B (en) | Crystal form of 7,8-dihydroxyflavone derivative, and preparation method and application thereof | |
WO2016203436A1 (en) | Amorphous and amorphous solid dispersion of lesinurad and their preparation | |
WO2016193994A1 (en) | Amorphous selexipag and process for preparation thereof | |
CN117545755A (en) | Lanifibror crystal form and preparation method thereof | |
WO2017115315A1 (en) | Solid forms of palbociclib | |
WO2022044040A1 (en) | Novel polymorphs of (s)-3-(1-(9h-purin-6-yl-amino)ethyl)-8-chloro-2-phenylisoquinolin-1(2h)-one | |
WO2017163258A1 (en) | Process for the preparation of n-[6-(cis-2,6-dimethylmorpholin-4-yl)pyridine-3-yl]-2- methyl-4'-(trifiuoromethoxy) [1,1' -biphenyi]-3-carboxamide and its polymorphs thereof | |
EP3377479B1 (en) | Supersaturated compositions of benzimidazole compounds | |
WO2017149550A1 (en) | Amorphous form of 4-methyl-n-[3-(4-methyl-1h-imidazol-1-yl)-5-(trifluoromethyl)phenyl]-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]-benzamide | |
WO2020049598A2 (en) | Apalutamide polymorphs | |
WO2011139414A2 (en) | Dexlansoprazole polymorphic forms | |
WO2022208552A1 (en) | Crystalline forms of [1,1'-Biphenyl]-3-carboxamide, N-[(1,2-dihydro-4,6-dimethyl-2-oxo-3-pyridinyl)methyl]-5-[ethyl(tetrahydro-2H-pyran-4-yl)amino]-4-methyl-4'-(4-morpholinylmethyl)-, hydrobromide (1:1) and process for its preparation thereof |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
121 | Ep: the epo has been informed by wipo that ep was designated in this application |
Ref document number: 21914904 Country of ref document: EP Kind code of ref document: A1 |
|
NENP | Non-entry into the national phase |
Ref country code: DE |
|
122 | Ep: pct application non-entry in european phase |
Ref document number: 21914904 Country of ref document: EP Kind code of ref document: A1 |