WO2024031226A1 - Composition pharmaceutique et substance polymorphe d'inhibiteur de fgfr, et leur utilisation pharmaceutique - Google Patents
Composition pharmaceutique et substance polymorphe d'inhibiteur de fgfr, et leur utilisation pharmaceutique Download PDFInfo
- Publication number
- WO2024031226A1 WO2024031226A1 PCT/CN2022/110810 CN2022110810W WO2024031226A1 WO 2024031226 A1 WO2024031226 A1 WO 2024031226A1 CN 2022110810 W CN2022110810 W CN 2022110810W WO 2024031226 A1 WO2024031226 A1 WO 2024031226A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- formula
- compound
- crystal form
- xrpd
- pharmaceutical composition
- Prior art date
Links
- 239000008194 pharmaceutical composition Substances 0.000 title claims abstract description 131
- 229940125829 fibroblast growth factor receptor inhibitor Drugs 0.000 title claims abstract description 6
- 239000000126 substance Substances 0.000 title abstract description 26
- 150000001875 compounds Chemical class 0.000 claims abstract description 313
- 239000003937 drug carrier Substances 0.000 claims abstract description 13
- 229940079593 drug Drugs 0.000 claims abstract description 10
- 239000003814 drug Substances 0.000 claims abstract description 10
- 239000013078 crystal Substances 0.000 claims description 288
- 238000000634 powder X-ray diffraction Methods 0.000 claims description 250
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 240
- 239000012453 solvate Substances 0.000 claims description 101
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 85
- 239000000203 mixture Substances 0.000 claims description 83
- 229920002153 Hydroxypropyl cellulose Polymers 0.000 claims description 61
- 239000001863 hydroxypropyl cellulose Substances 0.000 claims description 61
- 235000010977 hydroxypropyl cellulose Nutrition 0.000 claims description 61
- 238000002360 preparation method Methods 0.000 claims description 60
- JWUJQDFVADABEY-UHFFFAOYSA-N 2-methyltetrahydrofuran Chemical compound CC1CCCO1 JWUJQDFVADABEY-UHFFFAOYSA-N 0.000 claims description 52
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 claims description 36
- 239000000843 powder Substances 0.000 claims description 36
- 239000000314 lubricant Substances 0.000 claims description 35
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 claims description 34
- 239000008187 granular material Substances 0.000 claims description 34
- 239000002245 particle Substances 0.000 claims description 28
- 239000007884 disintegrant Substances 0.000 claims description 27
- 239000000945 filler Substances 0.000 claims description 25
- 238000001035 drying Methods 0.000 claims description 22
- 239000000463 material Substances 0.000 claims description 22
- 239000004088 foaming agent Substances 0.000 claims description 20
- OKMWKBLSFKFYGZ-UHFFFAOYSA-N 1-behenoylglycerol Chemical group CCCCCCCCCCCCCCCCCCCCCC(=O)OCC(O)CO OKMWKBLSFKFYGZ-UHFFFAOYSA-N 0.000 claims description 19
- 229940049654 glyceryl behenate Drugs 0.000 claims description 19
- 229920000168 Microcrystalline cellulose Polymers 0.000 claims description 18
- 239000011230 binding agent Substances 0.000 claims description 18
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 18
- 235000019359 magnesium stearate Nutrition 0.000 claims description 18
- 239000008108 microcrystalline cellulose Substances 0.000 claims description 18
- 229940016286 microcrystalline cellulose Drugs 0.000 claims description 18
- 235000019813 microcrystalline cellulose Nutrition 0.000 claims description 18
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 16
- ZLNQQNXFFQJAID-UHFFFAOYSA-L magnesium carbonate Chemical compound [Mg+2].[O-]C([O-])=O ZLNQQNXFFQJAID-UHFFFAOYSA-L 0.000 claims description 16
- 239000001095 magnesium carbonate Substances 0.000 claims description 16
- 229910000021 magnesium carbonate Inorganic materials 0.000 claims description 16
- 229930195725 Mannitol Natural products 0.000 claims description 15
- 239000000594 mannitol Substances 0.000 claims description 15
- 235000010355 mannitol Nutrition 0.000 claims description 15
- 239000000377 silicon dioxide Substances 0.000 claims description 14
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical group OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 claims description 13
- 239000011248 coating agent Substances 0.000 claims description 12
- 238000000576 coating method Methods 0.000 claims description 12
- VTYYLEPIZMXCLO-UHFFFAOYSA-L Calcium carbonate Chemical compound [Ca+2].[O-]C([O-])=O VTYYLEPIZMXCLO-UHFFFAOYSA-L 0.000 claims description 10
- 239000007864 aqueous solution Substances 0.000 claims description 10
- PPQREHKVAOVYBT-UHFFFAOYSA-H dialuminum;tricarbonate Chemical compound [Al+3].[Al+3].[O-]C([O-])=O.[O-]C([O-])=O.[O-]C([O-])=O PPQREHKVAOVYBT-UHFFFAOYSA-H 0.000 claims description 10
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 10
- XTUSEBKMEQERQV-UHFFFAOYSA-N propan-2-ol;hydrate Chemical compound O.CC(C)O XTUSEBKMEQERQV-UHFFFAOYSA-N 0.000 claims description 8
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 8
- 235000010980 cellulose Nutrition 0.000 claims description 7
- 229920002678 cellulose Polymers 0.000 claims description 7
- 239000001913 cellulose Substances 0.000 claims description 7
- 238000007908 dry granulation Methods 0.000 claims description 7
- 229940079832 sodium starch glycolate Drugs 0.000 claims description 7
- 239000008109 sodium starch glycolate Substances 0.000 claims description 7
- 229920003109 sodium starch glycolate Polymers 0.000 claims description 7
- 238000011282 treatment Methods 0.000 claims description 7
- 206010060862 Prostate cancer Diseases 0.000 claims description 6
- 208000000236 Prostatic Neoplasms Diseases 0.000 claims description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 6
- 239000002552 dosage form Substances 0.000 claims description 6
- 238000002156 mixing Methods 0.000 claims description 6
- -1 organic acid salt Chemical class 0.000 claims description 6
- 206010006187 Breast cancer Diseases 0.000 claims description 5
- 208000026310 Breast neoplasm Diseases 0.000 claims description 5
- 206010009944 Colon cancer Diseases 0.000 claims description 5
- 229920002785 Croscarmellose sodium Polymers 0.000 claims description 5
- 208000000461 Esophageal Neoplasms Diseases 0.000 claims description 5
- 206010058467 Lung neoplasm malignant Diseases 0.000 claims description 5
- 206010030155 Oesophageal carcinoma Diseases 0.000 claims description 5
- 206010033128 Ovarian cancer Diseases 0.000 claims description 5
- 206010061535 Ovarian neoplasm Diseases 0.000 claims description 5
- 206010061902 Pancreatic neoplasm Diseases 0.000 claims description 5
- 208000000453 Skin Neoplasms Diseases 0.000 claims description 5
- 208000005718 Stomach Neoplasms Diseases 0.000 claims description 5
- DPXJVFZANSGRMM-UHFFFAOYSA-N acetic acid;2,3,4,5,6-pentahydroxyhexanal;sodium Chemical compound [Na].CC(O)=O.OCC(O)C(O)C(O)C(O)C=O DPXJVFZANSGRMM-UHFFFAOYSA-N 0.000 claims description 5
- 229940118662 aluminum carbonate Drugs 0.000 claims description 5
- 229910000019 calcium carbonate Inorganic materials 0.000 claims description 5
- 208000029742 colonic neoplasm Diseases 0.000 claims description 5
- 229960001681 croscarmellose sodium Drugs 0.000 claims description 5
- 235000010947 crosslinked sodium carboxy methyl cellulose Nutrition 0.000 claims description 5
- 201000004101 esophageal cancer Diseases 0.000 claims description 5
- 206010017758 gastric cancer Diseases 0.000 claims description 5
- 208000005017 glioblastoma Diseases 0.000 claims description 5
- 201000007270 liver cancer Diseases 0.000 claims description 5
- 208000014018 liver neoplasm Diseases 0.000 claims description 5
- 201000005202 lung cancer Diseases 0.000 claims description 5
- 208000020816 lung neoplasm Diseases 0.000 claims description 5
- 208000015486 malignant pancreatic neoplasm Diseases 0.000 claims description 5
- 229960001855 mannitol Drugs 0.000 claims description 5
- 201000002528 pancreatic cancer Diseases 0.000 claims description 5
- 208000008443 pancreatic carcinoma Diseases 0.000 claims description 5
- 229910000028 potassium bicarbonate Inorganic materials 0.000 claims description 5
- 235000015497 potassium bicarbonate Nutrition 0.000 claims description 5
- 239000011736 potassium bicarbonate Substances 0.000 claims description 5
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 5
- 235000011181 potassium carbonates Nutrition 0.000 claims description 5
- TYJJADVDDVDEDZ-UHFFFAOYSA-M potassium hydrogencarbonate Chemical compound [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 claims description 5
- 201000009410 rhabdomyosarcoma Diseases 0.000 claims description 5
- 235000012239 silicon dioxide Nutrition 0.000 claims description 5
- 201000000849 skin cancer Diseases 0.000 claims description 5
- 201000011549 stomach cancer Diseases 0.000 claims description 5
- GUBGYTABKSRVRQ-UHFFFAOYSA-N 2-(hydroxymethyl)-6-[4,5,6-trihydroxy-2-(hydroxymethyl)oxan-3-yl]oxyoxane-3,4,5-triol Chemical compound OCC1OC(OC2C(O)C(O)C(O)OC2CO)C(O)C(O)C1O GUBGYTABKSRVRQ-UHFFFAOYSA-N 0.000 claims description 4
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 claims description 4
- NKWPZUCBCARRDP-UHFFFAOYSA-L calcium bicarbonate Chemical compound [Ca+2].OC([O-])=O.OC([O-])=O NKWPZUCBCARRDP-UHFFFAOYSA-L 0.000 claims description 4
- 229910000020 calcium bicarbonate Inorganic materials 0.000 claims description 4
- FUFJGUQYACFECW-UHFFFAOYSA-L calcium hydrogenphosphate Chemical compound [Ca+2].OP([O-])([O-])=O FUFJGUQYACFECW-UHFFFAOYSA-L 0.000 claims description 4
- 229940057948 magnesium stearate Drugs 0.000 claims description 4
- 239000001267 polyvinylpyrrolidone Substances 0.000 claims description 4
- 229920000036 polyvinylpyrrolidone Polymers 0.000 claims description 4
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 claims description 4
- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 claims description 3
- TTXJCBSXIAQUKP-UHFFFAOYSA-M C(O)(O)=O.NCC(=O)O.NCC(=O)[O-].[Na+] Chemical group C(O)(O)=O.NCC(=O)O.NCC(=O)[O-].[Na+] TTXJCBSXIAQUKP-UHFFFAOYSA-M 0.000 claims description 3
- KMTRUDSVKNLOMY-UHFFFAOYSA-N Ethylene carbonate Chemical compound O=C1OCCO1 KMTRUDSVKNLOMY-UHFFFAOYSA-N 0.000 claims description 3
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 claims description 3
- IEJIGPNLZYLLBP-UHFFFAOYSA-N dimethyl carbonate Chemical compound COC(=O)OC IEJIGPNLZYLLBP-UHFFFAOYSA-N 0.000 claims description 3
- MVPICKVDHDWCJQ-UHFFFAOYSA-N ethyl 3-pyrrolidin-1-ylpropanoate Chemical compound CCOC(=O)CCN1CCCC1 MVPICKVDHDWCJQ-UHFFFAOYSA-N 0.000 claims description 3
- 229960001375 lactose Drugs 0.000 claims description 3
- 239000008101 lactose Substances 0.000 claims description 3
- 150000005677 organic carbonates Chemical class 0.000 claims description 3
- 229940045902 sodium stearyl fumarate Drugs 0.000 claims description 3
- 239000000454 talc Substances 0.000 claims description 3
- 229910052623 talc Inorganic materials 0.000 claims description 3
- 229940033134 talc Drugs 0.000 claims description 3
- WSVLPVUVIUVCRA-KPKNDVKVSA-N Alpha-lactose monohydrate Chemical compound O.O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O WSVLPVUVIUVCRA-KPKNDVKVSA-N 0.000 claims description 2
- 235000019739 Dicalciumphosphate Nutrition 0.000 claims description 2
- 239000001506 calcium phosphate Substances 0.000 claims description 2
- 229940075614 colloidal silicon dioxide Drugs 0.000 claims description 2
- 229940038472 dicalcium phosphate Drugs 0.000 claims description 2
- 229910000390 dicalcium phosphate Inorganic materials 0.000 claims description 2
- BNIILDVGGAEEIG-UHFFFAOYSA-L disodium hydrogen phosphate Chemical compound [Na+].[Na+].OP([O-])([O-])=O BNIILDVGGAEEIG-UHFFFAOYSA-L 0.000 claims description 2
- 239000007888 film coating Substances 0.000 claims description 2
- 238000009501 film coating Methods 0.000 claims description 2
- 229960001021 lactose monohydrate Drugs 0.000 claims description 2
- 229910000403 monosodium phosphate Inorganic materials 0.000 claims description 2
- 235000019799 monosodium phosphate Nutrition 0.000 claims description 2
- AJPJDKMHJJGVTQ-UHFFFAOYSA-M sodium dihydrogen phosphate Chemical compound [Na+].OP(O)([O-])=O AJPJDKMHJJGVTQ-UHFFFAOYSA-M 0.000 claims description 2
- 150000003626 triacylglycerols Chemical class 0.000 claims description 2
- 229910017053 inorganic salt Inorganic materials 0.000 claims 2
- NEFBYIFKOOEVPA-UHFFFAOYSA-K dicalcium phosphate Chemical compound [Ca+2].[Ca+2].[O-]P([O-])([O-])=O NEFBYIFKOOEVPA-UHFFFAOYSA-K 0.000 claims 1
- 235000015112 vegetable and seed oil Nutrition 0.000 claims 1
- 239000008158 vegetable oil Substances 0.000 claims 1
- 230000001070 adhesive effect Effects 0.000 abstract description 15
- 239000000853 adhesive Substances 0.000 abstract description 14
- 238000011160 research Methods 0.000 abstract description 13
- 238000009776 industrial production Methods 0.000 abstract description 3
- 239000000825 pharmaceutical preparation Substances 0.000 abstract description 3
- 238000002474 experimental method Methods 0.000 description 62
- 238000000034 method Methods 0.000 description 48
- 239000000243 solution Substances 0.000 description 41
- 238000000113 differential scanning calorimetry Methods 0.000 description 32
- 230000000694 effects Effects 0.000 description 29
- 238000002411 thermogravimetry Methods 0.000 description 29
- 238000005550 wet granulation Methods 0.000 description 27
- 238000004090 dissolution Methods 0.000 description 26
- 230000008569 process Effects 0.000 description 24
- 239000004677 Nylon Substances 0.000 description 23
- 239000012528 membrane Substances 0.000 description 23
- 229920001778 nylon Polymers 0.000 description 23
- 238000005160 1H NMR spectroscopy Methods 0.000 description 22
- 238000004458 analytical method Methods 0.000 description 22
- 239000002904 solvent Substances 0.000 description 22
- 230000008859 change Effects 0.000 description 21
- 238000011156 evaluation Methods 0.000 description 16
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 15
- 108091008794 FGF receptors Proteins 0.000 description 13
- 238000005469 granulation Methods 0.000 description 13
- 238000012360 testing method Methods 0.000 description 13
- 102000044168 Fibroblast Growth Factor Receptor Human genes 0.000 description 12
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 12
- 230000003179 granulation Effects 0.000 description 12
- 238000002844 melting Methods 0.000 description 12
- 238000003756 stirring Methods 0.000 description 12
- 239000000725 suspension Substances 0.000 description 12
- 238000010586 diagram Methods 0.000 description 11
- 230000002829 reductive effect Effects 0.000 description 11
- 230000004580 weight loss Effects 0.000 description 11
- 108050007372 Fibroblast Growth Factor Proteins 0.000 description 10
- 238000005119 centrifugation Methods 0.000 description 10
- 229940126864 fibroblast growth factor Drugs 0.000 description 10
- 238000003760 magnetic stirring Methods 0.000 description 10
- 238000005259 measurement Methods 0.000 description 10
- 230000008018 melting Effects 0.000 description 10
- 102000018233 Fibroblast Growth Factor Human genes 0.000 description 9
- 239000002244 precipitate Substances 0.000 description 9
- 239000007787 solid Substances 0.000 description 9
- 238000001179 sorption measurement Methods 0.000 description 9
- 238000007906 compression Methods 0.000 description 8
- 230000006835 compression Effects 0.000 description 8
- 239000011521 glass Substances 0.000 description 8
- 238000001228 spectrum Methods 0.000 description 8
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 7
- 238000001914 filtration Methods 0.000 description 7
- 239000000047 product Substances 0.000 description 7
- 150000003839 salts Chemical class 0.000 description 7
- 239000000758 substrate Substances 0.000 description 7
- 206010028980 Neoplasm Diseases 0.000 description 6
- 239000008186 active pharmaceutical agent Substances 0.000 description 6
- 239000003795 chemical substances by application Substances 0.000 description 6
- 238000011067 equilibration Methods 0.000 description 6
- 238000010438 heat treatment Methods 0.000 description 6
- 230000004584 weight gain Effects 0.000 description 6
- 235000019786 weight gain Nutrition 0.000 description 6
- 238000009472 formulation Methods 0.000 description 5
- 230000011664 signaling Effects 0.000 description 5
- 102000001253 Protein Kinase Human genes 0.000 description 4
- 238000006243 chemical reaction Methods 0.000 description 4
- 239000008119 colloidal silica Substances 0.000 description 4
- 238000004807 desolvation Methods 0.000 description 4
- 238000003795 desorption Methods 0.000 description 4
- OAMZXMDZZWGPMH-UHFFFAOYSA-N ethyl acetate;toluene Chemical compound CCOC(C)=O.CC1=CC=CC=C1 OAMZXMDZZWGPMH-UHFFFAOYSA-N 0.000 description 4
- 239000003112 inhibitor Substances 0.000 description 4
- 239000000155 melt Substances 0.000 description 4
- 230000004660 morphological change Effects 0.000 description 4
- 229910052757 nitrogen Inorganic materials 0.000 description 4
- 239000012299 nitrogen atmosphere Substances 0.000 description 4
- 239000000546 pharmaceutical excipient Substances 0.000 description 4
- 108060006633 protein kinase Proteins 0.000 description 4
- 102000004169 proteins and genes Human genes 0.000 description 4
- 108090000623 proteins and genes Proteins 0.000 description 4
- 238000005070 sampling Methods 0.000 description 4
- 238000004088 simulation Methods 0.000 description 4
- 239000004604 Blowing Agent Substances 0.000 description 3
- VYZAMTAEIAYCRO-UHFFFAOYSA-N Chromium Chemical compound [Cr] VYZAMTAEIAYCRO-UHFFFAOYSA-N 0.000 description 3
- 229920002472 Starch Polymers 0.000 description 3
- 239000002253 acid Substances 0.000 description 3
- 201000011510 cancer Diseases 0.000 description 3
- 239000003153 chemical reaction reagent Substances 0.000 description 3
- 238000011161 development Methods 0.000 description 3
- 230000018109 developmental process Effects 0.000 description 3
- 238000009826 distribution Methods 0.000 description 3
- 239000003102 growth factor Substances 0.000 description 3
- 239000007788 liquid Substances 0.000 description 3
- 238000005461 lubrication Methods 0.000 description 3
- 238000004519 manufacturing process Methods 0.000 description 3
- 238000005457 optimization Methods 0.000 description 3
- 102000005962 receptors Human genes 0.000 description 3
- 108020003175 receptors Proteins 0.000 description 3
- 239000012047 saturated solution Substances 0.000 description 3
- 239000011734 sodium Substances 0.000 description 3
- 229910052708 sodium Inorganic materials 0.000 description 3
- 229940032147 starch Drugs 0.000 description 3
- 239000008107 starch Substances 0.000 description 3
- 235000019698 starch Nutrition 0.000 description 3
- 230000001225 therapeutic effect Effects 0.000 description 3
- ZKHQWZAMYRWXGA-KQYNXXCUSA-J ATP(4-) Chemical compound C1=NC=2C(N)=NC=NC=2N1[C@@H]1O[C@H](COP([O-])(=O)OP([O-])(=O)OP([O-])([O-])=O)[C@@H](O)[C@H]1O ZKHQWZAMYRWXGA-KQYNXXCUSA-J 0.000 description 2
- ZKHQWZAMYRWXGA-UHFFFAOYSA-N Adenosine triphosphate Natural products C1=NC=2C(N)=NC=NC=2N1C1OC(COP(O)(=O)OP(O)(=O)OP(O)(O)=O)C(O)C1O ZKHQWZAMYRWXGA-UHFFFAOYSA-N 0.000 description 2
- BVKZGUZCCUSVTD-UHFFFAOYSA-M Bicarbonate Chemical group OC([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-M 0.000 description 2
- 206010005003 Bladder cancer Diseases 0.000 description 2
- CURLTUGMZLYLDI-UHFFFAOYSA-N Carbon dioxide Chemical compound O=C=O CURLTUGMZLYLDI-UHFFFAOYSA-N 0.000 description 2
- 102000004127 Cytokines Human genes 0.000 description 2
- 108090000695 Cytokines Proteins 0.000 description 2
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 2
- 108091000080 Phosphotransferase Proteins 0.000 description 2
- 102000004022 Protein-Tyrosine Kinases Human genes 0.000 description 2
- 108090000412 Protein-Tyrosine Kinases Proteins 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- 208000007097 Urinary Bladder Neoplasms Diseases 0.000 description 2
- 230000004913 activation Effects 0.000 description 2
- 150000004649 carbonic acid derivatives Chemical class 0.000 description 2
- 150000007942 carboxylates Chemical class 0.000 description 2
- 210000004027 cell Anatomy 0.000 description 2
- 238000005056 compaction Methods 0.000 description 2
- 230000000052 comparative effect Effects 0.000 description 2
- 238000001816 cooling Methods 0.000 description 2
- 230000003247 decreasing effect Effects 0.000 description 2
- 230000018044 dehydration Effects 0.000 description 2
- 238000006297 dehydration reaction Methods 0.000 description 2
- 239000002274 desiccant Substances 0.000 description 2
- 201000010099 disease Diseases 0.000 description 2
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 2
- 239000012738 dissolution medium Substances 0.000 description 2
- 238000009509 drug development Methods 0.000 description 2
- 239000000835 fiber Substances 0.000 description 2
- 239000010419 fine particle Substances 0.000 description 2
- 238000012395 formulation development Methods 0.000 description 2
- 239000008172 hydrogenated vegetable oil Substances 0.000 description 2
- 230000006872 improvement Effects 0.000 description 2
- 230000000873 masking effect Effects 0.000 description 2
- 229910052751 metal Inorganic materials 0.000 description 2
- 239000002184 metal Substances 0.000 description 2
- 239000008188 pellet Substances 0.000 description 2
- 239000008055 phosphate buffer solution Substances 0.000 description 2
- 125000002467 phosphate group Chemical group [H]OP(=O)(O[H])O[*] 0.000 description 2
- 102000020233 phosphotransferase Human genes 0.000 description 2
- BASFCYQUMIYNBI-UHFFFAOYSA-N platinum Chemical compound [Pt] BASFCYQUMIYNBI-UHFFFAOYSA-N 0.000 description 2
- 210000002307 prostate Anatomy 0.000 description 2
- 239000008213 purified water Substances 0.000 description 2
- 239000002994 raw material Substances 0.000 description 2
- 239000013557 residual solvent Substances 0.000 description 2
- 238000012552 review Methods 0.000 description 2
- 238000007873 sieving Methods 0.000 description 2
- 229940080313 sodium starch Drugs 0.000 description 2
- 239000012086 standard solution Substances 0.000 description 2
- 230000008685 targeting Effects 0.000 description 2
- 238000012546 transfer Methods 0.000 description 2
- 201000005112 urinary bladder cancer Diseases 0.000 description 2
- GNWCZBXSKIIURR-UHFFFAOYSA-N (2-docosanoyloxy-3-hydroxypropyl) docosanoate Chemical compound CCCCCCCCCCCCCCCCCCCCCC(=O)OCC(CO)OC(=O)CCCCCCCCCCCCCCCCCCCCC GNWCZBXSKIIURR-UHFFFAOYSA-N 0.000 description 1
- DMBUODUULYCPAK-UHFFFAOYSA-N 1,3-bis(docosanoyloxy)propan-2-yl docosanoate Chemical compound CCCCCCCCCCCCCCCCCCCCCC(=O)OCC(OC(=O)CCCCCCCCCCCCCCCCCCCCC)COC(=O)CCCCCCCCCCCCCCCCCCCCC DMBUODUULYCPAK-UHFFFAOYSA-N 0.000 description 1
- ZEOWTGPWHLSLOG-UHFFFAOYSA-N Cc1ccc(cc1-c1ccc2c(n[nH]c2c1)-c1cnn(c1)C1CC1)C(=O)Nc1cccc(c1)C(F)(F)F Chemical compound Cc1ccc(cc1-c1ccc2c(n[nH]c2c1)-c1cnn(c1)C1CC1)C(=O)Nc1cccc(c1)C(F)(F)F ZEOWTGPWHLSLOG-UHFFFAOYSA-N 0.000 description 1
- 102000004190 Enzymes Human genes 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- 239000004605 External Lubricant Substances 0.000 description 1
- 101150021185 FGF gene Proteins 0.000 description 1
- 102100023593 Fibroblast growth factor receptor 1 Human genes 0.000 description 1
- 101710182386 Fibroblast growth factor receptor 1 Proteins 0.000 description 1
- 102100023600 Fibroblast growth factor receptor 2 Human genes 0.000 description 1
- 101710182389 Fibroblast growth factor receptor 2 Proteins 0.000 description 1
- 102100027842 Fibroblast growth factor receptor 3 Human genes 0.000 description 1
- 101710182396 Fibroblast growth factor receptor 3 Proteins 0.000 description 1
- 102100027844 Fibroblast growth factor receptor 4 Human genes 0.000 description 1
- 101000917134 Homo sapiens Fibroblast growth factor receptor 4 Proteins 0.000 description 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- 239000005434 MCC/mannitol excipient Substances 0.000 description 1
- 208000034578 Multiple myelomas Diseases 0.000 description 1
- WHNWPMSKXPGLAX-UHFFFAOYSA-N N-Vinyl-2-pyrrolidone Chemical compound C=CN1CCCC1=O WHNWPMSKXPGLAX-UHFFFAOYSA-N 0.000 description 1
- 229910019142 PO4 Inorganic materials 0.000 description 1
- 229920003075 Plasdone™ K-29/32 polymer Polymers 0.000 description 1
- 229920003072 Plasdone™ povidone Polymers 0.000 description 1
- 206010035226 Plasma cell myeloma Diseases 0.000 description 1
- 235000021355 Stearic acid Nutrition 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 230000035508 accumulation Effects 0.000 description 1
- 238000009825 accumulation Methods 0.000 description 1
- 230000003213 activating effect Effects 0.000 description 1
- 239000004480 active ingredient Substances 0.000 description 1
- 239000002671 adjuvant Substances 0.000 description 1
- 230000002776 aggregation Effects 0.000 description 1
- 238000004220 aggregation Methods 0.000 description 1
- 229910052782 aluminium Inorganic materials 0.000 description 1
- XAGFODPZIPBFFR-UHFFFAOYSA-N aluminium Chemical compound [Al] XAGFODPZIPBFFR-UHFFFAOYSA-N 0.000 description 1
- CEGOLXSVJUTHNZ-UHFFFAOYSA-K aluminium tristearate Chemical compound [Al+3].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O CEGOLXSVJUTHNZ-UHFFFAOYSA-K 0.000 description 1
- 229940063655 aluminum stearate Drugs 0.000 description 1
- 150000001413 amino acids Chemical class 0.000 description 1
- 230000019552 anatomical structure morphogenesis Effects 0.000 description 1
- 239000002870 angiogenesis inducing agent Substances 0.000 description 1
- 150000008064 anhydrides Chemical class 0.000 description 1
- 230000002744 anti-aggregatory effect Effects 0.000 description 1
- 239000012300 argon atmosphere Substances 0.000 description 1
- 230000004071 biological effect Effects 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 239000000872 buffer Substances 0.000 description 1
- 239000001569 carbon dioxide Substances 0.000 description 1
- 229910002092 carbon dioxide Inorganic materials 0.000 description 1
- 125000002057 carboxymethyl group Chemical group [H]OC(=O)C([H])([H])[*] 0.000 description 1
- 239000000969 carrier Substances 0.000 description 1
- 239000012159 carrier gas Substances 0.000 description 1
- 230000024245 cell differentiation Effects 0.000 description 1
- 230000003915 cell function Effects 0.000 description 1
- 230000012292 cell migration Effects 0.000 description 1
- 230000004663 cell proliferation Effects 0.000 description 1
- 230000019522 cellular metabolic process Effects 0.000 description 1
- 239000011362 coarse particle Substances 0.000 description 1
- 239000003086 colorant Substances 0.000 description 1
- 230000002860 competitive effect Effects 0.000 description 1
- 229910052593 corundum Inorganic materials 0.000 description 1
- 239000010431 corundum Substances 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- 230000001086 cytosolic effect Effects 0.000 description 1
- 230000007423 decrease Effects 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 235000019700 dicalcium phosphate Nutrition 0.000 description 1
- 239000003085 diluting agent Substances 0.000 description 1
- 238000006471 dimerization reaction Methods 0.000 description 1
- 230000007783 downstream signaling Effects 0.000 description 1
- 239000002706 dry binder Substances 0.000 description 1
- 230000005611 electricity Effects 0.000 description 1
- 239000003995 emulsifying agent Substances 0.000 description 1
- 210000002889 endothelial cell Anatomy 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 230000002255 enzymatic effect Effects 0.000 description 1
- 102000052178 fibroblast growth factor receptor activity proteins Human genes 0.000 description 1
- 239000000796 flavoring agent Substances 0.000 description 1
- 230000006870 function Effects 0.000 description 1
- 239000007789 gas Substances 0.000 description 1
- 238000000227 grinding Methods 0.000 description 1
- 239000001866 hydroxypropyl methyl cellulose Substances 0.000 description 1
- 235000010979 hydroxypropyl methyl cellulose Nutrition 0.000 description 1
- 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 description 1
- UFVKGYZPFZQRLF-UHFFFAOYSA-N hydroxypropyl methyl cellulose Chemical compound OC1C(O)C(OC)OC(CO)C1OC1C(O)C(O)C(OC2C(C(O)C(OC3C(C(O)C(O)C(CO)O3)O)C(CO)O2)O)C(CO)O1 UFVKGYZPFZQRLF-UHFFFAOYSA-N 0.000 description 1
- 230000003463 hyperproliferative effect Effects 0.000 description 1
- 238000000338 in vitro Methods 0.000 description 1
- 239000005414 inactive ingredient Substances 0.000 description 1
- 239000004615 ingredient Substances 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 230000003834 intracellular effect Effects 0.000 description 1
- 150000002500 ions Chemical class 0.000 description 1
- 239000002085 irritant Substances 0.000 description 1
- 231100000021 irritant Toxicity 0.000 description 1
- 108020001756 ligand binding domains Proteins 0.000 description 1
- 230000000670 limiting effect Effects 0.000 description 1
- 238000011068 loading method Methods 0.000 description 1
- 235000014380 magnesium carbonate Nutrition 0.000 description 1
- 229920000609 methyl cellulose Polymers 0.000 description 1
- 239000001923 methylcellulose Substances 0.000 description 1
- 235000010981 methylcellulose Nutrition 0.000 description 1
- 238000013508 migration Methods 0.000 description 1
- 229910021421 monocrystalline silicon Inorganic materials 0.000 description 1
- 239000004570 mortar (masonry) Substances 0.000 description 1
- 238000000465 moulding Methods 0.000 description 1
- 230000035772 mutation Effects 0.000 description 1
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 1
- OQCDKBAXFALNLD-UHFFFAOYSA-N octadecanoic acid Natural products CCCCCCCC(C)CCCCCCCCC(O)=O OQCDKBAXFALNLD-UHFFFAOYSA-N 0.000 description 1
- 238000000643 oven drying Methods 0.000 description 1
- 230000020477 pH reduction Effects 0.000 description 1
- 238000012856 packing Methods 0.000 description 1
- 239000008177 pharmaceutical agent Substances 0.000 description 1
- 229940124531 pharmaceutical excipient Drugs 0.000 description 1
- 239000012071 phase Substances 0.000 description 1
- 239000010452 phosphate Substances 0.000 description 1
- 230000026731 phosphorylation Effects 0.000 description 1
- 238000006366 phosphorylation reaction Methods 0.000 description 1
- 230000000865 phosphorylative effect Effects 0.000 description 1
- 230000000704 physical effect Effects 0.000 description 1
- 230000035790 physiological processes and functions Effects 0.000 description 1
- 238000007747 plating Methods 0.000 description 1
- 229910052697 platinum Inorganic materials 0.000 description 1
- 230000003389 potentiating effect Effects 0.000 description 1
- 239000003755 preservative agent Substances 0.000 description 1
- 238000003825 pressing Methods 0.000 description 1
- 238000012545 processing Methods 0.000 description 1
- 238000003672 processing method Methods 0.000 description 1
- 239000000651 prodrug Substances 0.000 description 1
- 229940002612 prodrug Drugs 0.000 description 1
- 230000002062 proliferating effect Effects 0.000 description 1
- 230000002035 prolonged effect Effects 0.000 description 1
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 description 1
- 238000004080 punching Methods 0.000 description 1
- 230000005855 radiation Effects 0.000 description 1
- 230000021014 regulation of cell growth Effects 0.000 description 1
- 230000004044 response Effects 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 238000001878 scanning electron micrograph Methods 0.000 description 1
- 238000012216 screening Methods 0.000 description 1
- 239000003352 sequestering agent Substances 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 239000008247 solid mixture Substances 0.000 description 1
- 239000007790 solid phase Substances 0.000 description 1
- 238000013112 stability test Methods 0.000 description 1
- 239000003381 stabilizer Substances 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 230000003068 static effect Effects 0.000 description 1
- 239000008117 stearic acid Substances 0.000 description 1
- 230000000638 stimulation Effects 0.000 description 1
- 239000004094 surface-active agent Substances 0.000 description 1
- 230000004083 survival effect Effects 0.000 description 1
- 230000009747 swallowing Effects 0.000 description 1
- 230000009466 transformation Effects 0.000 description 1
- 230000007704 transition Effects 0.000 description 1
- UFTFJSFQGQCHQW-UHFFFAOYSA-N triformin Chemical compound O=COCC(OC=O)COC=O UFTFJSFQGQCHQW-UHFFFAOYSA-N 0.000 description 1
- 230000005747 tumor angiogenesis Effects 0.000 description 1
- 210000004881 tumor cell Anatomy 0.000 description 1
- 230000005740 tumor formation Effects 0.000 description 1
- 125000001493 tyrosinyl group Chemical group [H]OC1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])C([H])(N([H])[H])C(*)=O 0.000 description 1
- 230000004862 vasculogenesis Effects 0.000 description 1
- 235000013311 vegetables Nutrition 0.000 description 1
- 239000011345 viscous material Substances 0.000 description 1
- 229920003169 water-soluble polymer Polymers 0.000 description 1
Images
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/415—1,2-Diazoles
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
- A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
- A61K47/38—Cellulose; Derivatives thereof
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
Definitions
- the invention belongs to the field of drug development, and specifically relates to pharmaceutical compositions and polymorphs of FGFR inhibitors and their pharmaceutical applications.
- Protein kinases are a class of proteins (enzymes) that regulate various cellular functions. This is accomplished by phosphorylating specific amino acids on the protein substrate, causing conformational changes in the substrate protein. Conformational changes modulate the substrate activity or its ability to interact with other binding partners.
- the enzymatic activity of a protein kinase refers to the rate at which the kinase adds phosphate groups to a substrate. This can be determined, for example, by measuring the amount of substrate converted to product as a function of time. Phosphorylation of substrate occurs in the active site of protein kinases.
- Tyrosine kinases are a subgroup of protein kinases that catalyze the conversion of the terminal phosphate of adenosine triphosphate (ATP) to tyrosine residues on protein substrates. These kinases play an important role in the propagation of growth factor signaling that leads to cell proliferation, differentiation, and migration.
- ATP adenosine triphosphate
- Fibroblast growth factor is considered an important mediator of many physiological processes such as morphogenesis during development and vasculogenesis.
- FGF Fibroblast growth factor
- the fibroblast growth factor receptor (FGFR) family includes four members, FGFR1, FGFR2, FGFR3, and FGFR4, each of which consists of an extracellular ligand-binding domain, a single transmembrane domain, and an intracellular cytoplasmic protein tyrosine kinase domain.
- FGFR dimerization and transphosphorylation occur, which results in receptor activation.
- Activation of the receptor is sufficient to restore and activate specific downstream signaling partners involved in various processes such as the regulation of cell growth, cell metabolism and cell survival (reviewed in Eswarakumar, V.P. et al., Cytokine & Growth Factor Reviews 2005, 16 , pp. 139-149).
- FGF and FGFR may cause and/or promote tumor formation.
- FGF signaling directly in human cancer Increased expression of various FGFs has been reported in a diverse range of tumor types such as bladder, renal cell and prostate (among others) tumors. FGF has also been described as a potent angiogenic factor. It has also been reported that FGFR is expressed in endothelial cells. Activating mutations of various FGFRs are associated with bladder cancer and multiple myeloma (among others), and there is evidence that the receptor is also expressed in prostate and bladder cancer, among others (reviewed in Grose, R. et al., Cytokine & Growth Factor Reviews 2005, 16 , pp. 179-186 and Kwabi-Addo, B.
- AstraZeneca (Sweden) Ltd. ASTRAZENECA AB
- AstraZeneca (Sweden) Ltd. ASTRAZENECA AB
- the most representative compound is the compound of Example 154. Chemistry The structure is as follows:
- the Chinese name is: N-(3-(3,5-dimethoxyphenylethyl)-1H-pyrazol-5-yl)-4-((3S,5R)-3,5-dimethylpiper Azin-1-yl)benzamide (AZD4547), referred to as the compound of formula (I) herein, can be used as an FGFR activity modulator or inhibitor to meet the current domestic and foreign requirements for the treatment of proliferative and hyperproliferative diseases/diseases.
- cancer including but not limited to liver cancer, prostate cancer, pancreatic cancer, esophageal cancer, gastric cancer, lung cancer, breast cancer, ovarian cancer, colon cancer, skin cancer, glioblastoma or rhabdomyosarcoma.
- liver cancer prostate cancer
- pancreatic cancer pancreatic cancer
- esophageal cancer gastric cancer
- lung cancer breast cancer
- ovarian cancer colon cancer
- skin cancer glioblastoma or rhabdomyosarcoma
- the purpose of the present invention is to provide pharmaceutical compositions and polymorphs of FGFR inhibitors to solve the problem of drug accessibility and meet the needs of AZD4547 clinical research and drug marketing.
- the inventors optimized the types and proportions of pharmaceutical carriers such as lubricants, disintegrants, and fillers by using appropriate binders, and at the same time conducted in-depth research on the aggregation state of the compound of formula (I).
- pharmaceutical carriers such as lubricants, disintegrants, and fillers
- binders such as binders
- crystal form screening experiments screen out crystal forms of compounds of formula (I) that can be used in formulation development.
- Combining the results of preparation research and crystal form research we developed a pharmaceutical composition that is highly compressible and suitable for industrial production.
- We obtained a pharmaceutical preparation that meets clinical requirements in terms of stability, solubility and other physical and chemical properties, and can meet the clinical research of AZD4547. and the need for drug launches.
- the first aspect of the present invention provides a pharmaceutical composition, which contains the crystal form of a compound of formula (I) as follows and one or more pharmaceutically acceptable carriers.
- the pharmaceutically acceptable carrier is a lubricant, a disintegrating agent, or a disintegrating agent.
- the pharmaceutical composition also includes hydroxypropyl cellulose as a binder, the binder is hydroxypropyl cellulose of LF and/or JF grade specifications, or the above Specifications mixed with other specifications of hydroxypropylcellulose,
- the pharmaceutical composition contains 0.1%-50% W/W crystalline form of the compound of formula (I) relative to the total weight of the composition.
- the pharmaceutical composition contains 1.0%-30% W/W crystalline form of the compound of formula (I) relative to the total weight of the composition.
- the pharmaceutical composition contains 10.0%-30% W/W crystalline form of the compound of formula (I) relative to the total weight of the composition.
- the pharmaceutical composition contains 0.5%-20.0% W/W LF and/or JF grade specifications of hydroxypropyl cellulose relative to the total weight of the composition, or the above specifications are combined with other specifications of hydroxypropyl cellulose. Mixture of vegetarian ingredients.
- hydroxypropyl cellulose refers to EF, GF, MF or HXF grade hydroxypropyl cellulose.
- the pharmaceutical composition contains 1.0%-10.0% W/W LF and/or JF grade hydroxypropyl cellulose relative to the total weight of the composition, or the above specifications are combined with other specifications of hydroxypropyl cellulose.
- a mixture of cellulose 1.0%-10.0% W/W LF and/or JF grade hydroxypropyl cellulose relative to the total weight of the composition, or the above specifications are combined with other specifications of hydroxypropyl cellulose. A mixture of cellulose.
- the pharmaceutical composition contains 2.0%-8.0% W/W LF and/or JF grade hydroxypropyl cellulose relative to the total weight of the composition, or the above specifications are combined with other specifications of hydroxypropyl cellulose.
- the pharmaceutical composition contains hydroxypropyl cellulose in LF and/or JF grade specifications.
- the pharmaceutical composition contains LF and/or JF grade hydroxypropylcellulose in an aqueous solution.
- the pharmaceutical composition contains an aqueous solution of hydroxypropylcellulose of LF and/or JF grade specifications at a concentration of 5% to 25% W/V relative to the total weight of the composition.
- the pharmaceutical composition contains the hydroxypropylcellulose aqueous solution of LF and/or JF grade specifications at a concentration of 8% to 15% W/V relative to the total weight of the composition.
- the pharmaceutical composition further contains one or more foaming agents, which are inorganic salts or organic carbonates.
- the inorganic salts are selected from the group consisting of sodium carbonate, potassium carbonate, and magnesium carbonate. , calcium carbonate, aluminum carbonate, sodium bicarbonate, potassium bicarbonate, calcium bicarbonate, disodium hydrogen phosphate, sodium dihydrogen phosphate and sodium hydroxide; the organic acid salt is selected from sodium diglycinate carbonate, dimethyl Carbonate and ethylene carbonate.
- the foaming agent is selected from the group consisting of sodium carbonate, potassium carbonate, magnesium carbonate, calcium carbonate, aluminum carbonate, sodium bicarbonate, potassium bicarbonate and calcium bicarbonate.
- the pharmaceutical composition contains 0.5%-50.0% W/W foaming agent relative to the total weight of the composition.
- the pharmaceutical composition contains 2.0%-40.0% W/W foaming agent relative to the total weight of the composition.
- the pharmaceutical composition contains 10.0%-30.0% W/W foaming agent relative to the total weight of the composition.
- the lubricant is one of glyceryl behenate, magnesium stearate, sodium stearyl fumarate, colloidal silicon dioxide, talc, hydrogenated vegetable oil and triglyceride. kind or variety.
- the pharmaceutical composition contains 0.1%-30.0% W/W lubricant relative to the total weight of the composition.
- the pharmaceutical composition contains 1.0%-25.0% W/W lubricant relative to the total weight of the composition.
- the pharmaceutical composition contains 3.0%-18.0% W/W lubricant relative to the total weight of the composition.
- the disintegrant is one or more of sodium starch glycolate, sodium starch glycolate, cross-linked polyvinylpyrrolidone and croscarmellose sodium.
- the pharmaceutical composition contains 0.5%-20.0% W/W disintegrant relative to the total weight of the composition.
- the pharmaceutical composition contains 1.0%-10.0% W/W disintegrant relative to the total weight of the composition.
- the pharmaceutical composition contains 2.0%-8.0% W/W disintegrant relative to the total weight of the composition.
- the filler is one or more of mannitol, lactose, microcrystalline cellulose, silicified microcrystalline cellulose, dicalcium phosphate, anhydrous calcium hydrogen phosphate and lactose monohydrate.
- the pharmaceutical composition contains 1.0%-90.0% W/W filler relative to the total weight of the composition.
- the pharmaceutical composition contains 5.0%-60.0% W/W filler relative to the total weight of the composition.
- the pharmaceutical composition contains 10.0%-45.0% W/W filler relative to the total weight of the composition.
- the pharmaceutical composition includes the crystal form of the compound of formula (I), LF grade hydroxypropyl cellulose and a lubricant, with a W/W mass ratio of (10.0-30.0): (2.0-8.0 ): (3.0-10.0), the lubricant is one or more of glyceryl behenate, magnesium stearate and silicon dioxide.
- the pharmaceutical composition further contains sodium carbonate and/or magnesium carbonate as a foaming agent, the content of which is 2.0%-40.0% W/W relative to the total weight of the composition.
- the pharmaceutical composition further contains sodium carbonate and/or magnesium carbonate as a foaming agent, the content of which is 10.0%-30.0% W/W relative to the total weight of the composition.
- the pharmaceutical composition further contains sodium starch glycolate as a disintegrant, the content of which is 2.0%-8.0% W/W relative to the total weight of the composition.
- the pharmaceutical composition further contains microcrystalline cellulose and/or mannitol as fillers, the content of which is 5.0%-45.0% W/W relative to the total weight of the composition.
- the pharmaceutical composition further contains microcrystalline cellulose and/or mannitol as fillers, the content of which is 10.0%-35.0% W/W relative to the total weight of the composition.
- the pharmaceutical composition further contains microcrystalline cellulose and/or mannitol as fillers, the content of which is 15.0%-25.0% W/W relative to the total weight of the composition.
- the pharmaceutical composition further includes one or more coating powders as coating materials.
- the coating powder contained in the pharmaceutical composition is gastric-soluble film coating premix Opadry.
- the pharmaceutical composition is a tablet.
- the unit dosage form of the tablet contains 1 mg to 500 mg of the crystalline form of the compound of formula (I).
- the unit dosage form of the tablet contains 1 mg to 200 mg of the crystalline form of the compound of formula (I).
- the unit dosage form of the tablet contains 1 mg, 5 mg, 20 mg, 80 mg or 200 mg of the crystalline form of the compound of formula (I).
- the crystal form of the compound of formula (I) is anhydrous, hydrate or solvate of the compound of formula (I).
- the solvate of the compound of formula (I) is 2-methyltetrahydrofuran solvate, isopropanol solvate and isopropanol-aqueous solvate.
- the pharmaceutical composition contains anhydrous crystal form I of the compound of formula (I), and the X-ray powder diffraction pattern (XRPD) of the anhydrous crystal form I of the compound of formula (I) includes a Peaks at diffraction angles (2 ⁇ ) of 22.86 ⁇ 0.2°, 7.81 ⁇ 0.2°, 29.89 ⁇ 0.2°, 21.35 ⁇ 0.2°, 16.16 ⁇ 0.2°, 20.73 ⁇ 0.2° and 27.04 ⁇ 0.2°.
- the pharmaceutical composition comprises the anhydrous crystalline form I of the compound of formula (I).
- the X-ray powder diffraction pattern (XRPD) of the anhydrous crystalline form I of the compound of formula (I) includes a position at 22.86 ⁇ 0.2°, 7.81 ⁇ 0.2°, 29.89 ⁇ 0.2°, 21.35 ⁇ 0.2°, 16.16 ⁇ 0.2°, 20.73 ⁇ 0.2°, 27.04 ⁇ 0.2°, 16.64 ⁇ 0.2°, 24.89 ⁇ 0.2°, 25.09 ⁇ 0.2°, 23.51 Peaks at diffraction angles (2 ⁇ ) of ⁇ 0.2°, 13.37 ⁇ 0.2°, 21.84 ⁇ 0.2°, 12.71 ⁇ 0.2° and 17.85 ⁇ 0.2°.
- the pharmaceutical composition contains the anhydrous crystalline form I of the compound of formula (I), and the X-ray powder diffraction pattern (XRPD) of the anhydrous crystalline form I of the compound of formula (I) includes a position at 22.86 ⁇ 0.2°, 7.81 ⁇ 0.2°, 29.89 ⁇ 0.2°, 21.35 ⁇ 0.2°, 16.16 ⁇ 0.2°, 20.73 ⁇ 0.2°, 27.04 ⁇ 0.2°, 16.64 ⁇ 0.2°, 24.89 ⁇ 0.2°, 25.09 ⁇ 0.2°, 23.51 ⁇ 0.2°, 13.37 ⁇ 0.2°, 21.84 ⁇ 0.2°, 12.71 ⁇ 0.2°, 17.85 ⁇ 0.2°, 12.86 ⁇ 0.2°, 24.30 ⁇ 0.2°, 26.53 ⁇ 0.2°, 23.74 ⁇ 0.2°, 18.24 ⁇ 0.2°, 28.75 Peaks at diffraction angles (2 ⁇ ) of ⁇ 0.2°, 19.65 ⁇ 0.2°, 11.23 ⁇ 0.2°, 32.66 ⁇ 0.2° and 18.91 ⁇ 0.2°.
- XRPD X-ray powder diffraction pattern
- the pharmaceutical composition contains the anhydrous crystalline form II of the compound of formula (I), and the X-ray powder diffraction pattern (XRPD) of the anhydrous crystalline form II of the compound of formula (I) includes a Peaks at diffraction angles (2 ⁇ ) of 22.88 ⁇ 0.2°, 7.82 ⁇ 0.2°, 29.92 ⁇ 0.2°, 23.51 ⁇ 0.2°, 21.37 ⁇ 0.2°, 27.06 ⁇ 0.2° and 24.90 ⁇ 0.2°.
- XRPD X-ray powder diffraction pattern
- the pharmaceutical composition contains the anhydrous crystalline form II of the compound of formula (I), and the X-ray powder diffraction pattern (XRPD) of the anhydrous crystalline form II of the compound of formula (I) includes a 22.88 ⁇ 0.2°, 7.82 ⁇ 0.2°, 29.92 ⁇ 0.2°, 23.51 ⁇ 0.2°, 21.37 ⁇ 0.2°, 27.06 ⁇ 0.2°, 24.90 ⁇ 0.2°, 16.65 ⁇ 0.2°, 20.76 ⁇ 0.2°, 25.11 ⁇ 0.2°, Peaks at diffraction angles (2 ⁇ ) of 16.18 ⁇ 0.2°, 13.38 ⁇ 0.2°, 21.86 ⁇ 0.2°, 32.58 ⁇ 0.2° and 12.72 ⁇ 0.2°.
- XRPD X-ray powder diffraction pattern
- the pharmaceutical composition contains the anhydrous crystalline form II of the compound of formula (I), and the X-ray powder diffraction pattern (XRPD) of the anhydrous crystalline form II of the compound of formula (I) includes a position at 22.88 ⁇ 0.2°, 7.82 ⁇ 0.2°, 29.92 ⁇ 0.2°, 23.51 ⁇ 0.2°, 21.37 ⁇ 0.2°, 27.06 ⁇ 0.2°, 24.90 ⁇ 0.2°, 16.65 ⁇ 0.2°, 20.76 ⁇ 0.2°, 25.11 ⁇ 0.2°, 16.18 ⁇ 0.2°, 13.38 ⁇ 0.2°, 21.86 ⁇ 0.2°, 32.58 ⁇ 0.2°, 12.72 ⁇ 0.2°, 24.31 ⁇ 0.2°, 15.05 ⁇ 0.2°, 28.77 ⁇ 0.2°, 26.55 ⁇ 0.2°, 12.87 ⁇ 0.2°, 22.56 Peaks at diffraction angles (2 ⁇ ) of ⁇ 0.2°, 17.85 ⁇ 0.2°, 23.76 ⁇ 0.2°, 18.26 ⁇ 0.2° and 31.11 ⁇ 0.2°.
- the pharmaceutical composition contains the anhydrous crystalline form III of the compound of formula (I), and the X-ray powder diffraction pattern (XRPD) of the anhydrous crystalline form III of the compound of formula (I) includes the Peaks at diffraction angles (2 ⁇ ) of 5.85 ⁇ 0.2°, 21.34 ⁇ 0.2°, 14.96 ⁇ 0.2°, 20.57 ⁇ 0.2°, 19.78 ⁇ 0.2°, 24.12 ⁇ 0.2° and 18.71 ⁇ 0.2°.
- XRPD X-ray powder diffraction pattern
- the pharmaceutical composition contains the anhydrous crystalline form III of the compound of formula (I), and the X-ray powder diffraction pattern (XRPD) of the anhydrous crystalline form III of the compound of formula (I) includes the 5.85 ⁇ 0.2°, 21.34 ⁇ 0.2°, 14.96 ⁇ 0.2°, 20.57 ⁇ 0.2°, 19.78 ⁇ 0.2°, 24.12 ⁇ 0.2°, 18.71 ⁇ 0.2°, 25.13 ⁇ 0.2°, 13.72 ⁇ 0.2°, 24.65 ⁇ 0.2°, Peaks at diffraction angles (2 ⁇ ) of 22.76 ⁇ 0.2°, 26.75 ⁇ 0.2°, 14.61 ⁇ 0.2°, 10.81 ⁇ 0.2° and 16.81 ⁇ 0.2°.
- XRPD X-ray powder diffraction pattern
- the pharmaceutical composition contains the anhydrous crystalline form III of the compound of formula (I), and the X-ray powder diffraction pattern (XRPD) of the anhydrous crystalline form III of the compound of formula (I) includes a position at 5.85 ⁇ 0.2°, 21.34 ⁇ 0.2°, 14.96 ⁇ 0.2°, 20.57 ⁇ 0.2°, 19.78 ⁇ 0.2°, 24.12 ⁇ 0.2°, 18.71 ⁇ 0.2°, 25.13 ⁇ 0.2°, 13.72 ⁇ 0.2°, 24.65 ⁇ 0.2°, 22.76 ⁇ 0.2°, 26.75 ⁇ 0.2°, 14.61 ⁇ 0.2°, 10.81 ⁇ 0.2°, 16.81 ⁇ 0.2°, 21.14 ⁇ 0.2°, 22.54 ⁇ 0.2°, 9.74 ⁇ 0.2°, 21.79 ⁇ 0.2°, 25.74 ⁇ 0.2°, 17.71 Peaks at diffraction angles (2 ⁇ ) of ⁇ 0.2°, 19.33 ⁇ 0.2°, 30.36 ⁇ 0.2°, 13.39 ⁇ 0.2° and 14.07 ⁇ 0.2°.
- the pharmaceutical composition contains the hydrate crystal form IV of the compound of formula (I), and the X-ray powder diffraction pattern (XRPD) of the hydrate crystal form IV of the compound of formula (I) includes a position located at 13.34 ⁇ Peaks at diffraction angles (2 ⁇ ) of 0.2°, 17.41 ⁇ 0.2°, 21.78 ⁇ 0.2°, 20.02 ⁇ 0.2°, 14.85 ⁇ 0.2° and 16.53 ⁇ 0.2°.
- XRPD X-ray powder diffraction pattern
- the pharmaceutical composition contains the hydrate crystal form IV of the compound of formula (I), and the X-ray powder diffraction pattern (XRPD) of the hydrate crystal form IV of the compound of formula (I) includes a position located at 13.34 ⁇ 0.2°, 17.41 ⁇ 0.2°, 21.78 ⁇ 0.2°, 20.02 ⁇ 0.2°, 14.85 ⁇ 0.2°, 16.53 ⁇ 0.2°, 19.35 ⁇ 0.2°, 18.64 ⁇ 0.2°, 11.19 ⁇ 0.2°, 5.98 ⁇ 0.2° and 22.67 ⁇ Peak at diffraction angle (2 ⁇ ) of 0.2°.
- XRPD X-ray powder diffraction pattern
- the pharmaceutical composition contains the hydrate crystalline form IV of the compound of formula (I), and the X-ray powder diffraction pattern (XRPD) of the hydrate crystalline form IV of the compound of formula (I) includes a position at 13.34 ⁇ 0.2 °, 17.41 ⁇ 0.2°, 21.78 ⁇ 0.2°, 20.02 ⁇ 0.2°, 14.85 ⁇ 0.2°, 16.53 ⁇ 0.2°, 19.35 ⁇ 0.2°, 18.64 ⁇ 0.2°, 11.19 ⁇ 0.2°, 5.98 ⁇ 0.2°, 22.67 ⁇ 0.2 °, 20.62 ⁇ 0.2°, 26.72 ⁇ 0.2°, 14.08 ⁇ 0.2°, 23.82 ⁇ 0.2° and 25.37 ⁇ 0.2° peaks at diffraction angles (2 ⁇ ).
- XRPD X-ray powder diffraction pattern
- the pharmaceutical composition contains the hydrate crystal form VIII of the compound of formula (I), and the X-ray powder diffraction pattern (XRPD) of the hydrate crystal form VIII of the compound of formula (I) includes a position at 23.05 ⁇ Peaks at diffraction angles (2 ⁇ ) of 0.2°, 8.73 ⁇ 0.2°, 21.41 ⁇ 0.2°, 15.95 ⁇ 0.2°, 23.50 ⁇ 0.2°, 15.50 ⁇ 0.2° and 25.14 ⁇ 0.2°.
- the pharmaceutical composition contains the hydrate crystal form VIII of the compound of formula (I), and the X-ray powder diffraction pattern (XRPD) of the hydrate crystal form VIII of the compound of formula (I) includes a position at 23.05 ⁇ 0.2°, 8.73 ⁇ 0.2°, 21.41 ⁇ 0.2°, 15.95 ⁇ 0.2°, 23.50 ⁇ 0.2°, 15.50 ⁇ 0.2°, 25.14 ⁇ 0.2°, 27.00 ⁇ 0.2°, 31.15 ⁇ 0.2°, 27.70 ⁇ 0.2°, 16.81 ⁇ Peaks at diffraction angles (2 ⁇ ) of 0.2°, 19.70 ⁇ 0.2°, 13.22 ⁇ 0.2°, 24.34 ⁇ 0.2° and 19.32 ⁇ 0.2°.
- XRPD X-ray powder diffraction pattern
- the pharmaceutical composition contains the hydrate crystal form VIII of the compound of formula (I), and the X-ray powder diffraction pattern (XRPD) of the hydrate crystal form VIII of the compound of formula (I) includes a position at 23.05 ⁇ 0.2 °, 8.73 ⁇ 0.2°, 21.41 ⁇ 0.2°, 15.95 ⁇ 0.2°, 23.50 ⁇ 0.2°, 15.50 ⁇ 0.2°, 25.14 ⁇ 0.2°, 27.00 ⁇ 0.2°, 31.15 ⁇ 0.2°, 27.70 ⁇ 0.2°, 16.81 ⁇ 0.2 °, 19.70 ⁇ 0.2°, 13.22 ⁇ 0.2°, 24.34 ⁇ 0.2°, 19.32 ⁇ 0.2°, 20.44 ⁇ 0.2°, 35.08 ⁇ 0.2°, 29.93 ⁇ 0.2°, 27.32 ⁇ 0.2°, 13.54 ⁇ 0.2°, 18.99 ⁇ 0.2 °, 12.89 ⁇ 0.2°, 17.49 ⁇ 0.2°, 30.49 ⁇ 0.2° and 18.59 ⁇ 0.2° peaks at diffraction angles (2 ⁇ ).
- the pharmaceutical composition contains a crystalline form of a hydrate of the compound of formula (I), and the hydrate of the compound of formula (I) contains 0.5-3.0 water molecules per molecule.
- the pharmaceutical composition contains a crystalline form of a hydrate of the compound of formula (I), and the hydrate of the compound of formula (I) contains 0.9-1.8 water molecules per molecule.
- the pharmaceutical composition contains the compound of formula (I) 2-methyltetrahydrofuran solvate crystal form VI, and the X of the compound of formula (I) 2-methyltetrahydrofuran solvate crystal form VI - Ray powder diffraction pattern (XRPD) includes diffraction angles (2 ⁇ ) at 22.44 ⁇ 0.2°, 5.63 ⁇ 0.2°, 16.81 ⁇ 0.2°, 20.43 ⁇ 0.2°, 21.57 ⁇ 0.2°, 16.15 ⁇ 0.2° and 22.71 ⁇ 0.2° The peak at.
- the pharmaceutical composition contains the compound of formula (I) 2-methyltetrahydrofuran solvate crystal form VI, and the X of the compound of formula (I) 2-methyltetrahydrofuran solvate crystal form VI -Ray powder diffraction pattern (XRPD) includes locations at 22.44 ⁇ 0.2°, 5.63 ⁇ 0.2°, 16.81 ⁇ 0.2°, 20.43 ⁇ 0.2°, 21.57 ⁇ 0.2°, 16.15 ⁇ 0.2°, 22.71 ⁇ 0.2°, 6.36 ⁇ 0.2°, Peaks at diffraction angles (2 ⁇ ) of 12.60 ⁇ 0.2°, 25.95 ⁇ 0.2°, 24.92 ⁇ 0.2°, 13.69 ⁇ 0.2°, 19.65 ⁇ 0.2°, 15.13 ⁇ 0.2° and 12.11 ⁇ 0.2°.
- the pharmaceutical composition contains the compound of formula (I) 2-methyltetrahydrofuran solvate crystal form VI, and the X- of the compound of formula (I) 2-methyltetrahydrofuran solvate crystal form VI
- the XRPD patterns include 22.44 ⁇ 0.2°, 5.63 ⁇ 0.2°, 16.81 ⁇ 0.2°, 20.43 ⁇ 0.2°, 21.57 ⁇ 0.2°, 16.15 ⁇ 0.2°, 22.71 ⁇ 0.2°, 6.36 ⁇ 0.2°, 12.60 ⁇ 0.2°, 25.95 ⁇ 0.2°, 24.92 ⁇ 0.2°, 13.69 ⁇ 0.2°, 19.65 ⁇ 0.2°, 15.13 ⁇ 0.2°, 12.11 ⁇ 0.2°, 24.25 ⁇ 0.2°, 11.16 ⁇ 0.2°, 31.57 ⁇ 0.2°, 14.55 Peaks at diffraction angles (2 ⁇ ) of ⁇ 0.2°, 27.00 ⁇ 0.2°, 17.90 ⁇ 0.2°, 21.12 ⁇ 0.2°, 11.27 ⁇ 0.2°, 23.18 ⁇ 0.2° and 14.12 ⁇ 0.2°.
- the pharmaceutical composition contains the crystal form of the 2-methyltetrahydrofuran solvate of the compound of formula (I), and each molecule of the 2-methyltetrahydrofuran solvate of the compound of formula (I) contains 0.5 -3.0 molecules of 2-methyltetrahydrofuran.
- the pharmaceutical composition contains the crystal form of the 2-methyltetrahydrofuran solvate of the compound of formula (I), and each molecule of the 2-methyltetrahydrofuran solvate of the compound of formula (I) contains 1.0 2-methyltetrahydrofuran molecules.
- the pharmaceutical composition contains the isopropanol solvate crystal form V of the compound of formula (I), and the X-ray powder diffraction of the isopropyl alcohol solvate crystal form V of the compound of formula (I)
- the pattern (XRPD) includes peaks at diffraction angles (2 ⁇ ) of 5.28 ⁇ 0.2°, 10.52 ⁇ 0.2°, 21.29 ⁇ 0.2°, 5.66 ⁇ 0.2°, 13.52 ⁇ 0.2°, 22.44 ⁇ 0.2° and 19.35 ⁇ 0.2°.
- the pharmaceutical composition contains the isopropanol solvate crystal form V of the compound of formula (I), and the X-ray powder diffraction of the isopropyl alcohol solvate crystal form V of the compound of formula (I)
- the graph (XRPD) includes locations at 5.28 ⁇ 0.2°, 10.52 ⁇ 0.2°, 21.29 ⁇ 0.2°, 5.66 ⁇ 0.2°, 13.52 ⁇ 0.2°, 22.44 ⁇ 0.2°, 19.35 ⁇ 0.2°, 18.48 ⁇ 0.2°, 16.77 ⁇ 0.2° , 24.68 ⁇ 0.2°, 19.97 ⁇ 0.2°, 25.67 ⁇ 0.2°, 15.13 ⁇ 0.2°, 17.82 ⁇ 0.2° and 20.96 ⁇ 0.2° peaks at diffraction angles (2 ⁇ ).
- the pharmaceutical composition contains the isopropyl alcohol solvate crystal form V of the compound of formula (I), and the X-ray powder diffraction pattern of the isopropyl alcohol solvate crystal form V of the compound of formula (I) (XRPD) includes locations at 5.28 ⁇ 0.2°, 10.52 ⁇ 0.2°, 21.29 ⁇ 0.2°, 5.66 ⁇ 0.2°, 13.52 ⁇ 0.2°, 22.44 ⁇ 0.2°, 19.35 ⁇ 0.2°, 18.48 ⁇ 0.2°, 16.77 ⁇ 0.2°, 24.68 ⁇ 0.2°, 19.97 ⁇ 0.2°, 25.67 ⁇ 0.2°, 15.13 ⁇ 0.2°, 17.82 ⁇ 0.2°, 20.96 ⁇ 0.2°, 14.86 ⁇ 0.2°, 12.48 ⁇ 0.2°, 11.94 ⁇ 0.2°, 14.24 ⁇ 0.2°, Peaks at diffraction angles (2 ⁇ ) of 23.87 ⁇ 0.2°, 23.25 ⁇ 0.2°, 29.51 ⁇ 0.2° and 27.70 ⁇ 0.2°.
- XRPD X-ray powder diffraction pattern of the isopropyl alcohol solvate crystal
- the pharmaceutical composition contains the isopropanol solvate crystal form of the compound of formula (I), and the isopropyl alcohol solvate of the compound of formula (I) contains 1.0-5.0 isopropanol in each molecule. Propanol molecule.
- the pharmaceutical composition contains the isopropyl alcohol solvate crystal form of the compound of formula (I), and the isopropyl alcohol solvate of the compound of formula (I) contains 4.2 isopropyl alcohols per molecule. molecular.
- the pharmaceutical composition contains the isopropyl alcohol-aqueous solvate crystal form VII of the compound of formula (I), and the isopropyl alcohol-aqua solvate crystal form VII of the compound of formula (I)
- the X-ray powder diffraction pattern (XRPD) includes diffraction angles located at 23.77 ⁇ 0.2°, 24.36 ⁇ 0.2°, 18.56 ⁇ 0.2°, 5.94 ⁇ 0.2°, 22.59 ⁇ 0.2°, 20.30 ⁇ 0.2° and 17.79 ⁇ 0.2° ( 2 ⁇ ) peak.
- the pharmaceutical composition contains the isopropyl alcohol-aqueous solvate crystal form VII of the compound of formula (I), and the isopropyl alcohol-aqua solvate crystal form VII of the compound of formula (I)
- the X-ray powder diffraction pattern includes locations at 23.77 ⁇ 0.2°, 24.36 ⁇ 0.2°, 18.56 ⁇ 0.2°, 5.94 ⁇ 0.2°, 22.59 ⁇ 0.2°, 20.30 ⁇ 0.2°, 17.79 ⁇ 0.2°, 10.33 ⁇ 0.2 °, 12.10 ⁇ 0.2°, 22.26 ⁇ 0.2°, 19.48 ⁇ 0.2°, 21.73 ⁇ 0.2°, 5.29 ⁇ 0.2°, 25.80 ⁇ 0.2° and 16.45 ⁇ 0.2° at diffraction angles (2 ⁇ ).
- the pharmaceutical composition contains the isopropyl alcohol-aqueous solvate crystal form VII of the compound of formula (I), and the isopropyl alcohol-aqueous solvate crystal form VII of the compound of formula (I) is X-ray powder diffraction patterns (XRPD) include locations at 23.77 ⁇ 0.2°, 24.36 ⁇ 0.2°, 18.56 ⁇ 0.2°, 5.94 ⁇ 0.2°, 22.59 ⁇ 0.2°, 20.30 ⁇ 0.2°, 17.79 ⁇ 0.2°, 10.33 ⁇ 0.2° , 12.10 ⁇ 0.2°, 22.26 ⁇ 0.2°, 19.48 ⁇ 0.2°, 21.73 ⁇ 0.2°, 5.29 ⁇ 0.2°, 25.80 ⁇ 0.2°, 16.45 ⁇ 0.2°, 21.94 ⁇ 0.2°, 28.33 ⁇ 0.2°, 25.04 ⁇ 0.2° , 11.89 ⁇ 0.2°, 17.26 ⁇ 0.2°, 28.85 ⁇ 0.2°, 16.79 ⁇ 0.2°, 23.34 ⁇ 0.2°, 30.31 ⁇ 0.2° and 14.26 ⁇ 0.2° peaks at diffraction angles (2 ⁇ ).
- the pharmaceutical composition contains the isopropanol-aqueous solvate crystal form of the compound of formula (I), and each molecule of the isopropyl alcohol-aqueous solvate of the compound of formula (I) contains Contains 0.5-3 isopropyl alcohol molecules and 0.5-3.0 water molecules.
- the pharmaceutical composition contains the isopropanol-aqueous solvate crystal form of the compound of formula (I), and each molecule of the isopropyl alcohol-aqueous solvate of the compound of formula (I) contains Contains 2.0 molecules of isopropyl alcohol and contains 1.5 molecules of water.
- a second aspect of the present invention provides a preparation method of the aforementioned pharmaceutical composition, comprising the following steps:
- Step A Mix the crystal form of the compound of formula (I) and/or one or more pharmaceutically acceptable carriers to obtain a premixed material;
- Step B Add the binder hydroxypropyl cellulose to the above premixed materials to form mixed particles;
- step C add lubricant and/or disintegrant to the above mixed particles to form final mixed particles;
- step D compress the final mixed granules prepared in the above step C to form tablets;
- the pharmaceutically acceptable carrier is one or more of lubricants, disintegrants and fillers.
- a foaming agent is added during premixing in step A of the preparation method.
- the preparation method can mix the compound of formula (I), the binder hydroxypropyl cellulose, the foaming agent and one or more pharmaceutically acceptable carriers to obtain a premixed material.
- step B of the preparation method is performed after mixing to form wet granules and then drying and/or dry granulation.
- step A and/or step B of the preparation method is passed through a 30-100 mesh sieve.
- a third aspect of the present invention provides the crystalline form of anhydride, hydrate or solvate of the compound of formula (I):
- the solvate of the compound of formula (I) is 2-methyltetrahydrofuran solvate, isopropyl alcohol solvate and isopropyl alcohol-water heterosolvate.
- the crystal form is the anhydrous crystal form I of the compound of formula (I), and the X-ray powder diffraction pattern (XRPD) of the anhydrous crystal form I of the compound of formula (I) includes a position at 22.86 ⁇ Peaks at diffraction angles (2 ⁇ ) of 0.2°, 7.81 ⁇ 0.2°, 29.89 ⁇ 0.2°, 21.35 ⁇ 0.2°, 16.16 ⁇ 0.2°, 20.73 ⁇ 0.2° and 27.04 ⁇ 0.2°.
- XRPD X-ray powder diffraction pattern
- the X-ray powder diffraction pattern (XRPD) of the anhydrous crystal form I of the compound of formula (I) includes positions at 22.86 ⁇ 0.2°, 7.81 ⁇ 0.2°, 29.89 ⁇ 0.2°, and 21.35 ⁇ 0.2 °, 16.16 ⁇ 0.2°, 20.73 ⁇ 0.2°, 27.04 ⁇ 0.2°, 16.64 ⁇ 0.2°, 24.89 ⁇ 0.2°, 25.09 ⁇ 0.2°, 23.51 ⁇ 0.2°, 13.37 ⁇ 0.2°, 21.84 ⁇ 0.2°, 12.71 ⁇ 0.2 ° and peaks at diffraction angles (2 ⁇ ) of 17.85 ⁇ 0.2°.
- the X-ray powder diffraction pattern (XRPD) of the anhydrous crystal form I of the compound of formula (I) includes positions at 22.86 ⁇ 0.2°, 7.81 ⁇ 0.2°, 29.89 ⁇ 0.2°, and 21.35 ⁇ 0.2°.
- the crystal form is the anhydrous crystal form II of the compound of formula (I), and the X-ray powder diffraction pattern (XRPD) of the anhydrous crystal form II of the compound of formula (I) includes a position at 22.88 ⁇ 0.2 °, 7.82 ⁇ 0.2°, 29.92 ⁇ 0.2°, 23.51 ⁇ 0.2°, 21.37 ⁇ 0.2°, 27.06 ⁇ 0.2° and 24.90 ⁇ 0.2° peaks at diffraction angles (2 ⁇ ).
- XRPD X-ray powder diffraction pattern
- the X-ray powder diffraction pattern (XRPD) of the anhydrous crystal form II of the compound of formula (I) includes positions at 22.88 ⁇ 0.2°, 7.82 ⁇ 0.2°, 29.92 ⁇ 0.2°, and 23.51 ⁇ 0.2°. , 21.37 ⁇ 0.2°, 27.06 ⁇ 0.2°, 24.90 ⁇ 0.2°, 16.65 ⁇ 0.2°, 20.76 ⁇ 0.2°, 25.11 ⁇ 0.2°, 16.18 ⁇ 0.2°, 13.38 ⁇ 0.2°, 21.86 ⁇ 0.2°, 32.58 ⁇ 0.2° and a peak at a diffraction angle (2 ⁇ ) of 12.72 ⁇ 0.2°.
- the X-ray powder diffraction pattern (XRPD) of the anhydrous crystal form II of the compound of formula (I) includes positions at 22.88 ⁇ 0.2°, 7.82 ⁇ 0.2°, 29.92 ⁇ 0.2°, and 23.51 ⁇ 0.2°.
- the crystal form is the anhydrous crystal form III of the compound of formula (I), and the X-ray powder diffraction pattern (XRPD) of the anhydrous crystal form III of the compound of formula (I) includes a position at 5.85 ⁇ 0.2 °, 21.34 ⁇ 0.2°, 14.96 ⁇ 0.2°, 20.57 ⁇ 0.2°, 19.78 ⁇ 0.2°, 24.12 ⁇ 0.2° and 18.71 ⁇ 0.2° peaks at diffraction angles (2 ⁇ ).
- XRPD X-ray powder diffraction pattern
- the X-ray powder diffraction pattern (XRPD) of the anhydrous crystal form III of the compound of formula (I) includes positions at 5.85 ⁇ 0.2°, 21.34 ⁇ 0.2°, 14.96 ⁇ 0.2°, and 20.57 ⁇ 0.2°. , 19.78 ⁇ 0.2°, 24.12 ⁇ 0.2°, 18.71 ⁇ 0.2°, 25.13 ⁇ 0.2°, 13.72 ⁇ 0.2°, 24.65 ⁇ 0.2°, 22.76 ⁇ 0.2°, 26.75 ⁇ 0.2°, 14.61 ⁇ 0.2°, 10.81 ⁇ 0.2° and a peak at a diffraction angle (2 ⁇ ) of 16.81 ⁇ 0.2°.
- the X-ray powder diffraction pattern (XRPD) of the anhydrous crystal form III of the compound of formula (I) includes positions at 5.85 ⁇ 0.2°, 21.34 ⁇ 0.2°, 14.96 ⁇ 0.2°, and 20.57 ⁇ 0.2 °, 19.78 ⁇ 0.2°, 24.12 ⁇ 0.2°, 18.71 ⁇ 0.2°, 25.13 ⁇ 0.2°, 13.72 ⁇ 0.2°, 24.65 ⁇ 0.2°, 22.76 ⁇ 0.2°, 26.75 ⁇ 0.2°, 14.61 ⁇ 0.2°, 10.81 ⁇ 0.2 °, 16.81 ⁇ 0.2°, 21.14 ⁇ 0.2°, 22.54 ⁇ 0.2°, 9.74 ⁇ 0.2°, 21.79 ⁇ 0.2°, 25.74 ⁇ 0.2°, 17.71 ⁇ 0.2°, 19.33 ⁇ 0.2°, 30.36 ⁇ 0.2°, 13.39 ⁇ 0.2 ° and peaks at diffraction angles (2 ⁇ ) of 14.07 ⁇ 0.2°.
- the crystal form is the hydrate crystal form IV of the compound of formula (I).
- the X-ray powder diffraction pattern (XRPD) of the hydrate crystal form IV of the compound of formula (I) includes 13.34 ⁇ 0.2°, Peaks at diffraction angles (2 ⁇ ) of 17.41 ⁇ 0.2°, 21.78 ⁇ 0.2°, 20.02 ⁇ 0.2°, 14.85 ⁇ 0.2° and 16.53 ⁇ 0.2°.
- the X-ray powder diffraction pattern (XRPD) of the hydrate crystal form IV of the compound of formula (I) includes positions at 13.34 ⁇ 0.2°, 17.41 ⁇ 0.2°, 21.78 ⁇ 0.2°, 20.02 ⁇ 0.2°, Peaks at diffraction angles (2 ⁇ ) of 14.85 ⁇ 0.2°, 16.53 ⁇ 0.2°, 19.35 ⁇ 0.2°, 18.64 ⁇ 0.2°, 11.19 ⁇ 0.2°, 5.98 ⁇ 0.2° and 22.67 ⁇ 0.2°.
- the X-ray powder diffraction pattern (XRPD) of the hydrate crystal form IV of the compound of formula (I) includes positions at 13.34 ⁇ 0.2°, 17.41 ⁇ 0.2°, 21.78 ⁇ 0.2°, 20.02 ⁇ 0.2°, 14.85 ⁇ 0.2°, 16.53 ⁇ 0.2°, 19.35 ⁇ 0.2°, 18.64 ⁇ 0.2°, 11.19 ⁇ 0.2°, 5.98 ⁇ 0.2°, 22.67 ⁇ 0.2°, 20.62 ⁇ 0.2°, 26.72 ⁇ 0.2°, 14.08 ⁇ 0.2°, Peaks at diffraction angles (2 ⁇ ) of 23.82 ⁇ 0.2° and 25.37 ⁇ 0.2°.
- the crystal form is the hydrate crystal form VIII of the compound of formula (I), and the X-ray powder diffraction pattern (XRPD) of the hydrate crystal form VIII of the compound of formula (I) includes positions at 23.05 ⁇ 0.2°, Peaks at diffraction angles (2 ⁇ ) of 8.73 ⁇ 0.2°, 21.41 ⁇ 0.2°, 15.95 ⁇ 0.2°, 23.50 ⁇ 0.2°, 15.50 ⁇ 0.2° and 25.14 ⁇ 0.2°.
- the X-ray powder diffraction pattern (XRPD) of the hydrate crystal form VIII of the compound of formula (I) includes positions at 23.05 ⁇ 0.2°, 8.73 ⁇ 0.2°, 21.41 ⁇ 0.2°, 15.95 ⁇ 0.2°, and Peak at diffraction angle (2 ⁇ ) of 19.32 ⁇ 0.2°.
- the X-ray powder diffraction pattern (XRPD) of the hydrate crystal form VIII of the compound of formula (I) includes locations at 23.05 ⁇ 0.2°, 8.73 ⁇ 0.2°, 21.41 ⁇ 0.2°, 15.95 ⁇ 0.2°, 23.50 ⁇ 0.2°, 15.50 ⁇ 0.2°, 25.14 ⁇ 0.2°, 27.00 ⁇ 0.2°, 31.15 ⁇ 0.2°, 27.70 ⁇ 0.2°, 16.81 ⁇ 0.2°, 19.70 ⁇ 0.2°, 13.22 ⁇ 0.2°, 24.34 ⁇ 0.2°, and Peak at diffraction angle (2 ⁇ ) of 18.59 ⁇ 0.2°.
- the hydrate of the compound of formula (I) contains 0.5-3.0 water molecules per molecule.
- the hydrate of the compound of formula (I) contains 0.9-1.8 water molecules per molecule.
- the crystal form is the compound of formula (I) 2-methyltetrahydrofuran solvate crystal form VI
- Powder diffraction patterns (XRPD) include diffraction angles (2 ⁇ ) at 22.44 ⁇ 0.2°, 5.63 ⁇ 0.2°, 16.81 ⁇ 0.2°, 20.43 ⁇ 0.2°, 21.57 ⁇ 0.2°, 16.15 ⁇ 0.2° and 22.71 ⁇ 0.2°. peak.
- the X-ray powder diffraction pattern (XRPD) of the crystal form VI of the 2-methyltetrahydrofuran solvate of the compound of formula (I) includes positions at 22.44 ⁇ 0.2°, 5.63 ⁇ 0.2°, and 16.81 ⁇ 0.2 °, 20.43 ⁇ 0.2°, 21.57 ⁇ 0.2°, 16.15 ⁇ 0.2°, 22.71 ⁇ 0.2°, 6.36 ⁇ 0.2°, 12.60 ⁇ 0.2°, 25.95 ⁇ 0.2°, 24.92 ⁇ 0.2°, 13.69 ⁇ 0.2°, 19.65 ⁇ 0.2 °, 15.13 ⁇ 0.2° and 12.11 ⁇ 0.2° peaks at diffraction angles (2 ⁇ ).
- the X-ray powder diffraction pattern (XRPD) of the crystal form VI of the 2-methyltetrahydrofuran solvate of the compound of formula (I) includes positions at 22.44 ⁇ 0.2°, 5.63 ⁇ 0.2°, and 16.81 ⁇ 0.2°.
- each molecule of the 2-methyltetrahydrofuran solvate of the compound of formula (I) contains 0.5-3.0 2-methyltetrahydrofuran molecules.
- each molecule of the 2-methyltetrahydrofuran solvate of the compound of formula (I) contains 1.0 2-methyltetrahydrofuran molecules.
- the crystal form is the isopropyl alcohol solvate crystal form V of the compound of formula (I)
- the X-ray powder diffraction pattern of the isopropyl alcohol solvate crystal form V of the compound of formula (I) is ( XRPD) includes peaks at diffraction angles (2 ⁇ ) of 5.28 ⁇ 0.2°, 10.52 ⁇ 0.2°, 21.29 ⁇ 0.2°, 5.66 ⁇ 0.2°, 13.52 ⁇ 0.2°, 22.44 ⁇ 0.2° and 19.35 ⁇ 0.2°.
- the X-ray powder diffraction pattern (XRPD) of the isopropanol solvate crystal form V of the compound of formula (I) includes positions at 5.28 ⁇ 0.2°, 10.52 ⁇ 0.2°, 21.29 ⁇ 0.2°, 5.66 ⁇ 0.2°, 13.52 ⁇ 0.2°, 22.44 ⁇ 0.2°, 19.35 ⁇ 0.2°, 18.48 ⁇ 0.2°, 16.77 ⁇ 0.2°, 24.68 ⁇ 0.2°, 19.97 ⁇ 0.2°, 25.67 ⁇ 0.2°, 15.13 ⁇ 0.2°, Peaks at diffraction angles (2 ⁇ ) of 17.82 ⁇ 0.2° and 20.96 ⁇ 0.2°.
- the X-ray powder diffraction pattern (XRPD) of the isopropanol solvate crystal form V of the compound of formula (I) includes positions at 5.28 ⁇ 0.2°, 10.52 ⁇ 0.2°, 21.29 ⁇ 0.2°, 5.66 ⁇ 0.2°, 13.52 ⁇ 0.2°, 22.44 ⁇ 0.2°, 19.35 ⁇ 0.2°, 18.48 ⁇ 0.2°, 16.77 ⁇ 0.2°, 24.68 ⁇ 0.2°, 19.97 ⁇ 0.2°, 25.67 ⁇ 0.2°, 15.13 ⁇ 0.2°, 17.82 Diffraction of ⁇ 0.2°, 20.96 ⁇ 0.2°, 14.86 ⁇ 0.2°, 12.48 ⁇ 0.2°, 11.94 ⁇ 0.2°, 14.24 ⁇ 0.2°, 23.87 ⁇ 0.2°, 23.25 ⁇ 0.2°, 29.51 ⁇ 0.2° and 27.70 ⁇ 0.2° Peak at angle (2 ⁇ ).
- each molecule of the isopropyl alcohol solvate of the compound of formula (I) contains 1.0-5.0 isopropyl alcohol molecules.
- each molecule of the isopropyl alcohol solvate of the compound of formula (I) contains 4.2 isopropyl alcohol molecules.
- the crystal form is the isopropanol-aqueous solvate crystal form VII of the compound of formula (I), and the X of the isopropyl alcohol-aqueous solvate crystal form VII of the compound of formula (I) - Ray powder diffraction pattern (XRPD) includes diffraction angles (2 ⁇ ) at 23.77 ⁇ 0.2°, 24.36 ⁇ 0.2°, 18.56 ⁇ 0.2°, 5.94 ⁇ 0.2°, 22.59 ⁇ 0.2°, 20.30 ⁇ 0.2° and 17.79 ⁇ 0.2° The peak at.
- the X-ray powder diffraction pattern (XRPD) of the isopropyl alcohol-aqueous heterosolvate crystal form VII of the compound of formula (I) includes positions at 23.77 ⁇ 0.2°, 24.36 ⁇ 0.2°, and 18.56 ⁇ 0.2°, 5.94 ⁇ 0.2°, 22.59 ⁇ 0.2°, 20.30 ⁇ 0.2°, 17.79 ⁇ 0.2°, 10.33 ⁇ 0.2°, 12.10 ⁇ 0.2°, 22.26 ⁇ 0.2°, 19.48 ⁇ 0.2°, 21.73 ⁇ 0.2°, 5.29 ⁇ Peaks at diffraction angles (2 ⁇ ) of 0.2°, 25.80 ⁇ 0.2° and 16.45 ⁇ 0.2°.
- the X-ray powder diffraction pattern (XRPD) of the isopropyl alcohol-aqueous heterosolvate crystal form VII of the compound of formula (I) includes positions at 23.77 ⁇ 0.2°, 24.36 ⁇ 0.2°, and 18.56 ⁇ 0.2 °, 5.94 ⁇ 0.2°, 22.59 ⁇ 0.2°, 20.30 ⁇ 0.2°, 17.79 ⁇ 0.2°, 10.33 ⁇ 0.2°, 12.10 ⁇ 0.2°, 22.26 ⁇ 0.2°, 19.48 ⁇ 0.2°, 21.73 ⁇ 0.2°, 5.29 ⁇ 0.2 °, 25.80 ⁇ 0.2°, 16.45 ⁇ 0.2°, 21.94 ⁇ 0.2°, 28.33 ⁇ 0.2°, 25.04 ⁇ 0.2°, 11.89 ⁇ 0.2°, 17.26 ⁇ 0.2°, 28.85 ⁇ 0.2°, 16.79 ⁇ 0.2°, 23.34 ⁇ 0.2 °, 30.31 ⁇ 0.2° and 14.26 ⁇ 0.2° peaks at diffraction angles (2 ⁇ ).
- each molecule of the isopropyl alcohol-water heterosolvate of the compound of formula (I) contains 0.5-3 isopropyl alcohol molecules and 0.5-3.0 water molecules.
- each molecule of the isopropanol-water heterosolvate of the compound of formula (I) contains 2.0 isopropanol molecules and 1.5 water molecules.
- the fourth aspect of the present invention relates to the use of the above-mentioned pharmaceutical composition or crystal form in the preparation of FGFR inhibitors.
- the fifth aspect of the present invention relates to the use of the above pharmaceutical composition or crystal form in the preparation and treatment of liver cancer, prostate cancer, pancreatic cancer, esophageal cancer, gastric cancer, lung cancer, breast cancer, ovarian cancer, colon cancer, skin cancer, glioblastoma or Uses in drugs for rhabdomyosarcoma.
- the present invention also provides a method for inhibiting FGFR activity, which method includes administering an effective therapeutic amount of the above pharmaceutical composition or crystal form to a patient in need of treatment.
- the present invention also provides a method for treating liver cancer, prostate cancer, pancreatic cancer, esophageal cancer, gastric cancer, lung cancer, breast cancer, ovarian cancer, colon cancer, skin cancer, glioblastoma or rhabdomyosarcoma, the method comprising Administer an effective therapeutic amount of the above-mentioned pharmaceutical composition or crystal form to a patient in need of treatment.
- the present invention also provides an above-mentioned pharmaceutical composition or crystal form, which is used as an FGFR inhibitor.
- the present invention also provides the above pharmaceutical composition or crystal form, which is used to treat liver cancer, prostate cancer, pancreatic cancer, esophageal cancer, gastric cancer, lung cancer, breast cancer, ovarian cancer, colon cancer, skin cancer, and glioblastoma. tumor or rhabdomyosarcoma.
- Figure 1 is a DSC analysis chart of the compound of formula (I).
- the abscissa represents temperature (°C), and the ordinate represents heat flow A (w/g).
- Figure 2 is a DSC analysis chart of glyceryl behenate.
- the abscissa represents temperature (°C), and the ordinate represents heat flow A (w/g).
- Figure 3 is the XRPD pattern of the compound of formula (I) after different processing methods.
- the abscissa represents the 2 ⁇ value (degrees), and the ordinate represents the peak intensity. From top to bottom, the compound of formula (I) after wet granulation, unprocessed XRPD patterns of compounds of formula (I) and grinded compounds of formula (I).
- Figure 4 is the XRPD pattern of granules at different stages of granulation.
- the abscissa represents the 2 ⁇ value (degrees), and the ordinate represents the peak intensity. From top to bottom are the compounds of formula (I) in the final mixture and the formula after fluidized bed drying. XRPD patterns of compound (I), wet granulated compound of formula (I), and untreated compound of formula (I).
- Figure 5 is a comparison of the dissolution curves of the original prescription and the tablets obtained in Experiment 13 and Experiment 17.
- the abscissa is time (min), and the ordinate is dissolution percentage (%). From top to bottom, the original prescription, Experiment 17, Experiment 13 dissolution curve.
- Figure 6 is a comparison chart of the dissolution curves of the tablets obtained from the original prescription and experiments 18-20.
- the abscissa is time (min), and the ordinate is dissolution percentage (%). From top to bottom, it is the original prescription, experiment 18, and experiment 20.
- Figure 7 is an XRPD diffraction spectrum of Form I.
- the abscissa represents the 2 ⁇ value (degrees), and the ordinate represents the peak intensity.
- Figure 8 is a DSC chart of crystal form I.
- the abscissa represents temperature (°C), and the ordinate represents heat flow A (w/g).
- Figure 9 is a TGA diagram of Form I.
- the abscissa represents temperature (° C.) and the ordinate represents weight change (%).
- Figure 10 is a 1 H-NMR chart of Form I, and the abscissa indicates chemical shift (ppm).
- Figure 11 is the XRPD diffraction spectrum of Form II.
- the abscissa represents the 2 ⁇ value (degrees), and the ordinate represents the peak intensity.
- Figure 12 is a DSC chart of crystal form II.
- the abscissa represents temperature (°C) and the ordinate represents heat flow A (w/g).
- Figure 13 is a TGA diagram of crystal form II.
- the abscissa represents temperature (°C) and the ordinate represents weight change (%).
- Figure 14 is a 1 H-NMR chart of the crystal form II, and the abscissa represents the chemical shift (ppm).
- Figure 15 is the XRPD diffraction spectrum of Form III.
- the abscissa represents the 2 ⁇ value (degrees), and the ordinate represents the peak intensity.
- Figure 16 is a DSC chart of crystal form III.
- the abscissa represents temperature (°C) and the ordinate represents heat flow A (w/g).
- Figure 17 is a TGA diagram of Form III.
- the abscissa represents temperature (°C) and the ordinate represents weight change (%).
- Figure 18 is a 1 H-NMR chart of Form III, and the abscissa represents the chemical shift (ppm).
- Figure 19 is the XRPD diffraction spectrum of Form IV.
- the abscissa represents the 2 ⁇ value (degrees), and the ordinate represents the peak intensity.
- Figure 20 is a DSC chart of crystal form IV.
- the abscissa represents temperature (°C), and the ordinate represents heat flow A (w/g).
- Figure 21 is a TGA diagram of Form IV.
- the abscissa represents temperature (° C.), and the ordinate represents weight change (%).
- Figure 22 is a 1 H-NMR chart of Form IV, and the abscissa indicates chemical shift (ppm).
- Figure 23 is the XRPD diffraction spectrum of crystal form V.
- the abscissa represents the 2 ⁇ value (degrees), and the ordinate represents the peak intensity.
- Figure 24 is a DSC chart of crystal form V.
- the abscissa represents temperature (°C), and the ordinate represents heat flow A (w/g).
- Figure 25 is a TGA diagram of crystal form V.
- the abscissa represents temperature (° C.), and the ordinate represents weight change (%).
- Figure 26 is a 1 H-NMR chart of Form V, and the abscissa indicates chemical shift (ppm).
- Figure 27 is the XRPD diffraction spectrum of Form VI.
- the abscissa represents the 2 ⁇ value (degrees), and the ordinate represents the peak intensity.
- Figure 28 is a DSC chart of Form VI.
- the abscissa represents temperature (°C), and the ordinate represents heat flow A (w/g).
- Figure 29 is a TGA diagram of Form VI.
- the abscissa represents temperature (° C.), and the ordinate represents weight change (%).
- Figure 30 is a 1 H-NMR chart of Form VI.
- the abscissa represents the chemical shift (ppm).
- Figure 31 is the XRPD diffraction spectrum of crystal form VII.
- the abscissa represents the 2 ⁇ value (degrees), and the ordinate represents the peak intensity.
- Figure 32 is a DSC chart of crystal form VII.
- the abscissa represents temperature (°C), and the ordinate represents heat flow A (w/g).
- Figure 33 is a TGA diagram of crystal form VII.
- the abscissa represents temperature (° C.), and the ordinate represents weight change (%).
- Figure 34 is a 1 H-NMR chart of Form VII.
- the abscissa represents the chemical shift (ppm).
- Figure 35 is the XRPD diffraction spectrum of Form VIII.
- the abscissa represents the 2 ⁇ value (degrees), and the ordinate represents the peak intensity.
- Figure 36 is a DSC chart of crystal form VIII.
- the abscissa represents temperature (°C), and the ordinate represents heat flow A (w/g).
- Figure 37 is a TGA diagram of crystal form VIII.
- the abscissa represents temperature (° C.), and the ordinate represents weight change (%).
- Figure 38 is a 1 H-NMR chart of Form VIII, and the abscissa represents chemical shift (ppm).
- Figure 39 is an electron microscope scanning image of Form I.
- Figure 40 is the XRPD pattern after the volume stability experiment of crystal form I.
- the abscissa represents the 2 ⁇ value (degrees), and the ordinate represents the peak intensity. From top to bottom in the figure are the anhydrate of the compound of formula (I). I was placed in an open container at 25°C/92%RH, an open container at 40°C/75%RH, and a closed container at 60°C for 1 week, and the crystal form I was subjected to 120°C under visible light at 25°C.
- Figure 41 is the water adsorption isotherm of crystalline form I.
- the abscissa is the water activity P/PO, and the ordinate is the mass scale change (%). From top to bottom in the figure are desorption in cycle 1, adsorption in cycle 1, and desorption in cycle 2. , cycle 2 adsorption curve.
- Figure 42 is a water activity change curve and a mass change curve of Form I, in which the abscissa is time (minutes), the ordinate on the left is mass change (%), and the ordinate on the right is water activity (P/PO), From top to bottom in the figure are the water activity change curve and mass change curve of Form I.
- Figure 43 shows the XRPD pattern of Form I before and after DSV testing.
- the abscissa represents the 2 ⁇ value (degrees), and the ordinate represents the peak intensity.
- Figure 44 is the XRPD diagram of crystal form I before and after the compression simulation test.
- the abscissa represents the 2 ⁇ value (degrees), and the ordinate represents the peak intensity. From top to bottom in the figure are the starting crystal form I, the hydraulic press and the XRPD patterns of Form I after compression at 2MPa, 5MPa and 10MPa.
- Figure 45 is the XRPD pattern of Form I before and after the wet granulation simulation experiment test.
- the abscissa indicates the 2 ⁇ value (degrees), and the ordinate indicates the peak intensity. From top to bottom in the figure, it is made with isopropyl alcohol and water.
- “Pharmaceutical composition” means a mixture containing one or more compounds described herein, or physiologically/pharmaceutically acceptable crystalline forms, salt forms or prodrugs thereof, and other chemical components, as well as other components such as physiologically/pharmaceutically acceptable Medicinal carrier.
- the purpose of pharmaceutical compositions is to facilitate administration to living organisms and facilitate the absorption of active ingredients to exert biological activity.
- the pharmaceutical composition of the present invention may include one or more pharmaceutically acceptable carriers, which include but are not limited to: binders, lubricants, diluents, stabilizers, buffers, adjuvants, carriers, emulsifiers, Viscosity regulators, surfactants, preservatives, flavoring or coloring agents.
- pharmaceutically acceptable carriers include but are not limited to: binders, lubricants, diluents, stabilizers, buffers, adjuvants, carriers, emulsifiers, Viscosity regulators, surfactants, preservatives, flavoring or coloring agents.
- binder refers to a pharmaceutically acceptable compound or composition added to a formulation to hold active pharmaceutical ingredients and inactive ingredients together in a cohesive mixture. Dry binders used for direct compaction must exhibit cohesion and adhesion so that the particles coalesce when compacted.
- the binders used in wet granulation are hydrophilic and soluble in water, and usually dissolve in water to form a wet mass which is then granulated.
- Suitable binders include (but are not limited to) providone, Plasdone K29/32, Plasdone S-630, hydroxypropyl cellulose, methyl cellulose, polyvinylpyrrolidone, aluminum stearate, hydroxypropyl Methylcellulose and its analogs. It is possible that these binders additionally act as water sequestrants (e.g. providone).
- blowing agent refers to any pharmaceutically acceptable substance that evolves gas in response to an irritant (eg, carbon dioxide upon acidification).
- irritant eg, carbon dioxide upon acidification
- blowing agents are carbonates, for example metal carbonates (such as sodium carbonate, potassium carbonate, magnesium carbonate, calcium carbonate or aluminum carbonate) or organic carbonates (such as sodium diglycinate carbonate, dimethyl carbonate acid salt or ethylene carbonate).
- metal carbonates such as sodium carbonate, potassium carbonate, magnesium carbonate, calcium carbonate or aluminum carbonate
- organic carbonates such as sodium diglycinate carbonate, dimethyl carbonate acid salt or ethylene carbonate
- a blowing agent is a bicarbonate, for example a metal bicarbonate (such as sodium bicarbonate or potassium bicarbonate).
- filler refers to any pharmaceutically acceptable substance or composition added to a formulation to increase volume. Suitable fillers include, but are not limited to, mannitol, lactose, microcrystalline cellulose, silicified microcrystalline cellulose, and dicalcium phosphate.
- lubricant refers to any pharmaceutically acceptable agent that reduces surface friction, lubricates the particle surface, reduces the tendency of static electricity to accumulate, and/or reduces the brittleness of the particle. Therefore, lubricants act as anti-aggregation agents.
- Conventional lubricants include stearic acid and related compounds such as magnesium stearate and sodium stearyl fumarate.
- Alternative lubricants include glycerol dibehenate, colloidal silica, talc, other hydrogenated vegetable oils, or triglycerides. Examples of suitable alternative lubricants include, but are not limited to, glyceryl dibehenate.
- disintegrant refers to a substance added to a composition to help it break apart (disintegrate) and release the pharmaceutical agent.
- examples of disintegrants include, but are not limited to, non-sugar water-soluble polymers such as cross-linked polyvinylpyrrolidone.
- Other disintegrants that may also be used include, for example, croscarmellose sodium, sodium starch glycolate and the like, see for example Khattab (1992) J. Pharm. Pharmacol. 45:687-691.
- hydroxypropyl cellulose is a partially substituted poly(hydroxypropyl) ether of cellulose.
- Commercially available hydroxypropylcellulose is divided into many specifications according to different molecular weights, and its aqueous solutions also have different viscosities.
- hydroxypropyl cellulose LF refers to hydroxypropyl cellulose with an average molecular weight of about 95,000, or hydroxypropyl cellulose with LF specifications.
- “Hydroxypropyl cellulose JF” refers to hydroxypropyl cellulose with an average molecular weight of about 140,000, or JF grade hydroxypropyl cellulose.
- Hydropropyl cellulose EXF or EF refers to hydroxypropyl cellulose with an average molecular weight of about 80,000, or hydroxypropyl cellulose with EXF or EF grade specifications.
- Silicified microcrystalline fiber is Silicified microcrystalline cellulose, which refers to the preparation of microcrystalline cellulose and colloidal silica by blending and drying in water. Calculated as a dry product, it generally contains 94.0 to 100% microcrystalline cellulose. .
- tablette refers to the process of applying compressive force (eg in a mold) to a formulation (powder or granules) to form tablets.
- tablette means any tablet formed by such a process.
- tablette is used in its common context and refers to a solid composition made by compressing and/or molding a mixture of the compositions into a form convenient for swallowing or application to any body cavity.
- punch sticking refers to the adhesion of material to the surface of the tablet punch. If sufficient material is built up on the punch surface, the tablet weight may fall below acceptable limits, among other defects. (Journal of Pharmaceutical Sciences, Vol. 93(2), 2004).
- Polymorph refers to a crystalline form that has the same chemical composition but different spatial arrangements of the molecules, atoms, and/or ions that make up the crystal. Although polymorphs have the same chemical composition, they differ in packing and geometric arrangement and may exhibit different physical properties such as melting point, shape, color, density, hardness, deformability, stability, solubility, dissolution velocity and similar properties. Depending on their temperature-stability relationship, two polymorphs can be monotropic or tautotropic. For a unidenaturing system, the relative stability between the two solid phases remains unchanged when the temperature changes. In contrast, in tautotropic systems, there is a transition temperature at which the stability of the two phases switches. The phenomenon of a compound existing in different crystal structures is called drug polymorphism.
- the various crystalline structures of the present invention can be distinguished from each other using various analytical techniques known to those of ordinary skill in the art. Such techniques include, but are not limited to, X-ray powder diffraction (XRPD), differential scanning calorimetry (DSC), and/or thermogravimetric analysis (TGA).
- XRPD X-ray powder diffraction
- DSC differential scanning calorimetry
- TGA thermogravimetric analysis
- X-ray powder diffraction patterns can be obtained with measurement errors that depend on the measurement conditions used.
- the intensity in an X-ray powder diffraction pattern may fluctuate depending on the conditions of the material used. Relative strengths may also vary with experimental conditions, and accordingly, the exact strengths should not be taken into account.
- the measurement error of conventional powder X-ray powder diffraction angles is usually about 5% or less, and this degree of measurement error should be regarded as belonging to the above-mentioned diffraction angles. Accordingly, the crystal structures of the present invention are not limited to crystal structures that provide an X-ray powder diffraction pattern that is identical to the X-ray powder diffraction pattern depicted in the figures disclosed herein.
- any crystal structure having an X-ray powder diffraction pattern substantially identical to those disclosed in the drawings falls within the scope of the present invention.
- Those skilled in the art should have the ability to determine that X-ray powder diffraction patterns are substantially the same.
- Other suitable standard calibrations are known to those skilled in the art.
- the relative strength may vary with crystal size and shape.
- Crystalline forms of the compounds of the invention are characterized by their X-ray powder diffraction patterns. Therefore, using Cu K ⁇ radiation with The X-ray powder diffraction pattern of the salt was collected on a Bruker D8 Discover X-ray powder diffractometer operated in reflection mode with a GADDS (General Area Diffraction Detector System) CS. The tube voltage and current were set to 40kV and 40mA for acquisition scan respectively. Scan the sample over a 2 ⁇ range of 3.0° to 40° for a period of 60 seconds. The diffractometer was calibrated using corundum standards for peak positions expressed in 2 ⁇ . All analyzes were performed at typically 20°C-30°C. Data were acquired and integrated using GADDS for WNT software version 4.1.14T. Diffractograms were analyzed using DiffracPlus software with version 9.0.0.2 of Eva released in 2003.
- GADDS General Area Diffraction Detector System
- Measurement differences associated with the results of such X-ray powder diffraction analysis arise from a variety of factors including: (a) errors in sample preparation (e.g., sample height), (b) instrument errors, (c) calibration differences, ( d) operator errors (including those occurring in determining peak positions), and (e) properties of the material (eg preferred orientation errors). Calibration errors and sample height errors often cause all peaks to be shifted in the same direction. Generally speaking, this calibration factor will bring the measured peak position consistent with the expected peak position and within ⁇ 0.2° of the expected 2 ⁇ value.
- DSC Differential scanning calorimetry
- Thermogravimetric analysis (TGA) experiments were performed in a TA Instruments TM model Q500. Samples (approximately 10-30 mg) were placed in pre-tare platinum pans. Accurately measure the sample weight by instrument and record to the nearest thousandth of a mg. The furnace was purged with nitrogen at 100 ml/minute. Data were collected between room temperature and 300°C at a heating rate of 10°C/minute.
- the experimental method of using the dynamic moisture adsorption method (DVS) to characterize the acid salt of the compound of crystalline form (I) is to take a small amount of the acid salt powder of the compound of crystalline form (I) and place it in a precision sample tray matched with the instrument. After loading the sample , sent to the instrument for testing. All instruments used in the dynamic moisture adsorption method in this patent are DVS Intrinsic.
- the reagents in the embodiments of the present invention are known and can be purchased on the market.
- the reagents used are commercially available industrial grade or analytical grade reagents, or can be synthesized using or according to methods known in the art.
- the formula ( I) Compound API raw materials are prepared according to patent WO2008075068A1.
- magnesium carbonate, microcrystalline cellulose, mannitol, and hydroxypropyl fiber were added according to the components and contents recorded in Table 1 below.
- Vegetable EXF, carboxymethyl starch sodium and the compound of formula (I) are sieved and premixed, then poured into a wet granulation pot, purified water is added to the powder, and a wet granulator is used for granulation. After wet granulation, use a fluidized bed dryer to dry to appropriate moisture ( ⁇ 2% w/w). After the dried granules are dried and granulated, glyceryl behenate is then added to the granules and mixed evenly to obtain final mixed granules, which are then compressed into tablets, resulting in sticking.
- NA means that it does not contain this component, and the following experiments have the same meaning.
- the API used in the original prescription was prepared according to WO2008075068A2, and the API used in Experiments 1-4 was the anhydrous crystal form I of the compound of formula (I).
- the API compound of formula (I) used in Example 6 which was prepared according to patent WO2008075068A1, other examples are not specifically specified.
- the APIs used in the experimental research are all anhydrous crystal form I of the compound of formula (I). .
- the experimental results are shown in Figures 1 to 4.
- the DSC and XRPD measurement results of the samples show that the melting point of the compound of formula (I) is 172.38°C, has no Tg value, and does not absorb moisture under the conditions of 25°C and 80% RH.
- the melting point of glyceryl behenate is: 71.63°C and has no Tg value. It is preliminarily determined that the XRPD of the compound of formula (I) after moist heat treatment and grinding shows no crystalline change.
- microcrystalline cellulose and mannitol in the original prescription were added internally and externally (1/2 was used for wet granulation and 1/2 was used for external mixing) to dilute the ungranulated compound of formula (I).
- the results show that : The prepared granules will stick to each other within 3 minutes of tableting.
- the tableting conditions of comparative experiments 11 and 15 show that when the amount of binder is reduced (the proportion of hydroxypropylcellulose LF is reduced from 7% to 5%, and the concentration is reduced from 12% to 10%), the fluidized bed is used at the same time. When drying, even if the dosage of glyceryl behenate is increased to 5%, sticking will still occur.
- Experiments 13 and 17 used a higher viscosity adhesive (hydroxypropyl cellulose LF), added the lubricant magnesium stearate, and increased the dosage of glyceryl behenate to solve the sticking problem. .
- the properties of the final mixed particles were changed, so the tablet dissolution efficiency of the coated tablets prepared in Experiment 13 and Experiment 17 was evaluated.
- the solubility was measured in a pH 6.8 phosphate buffer solution at 37°C ⁇ 0.5°C using a paddle method with a stirring speed of 50 rpm.
- the dissolution medium was withdrawn and the concentration in the solution was determined by UV broad spectrum method at 311 nm wavelength against an external standard solution.
- the experimental data are detailed in Table 5, and the dissolution curve comparison is shown in Figure 5.
- Solubility was measured in pH 6.8 phosphate buffer solution using a paddle method with a stirring speed of 50 rpm. At 15, 30, and 60 minutes, the dissolution medium was withdrawn and the concentration of the solution was determined by UV broad spectrum method at 311 nm wavelength against an external standard solution. The experimental data are detailed in Table 7, and the dissolution curve is shown in Figure 6.
- Experiment 18 examined the improvement of dissolution release by the amount of filler. The results showed that after the proportion of microcrystalline cellulose increased from 9.685% to 30.182%, the dissolution release of the tablets in Experiment 17 at 30 minutes improved to a certain extent. This may be due to the microcrystalline cellulose. When the amount of cellulose is greater than 30%, the disintegration ability is enhanced. However, it can still be observed that the tablet disintegrates slowly during the dissolution process, and larger lumps can be observed to accumulate at the bottom of the cup at 20 minutes.
- Experiment 19 examined the improvement of dissolution release by adjusting filler dosage, disintegrant dosage, and adding method. The results showed that based on Experiment 17, the disintegrant proportion was increased (7.5% to 10%) and the dosage was increased to 5. After % internal addition and 5% external addition, the dissolution difference was larger. Some tablets had less accumulation at the bottom of the cup. At this time, the dissolution and release degree was higher, reaching 90% in 30 minutes. However, some tablets have larger pieces accumulated at the bottom of the cup, resulting in reduced dissolution. Only 73% is released in 30 minutes. When accelerated to 250 rpm, the lumps can be seen to quickly disintegrate.
- Experiment 20 considers the insoluble particles that appear during the dissolution process. Based on Experiment 18, the proportion of water-soluble mannitol is increased and the proportion of microcrystalline cellulose is reduced (microcrystalline cellulose is 20% and mannitol is 20.63%). At the same time, after reducing the amount of lubricant (glyceryl behenate was reduced from 5% to 3%, and magnesium stearate was reduced from 3% to 1.5%), the results showed that although there were still small agglomerates during the dissolution process , but the dissolution release is the best.
- lubricant glyceryl behenate was reduced from 5% to 3%, and magnesium stearate was reduced from 3% to 1.5%
- Fluidized bed drying transfer the wet particles to a 3L fluidized bed for drying. When the moisture content of the particles is ⁇ 2%, drying is stopped. The final moisture content of the pellets was 1.4%.
- Dry granulation Use Comil U5 for wet granulation, with a screen aperture of 1575 ⁇ m and a rotation speed of 2500 rpm. Since a certain amount of larger particles remain on the screen and cannot pass through the screen, the rotation speed is increased to 2700 rpm. The granules after dry granulation have a larger amount of fine powder.
- Adding disintegrant and lubrication Calculate the proportion of external excipients based on the quality of the dried particles.
- the additional auxiliary materials are weighed and sieved and then mixed according to the set parameters.
- the mixing times for adding croscarmellose sodium, glyceryl behenate, and magnesium stearate are 8 minutes, 30 minutes, and 3 minutes respectively.
- BU sampling and powder central control Use a sampler to sample the final mixed particles to measure BU, and at the same time detect the powder bulk density, tap density, and particle size distribution.
- the experimental results are shown in Table 9. The BU result measurement showed that it was qualified (mean value: 100.9%), and there was no excess.
- the target tablet weight of 20mg specification is 96.81mg, the single tablet limit is 92.5%-107.5%, and the tablet weight range is 89.55-104.07mg.
- the 20mg specification uses two sets of 6mm non-chrome plated punches at 30rpm for tableting. Due to the large amount of fine powder, the main pressure fluctuates greatly during the tableting process, but the tablet weight is relatively stable.
- the tableting process of 20mg specification lasted for 90 minutes, and the appearance of the tablets was smooth and smooth, with no sticking phenomenon during the process. However, due to the large amount of fine powder, powder leakage occurred during the tableting process, and the yield was reduced.
- the final tablet was 442.74g (about 4500EA).
- Coating Coat the pressed tablets, and the solid content of the coating liquid is 18%.
- the target weight gain is 3%, and the weight gain range is 2.% to 3.4%.
- the final weight gain of the 20mg specification was 3.3%, and the final yield was 453.4g.
- the surface of the coated tablet was smooth and there was no color difference.
- Bottled Packed at 24EA/bottle, each bottle contains one bag of 1g desiccant.
- the equipment is debugged according to the set parameters for bottling, and finally the bottled samples are sent to analysis and testing for sampling.
- Fluidized bed drying Transfer the combined wet particles to a 6L fluidized bed for drying. When the moisture content of the particles is ⁇ 2%, drying is stopped. The final moisture content of the pellets was 0.94%.
- Dry granulation Use Comil U5 to wet granulate the granules, the screen aperture is 1575 ⁇ m, and the rotation speed is 2250rpm. The granules after dry granulation have a larger amount of fine powder.
- Adding disintegrant and lubrication Calculate the proportion of external excipients based on the quality of the dried particles.
- the additional auxiliary materials are weighed and sieved and then mixed according to the set parameters.
- the mixing times for adding croscarmellose sodium, glyceryl behenate, and magnesium stearate are 8 minutes, 30 minutes, and 3 minutes respectively.
- BU sampling and powder central control Use a sampler to sample the final mixed particles to measure BU, and at the same time detect the powder bulk density, tap density, and particle size distribution.
- the experimental results are shown in Table 9. The BU result measurement showed that it was qualified (mean value: 101.7%), and no single value exceeded the limit.
- Tablet compression The target tablet weight of 80mg specification is 387.22mg, the single tablet limit is 95%-105%, and the tablet weight range is 367.86-406.58mg.
- the target tablet weight of 80mg specification is 387.22mg, the single tablet limit is 95%-105%, and the tablet weight range is 367.86-406.58mg.
- When pressing use 2 sets of 6mm and 11mm non-chrome plated punches and press at 30rpm. During the tableting process, the main pressure is relatively stable and powder leakage is significantly improved.
- the compression of 80 mg tablets lasted for 60 minutes. The appearance of the tablets was smooth and smooth, and there was no sticking phenomenon during the process.
- the final film was 1404.9g (about 3600EA).
- Coating Coat the pressed tablets, and the solid content of the coating liquid is 18%.
- the target weight gain is 3%, and the weight gain range is 2.% to 3.4%.
- the final weight gain of the 80mg specification is 2.84%, and the final yield is 1433.0g.
- the coated tablet has a smooth surface and no color difference.
- Bottled Packed at 24EA/bottle, each bottle contains one bag of 1g desiccant.
- the equipment is debugged according to the set parameters for bottling, and finally the bottled samples are sent to analysis and testing for sampling.
- Test results The test results all meet the release requirements.
- the XRPD diffraction patterns of the anhydrate (form I) crystals of the compound of formula (I) obtained by the above preparation methods are the same as shown in Figure 7, and the DSC, TGA, and 1 H-NMR analysis patterns are shown in Figures 8-10.
- DSC shows a melting point (Tonset) of 171.6°C and an enthalpy of approximately 87 J/g.
- TGA showed about 0.2% weight loss at about 150°C.
- 1 H-NMR showed no residual solvent detected.
- KF indicates that it contains approximately 0.1% water by weight.
- the SEM image is shown in Figure 39, and its sub-grain size is ⁇ 10 ⁇ m.
- Form I crystals were placed in an open container at 25°C/92%RH, an open container at 40°C/75%RH, and a closed container at 60°C for 1 week. A stress of 1.2 million lux-hrs was applied to the crystal under visible light at 25°C.
- the experimental report is shown in the table above, and the DVS analysis chart is shown in Figures 40-43.
- the results show that the crystalline form I does not absorb moisture when it is lower than 80% RH, and is slightly hygroscopic when it is higher than 80% RH. At 25°C, it absorbs ⁇ 0.1% water from 40% relative humidity to 80% relative humidity, and about 0.4% water from 80% relative humidity to 95% relative humidity. After the DVS test, the sample obtained was still Form I.
- Form I Approximately 10 mg of Form I crystals were pressed with a hydraulic press at 2 MPa, 5 MPa and 10 MPa, and potential morphological changes and crystallinity were evaluated by XRPD. The experimental results are shown in Figure 44. After compression, Form I showed no morphological changes, but its crystallinity decreased slightly with increasing pressure.
- the XRPD diffraction patterns of the anhydrous crystal form (form II) of the compound of formula (I) obtained by the above preparation methods are the same, as shown in Figure 11, and the DSC, TGA, and 1 H-NMR analysis patterns are shown in Figures 12-14.
- DSC shows an endothermic peak at T onset of 155.5°C, with an enthalpy of approximately 6J/g, a melting point (T onset ) of 171.3°C, and an enthalpy of approximately 87J/g.
- TGA showed about 1.4% weight loss at about 155°C and about 0.2% weight loss from about 155°C to 170°C.
- 1 H-NMR showed 0.2% by weight of ethyl acetate remaining.
- KF indicates that it contains approximately 0.4% water by weight.
- the XRPD diffraction patterns of the crystalline form (form IV) of the hydrate of the compound of formula (I) obtained by the above preparation methods are the same as shown in Figure 19, and the DSC, TGA, and 1 H-NMR analysis patterns are shown in Figures 20-22.
- DSC shows a dehydration peak at a T onset of 41.8°C with an enthalpy of approximately 23 J/g, an endothermic peak with an enthalpy of approximately 30 J/g at a T onset of 116.5°C, and an exothermic peak at a T onset of 127.4°C.
- the enthalpy is about 51J/g.
- TGA melts at a T onset of 171.0°C with an enthalpy of approximately 69 J/g.
- TGA showed a weight loss of approximately 2.8% at approximately 170°C.
- KF shows it contains about 6.4% water by weight, equivalent to 1.8 water molecules.
- the XRPD diffraction patterns of the crystalline form (form VI) of the 2-methyltetrahydrofuran solvate of the compound of formula (I) obtained by the above preparation methods are the same, as shown in Figure 27, and the DSC, TGA, and 1 H-NMR analysis patterns are as shown in Figure 28 -30 shown.
- DSC shows a desolvation peak at Tonset of 97.3°C with an enthalpy of approximately 62 J/g, and an exothermic peak at Tonset of 117.9°C with an enthalpy of approximately 41 J/g. It then melts at Tonset of 170.5°C with an enthalpy of about 61 J/g.
- TGA showed approximately 9.9% weight loss at approximately 150°C.
- 1 H-NMR showed 15.7% by weight of 2-methyltetrahydrofuran remaining, equivalent to 1.0 molecules of 2-methyltetrahydrofuran.
- the XRPD diffraction patterns of the isopropanol/water solvate crystal form (form VII) of the compound of formula (I) obtained by the above preparation methods are the same, as shown in Figure 31, and the DSC, TGA, and 1 H-NMR analysis patterns are as shown in Figure 32 -34 shown.
- DSC shows a desolvation peak at a Tonset of 37.8°C with an enthalpy of approximately 59 J/g, an endothermic peak at a Tonset of 88.1°C with an enthalpy of approximately 95 J/g, and a desolvation peak at a Tonset of 114.1°C.
- Thermal peak, enthalpy is about 36J/g.
- the weight loss is about 3.6% from about 65°C to 100°C, and the weight loss is about 2.2% from about 100°C to 130°C.
- 1 H-NMR showed 20.1% by weight of isopropanol remaining, equivalent to 2.0 molecules of isopropanol.
- KF indicates that it contains approximately 4.3% water, equivalent to 1.5 water molecules.
- Solvent activity experiments were performed in an isopropanol/water system at 25°C to determine the critical water activity between the free forms Form I, Form II, Form VII and Form VIII.
- Crystal form VII is a thermodynamic product, corresponding to the isopropyl alcohol/water (v/v) from 98/2 to 50/50; and at 25°C, when a.w. is between 0.66 and 0.96 and isopropanol activity is between 0.73 and 0.52,
- Form VII is a thermodynamic product corresponding to isopropanol/water ( v/v) from 90/10 to 50/50.
- Form I is the thermodynamic product.
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Veterinary Medicine (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Epidemiology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Organic Chemistry (AREA)
- Inorganic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
La présente invention concerne une composition pharmaceutique et une substance polymorphe d'un inhibiteur de FGFR, et leur utilisation pharmaceutique. L'inhibiteur de FGFR est un inhibiteur du récepteur du facteur de croissance des fibroblastes avec une structure de formule (I). En adoptant un adhésif approprié et un support pharmaceutiquement acceptable, une préparation pharmaceutique appropriée pour une production industrielle a été développée. Un polymorphe d'un composé représenté par la formule (I) a été en outre développé. Selon les solutions techniques, une préparation pharmaceutique répondant aux exigences de recherche clinique et d'entrée de marché de médicament peut être développée, et le problème d'accessibilité de médicament peut être résolu.
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
PCT/CN2022/110810 WO2024031226A1 (fr) | 2022-08-08 | 2022-08-08 | Composition pharmaceutique et substance polymorphe d'inhibiteur de fgfr, et leur utilisation pharmaceutique |
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
PCT/CN2022/110810 WO2024031226A1 (fr) | 2022-08-08 | 2022-08-08 | Composition pharmaceutique et substance polymorphe d'inhibiteur de fgfr, et leur utilisation pharmaceutique |
Publications (1)
Publication Number | Publication Date |
---|---|
WO2024031226A1 true WO2024031226A1 (fr) | 2024-02-15 |
Family
ID=89850133
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/CN2022/110810 WO2024031226A1 (fr) | 2022-08-08 | 2022-08-08 | Composition pharmaceutique et substance polymorphe d'inhibiteur de fgfr, et leur utilisation pharmaceutique |
Country Status (1)
Country | Link |
---|---|
WO (1) | WO2024031226A1 (fr) |
Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2008075068A2 (fr) * | 2006-12-21 | 2008-06-26 | Astrazeneca Ab | Nouveaux composés |
CN102170885A (zh) * | 2008-09-30 | 2011-08-31 | 安斯泰来制药株式会社 | 口服用药物组合物 |
CN104853750A (zh) * | 2012-12-21 | 2015-08-19 | 阿斯利康(瑞典)有限公司 | N-[5-[2-(3,5-二甲氧基苯基)乙基]-2h-吡唑-3-基]-4-[(3r,5s)-3,5-二甲基哌嗪-1-基]苯甲酰胺的医药配制品 |
-
2022
- 2022-08-08 WO PCT/CN2022/110810 patent/WO2024031226A1/fr unknown
Patent Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2008075068A2 (fr) * | 2006-12-21 | 2008-06-26 | Astrazeneca Ab | Nouveaux composés |
CN102170885A (zh) * | 2008-09-30 | 2011-08-31 | 安斯泰来制药株式会社 | 口服用药物组合物 |
CN104853750A (zh) * | 2012-12-21 | 2015-08-19 | 阿斯利康(瑞典)有限公司 | N-[5-[2-(3,5-二甲氧基苯基)乙基]-2h-吡唑-3-基]-4-[(3r,5s)-3,5-二甲基哌嗪-1-基]苯甲酰胺的医药配制品 |
Non-Patent Citations (2)
Title |
---|
GAVINE, PAUL R. ET AL.: "AZD4547: An Orally Bioavailable, Potent, and Selective Inhibitor of the Fibroblast Growth Factor Receptor Tyrosine Kinase Family", CANCER RESEARCH, vol. 72, no. 8, 15 April 2012 (2012-04-15), XP055065340, DOI: 10.1158/0008-5472.CAN-11-3034 * |
HUAXING LUO, FAN YA: "Progress in Pharmaceutical Sciences", PROGRESS IN PHARMACEUTICAL SCIENCES, vol. 33, no. 6, 25 June 2009 (2009-06-25), pages 279, XP093137287 * |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
US11123338B2 (en) | C-met modulator pharmaceutical compositions | |
TWI833686B (zh) | Lsd1 抑制劑之調配物 | |
CN111432803A (zh) | 包含血浆激肽释放酶抑制剂的剂型 | |
WO2018108101A1 (fr) | Nouvelles formes cristallines d'acide {[5-(3-chlorophényl)-3-hydroxypyridine-2-carbonyl]amino} acétique et leur procédé de préparation | |
JP2019214605A (ja) | ブルトンチロシンキナーゼの阻害剤を含む剤形組成物 | |
JP7437460B2 (ja) | N-{4-[(6,7-ジメトキシキノリン-4-イル)オキシ]フェニル}-n’-(4-フルオロフェニル)シクロプロパン-1,1-ジカルボキサミドの塩の結晶性固体形態、製造プロセス、及び使用方法 | |
US10583087B2 (en) | Pharmaceutical composition for oral administration | |
WO2024031226A1 (fr) | Composition pharmaceutique et substance polymorphe d'inhibiteur de fgfr, et leur utilisation pharmaceutique | |
WO2018233437A1 (fr) | Forme cristalline de baricitinib et procédé de préparation correspondant | |
WO2019205812A1 (fr) | Nouvelle forme cristalline de l'acalabrutinib, son procédé de préparation et son utilisation | |
TW201840320A (zh) | 包含5-氯-n4-[2-(二甲基磷醯基)苯基]-n2-{2-甲氧基-4-[4-(4-甲基哌嗪-1-基)哌啶-1-基]苯基}嘧啶-2,4-二胺之醫藥調配物 | |
CN106994121A (zh) | 一种用于治疗癌症的药物组合物 | |
WO2023198055A1 (fr) | Polymorphe de 7,8-dihydroxyflavone et son procédé de préparation |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
121 | Ep: the epo has been informed by wipo that ep was designated in this application |
Ref document number: 22954206 Country of ref document: EP Kind code of ref document: A1 |