WO2023067664A1 - Novel crystal form of benzothiophene compound and production method therefor - Google Patents
Novel crystal form of benzothiophene compound and production method therefor Download PDFInfo
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- WO2023067664A1 WO2023067664A1 PCT/JP2021/038493 JP2021038493W WO2023067664A1 WO 2023067664 A1 WO2023067664 A1 WO 2023067664A1 JP 2021038493 W JP2021038493 W JP 2021038493W WO 2023067664 A1 WO2023067664 A1 WO 2023067664A1
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- WIPO (PCT)
- Prior art keywords
- crystal
- thiophen
- butoxy
- quinolin
- piperazin
- Prior art date
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- 239000013078 crystal Substances 0.000 title claims abstract description 135
- 238000004519 manufacturing process Methods 0.000 title claims abstract description 38
- -1 benzothiophene compound Chemical class 0.000 title claims description 14
- FCEHBMOGCRZNNI-UHFFFAOYSA-N thianaphthalene Natural products C1=CC=C2SC=CC2=C1 FCEHBMOGCRZNNI-UHFFFAOYSA-N 0.000 title description 2
- ZKIAIYBUSXZPLP-UHFFFAOYSA-N brexpiprazole Chemical compound C1=C2NC(=O)C=CC2=CC=C1OCCCCN(CC1)CCN1C1=CC=CC2=C1C=CS2 ZKIAIYBUSXZPLP-UHFFFAOYSA-N 0.000 claims abstract description 60
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims abstract description 51
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 40
- 238000000034 method Methods 0.000 claims abstract description 33
- 150000003839 salts Chemical class 0.000 claims abstract description 26
- 238000001816 cooling Methods 0.000 claims abstract description 23
- 238000003756 stirring Methods 0.000 claims abstract description 21
- 239000000243 solution Substances 0.000 claims abstract description 19
- 239000003513 alkali Substances 0.000 claims abstract description 17
- 150000004683 dihydrates Chemical class 0.000 claims abstract description 17
- 239000007864 aqueous solution Substances 0.000 claims abstract description 12
- IOLCXVTUBQKXJR-UHFFFAOYSA-M potassium bromide Chemical compound [K+].[Br-] IOLCXVTUBQKXJR-UHFFFAOYSA-M 0.000 claims description 26
- 238000000862 absorption spectrum Methods 0.000 claims description 25
- 239000002245 particle Substances 0.000 claims description 24
- 238000000634 powder X-ray diffraction Methods 0.000 claims description 21
- 238000010521 absorption reaction Methods 0.000 claims description 17
- RYGMFSIKBFXOCR-UHFFFAOYSA-N Copper Chemical compound [Cu] RYGMFSIKBFXOCR-UHFFFAOYSA-N 0.000 claims description 13
- 229910052802 copper Inorganic materials 0.000 claims description 13
- 239000010949 copper Substances 0.000 claims description 13
- 230000005855 radiation Effects 0.000 claims description 13
- 125000004106 butoxy group Chemical group [*]OC([H])([H])C([H])([H])C(C([H])([H])[H])([H])[H] 0.000 claims description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 39
- 229960001210 brexpiprazole Drugs 0.000 description 37
- 238000005259 measurement Methods 0.000 description 18
- 238000010992 reflux Methods 0.000 description 13
- 150000001875 compounds Chemical class 0.000 description 8
- 239000000203 mixture Substances 0.000 description 8
- 238000002425 crystallisation Methods 0.000 description 7
- 230000008025 crystallization Effects 0.000 description 7
- 238000005033 Fourier transform infrared spectroscopy Methods 0.000 description 6
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 6
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 description 6
- 238000002360 preparation method Methods 0.000 description 6
- 230000032683 aging Effects 0.000 description 5
- 239000007787 solid Substances 0.000 description 5
- 239000002904 solvent Substances 0.000 description 5
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 4
- GQHTUMJGOHRCHB-UHFFFAOYSA-N 2,3,4,6,7,8,9,10-octahydropyrimido[1,2-a]azepine Chemical compound C1CCCCN2CCCN=C21 GQHTUMJGOHRCHB-UHFFFAOYSA-N 0.000 description 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 description 3
- SJRJJKPEHAURKC-UHFFFAOYSA-N N-Methylmorpholine Chemical compound CN1CCOCC1 SJRJJKPEHAURKC-UHFFFAOYSA-N 0.000 description 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- 238000005443 coulometric titration Methods 0.000 description 3
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 3
- 229960000448 lactic acid Drugs 0.000 description 3
- 238000007561 laser diffraction method Methods 0.000 description 3
- 239000007788 liquid Substances 0.000 description 3
- 238000002156 mixing Methods 0.000 description 3
- 239000002243 precursor Substances 0.000 description 3
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 description 3
- 238000000926 separation method Methods 0.000 description 3
- KKCBUQHMOMHUOY-UHFFFAOYSA-N sodium oxide Chemical compound [O-2].[Na+].[Na+] KKCBUQHMOMHUOY-UHFFFAOYSA-N 0.000 description 3
- 229910001948 sodium oxide Inorganic materials 0.000 description 3
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 2
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 description 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
- SMWDFEZZVXVKRB-UHFFFAOYSA-N Quinoline Chemical compound N1=CC=CC2=CC=CC=C21 SMWDFEZZVXVKRB-UHFFFAOYSA-N 0.000 description 2
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- 229910052783 alkali metal Inorganic materials 0.000 description 2
- 238000004458 analytical method Methods 0.000 description 2
- 230000003042 antagnostic effect Effects 0.000 description 2
- 208000015114 central nervous system disease Diseases 0.000 description 2
- 238000009826 distribution Methods 0.000 description 2
- VYFYYTLLBUKUHU-UHFFFAOYSA-N dopamine Chemical compound NCCC1=CC=C(O)C(O)=C1 VYFYYTLLBUKUHU-UHFFFAOYSA-N 0.000 description 2
- 230000002401 inhibitory effect Effects 0.000 description 2
- 239000004310 lactic acid Substances 0.000 description 2
- 235000014655 lactic acid Nutrition 0.000 description 2
- 238000000691 measurement method Methods 0.000 description 2
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 2
- 229910052757 nitrogen Inorganic materials 0.000 description 2
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 2
- QZAYGJVTTNCVMB-UHFFFAOYSA-N serotonin Chemical compound C1=C(O)C=C2C(CCN)=CNC2=C1 QZAYGJVTTNCVMB-UHFFFAOYSA-N 0.000 description 2
- 238000001228 spectrum Methods 0.000 description 2
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 2
- MFGOFGRYDNHJTA-UHFFFAOYSA-N 2-amino-1-(2-fluorophenyl)ethanol Chemical compound NCC(O)C1=CC=CC=C1F MFGOFGRYDNHJTA-UHFFFAOYSA-N 0.000 description 1
- BSKHPKMHTQYZBB-UHFFFAOYSA-N 2-methylpyridine Chemical compound CC1=CC=CC=N1 BSKHPKMHTQYZBB-UHFFFAOYSA-N 0.000 description 1
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 description 1
- LXEXGSUEHWGADU-UHFFFAOYSA-N 7-[4-[4-(1-benzothiophen-4-yl)piperazin-1-yl]butoxy]-1,2-dihydroquinoline Chemical compound S1C2=C(C=C1)C(=CC=C2)N2CCN(CC2)CCCCOC2=CC=C1C=CCNC1=C2 LXEXGSUEHWGADU-UHFFFAOYSA-N 0.000 description 1
- QNAKJJHSWWWWKD-UHFFFAOYSA-N 7-[4-[4-(1-benzothiophen-4-yl)piperazin-1-yl]butoxy]-1h-quinolin-2-one;dihydrate Chemical compound O.O.C1=C2NC(=O)C=CC2=CC=C1OCCCCN(CC1)CCN1C1=CC=CC2=C1C=CS2 QNAKJJHSWWWWKD-UHFFFAOYSA-N 0.000 description 1
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-L Carbonate Chemical compound [O-]C([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-L 0.000 description 1
- KRKNYBCHXYNGOX-UHFFFAOYSA-K Citrate Chemical compound [O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O KRKNYBCHXYNGOX-UHFFFAOYSA-K 0.000 description 1
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 1
- 102100029503 E3 ubiquitin-protein ligase TRIM32 Human genes 0.000 description 1
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 1
- 101000634982 Homo sapiens E3 ubiquitin-protein ligase TRIM32 Proteins 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 1
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 description 1
- WHUUTDBJXJRKMK-VKHMYHEASA-N L-glutamic acid Chemical compound OC(=O)[C@@H](N)CCC(O)=O WHUUTDBJXJRKMK-VKHMYHEASA-N 0.000 description 1
- JVTAAEKCZFNVCJ-UHFFFAOYSA-M Lactate Chemical compound CC(O)C([O-])=O JVTAAEKCZFNVCJ-UHFFFAOYSA-M 0.000 description 1
- OFOBLEOULBTSOW-UHFFFAOYSA-L Malonate Chemical compound [O-]C(=O)CC([O-])=O OFOBLEOULBTSOW-UHFFFAOYSA-L 0.000 description 1
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 1
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 1
- JLTDJTHDQAWBAV-UHFFFAOYSA-N N,N-dimethylaniline Chemical compound CN(C)C1=CC=CC=C1 JLTDJTHDQAWBAV-UHFFFAOYSA-N 0.000 description 1
- 229910002651 NO3 Inorganic materials 0.000 description 1
- NHNBFGGVMKEFGY-UHFFFAOYSA-N Nitrate Chemical compound [O-][N+]([O-])=O NHNBFGGVMKEFGY-UHFFFAOYSA-N 0.000 description 1
- 240000007594 Oryza sativa Species 0.000 description 1
- 235000007164 Oryza sativa Nutrition 0.000 description 1
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 1
- 229910019142 PO4 Inorganic materials 0.000 description 1
- XBDQKXXYIPTUBI-UHFFFAOYSA-M Propionate Chemical compound CCC([O-])=O XBDQKXXYIPTUBI-UHFFFAOYSA-M 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 description 1
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical class CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 239000013543 active substance Substances 0.000 description 1
- 230000001800 adrenalinergic effect Effects 0.000 description 1
- 230000001270 agonistic effect Effects 0.000 description 1
- 150000001298 alcohols Chemical class 0.000 description 1
- 229910000288 alkali metal carbonate Inorganic materials 0.000 description 1
- 150000008041 alkali metal carbonates Chemical class 0.000 description 1
- 150000008044 alkali metal hydroxides Chemical class 0.000 description 1
- 229910052784 alkaline earth metal Inorganic materials 0.000 description 1
- 125000005233 alkylalcohol group Chemical group 0.000 description 1
- 150000003863 ammonium salts Chemical class 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 description 1
- 229910000024 caesium carbonate Inorganic materials 0.000 description 1
- HUCVOHYBFXVBRW-UHFFFAOYSA-M caesium hydroxide Inorganic materials [OH-].[Cs+] HUCVOHYBFXVBRW-UHFFFAOYSA-M 0.000 description 1
- 159000000007 calcium salts Chemical class 0.000 description 1
- 125000004432 carbon atom Chemical group C* 0.000 description 1
- 229940001468 citrate Drugs 0.000 description 1
- 239000000470 constituent Substances 0.000 description 1
- 230000007423 decrease Effects 0.000 description 1
- 229960003638 dopamine Drugs 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- CCIVGXIOQKPBKL-UHFFFAOYSA-M ethanesulfonate Chemical compound CCS([O-])(=O)=O CCIVGXIOQKPBKL-UHFFFAOYSA-M 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 235000019253 formic acid Nutrition 0.000 description 1
- 229930195712 glutamate Natural products 0.000 description 1
- 229940093915 gynecological organic acid Drugs 0.000 description 1
- XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical compound I XMBWDFGMSWQBCA-UHFFFAOYSA-N 0.000 description 1
- 150000007529 inorganic bases Chemical class 0.000 description 1
- 238000010255 intramuscular injection Methods 0.000 description 1
- 239000007927 intramuscular injection Substances 0.000 description 1
- 238000002955 isolation Methods 0.000 description 1
- 229940001447 lactate Drugs 0.000 description 1
- XGZVUEUWXADBQD-UHFFFAOYSA-L lithium carbonate Chemical compound [Li+].[Li+].[O-]C([O-])=O XGZVUEUWXADBQD-UHFFFAOYSA-L 0.000 description 1
- 229910052808 lithium carbonate Inorganic materials 0.000 description 1
- 229910000032 lithium hydrogen carbonate Inorganic materials 0.000 description 1
- HQRPHMAXFVUBJX-UHFFFAOYSA-M lithium;hydrogen carbonate Chemical compound [Li+].OC([O-])=O HQRPHMAXFVUBJX-UHFFFAOYSA-M 0.000 description 1
- 159000000003 magnesium salts Chemical class 0.000 description 1
- 229940049920 malate Drugs 0.000 description 1
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 1
- BJEPYKJPYRNKOW-UHFFFAOYSA-N malic acid Chemical compound OC(=O)C(O)CC(O)=O BJEPYKJPYRNKOW-UHFFFAOYSA-N 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- 239000011259 mixed solution Substances 0.000 description 1
- PSHKMPUSSFXUIA-UHFFFAOYSA-N n,n-dimethylpyridin-2-amine Chemical compound CN(C)C1=CC=CC=N1 PSHKMPUSSFXUIA-UHFFFAOYSA-N 0.000 description 1
- 238000006386 neutralization reaction Methods 0.000 description 1
- 230000003472 neutralizing effect Effects 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- 150000007530 organic bases Chemical class 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 1
- 239000010452 phosphate Substances 0.000 description 1
- 229940075930 picrate Drugs 0.000 description 1
- OXNIZHLAWKMVMX-UHFFFAOYSA-M picrate anion Chemical compound [O-]C1=C([N+]([O-])=O)C=C([N+]([O-])=O)C=C1[N+]([O-])=O OXNIZHLAWKMVMX-UHFFFAOYSA-M 0.000 description 1
- 229910000028 potassium bicarbonate Inorganic materials 0.000 description 1
- 235000015497 potassium bicarbonate Nutrition 0.000 description 1
- 239000011736 potassium bicarbonate Substances 0.000 description 1
- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
- 235000011181 potassium carbonates Nutrition 0.000 description 1
- TYJJADVDDVDEDZ-UHFFFAOYSA-M potassium hydrogencarbonate Chemical compound [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 description 1
- 229940086066 potassium hydrogencarbonate Drugs 0.000 description 1
- 159000000001 potassium salts Chemical class 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- 235000009566 rice Nutrition 0.000 description 1
- 201000000980 schizophrenia Diseases 0.000 description 1
- 229940076279 serotonin Drugs 0.000 description 1
- 230000000697 serotonin reuptake Effects 0.000 description 1
- 230000013275 serotonin uptake Effects 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- 159000000000 sodium salts Chemical class 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-L succinate(2-) Chemical compound [O-]C(=O)CCC([O-])=O KDYFGRWQOYBRFD-UHFFFAOYSA-L 0.000 description 1
- BDHFUVZGWQCTTF-UHFFFAOYSA-M sulfonate Chemical compound [O-]S(=O)=O BDHFUVZGWQCTTF-UHFFFAOYSA-M 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 229940095064 tartrate Drugs 0.000 description 1
- 229940126585 therapeutic drug Drugs 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- IMNIMPAHZVJRPE-UHFFFAOYSA-N triethylenediamine Chemical class C1CN2CCN1CC2 IMNIMPAHZVJRPE-UHFFFAOYSA-N 0.000 description 1
Images
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
- C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
- C07D409/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
Definitions
- the present invention relates to a novel crystalline form of a benzothiophene compound, a method for producing the same, and the like. It should be noted that the contents of all documents described in this specification (especially Patent Document 1 and Patent Document 2 below) are incorporated herein by reference.
- brexpiprazole 7-[4-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)butoxy]-1H-quinolin-2-one (hereinafter also referred to as brexpiprazole or compound (I)) is It has dopamine D2 receptor partial agonistic action, serotonin 5- HT2A receptor antagonistic action and adrenergic ⁇ 1 receptor antagonistic action. In addition to these actions, compound (I) is known to have a serotonin uptake inhibitory action (or serotonin reuptake inhibitory action) and has a wide therapeutic spectrum for central nervous system diseases (particularly schizophrenia). (Patent Document 1).
- brexpiprazole or a dihydrate of its salt is stable and is a pharmacologically active substance that is particularly effective when used as an intramuscular injection (Patent Document 2).
- the brexpiprazole dihydrate is a crystal that can be a better therapeutic drug for central nervous system diseases (hereinafter, the brexpiprazole dihydrate crystal is referred to as "Form I" or "hydrate form I”).
- the brexpiprazole dihydrate is obtained by dissolving brexpiprazole in an acid (e.g., acetic acid or lactic acid)-containing solvent and neutralizing it with an alkali (e.g., sodium hydroxide) to crystallize (neutralization crystallization), low-temperature aging (for example, 5° C. or less for about 1 hour), and further high-temperature aging (for example, 20-30° C. for about 7 hours).
- an acid e.g., acetic acid or lactic acid
- an alkali e.g., sodium hydroxide
- the present inventors conducted repeated studies to find a method for preparing hydrate form I crystals with a large particle size with good reproducibility. Then, brexpiprazole is dissolved in an alkali (e.g., sodium hydroxide)-containing solvent, cooled to crystallize (cooling crystallization), water is added, and then aged at high temperature to give hydrate I It was found that crystals of this type could be prepared. They also found that hydrate form I crystals having a large particle size can be obtained with good reproducibility by the production method, and that the crystals obtained by the cooling crystallization are novel crystals.
- an alkali e.g., sodium hydroxide
- the crystal according to Item 2 or 3 having an infrared absorption band at 637 ⁇ 3.
- Item 5 Item 5.
- Item 6. (1) cooling an aqueous alcohol solution in which 7-[4-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)butoxy]-1H-quinolin-2-one and an alkali are dissolved; (2) adding more water to the cooled aqueous solution; and (3) standing or stirring at a temperature higher than the cooling temperature for 10 minutes to 19 hours.
- a method for producing a dihydrate crystal of thiophen-4-yl-piperazin-1-yl)butoxy]-1H-quinolin-2-one or a salt thereof Item 7.
- Aqueous alcohol solution containing 7-[4-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)butoxy]-1H-quinolin-2-one and alkali in the amount added in step (2) Item 7.
- a production method capable of reproducibly preparing crystals of brexpiprazole dihydrate having a relatively large particle size, and a novel crystal that is a precursor for preparing the stable crystal are provided.
- the novel crystals are crystals that can be prepared during the production method. can get.
- a large particle size can improve filterability and reduce operating time.
- 1 shows the results of infrared absorption spectrum measurement of brexpiprazole hydrate crystals with a water content of 10.4%.
- 1 shows the results of measurement of infrared absorption spectrum of brexpiprazole hydrate crystals with a water content of 37.6%.
- 1 shows the measurement results of the infrared absorption spectrum of brexpiprazole hydrate Form I crystals.
- 1 shows a powder X-ray diffraction pattern of brexpiprazole hydrate Form I crystals.
- 1 shows the measurement results of the infrared absorption spectrum of brexpiprazole hydrate Form I crystals.
- Crystals encompassed by the present disclosure are 7-[4-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)butoxy]-1H-quinolin-2-one (brexpiprazole) or It is a salt hydrate crystal.
- 7-[4-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)butoxy]-1H-quinolin-2-one (brexpiprazole) has the following formula (I):
- salts of compound (I) include salts described in Patent Document 1, and more specifically, for example, alkali metal salts (e.g., sodium salts, potassium salts, etc.), alkaline earth metal salts (e.g., calcium salts, magnesium salts, etc.), ammonium salts, alkali metal carbonates (e.g., lithium carbonate, potassium carbonate, sodium carbonate, cesium carbonate, etc.), alkali metal hydrogen carbonates (e.g., lithium hydrogen carbonate, sodium hydrogen carbonate, potassium hydrogen carbonate, etc.), salts of inorganic bases such as alkali metal hydroxides (e.g., lithium hydroxide, sodium hydroxide, potassium hydroxide, cesium hydroxide, etc.); , triethylamine, N-ethyldiisopropylamine, etc.), pyridine, quinoline, piperidine
- alkali metal salts e.g., sodium salts, potassium salts, etc.
- Compound (I) or a salt thereof can be produced by a known method (for example, the method described in Patent Document 1 or 2).
- a hydrate crystal of compound (I) or a salt thereof included in the present disclosure has at least one of the following characteristics (i) and (ii), and more preferably has both characteristics.
- the crystal may be referred to as "the crystal of the present disclosure”.
- D8 ADVANCE X-ray diffractometer
- the specific peaks of these diffraction angles 2 ⁇ may shift slightly depending on the water content (moisture content).
- the diffraction angle tends to shift slightly to the high angle side.
- the table below shows the values of the above-mentioned characteristic peaks when the water content of the crystals of the present disclosure is 30-45%.
- the water content value of the crystal is the value (% by weight) measured by the Karl Fischer method (coulometric titration method).
- Karl Fischer method coulometric titration method
- it can be measured using a Karl Fischer trace moisture analyzer (CA-200) manufactured by Nitto Seiko Analyticc.
- the infrared absorption spectrum can be measured by the KBr tablet method using an infrared spectrophotometer (for example, a Fourier transform infrared spectrophotometer (FT-IR IRAffinity-1S) manufactured by Shimadzu Corporation).
- an infrared spectrophotometer for example, a Fourier transform infrared spectrophotometer (FT-IR IRAffinity-1S) manufactured by Shimadzu Corporation.
- one or more (2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, or 13) infrared absorption band wavenumbers (cm -1 ) may be ⁇ 10, ⁇ 9, ⁇ 8, ⁇ 7, ⁇ 6, ⁇ 5, ⁇ 4, ⁇ 3, ⁇ 2, or ⁇ 1.
- the present inventors dissolved brexpiprazole in an alkali (e.g., sodium hydroxide)-containing solvent, crystallized it by cooling (cooling crystallization), added water, and then dissolved at high temperature. It was found that hydrate form I crystals can be prepared by aging, and that the production method yields hydrate form I crystals having a large particle size with good reproducibility.
- the crystals of the present disclosure were found as crystals obtained by the cooling crystallization. Therefore, the crystal of the present disclosure can be preferably used as a precursor of hydrate form I crystal.
- hydrate form I crystals can be obtained with good reproducibility. Furthermore, it is also possible to efficiently obtain hydrate form I crystals having a large particle size.
- brexpiprazole can be prepared by a known method, for example, by the method described in Patent Document 1 or 2.
- the crystals of the present disclosure are prepared, for example, by dissolving brexpiprazole in an alkali (e.g., sodium hydroxide)-containing solvent and crystallizing it by cooling (cooling crystallization). can do.
- alkali e.g., sodium hydroxide
- the present disclosure preferably also includes methods for producing the crystals of the present disclosure.
- the method for producing crystals of the present disclosure preferably includes (1) cooling an aqueous alcohol solution in which brexpiprazole and an alkali are dissolved.
- the cooling temperature here is a temperature lower than the temperature at which brexpiprazole is dissolved, specifically 40° C. or less. About 10 to 40°C is preferable, and about 15 to 40°C is more preferable. Furthermore, it is preferably about 15 to 35°C.
- alkalis examples include sodium hydroxide and potassium hydroxide, with sodium hydroxide being particularly preferred.
- alcohols include monohydric alkyl alcohols having 1 to 4 carbon atoms, such as ethanol and propanol (n-propanol, isopropanol), with ethanol being particularly preferred.
- the alcohol content of the alcohol aqueous solution here is preferably about 45 to 55% by mass.
- the content of brexpiprazole is about 1 to 10% by mass, more preferably about 3 to 6% by mass, and the content of alkali is preferably about 1 to 5% by mass, more preferably about 1 to 3% by mass. is.
- the method for producing crystals of the present disclosure includes (0) mixing brexpiprazole, alkali, alcohol, and water to obtain a solution in which brexpiprazole is dissolved before step (1).
- the mixing ratio of each component can be the same mixing ratio as described in step (1) above.
- brexpiprazole when dissolving brexpiprazole in an alkali-containing solvent, add 4 to 6 equivalents of sodium hydroxide to 50 to 60% by volume ethanol aqueous solution, and add an appropriate amount of brexpiprazole (for example, to the aqueous ethanol solution). about 1 to 5% by mass), mixed (preferably at a temperature of about 80 to 85° C. and stirred under reflux) to prepare a brexpiprazole solution, and the solution is cooled (dissolved at a temperature lower than the temperature at which the crystals of the present disclosure were obtained.
- the cooling temperature is, for example, about 10 to 40.degree. C., more preferably about 15 to 40.degree.
- the upper or lower limit of the cooling temperature may be 15, 20, 25, 30, or 35°C, for example.
- the cooling temperature may be about 15-35°C.
- step (1) with or without isolation of the crystals of the present disclosure, (2) further water is added to the cooled aqueous solution, and (3) high temperature aging.
- a method for preparing the dihydrate of spiprazole or a salt thereof is also preferably included in the present disclosure.
- the amount of water to be added in (2) is, for example, 0.3 to 3 times the volume of the cooled aqueous solution.
- the upper or lower limit of the range may be, for example, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1, 1.5, 2, or 2.5.
- the range may be 0.4 to 1 volume, or 0.4 to 0.8 volume.
- the temperature of the water to be added is preferably about the same as that of the cooled aqueous solution, such as 10 to 40°C, more preferably 15 to 40°C, and even more preferably 15 to 35°C.
- water may be added and further stirred.
- the stirring time can be appropriately set, for example, about 1 to 72 hours.
- the high-temperature aging in (3) can be carried out by standing or stirring at a temperature higher than the cooling temperature (for example, 35 to 50°C, more preferably 35 to 45°C).
- the standing or stirring time is preferably 10 minutes or more, more preferably about 10 minutes to 19 hours.
- the upper or lower limit of the stirring time (10 minutes to 19 hours) may be, for example, about 1, 2, 3, 5, 10, or 15 hours.
- Dihydrate crystals (hydrate form I crystals) of brexpiprazole or a salt thereof having a large average particle size can be obtained with good reproducibility.
- the dihydrate crystals of brexpiprazole or a salt thereof prepared as described above are sometimes referred to as "hydrate Form I crystals of the present disclosure.” It can also be said that the hydrate Form I crystals of the present disclosure can be prepared using the crystals of the present disclosure as precursors.
- the hydrate form I crystal of the present disclosure preferably has an average particle size of 26 ⁇ m or more, more preferably 35 or 45 ⁇ m or more.
- the upper limit is not particularly limited, for example, 60 ⁇ m or less is exemplified, and 55 or 50 ⁇ m or less may be exemplified.
- the average particle size in this specification is the volume average size measured by a laser diffraction method.
- an X-ray diffractometer (D8 ADVANCE) manufactured by Bruker AXS and a Fourier transform infrared spectrophotometer (FT-IR IRAffinity-1S) manufactured by Shimadzu Corporation were used.
- FT-IR IRAffinity-1S Fourier transform infrared spectrophotometer
- the water content (% by weight) was measured by the Karl Fischer method (coulometric titration method) using a Karl Fischer trace moisture analyzer (CA-200) manufactured by Nitto Seiko Analyticc. .
- the water content of crystal X (wet crystal) obtained in Production Example 3 was 37.6%. Moreover, the powder X-ray diffraction pattern measurement results are shown in FIG. 1 and Table 1b. Table 1b shows characteristic peaks.
- the crystal X obtained in Production Example 4 was placed in a desiccator adjusted to a humidity of about 7%, left to stand for 16 hours, and further dried.
- the moisture content of the dried crystals obtained in this manner was measured in the same manner as described above and found to be 10.4%.
- the infrared absorption spectrum of this dried crystal was also measured in the same manner as described above.
- Figures 3a to 3b show the measurement results of the infrared absorption spectrum.
- the moisture values for Crystal X, whose results are shown in Figures 3a-3b, are given in the table below.
- Peaks were observed at wave numbers (cm ⁇ 1 ) 2824, 1614, 1514, 1455, 1213, 1020, 841 and 637 in any infrared absorption spectrum. )
- Powder X-ray diffraction pattern measurement confirms that the dihydrate crystals obtained in the above "Preparation of brexpiprazole hydrate crystals" are the same crystals as the hydrate form I crystals obtained in Patent Document 2. It was confirmed from the results and infrared absorption spectrum measurement.
- the average particle size of the hydrate form I crystals obtained in Production Example 1 was measured using a particle size distribution analyzer (MASTERSIZER 3000) manufactured by Malvern Panalytical Co., Ltd., by a particle size measurement method based on a laser diffraction method. bottom.
- the average particle size of the hydrate form I crystals obtained in Production Example 1 was 45.6 ⁇ m.
- the average particle diameter here means a volume average diameter.
- FIG. 5b the infrared absorption spectrum measurement result is shown in FIG. 5b.
- absorption was observed near wavenumbers of 3505 cm ⁇ 1 , 2934 cm ⁇ 1 , 2810 cm ⁇ 1 , 1653 cm ⁇ 1 , 1624 cm ⁇ 1 , 1447 cm ⁇ 1 , 1223 cm ⁇ 1 and 839 cm ⁇ 1 .
- the water content (% by weight) of the hydrate I crystals obtained in Production Example 2 was measured by the Karl Fischer method (coulometric titration method) using a water content analyzer (MKC-610) manufactured by Kyoto Electronics Industry Co., Ltd. bottom.
- the average particle size was measured by a particle size measurement method based on a laser diffraction method using a particle size distribution analyzer (MT3300EX) manufactured by Nikkiso Co., Ltd.
- the average particle diameter here means a volume average diameter.
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Abstract
Provided is a means by which a stable dihydrate crystal of 7-[4-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)butoxy]-1H-quinolin-2-one or a salt thereof can be efficiently produced. Specifically, a method for producing a dihydrate crystal of 7-[4-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)butoxy]-1H-quinolin-2-one or a salt thereof is provided, the method comprising (1) cooling an aqueous alcohol solution containing, dissolved therein, 7-[4-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)butoxy]-1H-quinolin-2-one and an alkali, (2) adding water to the cooled aqueous solution, and (3) leaving the solution to rest or stirring the solution for 10 minutes to 19 hours at a temperature that is higher than the cooling temperature.
Description
本発明は、ベンゾチオフェン化合物の新規結晶形、及びその製造方法等に関する。なお、本明細書に記載される全ての文献(特に下記特許文献1及び特許文献2)の内容は参照により本明細書に組み込まれる。
The present invention relates to a novel crystalline form of a benzothiophene compound, a method for producing the same, and the like. It should be noted that the contents of all documents described in this specification (especially Patent Document 1 and Patent Document 2 below) are incorporated herein by reference.
7-[4-(4-ベンゾ[b]チオフェン-4-イル-ピペラジン-1-イル)ブトキシ]-1H-キノリン-2-オン(以下、ブレクスピプラゾール又は化合物(I)ともいう)は、ドパミンD2受容体パーシャルアゴニスト作用、セロトニン5-HT2A受容体アンタゴニスト作用及びアドレナリンα1受容体アンタゴニスト作用を有する。また化合物(I)は、それらの作用に加えてセロトニン取り込み阻害作用(あるいはセロトニン再取り込み阻害作用)を併有し、中枢神経疾患(特に統合失調症)に対して広い治療スペクラムを有することが知られている(特許文献1)。
7-[4-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)butoxy]-1H-quinolin-2-one (hereinafter also referred to as brexpiprazole or compound (I)) is It has dopamine D2 receptor partial agonistic action, serotonin 5- HT2A receptor antagonistic action and adrenergic α1 receptor antagonistic action. In addition to these actions, compound (I) is known to have a serotonin uptake inhibitory action (or serotonin reuptake inhibitory action) and has a wide therapeutic spectrum for central nervous system diseases (particularly schizophrenia). (Patent Document 1).
また、ブレクスピプラゾール又はその塩の二水和物が安定であり、特に筋肉注射剤として用いるにあたって有効な薬理活性物質であることについても知られている(特許文献2)。
It is also known that brexpiprazole or a dihydrate of its salt is stable and is a pharmacologically active substance that is particularly effective when used as an intramuscular injection (Patent Document 2).
前記ブレクスピプラゾール二水和物は、中枢神経疾患に対して、より優れた治療薬になり得る結晶(以下当該ブレクスピプラゾール二水和物結晶を「FormI」又は「水和物I形」ということがある)として調製される(特許文献2)。ただ、当該ブレクスピプラゾール二水和物は、ブレクスピプラゾールを、酸(例えば酢酸や乳酸)含有溶媒へ溶解させ、これをアルカリ(例えば水酸化ナトリウム)で中和して結晶化させ(中和晶析)、これを低温熟成(例えば5℃以下で1時間程度)させ、そしてさらに高温熟成(例えば20~30℃で7時間程度)させて、ようやく得られるものであり、しかも、この中和晶析を経由する方法では、粒子径の大きな水和物I形結晶を再現性良く得ることが難しく、また、効率的に製造することも難しいことから、当該製造方法は工業スケールでの大量生産に用いるには好適とは言い難い方法であった。
The brexpiprazole dihydrate is a crystal that can be a better therapeutic drug for central nervous system diseases (hereinafter, the brexpiprazole dihydrate crystal is referred to as "Form I" or "hydrate form I"). (Patent Document 2). However, the brexpiprazole dihydrate is obtained by dissolving brexpiprazole in an acid (e.g., acetic acid or lactic acid)-containing solvent and neutralizing it with an alkali (e.g., sodium hydroxide) to crystallize (neutralization crystallization), low-temperature aging (for example, 5° C. or less for about 1 hour), and further high-temperature aging (for example, 20-30° C. for about 7 hours). In a method via crystallization, it is difficult to obtain hydrate form I crystals with a large particle size with good reproducibility, and it is also difficult to produce them efficiently. It is difficult to say that this method is suitable for use in
本発明者らは、再現性よく粒子径の大きな水和物I形結晶を調製できる方法を見いだすべく、検討を重ねた。そして、ブレクスピプラゾールを、アルカリ(例えば水酸化ナトリウム)含有溶媒へ溶解させ、これを冷却して結晶化させ(冷却晶析)、さらに水を加えたうえで高温熟成させると、水和物I形結晶が調製できることを見いだした。そして、当該製造方法であれば再現性よく粒子径の大きな水和物I形結晶が得られること、並びに、前記冷却晶析により得られる結晶が新規結晶であること、も見いだした。
The present inventors conducted repeated studies to find a method for preparing hydrate form I crystals with a large particle size with good reproducibility. Then, brexpiprazole is dissolved in an alkali (e.g., sodium hydroxide)-containing solvent, cooled to crystallize (cooling crystallization), water is added, and then aged at high temperature to give hydrate I It was found that crystals of this type could be prepared. They also found that hydrate form I crystals having a large particle size can be obtained with good reproducibility by the production method, and that the crystals obtained by the cooling crystallization are novel crystals.
本発明は例えば以下の項に記載の主題を包含する。
項1.
7-[4-(4-ベンゾ[b]チオフェン-4-イル-ピペラジン-1-イル)ブトキシ]-1H-キノリン-2-オン又はその塩の水和物の結晶であって、
臭化カリウム錠剤法により測定される赤外線吸収スペクトルにおいて、波数(cm-1)=2824±10、1614±3、1514±3、1455±3、1213±3、1020±3、841±3、及び637±3 に赤外線吸収バンドを有する、結晶。
項2.
7-[4-(4-ベンゾ[b]チオフェン-4-イル-ピペラジン-1-イル)ブトキシ]-1H-キノリン-2-オン又はその塩の水和物の結晶であって、その水分値が30~45%のとき、
λ=1.5418Åの銅放射線 により測定される粉末X線回折パターンにおいて、
回折角2θ(°)= 11.4±0.2、12.4±0.2、15.8±0.2、18.2±0.2、及び22.8±0.2にピークを有する、結晶。
項3.
λ=1.5418Åの銅放射線により測定される粉末X線回折パターンにおいて、
さらに、回折角2θ(°)=19.5±0.2にピークを有する、請求項2に記載の結晶。
項4.
臭化カリウム錠剤法により測定された赤外線吸収スペクトルにおいて、波数(cm-1)=2824±10、1614±3、1514±3、1455±3、1213±3、1020±3、841±3、及び637±3 に赤外線吸収バンドを有する、項2又は3に記載の結晶。
項5.
(1)7-[4-(4-ベンゾ[b]チオフェン-4-イル-ピペラジン-1-イル)ブトキシ]-1H-キノリン-2-オン及びアルカリが溶解したアルコール水溶液を冷却すること
を含む、項1~4のいずれかに記載の結晶の製造方法。
項6.
(1)7-[4-(4-ベンゾ[b]チオフェン-4-イル-ピペラジン-1-イル)ブトキシ]-1H-キノリン-2-オン及びアルカリが溶解したアルコール水溶液を冷却すること、
(2)冷却した前記水溶液にさらに水を加えること、及び
(3)前記冷却温度より高い温度で10分~19時間静置又は撹拌すること
を含む、7-[4-(4-ベンゾ[b]チオフェン-4-イル-ピペラジン-1-イル)ブトキシ]-1H-キノリン-2-オン又はその塩の二水和物結晶の製造方法。
項7.
工程(2)における加水量が、7-[4-(4-ベンゾ[b]チオフェン-4-イル-ピペラジン-1-イル)ブトキシ]-1H-キノリン-2-オン及びアルカリを含有するアルコール水溶液の容量の、0.4~0.8倍容量である、項6に記載の製造方法。
項8.
工程(1)における冷却の温度が、10~40℃である、項5~7のいずれかに記載の製造方法。
項9.
請求項1~4のいずれかに記載の結晶及びアルカリを含有する10~40℃のアルコール水溶液を、当該アルコール水溶液の温度より高い温度であって且つ35~50℃の温度で、10分~19時間静置又は撹拌すること
を含む、7-[4-(4-ベンゾ[b]チオフェン-4-イル-ピペラジン-1-イル)ブトキシ]-1H-キノリン-2-オン又はその塩の二水和物結晶の製造方法。
項10.
7-[4-(4-ベンゾ[b]チオフェン-4-イル-ピペラジン-1-イル)ブトキシ]-1H-キノリン-2-オン又はその塩の二水和物結晶であって、
モノクロメーターを通したλ=1.5418Åの銅放射線により測定される粉末X線回折パターンにおいて、回折角2θ(°)= 8.1±0.2、8.9±0.2、15.1±0.2、15.6±0.2、及び24.4±0.2にピークを有し、
平均粒子径が26μm 以上である、
結晶。
項11.
7-[4-(4-ベンゾ[b]チオフェン-4-イル-ピペラジン-1-イル)ブトキシ]-1H-キノリン-2-オン又はその塩の二水和物結晶であって、
臭化カリウム錠剤法により測定された赤外線吸収スペクトルにおいて、波数(cm-1)=3509±10、2934±10、2812±10、1651±3、1626±3、1447±3、1223±3、及び839±3 に赤外線吸収バンドを有し、
平均粒子径が26μm 以上である、
結晶。
項12.
臭化カリウム錠剤法により測定された赤外線吸収スペクトルにおいて、波数(cm-1)=3509±10、2934±10、2812±10、1651±3、1626±3、1447±3、1223±3、及び839±3 に赤外線吸収バンドを有する 、
項10に記載の結晶。 The invention includes, for example, the subject matter described in the following sections.
Section 1.
A hydrate crystal of 7-[4-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)butoxy]-1H-quinolin-2-one or a salt thereof,
In the infrared absorption spectrum measured by the potassium bromide tablet method, wave numbers (cm -1 ) = 2824 ± 10, 1614 ± 3, 1514 ± 3, 1455 ± 3, 1213 ± 3, 1020 ± 3, 841 ± 3, and A crystal with an infrared absorption band at 637±3.
Section 2.
7-[4-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)butoxy]-1H-quinolin-2-one or a hydrate crystal of a salt thereof, the water content thereof is 30 to 45%,
In the powder X-ray diffraction pattern measured by copper radiation at λ=1.5418 Å,
Peaks at diffraction angles 2θ (°) = 11.4 ± 0.2, 12.4 ± 0.2, 15.8 ± 0.2, 18.2 ± 0.2, and 22.8 ± 0.2 have crystals.
Item 3.
In the powder X-ray diffraction pattern measured by copper radiation at λ=1.5418 Å,
3. The crystal according toclaim 2, further having a peak at a diffraction angle 2[theta]([deg.])=19.5±0.2.
Section 4.
In the infrared absorption spectrum measured by the potassium bromide tablet method, wave numbers (cm -1 ) = 2824 ± 10, 1614 ± 3, 1514 ± 3, 1455 ± 3, 1213 ± 3, 1020 ± 3, 841 ± 3, and Item 4. The crystal according to Item 2 or 3, having an infrared absorption band at 637±3.
Item 5.
(1) including cooling an aqueous alcohol solution in which 7-[4-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)butoxy]-1H-quinolin-2-one and alkali are dissolved; , a method for producing a crystal according to any one ofItems 1 to 4.
Item 6.
(1) cooling an aqueous alcohol solution in which 7-[4-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)butoxy]-1H-quinolin-2-one and an alkali are dissolved;
(2) adding more water to the cooled aqueous solution; and (3) standing or stirring at a temperature higher than the cooling temperature for 10 minutes to 19 hours. ] A method for producing a dihydrate crystal of thiophen-4-yl-piperazin-1-yl)butoxy]-1H-quinolin-2-one or a salt thereof.
Item 7.
Aqueous alcohol solution containing 7-[4-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)butoxy]-1H-quinolin-2-one and alkali in the amount added in step (2) Item 7. The production method according to Item 6, wherein the capacity is 0.4 to 0.8 times the capacity of.
Item 8.
Item 8. The production method according to any one of items 5 to 7, wherein the cooling temperature in step (1) is 10 to 40°C.
Item 9.
10 to 40 ° C. alcohol aqueous solution containing the crystal and alkali according to any one ofclaims 1 to 4, at a temperature higher than the temperature of the alcohol aqueous solution and at a temperature of 35 to 50 ° C., for 10 minutes to 19 Dihydrate of 7-[4-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)butoxy]-1H-quinolin-2-one or its salt, including standing or stirring for a period of time A method for producing a hydrate crystal.
Item 10.
A dihydrate crystal of 7-[4-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)butoxy]-1H-quinolin-2-one or a salt thereof,
Diffraction angle 2θ (°) = 8.1 ± 0.2, 8.9 ± 0.2, 15.1 in powder X-ray diffraction pattern measured by copper radiation at λ = 1.5418 Å through a monochromator with peaks at ±0.2, 15.6 ±0.2, and 24.4 ±0.2,
An average particle size of 26 μm or more,
crystal.
Item 11.
A dihydrate crystal of 7-[4-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)butoxy]-1H-quinolin-2-one or a salt thereof,
In the infrared absorption spectrum measured by the potassium bromide tablet method, wave numbers (cm -1 ) = 3509 ± 10, 2934 ± 10, 2812 ± 10, 1651 ± 3, 1626 ± 3, 1447 ± 3, 1223 ± 3, and has an infrared absorption band at 839±3,
An average particle size of 26 μm or more,
crystal.
Item 12.
In the infrared absorption spectrum measured by the potassium bromide tablet method, wave numbers (cm -1 ) = 3509 ± 10, 2934 ± 10, 2812 ± 10, 1651 ± 3, 1626 ± 3, 1447 ± 3, 1223 ± 3, and has an infrared absorption band at 839±3 ,
Item 11. The crystal according to item 10.
項1.
7-[4-(4-ベンゾ[b]チオフェン-4-イル-ピペラジン-1-イル)ブトキシ]-1H-キノリン-2-オン又はその塩の水和物の結晶であって、
臭化カリウム錠剤法により測定される赤外線吸収スペクトルにおいて、波数(cm-1)=2824±10、1614±3、1514±3、1455±3、1213±3、1020±3、841±3、及び637±3 に赤外線吸収バンドを有する、結晶。
項2.
7-[4-(4-ベンゾ[b]チオフェン-4-イル-ピペラジン-1-イル)ブトキシ]-1H-キノリン-2-オン又はその塩の水和物の結晶であって、その水分値が30~45%のとき、
λ=1.5418Åの銅放射線 により測定される粉末X線回折パターンにおいて、
回折角2θ(°)= 11.4±0.2、12.4±0.2、15.8±0.2、18.2±0.2、及び22.8±0.2にピークを有する、結晶。
項3.
λ=1.5418Åの銅放射線により測定される粉末X線回折パターンにおいて、
さらに、回折角2θ(°)=19.5±0.2にピークを有する、請求項2に記載の結晶。
項4.
臭化カリウム錠剤法により測定された赤外線吸収スペクトルにおいて、波数(cm-1)=2824±10、1614±3、1514±3、1455±3、1213±3、1020±3、841±3、及び637±3 に赤外線吸収バンドを有する、項2又は3に記載の結晶。
項5.
(1)7-[4-(4-ベンゾ[b]チオフェン-4-イル-ピペラジン-1-イル)ブトキシ]-1H-キノリン-2-オン及びアルカリが溶解したアルコール水溶液を冷却すること
を含む、項1~4のいずれかに記載の結晶の製造方法。
項6.
(1)7-[4-(4-ベンゾ[b]チオフェン-4-イル-ピペラジン-1-イル)ブトキシ]-1H-キノリン-2-オン及びアルカリが溶解したアルコール水溶液を冷却すること、
(2)冷却した前記水溶液にさらに水を加えること、及び
(3)前記冷却温度より高い温度で10分~19時間静置又は撹拌すること
を含む、7-[4-(4-ベンゾ[b]チオフェン-4-イル-ピペラジン-1-イル)ブトキシ]-1H-キノリン-2-オン又はその塩の二水和物結晶の製造方法。
項7.
工程(2)における加水量が、7-[4-(4-ベンゾ[b]チオフェン-4-イル-ピペラジン-1-イル)ブトキシ]-1H-キノリン-2-オン及びアルカリを含有するアルコール水溶液の容量の、0.4~0.8倍容量である、項6に記載の製造方法。
項8.
工程(1)における冷却の温度が、10~40℃である、項5~7のいずれかに記載の製造方法。
項9.
請求項1~4のいずれかに記載の結晶及びアルカリを含有する10~40℃のアルコール水溶液を、当該アルコール水溶液の温度より高い温度であって且つ35~50℃の温度で、10分~19時間静置又は撹拌すること
を含む、7-[4-(4-ベンゾ[b]チオフェン-4-イル-ピペラジン-1-イル)ブトキシ]-1H-キノリン-2-オン又はその塩の二水和物結晶の製造方法。
項10.
7-[4-(4-ベンゾ[b]チオフェン-4-イル-ピペラジン-1-イル)ブトキシ]-1H-キノリン-2-オン又はその塩の二水和物結晶であって、
モノクロメーターを通したλ=1.5418Åの銅放射線により測定される粉末X線回折パターンにおいて、回折角2θ(°)= 8.1±0.2、8.9±0.2、15.1±0.2、15.6±0.2、及び24.4±0.2にピークを有し、
平均粒子径が26μm 以上である、
結晶。
項11.
7-[4-(4-ベンゾ[b]チオフェン-4-イル-ピペラジン-1-イル)ブトキシ]-1H-キノリン-2-オン又はその塩の二水和物結晶であって、
臭化カリウム錠剤法により測定された赤外線吸収スペクトルにおいて、波数(cm-1)=3509±10、2934±10、2812±10、1651±3、1626±3、1447±3、1223±3、及び839±3 に赤外線吸収バンドを有し、
平均粒子径が26μm 以上である、
結晶。
項12.
臭化カリウム錠剤法により測定された赤外線吸収スペクトルにおいて、波数(cm-1)=3509±10、2934±10、2812±10、1651±3、1626±3、1447±3、1223±3、及び839±3 に赤外線吸収バンドを有する 、
項10に記載の結晶。 The invention includes, for example, the subject matter described in the following sections.
A hydrate crystal of 7-[4-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)butoxy]-1H-quinolin-2-one or a salt thereof,
In the infrared absorption spectrum measured by the potassium bromide tablet method, wave numbers (cm -1 ) = 2824 ± 10, 1614 ± 3, 1514 ± 3, 1455 ± 3, 1213 ± 3, 1020 ± 3, 841 ± 3, and A crystal with an infrared absorption band at 637±3.
7-[4-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)butoxy]-1H-quinolin-2-one or a hydrate crystal of a salt thereof, the water content thereof is 30 to 45%,
In the powder X-ray diffraction pattern measured by copper radiation at λ=1.5418 Å,
Peaks at diffraction angles 2θ (°) = 11.4 ± 0.2, 12.4 ± 0.2, 15.8 ± 0.2, 18.2 ± 0.2, and 22.8 ± 0.2 have crystals.
In the powder X-ray diffraction pattern measured by copper radiation at λ=1.5418 Å,
3. The crystal according to
Section 4.
In the infrared absorption spectrum measured by the potassium bromide tablet method, wave numbers (cm -1 ) = 2824 ± 10, 1614 ± 3, 1514 ± 3, 1455 ± 3, 1213 ± 3, 1020 ± 3, 841 ± 3, and Item 4. The crystal according to
Item 5.
(1) including cooling an aqueous alcohol solution in which 7-[4-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)butoxy]-1H-quinolin-2-one and alkali are dissolved; , a method for producing a crystal according to any one of
Item 6.
(1) cooling an aqueous alcohol solution in which 7-[4-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)butoxy]-1H-quinolin-2-one and an alkali are dissolved;
(2) adding more water to the cooled aqueous solution; and (3) standing or stirring at a temperature higher than the cooling temperature for 10 minutes to 19 hours. ] A method for producing a dihydrate crystal of thiophen-4-yl-piperazin-1-yl)butoxy]-1H-quinolin-2-one or a salt thereof.
Item 7.
Aqueous alcohol solution containing 7-[4-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)butoxy]-1H-quinolin-2-one and alkali in the amount added in step (2) Item 7. The production method according to Item 6, wherein the capacity is 0.4 to 0.8 times the capacity of.
Item 8.
Item 8. The production method according to any one of items 5 to 7, wherein the cooling temperature in step (1) is 10 to 40°C.
Item 9.
10 to 40 ° C. alcohol aqueous solution containing the crystal and alkali according to any one of
A dihydrate crystal of 7-[4-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)butoxy]-1H-quinolin-2-one or a salt thereof,
Diffraction angle 2θ (°) = 8.1 ± 0.2, 8.9 ± 0.2, 15.1 in powder X-ray diffraction pattern measured by copper radiation at λ = 1.5418 Å through a monochromator with peaks at ±0.2, 15.6 ±0.2, and 24.4 ±0.2,
An average particle size of 26 μm or more,
crystal.
A dihydrate crystal of 7-[4-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)butoxy]-1H-quinolin-2-one or a salt thereof,
In the infrared absorption spectrum measured by the potassium bromide tablet method, wave numbers (cm -1 ) = 3509 ± 10, 2934 ± 10, 2812 ± 10, 1651 ± 3, 1626 ± 3, 1447 ± 3, 1223 ± 3, and has an infrared absorption band at 839±3,
An average particle size of 26 μm or more,
crystal.
Item 12.
In the infrared absorption spectrum measured by the potassium bromide tablet method, wave numbers (cm -1 ) = 3509 ± 10, 2934 ± 10, 2812 ± 10, 1651 ± 3, 1626 ± 3, 1447 ± 3, 1223 ± 3, and has an infrared absorption band at 839±3 ,
比較的粒子径の大きなブレクスピプラゾール二水和物の結晶を再現性よく調製できる製造方法、及び、当該安定晶を調製するための前駆体である新規結晶が提供される。当該新規結晶は、当該製造方法の途中で調製され得る結晶であり、特に当該製造方法途中で調製される当該新規結晶が安定して得られるために、粒子径の大きな前記二水和物結晶が得られる。粒子径が大きいことにより、濾過性が改善され、操作時間が短縮され得る。
A production method capable of reproducibly preparing crystals of brexpiprazole dihydrate having a relatively large particle size, and a novel crystal that is a precursor for preparing the stable crystal are provided. The novel crystals are crystals that can be prepared during the production method. can get. A large particle size can improve filterability and reduce operating time.
以下、本発明の各実施形態について、さらに詳細に説明する。
Each embodiment of the present invention will be described in further detail below.
本開示に包含される結晶は、7-[4-(4-ベンゾ[b]チオフェン-4-イル-ピペラジン-1-イル)ブトキシ]-1H-キノリン-2-オン(ブレクスピプラゾール)又はその塩の水和物の結晶である。7-[4-(4-ベンゾ[b]チオフェン-4-イル-ピペラジン-1-イル)ブトキシ]-1H-キノリン-2-オン(ブレクスピプラゾール)は、以下の式(I):
Crystals encompassed by the present disclosure are 7-[4-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)butoxy]-1H-quinolin-2-one (brexpiprazole) or It is a salt hydrate crystal. 7-[4-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)butoxy]-1H-quinolin-2-one (brexpiprazole) has the following formula (I):
で表される化合物である。
It is a compound represented by
本明細書では、式(I)で表される当該化合物(ブレクスピプラゾール)を化合物(I)と称することがある。また、化合物(I)の塩としては、特許文献1に記載される塩が例示され、より具体的には例えば、アルカリ金属塩(例えばナトリウム塩、カリウム塩等)、アルカリ土類金属塩(例えばカルシウム塩、マグネシウム塩等)等の金属塩、アンモニウム塩、炭酸アルカリ金属(例えば、炭酸リチウム、炭酸カリウム、炭酸ナトリウム、炭酸セシウム等)、炭酸水素アルカリ金属(例えば、炭酸水素リチウム、炭酸水素ナトリウム、炭酸水素カリウム等)、アルカリ金属水酸化物(例えば、水酸化リチウム、水酸化ナトリウム、水酸化カリウム、水酸化セシウム等)等の無機塩基の塩;例えば、トリ(低級)アルキルアミン(例えば、トリメチルアミン、トリエチルアミン、N-エチルジイソプロピルアミン等)、ピリジン、キノリン、ピペリジン、イミダゾール、ピコリン、ジメチルアミノピリジン、ジメチルアニリン、N-(低級)アルキル-モルホリン(例えば、N-メチルモルホリン等)、1,5-ジアザビシクロ[4.3.0]ノネン-5(DBN)、1、8-ジアザビシクロ[5.4.0]ウンデセン-7(DBU)、1,4-ジアザビシクロ[2.2.2]オクタン(DABCO)等の有機塩基の塩;塩酸塩、臭化水素酸塩、ヨウ化水素酸塩、硫酸塩、硝酸塩、リン酸塩等の無機酸の塩;ギ酸、酢酸塩、プロピオン酸塩、シュウ酸塩、マロン酸塩、コハク酸塩、フマル酸塩、マレイン酸塩、乳酸塩、リンゴ酸塩、クエン酸塩、酒石酸塩、炭酸塩、ピクリン酸塩、メタンスルホン酸塩、エタンスルホン酸塩、p-トルエンスルホン酸塩、グルタミン酸塩等の有機酸の塩等が挙げられる。
In this specification, the compound represented by formula (I) (brexpiprazole) is sometimes referred to as compound (I). Examples of salts of compound (I) include salts described in Patent Document 1, and more specifically, for example, alkali metal salts (e.g., sodium salts, potassium salts, etc.), alkaline earth metal salts (e.g., calcium salts, magnesium salts, etc.), ammonium salts, alkali metal carbonates (e.g., lithium carbonate, potassium carbonate, sodium carbonate, cesium carbonate, etc.), alkali metal hydrogen carbonates (e.g., lithium hydrogen carbonate, sodium hydrogen carbonate, potassium hydrogen carbonate, etc.), salts of inorganic bases such as alkali metal hydroxides (e.g., lithium hydroxide, sodium hydroxide, potassium hydroxide, cesium hydroxide, etc.); , triethylamine, N-ethyldiisopropylamine, etc.), pyridine, quinoline, piperidine, imidazole, picoline, dimethylaminopyridine, dimethylaniline, N-(lower) alkyl-morpholine (e.g., N-methylmorpholine, etc.), 1,5- diazabicyclo[4.3.0]nonene-5 (DBN), 1,8-diazabicyclo[5.4.0]undecene-7 (DBU), 1,4-diazabicyclo[2.2.2]octane (DABCO) salts of organic bases such as; salts of inorganic acids such as hydrochloride, hydrobromide, hydroiodide, sulfate, nitrate, phosphate; formic acid, acetate, propionate, oxalate, Malonate, succinate, fumarate, maleate, lactate, malate, citrate, tartrate, carbonate, picrate, methanesulfonate, ethanesulfonate, p-toluene Salts of organic acids such as sulfonate and glutamate are included.
化合物(I)又はその塩は、公知の方法(例えば特許文献1又は2に記載の方法)より製造することができる。
Compound (I) or a salt thereof can be produced by a known method (for example, the method described in Patent Document 1 or 2).
本開示に包含される化合物(I)又はその塩の水和物結晶は、以下の特徴(i)及び(ii)のうち、少なくとも1つの特徴を有し、より好ましくは両方の特徴を有する。なお、当該結晶を、「本開示の結晶」ということがある。
A hydrate crystal of compound (I) or a salt thereof included in the present disclosure has at least one of the following characteristics (i) and (ii), and more preferably has both characteristics. In addition, the crystal may be referred to as "the crystal of the present disclosure".
特徴(i):特有の粉末X線回折パターン
本開示の結晶は、モノクロメーターを通したλ=1.5418Åの銅放射線により測定される粉末X線回折パターンにおいて、回折角2θ(°)= 11.4±0.2、12.4±0.2、15.8±0.2、18.2±0.2、及び22.8±0.2にピーク(特に、特徴的なピーク)を有することが好ましい。また、これら5本のピークに加えて、19.5±0.2の回折角2θ(°)にピークを有することが、さらに好ましい。特に、本開示の結晶は、結晶の水分値が30~45%、より好ましくは30~40%のときに、前記5本若しくは6本のピークを有することが好ましい。粉末X線回折は、X線回折装置(例えばBruker AXS社製のX線回折装置(D8 ADVANCE))を用いて測定することができる。 Feature (i): Unique Powder X-ray Diffraction Pattern The crystals of the present disclosure exhibit a diffraction angle 2θ (°) = 11 in the powder X-ray diffraction pattern measured by copper radiation at λ = 1.5418 Å through a monochromator. Peaks (particularly characteristic peaks) at 4±0.2, 12.4±0.2, 15.8±0.2, 18.2±0.2, and 22.8±0.2 It is preferable to have In addition to these five peaks, it is more preferable to have a peak at a diffraction angle 2θ (°) of 19.5±0.2. In particular, the crystals of the present disclosure preferably have the 5 or 6 peaks when the water content of the crystals is 30-45%, more preferably 30-40%. Powder X-ray diffraction can be measured using an X-ray diffractometer (for example, an X-ray diffractometer (D8 ADVANCE) manufactured by Bruker AXS).
本開示の結晶は、モノクロメーターを通したλ=1.5418Åの銅放射線により測定される粉末X線回折パターンにおいて、回折角2θ(°)= 11.4±0.2、12.4±0.2、15.8±0.2、18.2±0.2、及び22.8±0.2にピーク(特に、特徴的なピーク)を有することが好ましい。また、これら5本のピークに加えて、19.5±0.2の回折角2θ(°)にピークを有することが、さらに好ましい。特に、本開示の結晶は、結晶の水分値が30~45%、より好ましくは30~40%のときに、前記5本若しくは6本のピークを有することが好ましい。粉末X線回折は、X線回折装置(例えばBruker AXS社製のX線回折装置(D8 ADVANCE))を用いて測定することができる。 Feature (i): Unique Powder X-ray Diffraction Pattern The crystals of the present disclosure exhibit a diffraction angle 2θ (°) = 11 in the powder X-ray diffraction pattern measured by copper radiation at λ = 1.5418 Å through a monochromator. Peaks (particularly characteristic peaks) at 4±0.2, 12.4±0.2, 15.8±0.2, 18.2±0.2, and 22.8±0.2 It is preferable to have In addition to these five peaks, it is more preferable to have a peak at a diffraction angle 2θ (°) of 19.5±0.2. In particular, the crystals of the present disclosure preferably have the 5 or 6 peaks when the water content of the crystals is 30-45%, more preferably 30-40%. Powder X-ray diffraction can be measured using an X-ray diffractometer (for example, an X-ray diffractometer (D8 ADVANCE) manufactured by Bruker AXS).
なお、本開示の結晶は、その水分値(水分含有量)によって、若干これらの回折角2θ(°)の特有のピークが若干ずれる場合がある。特に、水分値が低下すると、回折角が高角度側に若干ずれる傾向がある。
It should be noted that, in the crystals of the present disclosure, the specific peaks of these diffraction angles 2θ (°) may shift slightly depending on the water content (moisture content). In particular, when the water content decreases, the diffraction angle tends to shift slightly to the high angle side.
下表に、本開示の結晶の水分値が30~45%のときの、上述した特有のピークの値を示す。
The table below shows the values of the above-mentioned characteristic peaks when the water content of the crystals of the present disclosure is 30-45%.
また、結晶の水分値は、カールフィッシャー法(電量滴定法)により測定した値(重量%)である。例えば、日東精工アナリテック社製のカールフィッシャー微量水分測定装置(CA-200)を用いて測定することができる。
Also, the water content value of the crystal is the value (% by weight) measured by the Karl Fischer method (coulometric titration method). For example, it can be measured using a Karl Fischer trace moisture analyzer (CA-200) manufactured by Nitto Seiko Analyticc.
特徴(ii):特有の赤外線吸収スペクトル
本開示の結晶は、臭化カリウム錠剤法により測定される赤外線吸収スペクトルにおいて、波数(cm-1)=2824±10、1614±3、1514±3、1455±3、1213±3、1020±3、841±3、及び637±3 に赤外線吸収バンドを有することが好ましい。これらの赤外線吸収バンドのなかでも、波数(cm-1)=1020±3の赤外線吸収バンドが、特に本開示の結晶に特徴的なバンドである。赤外線吸収スペクトルは、赤外分光光度計(例えば島津製作所社製のフーリエ変換赤外分光光度計(FT-IR IRAffinity-1S))を用いて、KBr錠剤法により測定することができる。 Feature (ii): Unique Infrared Absorption Spectrum The crystal of the present disclosure has wave numbers (cm −1 )=2824±10, 1614±3, 1514±3, 1455 in the infrared absorption spectrum measured by the potassium bromide tablet method. It preferably has infrared absorption bands at ±3, 1213±3, 1020±3, 841±3, and 637±3. Among these infrared absorption bands, the infrared absorption band at wavenumber (cm −1 )=1020±3 is particularly characteristic of the crystal of the present disclosure. The infrared absorption spectrum can be measured by the KBr tablet method using an infrared spectrophotometer (for example, a Fourier transform infrared spectrophotometer (FT-IR IRAffinity-1S) manufactured by Shimadzu Corporation).
本開示の結晶は、臭化カリウム錠剤法により測定される赤外線吸収スペクトルにおいて、波数(cm-1)=2824±10、1614±3、1514±3、1455±3、1213±3、1020±3、841±3、及び637±3 に赤外線吸収バンドを有することが好ましい。これらの赤外線吸収バンドのなかでも、波数(cm-1)=1020±3の赤外線吸収バンドが、特に本開示の結晶に特徴的なバンドである。赤外線吸収スペクトルは、赤外分光光度計(例えば島津製作所社製のフーリエ変換赤外分光光度計(FT-IR IRAffinity-1S))を用いて、KBr錠剤法により測定することができる。 Feature (ii): Unique Infrared Absorption Spectrum The crystal of the present disclosure has wave numbers (cm −1 )=2824±10, 1614±3, 1514±3, 1455 in the infrared absorption spectrum measured by the potassium bromide tablet method. It preferably has infrared absorption bands at ±3, 1213±3, 1020±3, 841±3, and 637±3. Among these infrared absorption bands, the infrared absorption band at wavenumber (cm −1 )=1020±3 is particularly characteristic of the crystal of the present disclosure. The infrared absorption spectrum can be measured by the KBr tablet method using an infrared spectrophotometer (for example, a Fourier transform infrared spectrophotometer (FT-IR IRAffinity-1S) manufactured by Shimadzu Corporation).
また、これらの特徴的な赤外線吸収バンドの他にも、2946±10、1242±3、1136±3、及び968±3、からなる群より選択される1又は2以上(2、3、4、5、6、又は7)の波数(cm-1)にさらに赤外線吸収バンドを有することがより好ましい。
In addition to these characteristic infrared absorption bands, one or two or more (2, 3, 4, More preferably, it additionally has an infrared absorption band at wavenumbers (cm −1 ) of 5, 6, or 7).
なお、当該赤外線吸収スペクトルにおいて、1又は2以上(2、3、4、5、6、7、8、9、10、11、12、又は13)の赤外線吸収バンドの波数(cm-1)の誤差は±10、±9、±8、±7、±6、±5、±4、±3、±2、又は±1であってもよい。
In the infrared absorption spectrum, one or more (2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, or 13) infrared absorption band wavenumbers (cm -1 ) The error may be ±10, ±9, ±8, ±7, ±6, ±5, ±4, ±3, ±2, or ±1.
上記の通り、本発明者らは、ブレクスピプラゾールを、アルカリ(例えば水酸化ナトリウム)含有溶媒へ溶解させ、これを冷却して結晶化させ(冷却晶析)、さらに水を加えたうえで高温熟成させると、水和物I形結晶が調製できること、そして、当該製造方法であれば再現性よく粒子径の大きな水和物I形結晶が得られることを見いだした。本開示の結晶は、前記冷却晶析により得られる結晶として見いだされたものである。このため、本開示の結晶は、水和物I形結晶の前駆体として好ましく用いることができる。そして、本開示の結晶を用いる水和物I形結晶調製方法により、再現性よく水和物I形結晶が得られる。さらには、粒子径の大きな水和物I形結晶を効率よく得ることもできる。なお、ブレクスピプラゾールは、公知の方法により、調製することができ、例えば特許文献1又は2に記載の方法で調製することができる。
As described above, the present inventors dissolved brexpiprazole in an alkali (e.g., sodium hydroxide)-containing solvent, crystallized it by cooling (cooling crystallization), added water, and then dissolved at high temperature. It was found that hydrate form I crystals can be prepared by aging, and that the production method yields hydrate form I crystals having a large particle size with good reproducibility. The crystals of the present disclosure were found as crystals obtained by the cooling crystallization. Therefore, the crystal of the present disclosure can be preferably used as a precursor of hydrate form I crystal. By the method for preparing hydrate form I crystals using the crystals of the present disclosure, hydrate form I crystals can be obtained with good reproducibility. Furthermore, it is also possible to efficiently obtain hydrate form I crystals having a large particle size. In addition, brexpiprazole can be prepared by a known method, for example, by the method described in Patent Document 1 or 2.
上記内容から理解できるように、本開示の結晶は、例えば、ブレクスピプラゾールを、アルカリ(例えば水酸化ナトリウム)含有溶媒へ溶解させ、これを冷却して結晶化させる(冷却晶析)ことで調製することができる。本開示は、本開示の結晶の製造方法も好ましく包含する。
As can be understood from the above content, the crystals of the present disclosure are prepared, for example, by dissolving brexpiprazole in an alkali (e.g., sodium hydroxide)-containing solvent and crystallizing it by cooling (cooling crystallization). can do. The present disclosure preferably also includes methods for producing the crystals of the present disclosure.
本開示の結晶の製造方法は、好ましくは、(1)ブレクスピプラゾール及びアルカリが溶解したアルコール水溶液を冷却すること、を含む。ここでの冷却温度は、ブレクスピプラゾールを溶解させた温度より低い温度であり、具体的には40℃以下が例示される。10~40℃程度が好ましく、15~40℃程度がより好ましい。更に、15~35℃程度が好ましい。
The method for producing crystals of the present disclosure preferably includes (1) cooling an aqueous alcohol solution in which brexpiprazole and an alkali are dissolved. The cooling temperature here is a temperature lower than the temperature at which brexpiprazole is dissolved, specifically 40° C. or less. About 10 to 40°C is preferable, and about 15 to 40°C is more preferable. Furthermore, it is preferably about 15 to 35°C.
アルカリとしては、例えば水酸化ナトリウム又は水酸化カリウムが例示され、特に水酸化ナトリウムが好ましく挙げられる。また、アルコールとしては、炭素数1~4の一価アルキルアルコールが例示され、具体的にはエタノール、プロパノール(n-プロパノール、イソプロパノール)等が挙げられ、特にエタノールが好ましく挙げられる。また、ここでのアルコール水溶液のアルコール含有量は、45~55質量%程度が好ましい。また、ブレクスピプラゾールの含有量は1~10質量%程度、より好ましくは3~6質量%であり、アルカリの含有量は好ましくは1~5質量%程度、より好ましくは1~3質量%程度である。
Examples of alkalis include sodium hydroxide and potassium hydroxide, with sodium hydroxide being particularly preferred. Examples of alcohols include monohydric alkyl alcohols having 1 to 4 carbon atoms, such as ethanol and propanol (n-propanol, isopropanol), with ethanol being particularly preferred. Further, the alcohol content of the alcohol aqueous solution here is preferably about 45 to 55% by mass. In addition, the content of brexpiprazole is about 1 to 10% by mass, more preferably about 3 to 6% by mass, and the content of alkali is preferably about 1 to 5% by mass, more preferably about 1 to 3% by mass. is.
また、本開示の結晶の製造方法では、工程(1)の前に、(0)ブレクスピプラゾール、アルカリ、アルコール、及び水を混合して、ブレクスピプラゾールを溶解した溶液を得ること、が含まれてもよい。この場合の各成分の混合割合は、上記工程(1)に記載したのと同様の混合割合を採用することができる。
In addition, the method for producing crystals of the present disclosure includes (0) mixing brexpiprazole, alkali, alcohol, and water to obtain a solution in which brexpiprazole is dissolved before step (1). may be In this case, the mixing ratio of each component can be the same mixing ratio as described in step (1) above.
例えば、ブレクスピプラゾールをアルカリ含有溶媒へ溶解させるにあたっては、50~60容量%エタノール水溶液に、水酸化ナトリウムを4~6当量となるよう、及び、ブレクスピプラゾールを適当量(例えばエタノール水溶液に対して1~5質量%程度)、混合して(好ましくは温度80~85℃程度で還流にて撹拌して)溶解させ、ブレクスピプラゾール溶解液を調製し、当該溶解液を冷却して(溶解させた温度より低い温度とする)、本開示の結晶を得ることができる。当該冷却温度としては、例えば10~40℃程度、より好ましくは15~40℃程度が上げられる。当該冷却温度の上限又は下限は、例えば15、20、25、30、又は35℃であってもよい。例えば、当該冷却温度は15~35℃程度であってもよい。
For example, when dissolving brexpiprazole in an alkali-containing solvent, add 4 to 6 equivalents of sodium hydroxide to 50 to 60% by volume ethanol aqueous solution, and add an appropriate amount of brexpiprazole (for example, to the aqueous ethanol solution). about 1 to 5% by mass), mixed (preferably at a temperature of about 80 to 85° C. and stirred under reflux) to prepare a brexpiprazole solution, and the solution is cooled (dissolved at a temperature lower than the temperature at which the crystals of the present disclosure were obtained. The cooling temperature is, for example, about 10 to 40.degree. C., more preferably about 15 to 40.degree. The upper or lower limit of the cooling temperature may be 15, 20, 25, 30, or 35°C, for example. For example, the cooling temperature may be about 15-35°C.
なお、工程(1)の後に、本開示の結晶を単離して若しくは単離することなく、(2)冷却した前記水溶液にさらに水を加え、(3)高温熟成すること、をさらに含む、ブレクスピプラゾール又はその塩の二水和物製造方法も、本開示に好ましく包含される。(2)において加える水の量としては、例えば冷却した前記水溶液の0.3~3倍容量が挙げられる。当該範囲の上限又は下限は例えば0.4、0.5、0.6、0.7、0.8、0.9、1、1.5、2、又は2.5であってもよい。例えば、当該範囲は0.4~1倍容量であってもよく、あるいは0.4~0.8倍容量であってもよい。
It should be noted that after step (1), with or without isolation of the crystals of the present disclosure, (2) further water is added to the cooled aqueous solution, and (3) high temperature aging. A method for preparing the dihydrate of spiprazole or a salt thereof is also preferably included in the present disclosure. The amount of water to be added in (2) is, for example, 0.3 to 3 times the volume of the cooled aqueous solution. The upper or lower limit of the range may be, for example, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1, 1.5, 2, or 2.5. For example, the range may be 0.4 to 1 volume, or 0.4 to 0.8 volume.
また、加える水の温度としては、冷却した前記水溶液と同程度の温度であることが好ましく、10~40℃、より好ましくは15~40℃、さらに好ましくは15~35℃が例示される。また、水を加えてさらに攪拌してもよい。この場合、攪拌時間は適宜設定することができ、例えば1~72時間程度が挙げられる。(3)における高温熟成は、前記冷却の温度より高い温度(例えば35~50℃、より好ましくは35~45℃)で静置又は撹拌することで行われ得る。静置又は攪拌する時間としては、10分以上が好ましく、10分~19時間程度がより好ましい。当該攪拌時間(10分から19時間)の上限又は下限は例えば1、2、3、5、10、又は15時間程度であってもよい。
The temperature of the water to be added is preferably about the same as that of the cooled aqueous solution, such as 10 to 40°C, more preferably 15 to 40°C, and even more preferably 15 to 35°C. Alternatively, water may be added and further stirred. In this case, the stirring time can be appropriately set, for example, about 1 to 72 hours. The high-temperature aging in (3) can be carried out by standing or stirring at a temperature higher than the cooling temperature (for example, 35 to 50°C, more preferably 35 to 45°C). The standing or stirring time is preferably 10 minutes or more, more preferably about 10 minutes to 19 hours. The upper or lower limit of the stirring time (10 minutes to 19 hours) may be, for example, about 1, 2, 3, 5, 10, or 15 hours.
なお、上記のブレクスピプラゾール又はその塩の二水和物結晶(水和物I形結晶)の製造方法を用いることにより、従来の製造方法(例えば特許文献2に記載の方法)に比べて、平均粒子径の大きいブレクスピプラゾール又はその塩の二水和物結晶(水和物I形結晶)を再現性よく得ることができる。上記のようにして調製されるブレクスピプラゾール又はその塩の二水和物結晶を、「本開示の水和物I形結晶」ということがある。本開示の水和物I形結晶は、本開示の結晶を前駆体として調製され得る、ということもできる。
By using the above-described method for producing dihydrate crystals of brexpiprazole or a salt thereof (hydrate form I crystals), compared to conventional production methods (for example, the method described in Patent Document 2), Dihydrate crystals (hydrate form I crystals) of brexpiprazole or a salt thereof having a large average particle size can be obtained with good reproducibility. The dihydrate crystals of brexpiprazole or a salt thereof prepared as described above are sometimes referred to as "hydrate Form I crystals of the present disclosure." It can also be said that the hydrate Form I crystals of the present disclosure can be prepared using the crystals of the present disclosure as precursors.
本開示の水和物I形結晶は、平均粒子径が26μm以上であることが好ましく、35、又は45μm以上であることがより好ましい。また、上限は特に限定はされないが、例えば60μm以下が例示され、55、又は50μm以下も例示され得る。本明細書における平均粒子径は、レーザー回折法により測定される体積平均径である。
The hydrate form I crystal of the present disclosure preferably has an average particle size of 26 µm or more, more preferably 35 or 45 µm or more. Although the upper limit is not particularly limited, for example, 60 μm or less is exemplified, and 55 or 50 μm or less may be exemplified. The average particle size in this specification is the volume average size measured by a laser diffraction method.
なお、本開示の水和物I形結晶は、モノクロメーターを通したλ=1.5418Åの銅放射線により測定される粉末X線回折パターンにおいて、回折角2θ(°)= 8.1±0.2、8.9±0.2、15.1±0.2、15.6±0.2、及び24.4±0.2にピークを有する。さらには、回折角2θ(°)=14.0±0.2、18.0±0.2、18.5±0.2、18.9±0.2、19.5±0.2、及び24.9±0.2にもピークを好ましく有し得る。
In addition, the hydrate form I crystal of the present disclosure has a diffraction angle 2θ (°) = 8.1 ± 0.5 in a powder X-ray diffraction pattern measured by copper radiation at λ = 1.5418 Å through a monochromator. It has peaks at 2, 8.9±0.2, 15.1±0.2, 15.6±0.2, and 24.4±0.2. Furthermore, diffraction angle 2θ (°) = 14.0 ± 0.2, 18.0 ± 0.2, 18.5 ± 0.2, 18.9 ± 0.2, 19.5 ± 0.2, and preferably also peaks at 24.9±0.2.
また、本開示の水和物I形結晶は、臭化カリウム錠剤法により測定された赤外線吸収スペクトルにおいて、波数(cm-1)=3509±10、2934±10、2812±10、1651±3、1626±3、1447±3、1223±3、及び839±3に赤外線吸収バンドを有する。
Further, the hydrate form I crystal of the present disclosure has wave numbers (cm -1 ) = 3509 ± 10, 2934 ± 10, 2812 ± 10, 1651 ± 3, in the infrared absorption spectrum measured by the potassium bromide tablet method. It has infrared absorption bands at 1626±3, 1447±3, 1223±3, and 839±3.
なお、本明細書において「含む」とは、「本質的にからなる」と、「からなる」をも包含する(The term "comprising" includes "consisting essentially of” and "consisting of.")。また、本発明は、本明細書に説明した構成要件を任意の組み合わせを全て包含する。
In this specification, the term "comprising" includes "consisting essentially of" and "consisting of." In addition, the present invention encompasses all arbitrary combinations of the constituent elements described herein.
また、上述した本発明の各実施形態について説明した各種特性(性質、構造、機能等)は、本発明に包含される主題を特定するにあたり、どのように組み合わせられてもよい。すなわち、本発明には、本明細書に記載される組み合わせ可能な各特性のあらゆる組み合わせからなる主題が全て包含される。
In addition, the various characteristics (property, structure, function, etc.) described for each of the embodiments of the present invention described above may be combined in any way to specify the subject matter included in the present invention. That is, the invention encompasses all subject matter consisting of any and all possible combinations of the features described herein.
以下、例を示して本開示の実施形態をより具体的に説明するが、本開示の実施形態は下記の例に限定されるものではない。
Hereinafter, the embodiments of the present disclosure will be described more specifically with examples, but the embodiments of the present disclosure are not limited to the following examples.
[ブレクスピプラゾールの合成]
特許文献2(国際公開第2013/162046号)の参考例1及び2に記載の方法により、7-[4-(4-ベンゾ[b]チオフェン-4-イル-ピペラジン-1-イル)ブトキシ]-1H-キノリン-2-オン(ブレクスピプラゾール)を調製し、以下の検討に用いた。 [Synthesis of brexpiprazole]
7-[4-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)butoxy] by the method described in Reference Examples 1 and 2 of Patent Document 2 (WO 2013/162046). -1H-quinolin-2-one (brexpiprazole) was prepared and used in the following studies.
特許文献2(国際公開第2013/162046号)の参考例1及び2に記載の方法により、7-[4-(4-ベンゾ[b]チオフェン-4-イル-ピペラジン-1-イル)ブトキシ]-1H-キノリン-2-オン(ブレクスピプラゾール)を調製し、以下の検討に用いた。 [Synthesis of brexpiprazole]
7-[4-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)butoxy] by the method described in Reference Examples 1 and 2 of Patent Document 2 (WO 2013/162046). -1H-quinolin-2-one (brexpiprazole) was prepared and used in the following studies.
[ブレクスピプラゾール水和物結晶の調製(製造例1)]
7-[4-(4-ベンゾ[b]チオフェン-4-イル-ピペラジン-1-イル)-ブトキシ]-1H-キノリン-2-オン8.0g、エタノール96.0mL、水92.0mL、水酸化ナトリウム4.06g を攪拌しながら還流することにより溶解させた(還流温度:約82℃)。還流にて攪拌後、70℃付近まで冷却し、熱時濾過を行い、エタノール16mLで洗浄した。熱時濾過後、還流温度まで再加熱し、攪拌を行った。攪拌後、30℃以下まで冷却し、さらに1時間攪拌した。この段階で得られた(再結晶した)水和物結晶を以下「結晶X」とも呼ぶ。 [Preparation of brexpiprazole hydrate crystals (Production Example 1)]
7-[4-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)-butoxy]-1H-quinolin-2-one 8.0 g, ethanol 96.0 mL, water 92.0 mL, water 4.06 g of sodium oxide was dissolved by refluxing with stirring (refluxing temperature: about 82°C). After stirring under reflux, the mixture was cooled to about 70° C., filtered while hot, and washed with 16 mL of ethanol. After hot filtration, the mixture was reheated to the reflux temperature and stirred. After stirring, the mixture was cooled to 30° C. or less and stirred for another hour. The (recrystallized) hydrate crystals obtained at this stage are hereinafter also referred to as "crystal X".
7-[4-(4-ベンゾ[b]チオフェン-4-イル-ピペラジン-1-イル)-ブトキシ]-1H-キノリン-2-オン8.0g、エタノール96.0mL、水92.0mL、水酸化ナトリウム4.06g を攪拌しながら還流することにより溶解させた(還流温度:約82℃)。還流にて攪拌後、70℃付近まで冷却し、熱時濾過を行い、エタノール16mLで洗浄した。熱時濾過後、還流温度まで再加熱し、攪拌を行った。攪拌後、30℃以下まで冷却し、さらに1時間攪拌した。この段階で得られた(再結晶した)水和物結晶を以下「結晶X」とも呼ぶ。 [Preparation of brexpiprazole hydrate crystals (Production Example 1)]
7-[4-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)-butoxy]-1H-quinolin-2-one 8.0 g, ethanol 96.0 mL, water 92.0 mL, water 4.06 g of sodium oxide was dissolved by refluxing with stirring (refluxing temperature: about 82°C). After stirring under reflux, the mixture was cooled to about 70° C., filtered while hot, and washed with 16 mL of ethanol. After hot filtration, the mixture was reheated to the reflux temperature and stirred. After stirring, the mixture was cooled to 30° C. or less and stirred for another hour. The (recrystallized) hydrate crystals obtained at this stage are hereinafter also referred to as "crystal X".
その後、30℃以下を保ちながら水116mLを加え、さらに64時間攪拌した後、38~43℃に昇温し、6.5時間攪拌した。攪拌後、固液分離を実施し、得られた固体を水240mlで洗浄した。洗浄後の固体をさらに水8mlとエタノール8mlの混合溶液にて洗浄し,得られた固体を恒量になるまで風乾し、7-[4-(4-ベンゾ[b]チオフェン-4-イル-ピペラジン-1-イル)-ブトキシ]-1H-キノリン-2-オン二水和物(水和物I形結晶)8.22g(収率:94.87%,化学純度:99.67%)を得た。
After that, 116 mL of water was added while maintaining the temperature at 30°C or less, and after stirring for an additional 64 hours, the temperature was raised to 38 to 43°C and the mixture was stirred for 6.5 hours. After stirring, solid-liquid separation was performed, and the obtained solid was washed with 240 ml of water. The washed solid is further washed with a mixed solution of 8 ml of water and 8 ml of ethanol, and the obtained solid is air-dried to a constant weight, and 7-[4-(4-benzo[b]thiophen-4-yl-piperazine. -1-yl)-butoxy]-1H-quinolin-2-one dihydrate (hydrate form I crystals) 8.22 g (yield: 94.87%, chemical purity: 99.67%) rice field.
[特許文献2の方法による水和物結晶の調製(製造例2)]
また、上記とは別に、特許文献2(国際公開第2013/162046号)の実施例1に記載の方法を参考にして、7-[4-(4-ベンゾ[b]チオフェン-4-イル-ピペラジン-1-イル)-ブトキシ]-1H-キノリン-2-オン二水和物(水和物I形結晶)を調製した。 [Preparation of hydrate crystals by the method of Patent Document 2 (Production Example 2)]
In addition to the above, 7-[4-(4-benzo[b]thiophen-4-yl- Piperazin-1-yl)-butoxy]-1H-quinolin-2-one dihydrate (hydrate form I crystals) was prepared.
また、上記とは別に、特許文献2(国際公開第2013/162046号)の実施例1に記載の方法を参考にして、7-[4-(4-ベンゾ[b]チオフェン-4-イル-ピペラジン-1-イル)-ブトキシ]-1H-キノリン-2-オン二水和物(水和物I形結晶)を調製した。 [Preparation of hydrate crystals by the method of Patent Document 2 (Production Example 2)]
In addition to the above, 7-[4-(4-benzo[b]thiophen-4-yl- Piperazin-1-yl)-butoxy]-1H-quinolin-2-one dihydrate (hydrate form I crystals) was prepared.
すなわち、水186.0kgに水酸化ナトリウム2.75kgを加え、攪拌、溶解させた。7-[4-(4-ベンゾ[b]チオフェン-4-イル-ピペラジン-1-イル)-ブトキシ]-1H-キノリン-2-オン9.3kg、水139.5kg、DL-乳酸4.25kg、エタノール110.2kgの懸濁液を、攪拌しながら還流することにより溶解させた(還流温度:約82℃)。得られた溶液を5℃以下まで冷却し、1℃以下に冷却した水酸化ナトリウム水溶液へと、3℃以下を保ちながら流入した。3℃以下で3時間以上攪拌した。
That is, 2.75 kg of sodium hydroxide was added to 186.0 kg of water and stirred to dissolve. 7-[4-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)-butoxy]-1H-quinolin-2-one 9.3 kg, water 139.5 kg, DL-lactic acid 4.25 kg , and 110.2 kg of ethanol were dissolved by refluxing with stirring (refluxing temperature: about 82° C.). The resulting solution was cooled to 5° C. or lower and poured into an aqueous sodium hydroxide solution cooled to 1° C. or lower while maintaining the temperature at 3° C. or lower. The mixture was stirred at 3° C. or below for 3 hours or more.
前記攪拌後、40℃まで昇温した。40℃から50℃にて2時間以上攪拌し、固液分離した。同様の操作を合計で3回実施した。3回分を合わせて水にて洗浄後、50%含水エタノールにて洗浄した。得られた固体を乾燥窒素及び加湿窒素を用いて40℃で乾燥し、7-[4-(4-ベンゾ[b]チオフェン-4-イル-ピペラジン-1-イル)-ブトキシ]-1H-キノリン-2-オン二水和物(水和物I形結晶)29.15kgを得た。
After the stirring, the temperature was raised to 40°C. The mixture was stirred at 40° C. to 50° C. for 2 hours or longer to effect solid-liquid separation. A similar operation was performed three times in total. The three batches were combined, washed with water, and then washed with ethanol containing 50% water. The resulting solid was dried with dry nitrogen and humidified nitrogen at 40° C. to yield 7-[4-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)-butoxy]-1H-quinoline. 29.15 kg of -2-one dihydrate (hydrate form I crystals) was obtained.
[結晶X(wet晶)の調製(製造例3)]
7-[4-(4-ベンゾ[b]チオフェン-4-イル-ピペラジン-1-イル)-ブトキシ]-1H-キノリン-2-オン8.0g,エタノール112.0mL,水92.0mL,水酸化ナトリウム4.06g を攪拌しながら還流することにより溶解させた。還流にて攪拌後,35℃まで冷却した。析出晶を一部取り出して、結晶X(wet晶)を得た。 [Preparation of crystal X (wet crystal) (Production Example 3)]
7-[4-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)-butoxy]-1H-quinolin-2-one 8.0 g, ethanol 112.0 mL, water 92.0 mL, water 4.06 g of sodium oxide was dissolved by refluxing with stirring. After stirring under reflux, the mixture was cooled to 35°C. A part of the precipitated crystal was taken out to obtain a crystal X (wet crystal).
7-[4-(4-ベンゾ[b]チオフェン-4-イル-ピペラジン-1-イル)-ブトキシ]-1H-キノリン-2-オン8.0g,エタノール112.0mL,水92.0mL,水酸化ナトリウム4.06g を攪拌しながら還流することにより溶解させた。還流にて攪拌後,35℃まで冷却した。析出晶を一部取り出して、結晶X(wet晶)を得た。 [Preparation of crystal X (wet crystal) (Production Example 3)]
7-[4-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)-butoxy]-1H-quinolin-2-one 8.0 g, ethanol 112.0 mL, water 92.0 mL, water 4.06 g of sodium oxide was dissolved by refluxing with stirring. After stirring under reflux, the mixture was cooled to 35°C. A part of the precipitated crystal was taken out to obtain a crystal X (wet crystal).
[結晶Xの調製(製造例4)]
7-[4-(4-ベンゾ[b]チオフェン-4-イル-ピペラジン-1-イル)-ブトキシ]-1H-キノリン-2-オン8.0g,エタノール112.0mL,水92.0mL,水酸化ナトリウム4.06g を攪拌しながら還流することにより溶解させた。還流にて攪拌後,35℃まで冷却し,固液分離した。得られた固体を50℃で4時間乾燥し,結晶Xを得た。 [Preparation of Crystal X (Production Example 4)]
7-[4-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)-butoxy]-1H-quinolin-2-one 8.0 g, ethanol 112.0 mL, water 92.0 mL, water 4.06 g of sodium oxide was dissolved by refluxing with stirring. After stirring under reflux, the mixture was cooled to 35° C. for solid-liquid separation. The obtained solid was dried at 50° C. for 4 hours to obtain crystal X.
7-[4-(4-ベンゾ[b]チオフェン-4-イル-ピペラジン-1-イル)-ブトキシ]-1H-キノリン-2-オン8.0g,エタノール112.0mL,水92.0mL,水酸化ナトリウム4.06g を攪拌しながら還流することにより溶解させた。還流にて攪拌後,35℃まで冷却し,固液分離した。得られた固体を50℃で4時間乾燥し,結晶Xを得た。 [Preparation of Crystal X (Production Example 4)]
7-[4-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)-butoxy]-1H-quinolin-2-one 8.0 g, ethanol 112.0 mL, water 92.0 mL, water 4.06 g of sodium oxide was dissolved by refluxing with stirring. After stirring under reflux, the mixture was cooled to 35° C. for solid-liquid separation. The obtained solid was dried at 50° C. for 4 hours to obtain crystal X.
[水和物II形結晶の調製(製造例5)]
水186.0mLに水酸化ナトリウム3.00gを加え,攪拌,溶解させ,水酸化ナトリウム水溶液を得た。7-[4-(4-ベンゾ[b]チオフェン-4-イル-ピペラジン-1-イル)-ブトキシ]-1H-キノリン-2-オン9.3g,水139.5mL,エタノール139.5mL,L-乳酸5.22gの懸濁液を,攪拌しながら還流することにより溶解させた(還流温度:約83℃)。得られた溶液を5℃以下まで冷却し,1℃以下に冷却した水酸化ナトリウム水溶液へと,3℃以下を保ちながら流入し,3℃以下で1時間攪拌し,結晶を析出させた。この段階で得られた結晶を以下「水和物II形結晶」とも呼ぶ。 [Preparation of hydrate form II crystals (Production Example 5)]
3.00 g of sodium hydroxide was added to 186.0 mL of water, stirred and dissolved to obtain an aqueous sodium hydroxide solution. 7-[4-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)-butoxy]-1H-quinolin-2-one 9.3 g, water 139.5 mL, ethanol 139.5 mL, L - A suspension of 5.22 g of lactic acid was dissolved by refluxing with stirring (reflux temperature: about 83°C). The resulting solution was cooled to 5° C. or lower, poured into an aqueous sodium hydroxide solution cooled to 1° C. or lower while maintaining the temperature at 3° C. or lower, and stirred at 3° C. or lower for 1 hour to precipitate crystals. The crystals obtained at this stage are hereinafter also referred to as "hydrate form II crystals".
水186.0mLに水酸化ナトリウム3.00gを加え,攪拌,溶解させ,水酸化ナトリウム水溶液を得た。7-[4-(4-ベンゾ[b]チオフェン-4-イル-ピペラジン-1-イル)-ブトキシ]-1H-キノリン-2-オン9.3g,水139.5mL,エタノール139.5mL,L-乳酸5.22gの懸濁液を,攪拌しながら還流することにより溶解させた(還流温度:約83℃)。得られた溶液を5℃以下まで冷却し,1℃以下に冷却した水酸化ナトリウム水溶液へと,3℃以下を保ちながら流入し,3℃以下で1時間攪拌し,結晶を析出させた。この段階で得られた結晶を以下「水和物II形結晶」とも呼ぶ。 [Preparation of hydrate form II crystals (Production Example 5)]
3.00 g of sodium hydroxide was added to 186.0 mL of water, stirred and dissolved to obtain an aqueous sodium hydroxide solution. 7-[4-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)-butoxy]-1H-quinolin-2-one 9.3 g, water 139.5 mL, ethanol 139.5 mL, L - A suspension of 5.22 g of lactic acid was dissolved by refluxing with stirring (reflux temperature: about 83°C). The resulting solution was cooled to 5° C. or lower, poured into an aqueous sodium hydroxide solution cooled to 1° C. or lower while maintaining the temperature at 3° C. or lower, and stirred at 3° C. or lower for 1 hour to precipitate crystals. The crystals obtained at this stage are hereinafter also referred to as "hydrate form II crystals".
[調製した結晶の解析]
製造例3で得られた結晶X(Wet晶)について、モノクロメーターを通したλ=1.5418Åの銅放射線(CuKα特性X線)により粉末X線回折パターンを、また、臭化カリウム錠剤法により赤外線吸収スペクトルを、それぞれ測定した。また、製造例1で得た水和物I形結晶についても、同様の測定を行った。 [Analysis of prepared crystals]
For the crystal X (wet crystal) obtained in Production Example 3, the powder X-ray diffraction pattern was measured by copper radiation (CuKα characteristic X-ray) of λ = 1.5418 Å through a monochromator, and by the potassium bromide tablet method. Infrared absorption spectra were measured respectively. Also, the hydrate type I crystal obtained in Production Example 1 was subjected to the same measurement.
製造例3で得られた結晶X(Wet晶)について、モノクロメーターを通したλ=1.5418Åの銅放射線(CuKα特性X線)により粉末X線回折パターンを、また、臭化カリウム錠剤法により赤外線吸収スペクトルを、それぞれ測定した。また、製造例1で得た水和物I形結晶についても、同様の測定を行った。 [Analysis of prepared crystals]
For the crystal X (wet crystal) obtained in Production Example 3, the powder X-ray diffraction pattern was measured by copper radiation (CuKα characteristic X-ray) of λ = 1.5418 Å through a monochromator, and by the potassium bromide tablet method. Infrared absorption spectra were measured respectively. Also, the hydrate type I crystal obtained in Production Example 1 was subjected to the same measurement.
なお、測定には、Bruker AXS社製のX線回折装置(D8 ADVANCE)及び島津製作所社製のフーリエ変換赤外分光光度計(FT-IR IRAffinity-1S)を用いた。また、測定に供する各結晶については、日東精工アナリテック社製のカールフィッシャー微量水分測定装置(CA-200)を用い、カールフィッシャー法(電量滴定法)により、水分値(重量%)を測定した。
For the measurement, an X-ray diffractometer (D8 ADVANCE) manufactured by Bruker AXS and a Fourier transform infrared spectrophotometer (FT-IR IRAffinity-1S) manufactured by Shimadzu Corporation were used. For each crystal used for measurement, the water content (% by weight) was measured by the Karl Fischer method (coulometric titration method) using a Karl Fischer trace moisture analyzer (CA-200) manufactured by Nitto Seiko Analyticc. .
製造例3で得られた結晶X(Wet晶)の水分値は37.6%であった。また、粉末X線回折パターン測定結果を、図1並びに表1bに示す。表1bには特徴的なピークを示す。
The water content of crystal X (wet crystal) obtained in Production Example 3 was 37.6%. Moreover, the powder X-ray diffraction pattern measurement results are shown in FIG. 1 and Table 1b. Table 1b shows characteristic peaks.
なお、製造例1で得た水和物I形結晶、及び製造例5で得た水和物II形結晶の粉末X線回折パターン測定結果を、それぞれ、図2a及び図2bに示す。
The powder X-ray diffraction pattern measurement results of the hydrate form I crystal obtained in Production Example 1 and the hydrate form II crystal obtained in Production Example 5 are shown in Figures 2a and 2b, respectively.
また、製造例4で得られた結晶Xを、約7%湿度に調湿したデシケータに入れ、16時間静置させて、さらに乾燥した。このようにして得られた、乾燥結晶の水分値を上記と同様にして測定したところ、10.4%であった。この乾燥結晶についても上記と同様にして赤外線吸収スペクトルを測定した。
In addition, the crystal X obtained in Production Example 4 was placed in a desiccator adjusted to a humidity of about 7%, left to stand for 16 hours, and further dried. The moisture content of the dried crystals obtained in this manner was measured in the same manner as described above and found to be 10.4%. The infrared absorption spectrum of this dried crystal was also measured in the same manner as described above.
赤外線吸収スペクトルの測定結果を図3a~3bに示す。図3a~3bに結果が示される結晶Xの水分値を下表に示す。
Figures 3a to 3b show the measurement results of the infrared absorption spectrum. The moisture values for Crystal X, whose results are shown in Figures 3a-3b, are given in the table below.
いずれの赤外線吸収スペクトルにおいても、波数(cm-1)=2824、1614、1514、1455、1213、1020、841、及び637にピークが観測された。)
Peaks were observed at wave numbers (cm −1 )=2824, 1614, 1514, 1455, 1213, 1020, 841 and 637 in any infrared absorption spectrum. )
なお、製造例1で得た水和物I形結晶の赤外線吸収スペクトルの測定結果を、図4に示す。
The measurement results of the infrared absorption spectrum of the hydrate form I crystal obtained in Production Example 1 are shown in FIG.
上記「ブレクスピプラゾール水和物結晶の調製」で得られた二水和物結晶が、特許文献2で得られた水和物I形結晶と同じ結晶であることが、粉末X線回折パターン測定結果及び赤外線吸収スペクトル測定から確認できた。特に、粉末X線回折パターン測定(図2a)では、回折角2θ(°)= 8.1、8.9、15.1、15.6、及び24.4に特徴的なピークが観察され、さらに回折角2θ(°)=14.0、18.0、18.5、18.9、19.5、及び24.9にもピークが観察された。また、赤外線吸収スペクトル測定(図4)では、波数(cm-1)=3507、2934、2810、1651、1626、1447、1223、839に特徴的なピークが観察された。
Powder X-ray diffraction pattern measurement confirms that the dihydrate crystals obtained in the above "Preparation of brexpiprazole hydrate crystals" are the same crystals as the hydrate form I crystals obtained in Patent Document 2. It was confirmed from the results and infrared absorption spectrum measurement. In particular, in the powder X-ray diffraction pattern measurement (Fig. 2a), characteristic peaks were observed at diffraction angles 2θ (°) = 8.1, 8.9, 15.1, 15.6, and 24.4, Furthermore, peaks were also observed at diffraction angles 2θ (°) = 14.0, 18.0, 18.5, 18.9, 19.5, and 24.9. Further, in infrared absorption spectrum measurement (FIG. 4), characteristic peaks were observed at wave numbers (cm −1 )=3507, 2934, 2810, 1651, 1626, 1447, 1223 and 839.
またさらに、製造例1で得た水和物I形結晶について、マルバーン・パナリティカル社製の粒度分布測定装置(MASTERSIZER3000)を用いて,レーザー回折法による粒子径測定法により,平均粒子径を測定した.その結果、製造例1で得た水和物I形結晶の平均粒子径は45.6μmであった。なお、ここでの平均粒子径とは体積平均径をいう。
Furthermore, the average particle size of the hydrate form I crystals obtained in Production Example 1 was measured using a particle size distribution analyzer (MASTERSIZER 3000) manufactured by Malvern Panalytical Co., Ltd., by a particle size measurement method based on a laser diffraction method. bottom. As a result, the average particle size of the hydrate form I crystals obtained in Production Example 1 was 45.6 μm. In addition, the average particle diameter here means a volume average diameter.
[製造例2で調製した結晶の解析]
製造例2で得た水和物I結晶について、モノクロメーターを通したλ=1.5418Åの銅放射線(CuKα特性X線)により粉末X線回折パターンを、また、臭化カリウム錠剤法により赤外線吸収スペクトルを、それぞれ測定した。なお、測定には、Bruker AXS社製のX線回折装置(D8 ADVANCE)及び島津製作所社製のフーリエ変換赤外分光光度計(FT-IR IRAffinity-1S)を用いた。 [Analysis of crystals prepared in Production Example 2]
For the hydrate I crystals obtained in Production Example 2, the powder X-ray diffraction pattern was measured by copper radiation (CuKα characteristic X-ray) of λ=1.5418 Å through a monochromator, and the infrared absorption by the potassium bromide tablet method. Spectra were measured respectively. For the measurement, an X-ray diffractometer (D8 ADVANCE) manufactured by Bruker AXS and a Fourier transform infrared spectrophotometer (FT-IR IRAffinity-1S) manufactured by Shimadzu Corporation were used.
製造例2で得た水和物I結晶について、モノクロメーターを通したλ=1.5418Åの銅放射線(CuKα特性X線)により粉末X線回折パターンを、また、臭化カリウム錠剤法により赤外線吸収スペクトルを、それぞれ測定した。なお、測定には、Bruker AXS社製のX線回折装置(D8 ADVANCE)及び島津製作所社製のフーリエ変換赤外分光光度計(FT-IR IRAffinity-1S)を用いた。 [Analysis of crystals prepared in Production Example 2]
For the hydrate I crystals obtained in Production Example 2, the powder X-ray diffraction pattern was measured by copper radiation (CuKα characteristic X-ray) of λ=1.5418 Å through a monochromator, and the infrared absorption by the potassium bromide tablet method. Spectra were measured respectively. For the measurement, an X-ray diffractometer (D8 ADVANCE) manufactured by Bruker AXS and a Fourier transform infrared spectrophotometer (FT-IR IRAffinity-1S) manufactured by Shimadzu Corporation were used.
図5aに粉末X線回折パターン測定結果を示す。図5aに示すように,2θ=8.1°、8.9°、15.1°、15.6°及び24.4回折ピークを認めた。それ以外のピークとしては、2θ=12.2°、14.0°18.1、18.4°、18.9°、19.5°、20.6°、22.5°、24.9°、26.1°、27.1°、28.6°、28.9°、30.4°及び34.0°に回折ピークを認めた。
Fig. 5a shows the results of powder X-ray diffraction pattern measurement. As shown in FIG. 5a, 2θ=8.1°, 8.9°, 15.1°, 15.6° and 24.4 diffraction peaks were observed. Other peaks at 2θ = 12.2°, 14.0°, 18.1, 18.4°, 18.9°, 19.5°, 20.6°, 22.5°, 24.9 , 26.1°, 27.1°, 28.6°, 28.9°, 30.4° and 34.0°.
また、図5bに、赤外線吸収スペクトル測定結果を示す。図5bに示すように、波数3505cm-1、2934cm-1、2810cm-1、1653cm-1、1624cm-1、1447cm-1、1223cm-1及び839cm-1付近に吸収を認めた。
Moreover, the infrared absorption spectrum measurement result is shown in FIG. 5b. As shown in FIG. 5b, absorption was observed near wavenumbers of 3505 cm −1 , 2934 cm −1 , 2810 cm −1 , 1653 cm −1 , 1624 cm −1 , 1447 cm −1 , 1223 cm −1 and 839 cm −1 .
また、製造例2で得た水和物I結晶について、京都電子工業社製の水分測定装置(MKC-610)を用い、カールフィッシャー法(電量滴定法)により、水分値(重量%)を測定した。また、日機装社製の粒度分布測定装置(MT3300EX)を用いて、レーザー回折法による粒子径測定法により、平均粒子径を測定した。その結果、水分値は7.50%、平均粒子径は7.9μmであった。なお、ここでの平均粒子径とは体積平均径をいう。
Further, the water content (% by weight) of the hydrate I crystals obtained in Production Example 2 was measured by the Karl Fischer method (coulometric titration method) using a water content analyzer (MKC-610) manufactured by Kyoto Electronics Industry Co., Ltd. bottom. In addition, the average particle size was measured by a particle size measurement method based on a laser diffraction method using a particle size distribution analyzer (MT3300EX) manufactured by Nikkiso Co., Ltd. As a result, the water content was 7.50% and the average particle size was 7.9 μm. In addition, the average particle diameter here means a volume average diameter.
Claims (12)
- 7-[4-(4-ベンゾ[b]チオフェン-4-イル-ピペラジン-1-イル)ブトキシ]-1H-キノリン-2-オン又はその塩の水和物の結晶であって、
臭化カリウム錠剤法により測定される赤外線吸収スペクトルにおいて、波数(cm-1)=2824±10、1614±3、1514±3、1455±3、1213±3、1020±3、841±3、及び637±3 に赤外線吸収バンドを有する、結晶。 A hydrate crystal of 7-[4-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)butoxy]-1H-quinolin-2-one or a salt thereof,
In the infrared absorption spectrum measured by the potassium bromide tablet method, wave numbers (cm -1 ) = 2824 ± 10, 1614 ± 3, 1514 ± 3, 1455 ± 3, 1213 ± 3, 1020 ± 3, 841 ± 3, and A crystal with an infrared absorption band at 637±3. - 7-[4-(4-ベンゾ[b]チオフェン-4-イル-ピペラジン-1-イル)ブトキシ]-1H-キノリン-2-オン又はその塩の水和物の結晶であって、その水分値が30~45%のとき、
λ=1.5418Åの銅放射線 により測定される粉末X線回折パターンにおいて、
回折角2θ(°)= 11.4±0.2、12.4±0.2、15.8±0.2、18.2±0.2、及び22.8±0.2にピークを有する、結晶。 7-[4-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)butoxy]-1H-quinolin-2-one or a hydrate crystal of a salt thereof, the water content thereof is 30 to 45%,
In the powder X-ray diffraction pattern measured by copper radiation at λ=1.5418 Å,
Peaks at diffraction angles 2θ (°) = 11.4 ± 0.2, 12.4 ± 0.2, 15.8 ± 0.2, 18.2 ± 0.2, and 22.8 ± 0.2 have crystals. - λ=1.5418Åの銅放射線により測定される粉末X線回折パターンにおいて、
さらに、回折角2θ(°)=19.5±0.2にピークを有する、請求項2に記載の結晶。 In the powder X-ray diffraction pattern measured by copper radiation at λ=1.5418 Å,
3. The crystal according to claim 2, further having a peak at a diffraction angle 2[theta]([deg.])=19.5±0.2. - 臭化カリウム錠剤法により測定された赤外線吸収スペクトルにおいて、波数(cm-1)=2824±10、1614±3、1514±3、1455±3、1213±3、1020±3、841±3、及び637±3 に赤外線吸収バンドを有する、請求項2又は3に記載の結晶。 In the infrared absorption spectrum measured by the potassium bromide tablet method, wave numbers (cm -1 ) = 2824 ± 10, 1614 ± 3, 1514 ± 3, 1455 ± 3, 1213 ± 3, 1020 ± 3, 841 ± 3, and 4. A crystal according to claim 2 or 3, having an infrared absorption band at 637±3.
- (1)7-[4-(4-ベンゾ[b]チオフェン-4-イル-ピペラジン-1-イル)ブトキシ]-1H-キノリン-2-オン及びアルカリが溶解したアルコール水溶液を冷却すること
を含む、請求項1~4のいずれかに記載の結晶の製造方法。 (1) including cooling an aqueous alcohol solution in which 7-[4-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)butoxy]-1H-quinolin-2-one and alkali are dissolved; , the method for producing the crystal according to any one of claims 1 to 4. - (1)7-[4-(4-ベンゾ[b]チオフェン-4-イル-ピペラジン-1-イル)ブトキシ]-1H-キノリン-2-オン及びアルカリが溶解したアルコール水溶液を冷却すること、
(2)冷却した前記水溶液にさらに水を加えること、及び
(3)前記冷却温度より高い温度で10分~19時間静置又は撹拌すること
を含む、7-[4-(4-ベンゾ[b]チオフェン-4-イル-ピペラジン-1-イル)ブトキシ]-1H-キノリン-2-オン又はその塩の二水和物結晶の製造方法。 (1) cooling an aqueous alcohol solution in which 7-[4-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)butoxy]-1H-quinolin-2-one and an alkali are dissolved;
(2) adding more water to the cooled aqueous solution; and (3) standing or stirring at a temperature higher than the cooling temperature for 10 minutes to 19 hours. ] A method for producing a dihydrate crystal of thiophen-4-yl-piperazin-1-yl)butoxy]-1H-quinolin-2-one or a salt thereof. - 工程(2)における加水量が、7-[4-(4-ベンゾ[b]チオフェン-4-イル-ピペラジン-1-イル)ブトキシ]-1H-キノリン-2-オン及びアルカリを含有するアルコール水溶液の容量の、0.4~0.8倍容量である、請求項6に記載の製造方法。 Aqueous alcohol solution containing 7-[4-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)butoxy]-1H-quinolin-2-one and alkali in the amount added in step (2) The production method according to claim 6, wherein the capacity is 0.4 to 0.8 times the capacity of.
- 工程(1)における冷却の温度が、10~40℃である、請求項5~7のいずれかに記載の製造方法。 The production method according to any one of claims 5 to 7, wherein the cooling temperature in step (1) is 10 to 40°C.
- 請求項1~4のいずれかに記載の結晶及びアルカリを含有する10~40℃のアルコール水溶液を、当該アルコール水溶液の温度より高い温度であって且つ35~50℃の温度で、10分~19時間静置又は撹拌すること
を含む、7-[4-(4-ベンゾ[b]チオフェン-4-イル-ピペラジン-1-イル)ブトキシ]-1H-キノリン-2-オン又はその塩の二水和物結晶の製造方法。 10 to 40 ° C. alcohol aqueous solution containing the crystal and alkali according to any one of claims 1 to 4, at a temperature higher than the temperature of the alcohol aqueous solution and at a temperature of 35 to 50 ° C., for 10 minutes to 19 Dihydrate of 7-[4-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)butoxy]-1H-quinolin-2-one or its salt, including standing or stirring for a period of time A method for producing a hydrate crystal. - 7-[4-(4-ベンゾ[b]チオフェン-4-イル-ピペラジン-1-イル)ブトキシ]-1H-キノリン-2-オン又はその塩の二水和物結晶であって、
モノクロメーターを通したλ=1.5418Åの銅放射線により測定される粉末X線回折パターンにおいて、回折角2θ(°)= 8.1±0.2、8.9±0.2、15.1±0.2、15.6±0.2、及び24.4±0.2にピークを有し、
平均粒子径が26μm 以上である、
結晶。 A dihydrate crystal of 7-[4-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)butoxy]-1H-quinolin-2-one or a salt thereof,
Diffraction angle 2θ (°) = 8.1 ± 0.2, 8.9 ± 0.2, 15.1 in powder X-ray diffraction pattern measured by copper radiation at λ = 1.5418 Å through a monochromator with peaks at ±0.2, 15.6 ±0.2, and 24.4 ±0.2,
An average particle size of 26 μm or more,
crystal. - 7-[4-(4-ベンゾ[b]チオフェン-4-イル-ピペラジン-1-イル)ブトキシ]-1H-キノリン-2-オン又はその塩の二水和物結晶であって、
臭化カリウム錠剤法により測定された赤外線吸収スペクトルにおいて、波数(cm-1)=3509±10、2934±10、2812±10、1651±3、1626±3、1447±3、1223±3、及び839±3 に赤外線吸収バンドを有し、
平均粒子径が26μm 以上である、
結晶。 A dihydrate crystal of 7-[4-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)butoxy]-1H-quinolin-2-one or a salt thereof,
In the infrared absorption spectrum measured by the potassium bromide tablet method, wave numbers (cm -1 ) = 3509 ± 10, 2934 ± 10, 2812 ± 10, 1651 ± 3, 1626 ± 3, 1447 ± 3, 1223 ± 3, and has an infrared absorption band at 839±3,
An average particle size of 26 μm or more,
crystal. - 臭化カリウム錠剤法により測定された赤外線吸収スペクトルにおいて、波数(cm-1)=3509±10、2934±10、2812±10、1651±3、1626±3、1447±3、1223±3、及び839±3 に赤外線吸収バンドを有する 、
請求項10に記載の結晶。 In the infrared absorption spectrum measured by the potassium bromide tablet method, wave numbers (cm -1 ) = 3509 ± 10, 2934 ± 10, 2812 ± 10, 1651 ± 3, 1626 ± 3, 1447 ± 3, 1223 ± 3, and has an infrared absorption band at 839±3 ,
A crystal according to claim 10 .
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---|
TAREK A. ZEIDAN, PRANOTI A. TILAK, JACOB T. TROTTA, ERIN CURRAN, MARK A. OLIVEIRA, RENATO A. CHIARELLA, ÖRN ALMARSSON, MAGALI: "Structural Diversity of Brexpiprazole and Related Analogues: Impact on Solubility and Drug Delivery", CRYSTAL GROWTH & DESIGN, vol. 18, no. 4, 4 April 2018 (2018-04-04), US , pages 2326 - 2334, XP055533458, ISSN: 1528-7483, DOI: 10.1021/acs.cgd.7b01747 * |
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