CN115260108A - Eutectic crystal of acid and preparation method thereof - Google Patents
Eutectic crystal of acid and preparation method thereof Download PDFInfo
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- CN115260108A CN115260108A CN202210289998.6A CN202210289998A CN115260108A CN 115260108 A CN115260108 A CN 115260108A CN 202210289998 A CN202210289998 A CN 202210289998A CN 115260108 A CN115260108 A CN 115260108A
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- Prior art keywords
- daprodustat
- crystal
- salt
- ray powder
- tromethamine
- Prior art date
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- 239000013078 crystal Substances 0.000 title claims abstract description 178
- 230000005496 eutectics Effects 0.000 title claims abstract description 24
- 238000002360 preparation method Methods 0.000 title abstract description 12
- 239000002253 acid Substances 0.000 title abstract description 4
- RUEYEZADQJCKGV-UHFFFAOYSA-N 2-[(1,3-dicyclohexyl-2,4,6-trioxo-1,3-diazinane-5-carbonyl)amino]acetic acid Chemical compound O=C1N(C2CCCCC2)C(=O)C(C(=O)NCC(=O)O)C(=O)N1C1CCCCC1 RUEYEZADQJCKGV-UHFFFAOYSA-N 0.000 claims description 179
- 229950010337 daprodustat Drugs 0.000 claims description 179
- 238000000634 powder X-ray diffraction Methods 0.000 claims description 77
- 239000000203 mixture Substances 0.000 claims description 43
- 150000003839 salts Chemical class 0.000 claims description 40
- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical group OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 claims description 39
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 36
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 35
- 229960003350 isoniazid Drugs 0.000 claims description 31
- QRXWMOHMRWLFEY-UHFFFAOYSA-N isoniazide Chemical compound NNC(=O)C1=CC=NC=C1 QRXWMOHMRWLFEY-UHFFFAOYSA-N 0.000 claims description 31
- 239000002904 solvent Substances 0.000 claims description 27
- 238000000034 method Methods 0.000 claims description 19
- 238000003756 stirring Methods 0.000 claims description 15
- 238000001757 thermogravimetry curve Methods 0.000 claims description 15
- 230000004580 weight loss Effects 0.000 claims description 15
- 238000001914 filtration Methods 0.000 claims description 14
- 239000000725 suspension Substances 0.000 claims description 11
- 229960000281 trometamol Drugs 0.000 claims description 10
- ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-Butanone Chemical compound CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 claims description 6
- XBDQKXXYIPTUBI-UHFFFAOYSA-M Propionate Chemical compound CCC([O-])=O XBDQKXXYIPTUBI-UHFFFAOYSA-M 0.000 claims description 6
- NMJJFJNHVMGPGM-UHFFFAOYSA-N butyl formate Chemical compound CCCCOC=O NMJJFJNHVMGPGM-UHFFFAOYSA-N 0.000 claims description 6
- TZIHFWKZFHZASV-UHFFFAOYSA-N methyl formate Chemical compound COC=O TZIHFWKZFHZASV-UHFFFAOYSA-N 0.000 claims description 6
- 238000001035 drying Methods 0.000 claims description 4
- KXKVLQRXCPHEJC-UHFFFAOYSA-N acetic acid trimethyl ester Natural products COC(C)=O KXKVLQRXCPHEJC-UHFFFAOYSA-N 0.000 claims description 3
- 239000003937 drug carrier Substances 0.000 claims description 3
- WBJINCZRORDGAQ-UHFFFAOYSA-N formic acid ethyl ester Natural products CCOC=O WBJINCZRORDGAQ-UHFFFAOYSA-N 0.000 claims description 3
- JMMWKPVZQRWMSS-UHFFFAOYSA-N isopropanol acetate Natural products CC(C)OC(C)=O JMMWKPVZQRWMSS-UHFFFAOYSA-N 0.000 claims description 3
- 229940011051 isopropyl acetate Drugs 0.000 claims description 3
- GWYFCOCPABKNJV-UHFFFAOYSA-N isovaleric acid Chemical compound CC(C)CC(O)=O GWYFCOCPABKNJV-UHFFFAOYSA-N 0.000 claims description 3
- 238000001938 differential scanning calorimetry curve Methods 0.000 claims 2
- 239000003814 drug Substances 0.000 abstract description 16
- 229940079593 drug Drugs 0.000 abstract description 14
- 239000000825 pharmaceutical preparation Substances 0.000 abstract description 4
- CUYKNJBYIJFRCU-UHFFFAOYSA-N 3-aminopyridine Chemical compound NC1=CC=CN=C1 CUYKNJBYIJFRCU-UHFFFAOYSA-N 0.000 description 54
- 238000002411 thermogravimetry Methods 0.000 description 47
- 238000000113 differential scanning calorimetry Methods 0.000 description 41
- 150000004885 piperazines Chemical class 0.000 description 24
- QLNJFJADRCOGBJ-UHFFFAOYSA-N propionamide Chemical compound CCC(N)=O QLNJFJADRCOGBJ-UHFFFAOYSA-N 0.000 description 23
- 229940080818 propionamide Drugs 0.000 description 23
- XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Chemical compound NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 description 22
- 239000004202 carbamide Substances 0.000 description 22
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 20
- 239000008213 purified water Substances 0.000 description 13
- GLUUGHFHXGJENI-UHFFFAOYSA-N Piperazine Chemical compound C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 description 12
- 238000012360 testing method Methods 0.000 description 11
- 238000001291 vacuum drying Methods 0.000 description 9
- -1 amino compound Chemical class 0.000 description 8
- 238000001514 detection method Methods 0.000 description 8
- 238000003760 magnetic stirring Methods 0.000 description 8
- 238000005286 illumination Methods 0.000 description 7
- 238000011160 research Methods 0.000 description 7
- 239000007787 solid Substances 0.000 description 7
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 6
- 238000004090 dissolution Methods 0.000 description 6
- JBTWLSYIZRCDFO-UHFFFAOYSA-N ethyl methyl carbonate Chemical compound CCOC(=O)OC JBTWLSYIZRCDFO-UHFFFAOYSA-N 0.000 description 6
- 150000002576 ketones Chemical group 0.000 description 6
- 238000005259 measurement Methods 0.000 description 6
- 229960005141 piperazine Drugs 0.000 description 6
- UEIZUEWXLJOVLD-UHFFFAOYSA-N 3-(1-methylpyrrolidin-3-yl)pyridine Chemical compound C1N(C)CCC1C1=CC=CN=C1 UEIZUEWXLJOVLD-UHFFFAOYSA-N 0.000 description 5
- 239000000463 material Substances 0.000 description 5
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 4
- 230000009286 beneficial effect Effects 0.000 description 4
- 238000004519 manufacturing process Methods 0.000 description 4
- 230000009466 transformation Effects 0.000 description 4
- 101710138860 Hypoxia-inducible factor prolyl hydroxylase Proteins 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 239000012296 anti-solvent Substances 0.000 description 3
- 238000006243 chemical reaction Methods 0.000 description 3
- 238000002474 experimental method Methods 0.000 description 3
- 238000012986 modification Methods 0.000 description 3
- 230000004048 modification Effects 0.000 description 3
- 238000003860 storage Methods 0.000 description 3
- 238000005303 weighing Methods 0.000 description 3
- 238000005160 1H NMR spectroscopy Methods 0.000 description 2
- BDKLKNJTMLIAFE-UHFFFAOYSA-N 2-(3-fluorophenyl)-1,3-oxazole-4-carbaldehyde Chemical compound FC1=CC=CC(C=2OC=C(C=O)N=2)=C1 BDKLKNJTMLIAFE-UHFFFAOYSA-N 0.000 description 2
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- PXHVJJICTQNCMI-UHFFFAOYSA-N Nickel Chemical compound [Ni] PXHVJJICTQNCMI-UHFFFAOYSA-N 0.000 description 2
- 208000005764 Peripheral Arterial Disease Diseases 0.000 description 2
- 208000030831 Peripheral arterial occlusive disease Diseases 0.000 description 2
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 description 2
- 238000004458 analytical method Methods 0.000 description 2
- 229940040526 anhydrous sodium acetate Drugs 0.000 description 2
- 239000002585 base Substances 0.000 description 2
- 239000003112 inhibitor Substances 0.000 description 2
- 208000023589 ischemic disease Diseases 0.000 description 2
- 229910000402 monopotassium phosphate Inorganic materials 0.000 description 2
- 235000019796 monopotassium phosphate Nutrition 0.000 description 2
- 229910052757 nitrogen Inorganic materials 0.000 description 2
- 239000000546 pharmaceutical excipient Substances 0.000 description 2
- PJNZPQUBCPKICU-UHFFFAOYSA-N phosphoric acid;potassium Chemical compound [K].OP(O)(O)=O PJNZPQUBCPKICU-UHFFFAOYSA-N 0.000 description 2
- 229960003506 piperazine hexahydrate Drugs 0.000 description 2
- AVRVZRUEXIEGMP-UHFFFAOYSA-N piperazine;hexahydrate Chemical compound O.O.O.O.O.O.C1CNCCN1 AVRVZRUEXIEGMP-UHFFFAOYSA-N 0.000 description 2
- BASFCYQUMIYNBI-UHFFFAOYSA-N platinum Chemical compound [Pt] BASFCYQUMIYNBI-UHFFFAOYSA-N 0.000 description 2
- 230000005855 radiation Effects 0.000 description 2
- 238000005070 sampling Methods 0.000 description 2
- 235000017281 sodium acetate Nutrition 0.000 description 2
- 229940087562 sodium acetate trihydrate Drugs 0.000 description 2
- 238000003892 spreading Methods 0.000 description 2
- 230000007480 spreading Effects 0.000 description 2
- 238000012546 transfer Methods 0.000 description 2
- KZEVSDGEBAJOTK-UHFFFAOYSA-N 1-(2,4,6,7-tetrahydrotriazolo[4,5-c]pyridin-5-yl)-2-[5-[2-[[3-(trifluoromethoxy)phenyl]methylamino]pyrimidin-5-yl]-1,3,4-oxadiazol-2-yl]ethanone Chemical compound N1N=NC=2CN(CCC=21)C(CC=1OC(=NN=1)C=1C=NC(=NC=1)NCC1=CC(=CC=C1)OC(F)(F)F)=O KZEVSDGEBAJOTK-UHFFFAOYSA-N 0.000 description 1
- HMUNWXXNJPVALC-UHFFFAOYSA-N 1-[4-[2-(2,3-dihydro-1H-inden-2-ylamino)pyrimidin-5-yl]piperazin-1-yl]-2-(2,4,6,7-tetrahydrotriazolo[4,5-c]pyridin-5-yl)ethanone Chemical compound C1C(CC2=CC=CC=C12)NC1=NC=C(C=N1)N1CCN(CC1)C(CN1CC2=C(CC1)NN=N2)=O HMUNWXXNJPVALC-UHFFFAOYSA-N 0.000 description 1
- VZSRBBMJRBPUNF-UHFFFAOYSA-N 2-(2,3-dihydro-1H-inden-2-ylamino)-N-[3-oxo-3-(2,4,6,7-tetrahydrotriazolo[4,5-c]pyridin-5-yl)propyl]pyrimidine-5-carboxamide Chemical compound C1C(CC2=CC=CC=C12)NC1=NC=C(C=N1)C(=O)NCCC(N1CC2=C(CC1)NN=N2)=O VZSRBBMJRBPUNF-UHFFFAOYSA-N 0.000 description 1
- LDXJRKWFNNFDSA-UHFFFAOYSA-N 2-(2,4,6,7-tetrahydrotriazolo[4,5-c]pyridin-5-yl)-1-[4-[2-[[3-(trifluoromethoxy)phenyl]methylamino]pyrimidin-5-yl]piperazin-1-yl]ethanone Chemical compound C1CN(CC2=NNN=C21)CC(=O)N3CCN(CC3)C4=CN=C(N=C4)NCC5=CC(=CC=C5)OC(F)(F)F LDXJRKWFNNFDSA-UHFFFAOYSA-N 0.000 description 1
- SXAMGRAIZSSWIH-UHFFFAOYSA-N 2-[3-[2-(2,3-dihydro-1H-inden-2-ylamino)pyrimidin-5-yl]-1,2,4-oxadiazol-5-yl]-1-(2,4,6,7-tetrahydrotriazolo[4,5-c]pyridin-5-yl)ethanone Chemical compound C1C(CC2=CC=CC=C12)NC1=NC=C(C=N1)C1=NOC(=N1)CC(=O)N1CC2=C(CC1)NN=N2 SXAMGRAIZSSWIH-UHFFFAOYSA-N 0.000 description 1
- WZFUQSJFWNHZHM-UHFFFAOYSA-N 2-[4-[2-(2,3-dihydro-1H-inden-2-ylamino)pyrimidin-5-yl]piperazin-1-yl]-1-(2,4,6,7-tetrahydrotriazolo[4,5-c]pyridin-5-yl)ethanone Chemical compound C1C(CC2=CC=CC=C12)NC1=NC=C(C=N1)N1CCN(CC1)CC(=O)N1CC2=C(CC1)NN=N2 WZFUQSJFWNHZHM-UHFFFAOYSA-N 0.000 description 1
- YJLUBHOZZTYQIP-UHFFFAOYSA-N 2-[5-[2-(2,3-dihydro-1H-inden-2-ylamino)pyrimidin-5-yl]-1,3,4-oxadiazol-2-yl]-1-(2,4,6,7-tetrahydrotriazolo[4,5-c]pyridin-5-yl)ethanone Chemical compound C1C(CC2=CC=CC=C12)NC1=NC=C(C=N1)C1=NN=C(O1)CC(=O)N1CC2=C(CC1)NN=N2 YJLUBHOZZTYQIP-UHFFFAOYSA-N 0.000 description 1
- CONKBQPVFMXDOV-QHCPKHFHSA-N 6-[(5S)-5-[[4-[2-(2,3-dihydro-1H-inden-2-ylamino)pyrimidin-5-yl]piperazin-1-yl]methyl]-2-oxo-1,3-oxazolidin-3-yl]-3H-1,3-benzoxazol-2-one Chemical compound C1C(CC2=CC=CC=C12)NC1=NC=C(C=N1)N1CCN(CC1)C[C@H]1CN(C(O1)=O)C1=CC2=C(NC(O2)=O)C=C1 CONKBQPVFMXDOV-QHCPKHFHSA-N 0.000 description 1
- 229960000583 acetic acid Drugs 0.000 description 1
- 239000003513 alkali Substances 0.000 description 1
- XAGFODPZIPBFFR-UHFFFAOYSA-N aluminium Chemical compound [Al] XAGFODPZIPBFFR-UHFFFAOYSA-N 0.000 description 1
- 229910052782 aluminium Inorganic materials 0.000 description 1
- 230000008901 benefit Effects 0.000 description 1
- 239000011230 binding agent Substances 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 229910052729 chemical element Inorganic materials 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 230000008094 contradictory effect Effects 0.000 description 1
- 229910052802 copper Inorganic materials 0.000 description 1
- 238000013480 data collection Methods 0.000 description 1
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- 239000003085 diluting agent Substances 0.000 description 1
- 239000007884 disintegrant Substances 0.000 description 1
- 230000000857 drug effect Effects 0.000 description 1
- 230000007613 environmental effect Effects 0.000 description 1
- 210000003743 erythrocyte Anatomy 0.000 description 1
- 230000002349 favourable effect Effects 0.000 description 1
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- 239000012362 glacial acetic acid Substances 0.000 description 1
- 239000011521 glass Substances 0.000 description 1
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- 230000000302 ischemic effect Effects 0.000 description 1
- 239000000314 lubricant Substances 0.000 description 1
- 238000002844 melting Methods 0.000 description 1
- 230000008018 melting Effects 0.000 description 1
- 229910052759 nickel Inorganic materials 0.000 description 1
- 230000005311 nuclear magnetism Effects 0.000 description 1
- 230000000737 periodic effect Effects 0.000 description 1
- 229910052697 platinum Inorganic materials 0.000 description 1
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- 239000007858 starting material Substances 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
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Images
Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
- C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
- C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
- C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
- C07D239/46—Two or more oxygen, sulphur or nitrogen atoms
- C07D239/60—Three or more oxygen or sulfur atoms
-
- 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
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/513—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim having oxo groups directly attached to the heterocyclic ring, e.g. cytosine
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P7/00—Drugs for disorders of the blood or the extracellular fluid
- A61P7/06—Antianaemics
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C213/00—Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton
- C07C213/10—Separation; Purification; Stabilisation; Use of additives
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C215/00—Compounds containing amino and hydroxy groups bound to the same carbon skeleton
- C07C215/02—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton
- C07C215/04—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being saturated
- C07C215/06—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being saturated and acyclic
- C07C215/10—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being saturated and acyclic with one amino group and at least two hydroxy groups bound to the carbon skeleton
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C233/00—Carboxylic acid amides
- C07C233/01—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
- C07C233/02—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having nitrogen atoms of carboxamide groups bound to hydrogen atoms or to carbon atoms of unsubstituted hydrocarbon radicals
- C07C233/04—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having nitrogen atoms of carboxamide groups bound to hydrogen atoms or to carbon atoms of unsubstituted hydrocarbon radicals with carbon atoms of carboxamide groups bound to acyclic carbon atoms of an acyclic saturated carbon skeleton
- C07C233/05—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having nitrogen atoms of carboxamide groups bound to hydrogen atoms or to carbon atoms of unsubstituted hydrocarbon radicals with carbon atoms of carboxamide groups bound to acyclic carbon atoms of an acyclic saturated carbon skeleton having the nitrogen atoms of the carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C273/00—Preparation of urea or its derivatives, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups
- C07C273/02—Preparation of urea or its derivatives, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups of urea, its salts, complexes or addition compounds
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D213/72—Nitrogen atoms
- C07D213/73—Unsubstituted amino or imino radicals
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07D213/81—Amides; Imides
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07D213/86—Hydrazides; Thio or imino analogues thereof
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
- C07D295/02—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms containing only hydrogen and carbon atoms in addition to the ring hetero elements
- C07D295/023—Preparation; Separation; Stabilisation; Use of additives
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
- C07D295/02—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms containing only hydrogen and carbon atoms in addition to the ring hetero elements
- C07D295/027—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms containing only hydrogen and carbon atoms in addition to the ring hetero elements containing only one hetero ring
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/13—Crystalline forms, e.g. polymorphs
Abstract
The invention mainly provides an acid eutectic and a preparation method thereof, belonging to the technical field of medicines. The co-crystal provided by the invention has better stability and solubility, and can be applied to pharmaceutical preparations.
Description
Technical Field
The invention belongs to the technical field of medicines, and relates to an acid eutectic crystal and a preparation method thereof.
Background
Daprodustat (CAS number 960539-70-2) is a novel, orally active inhibitor of the hypoxia inducible factor prolyl hydroxylase (HIF-PHD). Stabilization of HIF by HIF-PHD inhibitors may ameliorate ischemic conditions, such as Peripheral Arterial Disease (PAD). Daprodustat stimulates the synthesis of endogenous EPO and efficiently induces the production of erythrocytes, which have been approved for marketing in Japan.
The japanese summary of pharmaceuticals is described (in the year 2020, revised 8 months (2 nd edition) of 1250112457\\125401252, 1250112457\12512512512with a melting point of about 244 ℃ for Daprodustat, a solubility in water of 0.074mg/ml, which is almost insoluble. Daprodustat's compound is disclosed in patent application WO2007150011, two crystal forms thereof are disclosed in patent application WO2019052133, and 4 crystal forms thereof are disclosed in WO 2020102302. Although the prior art has disclosed a number of crystalline forms, these crystalline forms are typically characterized by low water solubility. Daprodustat has the structure shown in the following formula:
because the crystal form and the solid form of the drug have important influence on the preparation of the drug and the preparation, storage, application, dissolution, bioavailability and the like of the drug preparation and the drug preparation, different crystal forms may have difference in many aspects, which may cause the problems of obvious difference in the drug effect, safety and application of the drug preparation or being easy to be not in accordance with quality requirements, the solubility of the drug is provided, particularly the solubility of the insoluble drug is improved, the crystal form or the salt form or the eutectic form with better solubility performance is obtained, the effective way for solving the low solubility of the insoluble drug is provided, and the obtained crystal form with high solubility performance is beneficial to the preparation development of the drug, so that the crystal form and the solid form of the drug need to be researched so as to obtain the crystal form with better solubility performance.
Disclosure of Invention
Definition of terms
The invention is intended to cover alternatives, modifications and equivalents, which may be included within the scope of the invention as defined by the appended claims. Those skilled in the art will recognize that many methods and materials similar or equivalent to those described herein can be used in the practice of the present invention. The present invention is in no way limited to the methods and materials described herein. In the event that one or more of the incorporated documents, patents, and similar materials are different or contradictory to the present application (including but not limited to defined terminology, terminology application, described techniques, and the like), the present application controls.
It will be further appreciated that certain features of the invention, which are, for clarity, described in the context of separate embodiments, may also be provided in combination in a single embodiment. Conversely, various features of the invention which are, for brevity, described in the context of a single embodiment, may also be provided separately or in any suitable subcombination.
Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. All patents and publications referred to herein are incorporated by reference in their entirety.
The following definitions as used herein should be applied unless otherwise indicated. For the purposes of the present invention, the chemical elements are in accordance with the CAS version of the periodic Table of elements, and the 75 th version of the handbook of chemistry and Physics, 1994. In addition, general principles of Organic Chemistry can be referred to as described in "Organic Chemistry", thomas Sorrell, university Science Books, sausalito:1999, and "March's Advanced Organic Chemistry" by Michael B.Smith and Jerry March, john Wiley & Sons, new York:2007, the entire contents of which are incorporated herein by reference.
The term "comprising" or "comprises" is open-ended, i.e. comprising what is specified in the present invention, but not excluding other aspects.
The term "substantially as shown in the figure" means that substantially pure certain "crystalline form" has at least 50%, or at least 60%, or at least 70%, or at least 80%, or at least 90%, or at least 95%, or at least 99% of the peaks in its X-ray powder diffraction pattern that appear in the X-ray powder diffraction pattern given. When the content of a certain crystal form in a sample is gradually reduced, diffraction peaks in an X-ray powder diffraction pattern of the crystal form, which are attributed to the crystal form, may be reduced due to the detection sensitivity of an instrument.
The term "relative intensity" refers to the ratio of the intensity of the other peaks to the intensity of the first strong peak in a set of diffraction peaks assigned to a certain crystal form, when the intensity of the first strong peak is defined as 100%.
In the context of the present invention, the 2 θ (also called 2theta or diffraction peak) values in the X-ray powder diffraction pattern are all in degrees (°).
The term "diffraction peak" when referring to a map and/or data in a map refers to a feature that one skilled in the art would not attribute to background noise.
The X-ray powder diffraction peak, the measurement of the 2theta or diffraction peak of the X-ray powder diffraction pattern thereof, has experimental error, and the measurement of the 2theta or diffraction peak of the X-ray powder diffraction pattern may be slightly different between one machine and another machine and between one sample and another sample, the error of the 2theta is ± 0.2 °, so that the value of the 2theta or diffraction peak cannot be regarded as absolute.
The Differential Scanning Calorimetry (DSC) curve has experimental errors, the position and peak value of the endothermic peak may slightly differ between one machine and another machine and between one sample and another sample, and the value of the experimental error or difference may be 4 ℃ or less, 3 ℃ or less, 2 ℃ or less, or 1 ℃ or less, so the value of the peak position or peak value of the endothermic peak of the DSC cannot be regarded as absolute.
The thermogravimetric analysis curve (TGA) has experimental errors, the endothermic curve or weight loss may differ slightly between one machine and another and between one sample and another, and the value of the experimental error or difference may be less than or equal to 0.004% or 0.003% or 0.002% or 0.001%, so the thermogravimetric analysis curve or weight loss thereof cannot be regarded as absolute. A sample is considered to have no significant weight loss in a certain temperature range when its thermogravimetric analysis curve (TGA) has a weight loss below 0.5% in this temperature range.
In the context of the present invention, all numbers disclosed herein are approximate, whether or not the word "about" or "approximately" is used, and there may be a variation of +/-1%, +/-2%, +/-3%, +/-4%, or +/-5% between each number based on the disclosed numbers. When used to approximate the 2theta (also known as 2theta or diffraction peak) value used to describe the X-ray powder diffraction peak, approximately means that there may be a +/-0.2 unit or +/-0.1 unit or +/-0.05 unit difference in the 2theta value.
By "room temperature" is meant a temperature of about 20 ℃ to 35 ℃ or about 23 ℃ to 28 ℃ or about 25 ℃.
The term "good solvent" may be a single solvent or a mixture of solvents, meaning that the solubility of the sample in the single solvent or mixture of solvents is greater than 1g/L, or greater than 2g/L, or greater than 3g/L, or greater than 4g/L, or greater than 5g/L, or greater than 6g/L, or greater than 7g/L, or greater than 8g/L, or greater than 9g/L, or greater than 10g/L, or greater than 15g/L, or greater than 20g/L, or greater than 30g/L, or greater than 40g/L, or greater than 50g/L, or greater than 60g/L, or greater than 70g/L, or greater than 80g/L, or greater than 100g/L. In some embodiments, the sample has greater solubility in the good solvent than the anti-solvent; in some embodiments, the difference in solubility of the good solvent and the anti-solvent for the sample is about 10%,20%,30%,40%,50%,60%,70%,80%, or 90%; in some embodiments, the good solvent is more soluble in the sample than the anti-solvent, greater than 10%,20%,30%,40%,50%,60%,70%,80%, or 90%.
Detailed Description
In one aspect, the inventors have developed a co-crystal of daprodudstat with an amino compound that is isoniazid, isonicotin, propionamide, urea or 3-aminopyridine.
The X-ray powder diffraction pattern of the co-crystal of Daprodustat and isoniazid provided by the invention has diffraction peaks with 2theta (unit: degree, error +/-0.2 degree) of 5.5,8.1, 16.5 and 20.7 degrees.
In some embodiments, the co-crystal of daproductstat and isoniazid has an X-ray powder diffraction pattern with diffraction peaks at 5.5,8.1, 10.3, 12.4, 14.5, 16.5, 17.4, 19.3, 20.7, 22.2, 24.1, 24.8, 26.4, 27.0, and 27.7 degrees 2 Θ.
In some embodiments, the co-crystal of daproductstat with isoniazid has an X-ray powder diffraction (XRPD) pattern as shown in figure 1.
The co-crystal of Daprodustat and isoniazid also has the following characteristics that the Differential Scanning Calorimetry (DSC) curve thereof respectively has endothermic peaks in three temperature ranges of 100-150 ℃, 150-190 ℃ and 190-210 ℃. In some embodiments, the Differential Scanning Calorimetry (DSC) curve of the co-crystal of daprodudstat with isoniazid has endothermic peaks in three temperature ranges of 135 ℃ to 145 ℃,175 ℃ to 185 ℃, and 195 ℃ to 205 ℃, respectively. In some embodiments, the Differential Scanning Calorimetry (DSC) curve of the co-crystal of daprodudstat with isoniazid has endothermic peaks at temperatures in the three temperature ranges 137 ℃ to 143 ℃,178 ℃ to 183 ℃, and 197 ℃ to 203 ℃, respectively, with peak tops of 140.6 ℃,180.7 ℃, and 199.1 ℃. In some embodiments, the Differential Scanning Calorimetry (DSC) curve of a co-crystal of daprodudostat with isoniazid is shown in figure 2.
The thermogravimetric analysis curve (TGA) of the co-crystal of Daprodustat with isoniazid did not show significant weight loss below 150 ℃.
In some embodiments, the thermogravimetric analysis (TGA) of the co-crystal of daprodudostat with isoniazid is as shown in figure 3.
In the co-crystal of Daprodustat and isoniazid, the molar ratio of Daprodustat to isoniazid is 2.
According to experimental research, the co-crystal of Daprodustat and isoniazid is found to be a stable crystal form, is stable under the conditions of high temperature, high humidity or illumination, and can not generate crystal form transformation; and the co-crystal of Daprodustat and isoniazid is a crystal form with better solubility performance, has better solubility in various media, is more beneficial to the preparation of pharmaceutical preparations compared with the known crystal form, and has more competitiveness.
The co-crystal of Daprodustat and isonicotin provided by the invention has an X-ray powder diffraction pattern with diffraction peaks with 2theta (unit: degree, error +/-0.2 ℃) of 6.5,6.9,7.3,9.4, 16.5, 19.7, 21.2 and 21.5 degrees.
In some embodiments, the co-crystal of Daprodustat and isonicotin has an X-ray powder diffraction pattern with diffraction peaks at 6.5,6.9,7.3,9.4, 15.1, 16.5, 17.5, 19.7, 20.6, 21.2, 21.5, 22.0, 23.0, 24.9, 26.6, and 26.9 degrees 2 Θ.
In some embodiments, the co-crystal of Daprodustat with isonicotin has an X-ray powder diffraction pattern with diffraction peaks at 6.5,6.9,7.3,9.4, 15.1, 16.5, 17.5, 18.9, 19.7, 20.6, 21.2, 21.5, 22.0, 23.0, 23.8, 24.2, 24.4, 24.9, 26.6, and 26.9 degrees 2 Θ.
In some embodiments, the X-ray powder diffraction (XRPD) pattern of the co-crystal of daprodudstat with isonicotin is shown in figure 4.
The co-crystal of Daprodustat and isonicotine also has the following characteristics that the Differential Scanning Calorimetry (DSC) respectively has endothermic peaks in the temperature ranges of 125 ℃ -160 ℃ and 190 ℃ -210 ℃. In some embodiments, the co-crystal of Daprodustat with isonicotin has endothermic peaks in the Differential Scanning Calorimetry (DSC) curve in the temperature ranges of 145 ℃ to 155 ℃ and 200 ℃ to 205 ℃, respectively, with peak temperatures of the endothermic peaks at 150.6 ℃ and 203.3 ℃, respectively.
In some embodiments, the Differential Scanning Calorimetry (DSC) curve of the co-crystal of daprodudostat with isonicotine is shown in figure 5.
The thermogravimetric analysis curve (TGA) of the co-crystal of Daprodustat and isonicotinite has no obvious weight loss in the range of 30-150 ℃.
In some embodiments, the thermogravimetric analysis curve (TGA) of the co-crystal of daprodudstat with isonicotin is shown in figure 6.
In the co-crystal of Daprodustat and isonicotine, the molar ratio of Daprodustat to isonicotine is 2.
According to the experimental study on the stability of influencing factors, the co-crystal of Daprodustat and isonicotin is found to be a stable crystal form, is stable under the conditions of high temperature, high humidity or illumination, and can not generate crystal form conversion. According to the experimental results of the performance research of the co-crystal of Daprodustat and isonicotin, compared with the known crystal form, the co-crystal of Daprodustat and isonicotin is considered to be a crystal form which is not easy to absorb moisture and has higher water solubility.
The co-crystal of Daprodustat and propionamide provided by the invention has an X-ray powder diffraction pattern with diffraction peaks with 2theta (unit: degree, error +/-0.2 degree) of 6.4,7.2,7.5, 19.1 and 20.8 degrees.
In some embodiments, the co-crystal of Daprodustat with propionamide has an X-ray powder diffraction pattern with diffraction peaks at 6.4,7.2,7.5, 15.3, 15.7, 16.7, 18.7, 191, 19.6, 19.8, 20.1, 20.8, 22.8, 25.5, and 26.2 degrees 2 Θ.
In some embodiments, the co-crystal of daproductstat with propionamide has an X-ray powder diffraction pattern having diffraction peaks at 6.4,7.2,7.5, 12.9, 15.3, 15.7, 16.3, 16.7, 17.2, 18.7, 191, 19.6, 19.8, 20.1, 20.8, 22.8, 23.2, 24.7, 25.5, 26.2, 27.9, and 28.9 degrees 2 Θ.
In some embodiments, an X-ray powder diffraction (XRPD) pattern of a co-crystal of daprodudstat with propionamide is shown in fig. 7.
The co-crystal of Daprodustat and propionamide also has the following characteristics that the Differential Scanning Calorimetry (DSC) curve of the co-crystal respectively has endothermic peaks in the temperature ranges of 190 ℃ -210 ℃ and 225 ℃ -250 ℃. In some embodiments, the co-crystal of Daprodustat and propionamide has an endothermic peak in a Differential Scanning Calorimetry (DSC) curve with a peak temperature in the temperature range of 195 ℃ -205 ℃ and 235 ℃ -245 ℃, respectively, and an endothermic peak temperature of 201.6 ℃ and 241.5 ℃, respectively.
In some embodiments, the Differential Scanning Calorimetry (DSC) curve of the co-crystal of daprodudstat with propionamide is shown in fig. 8.
The thermogravimetric analysis curve (TGA) of the co-crystal of Daprodustat with propionamide shows no significant weight loss at 30-120 ℃.
In some embodiments, a thermogravimetric analysis curve (TGA) of a co-crystal of daprodudostat and propionamide is shown in fig. 9.
In the co-crystal of Daprodustat and propionamide, the molar ratio of Daprodustat to propionamide is 2.
According to the experimental study on the stability of influencing factors, the eutectic of Daprodustat and propionamide is a stable crystal form, is stable under the conditions of high temperature, high humidity or illumination, and cannot generate crystal form transformation. According to the performance research experiment result of the co-crystal of Daprodustat and propionamide, compared with the known crystal form, the co-crystal of Daprodustat and propionamide is considered to be a crystal form which is not easy to absorb moisture and has higher solubility.
The X-ray powder diffraction pattern of the co-crystal of Daprodustat and urea provided by the invention has diffraction peaks with 2theta (unit: degree, error +/-0.2 degree) of 6.4,7.5, 15.4, 19.3, 19.9, 20.9 and 22.9 degrees.
In some embodiments, the co-crystal of daproductstat and urea has an X-ray powder diffraction pattern with diffraction peaks at 6.4,7.5, 15.4, 16.7, 18.7, 18.9, 19.3, 19.9, 20.9, 22.5, 22.9, 24.9, 28.0 degrees 2 Θ.
In some embodiments, an X-ray powder diffraction (XRPD) pattern of the co-crystal of daprodudostat and urea described above is shown in fig. 10.
The co-crystal of Daprodustat and urea also has the following characteristics that the Differential Scanning Calorimetry (DSC) curve of the co-crystal has an endothermic peak in the temperature range of 175-225 ℃. In some embodiments, the above-described Differential Scanning Calorimetry (DSC) curve of the co-crystal of daprodudstat with urea has an endothermic peak in the temperature range of 210 ℃ to 220 ℃, with an endothermic peak temperature of 215.7 ℃.
In some embodiments, a Differential Scanning Calorimetry (DSC) curve of a co-crystal of daprodudstat with urea is shown in fig. 11.
The thermogravimetric analysis curve (TGA) of the co-crystal of Daprodustat with urea showed no significant weight loss below 170 ℃.
In some embodiments, the thermogravimetric analysis (TGA) of the co-crystal of daprodudstat with urea described above is shown in fig. 12.
In the co-crystal of Daprodustat and urea, the molar ratio of Daprodustat and urea is 2.
According to the experimental study on the stability of influencing factors, the co-crystal of Daprodustat and urea is found to be a stable crystal form, and is stable under the conditions of high temperature, high humidity or illumination, and crystal form transformation cannot occur. According to the performance research experiment result of the eutectic crystal of Daprodustat and urea, compared with the known crystal form, the eutectic crystal of Daprodustat and urea is considered to be a crystal form which is not easy to absorb moisture and has better water solubility.
The co-crystal of Daprodustat and 3-aminopyridine provided by the invention has an X-ray powder diffraction pattern with diffraction peaks with 2theta (unit: degree, error +/-0.2) of 5.6,8.0, 16.3, 16.7, 20.7, 24.2, 24.6, 26.5 and 27.4 degrees.
In some embodiments, the co-crystal of Daprodustat and 3-aminopyridine has an X-ray powder diffraction pattern with diffraction peaks at 5.6,8.0, 16.3, 16.7, 20.7, 24.2, 24.6, 26.5, and 27.4 degrees 2 Θ, and a relative intensity of these diffraction peaks is not less than 15%.
In some embodiments, the co-crystal of Daprodustat and 3-aminopyridine has an X-ray powder diffraction pattern with diffraction peaks at 5.6,8.0, 10.3, 12.2, 14.5, 14.8, 15.9, 16.3, 16.7, 17.0, 17.6, 18.0, 18.6, 19.1, 20.7, 21.1, 22.3, 24.2, 24.6, 26.5, and 27.4 degrees 2 Θ.
In some embodiments, the co-crystal of Daprodustat and 3-aminopyridine has an X-ray powder diffraction (XRPD) pattern as shown in figure 13.
The co-crystal of Daprodustat and 3-aminopyridine also has the following characteristics that a Differential Scanning Calorimetry (DSC) curve has an endothermic peak in a temperature range of 180-210 ℃. In some embodiments, the co-crystal of Daprodustat and 3-aminopyridine has an endothermic peak in a Differential Scanning Calorimetry (DSC) curve in the temperature range of 195 ℃ to 200 ℃ with an endothermic peak temperature of 198.8 ℃.
In some embodiments, the Differential Scanning Calorimetry (DSC) curve of the co-crystal of daprodudstat with 3-aminopyridine is shown in figure 14.
The thermogravimetric analysis curve (TGA) of the co-crystal of Daprodustat with 3-aminopyridine shows no significant weight loss in the temperature range of 50 ℃ to 150 ℃.
In some embodiments, the thermogravimetric analysis (TGA) of the co-crystal of daprodudostat with 3-aminopyridine is shown in fig. 15.
In the co-crystal of Daprodustat and 3-aminopyridine, the molar ratio of Daprodustat and 3-aminopyridine is 2.
According to the experimental study on the stability of influencing factors, the co-crystal of Daprodustat and 3-aminopyridine is found to be a stable crystal form, is stable under the conditions of high temperature, high humidity or illumination and can not generate crystal form conversion. According to the experimental results of the performance research of the co-crystal of Daprodustat and 3-aminopyridine, compared with the known crystal form, the co-crystal of Daprodustat and 3-aminopyridine is considered to be a crystal form which is not easy to absorb moisture and has relatively high solubility in various media.
In another aspect, the present invention provides a method for preparing the aforementioned co-crystal of daprodudstat and an amino compound.
A method of preparing the aforementioned co-crystal of daproductstat with an amino compound, comprising: suspending and stirring Daprodustat and an amino compound in a solvent, filtering, and drying to remove the solvent to obtain the eutectic; wherein the amino compound is isoniazid, isonicotin, propionamide, urea or 3-aminopyridine.
In the method, the molar ratio of Daprodustat to amino compound is 1.
In the method, the solvent is a ketone solvent, an ester solvent, or a combination thereof.
In the method, the mass-volume ratio of Daprodustat to the solvent is 4.0mg to 1ml.
The ketone solvent is at least one selected from acetone and butanone. In some embodiments, the ketone solvent is acetone, which is more advantageous for handling and for obtaining the co-crystals.
The ester solvent is at least one selected from methyl formate, ethyl formate, butyl formate, methyl acetate, ethyl acetate and isopropyl acetate. In some embodiments, the ester solvent is ethyl acetate, which is more advantageous for handling and obtaining the co-crystals.
The temperature of the suspension stirring is 20-35 ℃.
The suspension stirring time is 4-72 h. In some embodiments, the suspension is stirred for a time period ranging from 4h to 24h.
In another aspect, the present invention provides base addition salts of daprodudstat. The alkali is piperazine or tromethamine. In the salt, the molar ratio of Daprodustat to base is 1.
The salts are salts of Daprodustat and piperazine and salts of Daprodustat and tromethamine.
A salt of dapprodustat and piperazine, referred to as dapprodustat piperazine salt, in a molar ratio of dapprodustat to piperazine of 1.
The piperazine salt of Daprodustat has an X-ray powder diffraction pattern having diffraction peaks at 5.0,6.9,8.3, 12.7, 16.5, 18.5, 19.8, 23.4, and 25.4 degrees 2 θ (units: degrees, °, error ± 0.2).
In some embodiments, the dapprodustat piperazine salt has an X-ray powder diffraction pattern with diffraction peaks at 5.0,5.6,6.9,8.3,8.7, 11.1, 12.7, 16.0, 16.5, 16.7, 18.5, 19.1, 19.8, 20.3, 21.3, 23.4, 24.9, and 25.4 degrees 2 Θ.
In some embodiments, the piperazine salt of Daprodustat has an X-ray powder diffraction (XRPD) pattern as shown in figure 16.
The piperazine salt of Daprodustat also has the following characteristics that the piperazine salt of Daprodustat has endothermic peaks in the temperature ranges of 200 ℃ to 230 ℃ and 230 ℃ to 250 ℃ respectively in a Differential Scanning Calorimetry (DSC) curve. In some embodiments, daprodustat has endothermic peaks in the Differential Scanning Calorimetry (DSC) curve for the piperazine salt in the temperature ranges 220 ℃ to 230 ℃ and 235 ℃ to 245 ℃ and peak endothermic peaks at 225.2 ℃ and 240.9 ℃, respectively.
In some embodiments, the Differential Scanning Calorimetry (DSC) curve of the piperazine salt of Daprodustat is shown in figure 17.
The thermogravimetric analysis curve (TGA) of the piperazine salt of Daprodustat shows no significant weight loss over the temperature range of 70 ℃ to 170 ℃.
In some embodiments, the thermogravimetric analysis (TGA) of the piperazine salt of Daprodustat is as shown in figure 18.
According to the experimental study on the stability of influencing factors, the piperazine salt of Daprodustat is found to be a stable crystal form, is stable under the conditions of high temperature, high humidity or illumination, and cannot generate crystal form conversion. According to the experimental results of the performance research of the piperazine salt of Daprodustat, the piperazine salt of Daprodustat is considered to be a more soluble crystal form compared with the known crystal form.
A salt of Daprodustat with tromethamine, referred to as the tromethamine salt of daprodudstat, in a molar ratio of 1.
The tromethamine salt of Daprodustat has an X-ray powder diffraction pattern having diffraction peaks at 4.2,6.7,9.7, 14.1, 15.8, 16.3, 16.8, 18.2, 20.4, 21.0, 24.4, 25.9 and 26.7 degrees 2theta (units: degrees, °, error ± 0.2).
In some embodiments, the dapprodustat tromethamine salt has an X-ray powder diffraction pattern having diffraction peaks at 4.2,6.7,9.7, 10.5, 12.3, 14.1, 15.8, 16.3, 16.8, 18.2, 20.4, 21.0, 21.4, 21.7, 22.5, 23.6, 24.4, 25.9, 26.2, 26.7, 27.1, 29.4, and 31.7 degrees 2 Θ.
In some embodiments, an X-ray powder diffraction (XRPD) pattern of tromethamine salt of daprodudstat is shown in figure 19.
The tromethamine salt of Daprodustat also has the characteristic that it has endothermic peaks in the Differential Scanning Calorimetry (DSC) curve in the temperature ranges of 75 ℃ to 125 ℃ and 200 ℃ to 250 ℃, respectively. In some embodiments, the tromethamine salt of daprodudostat has endothermic peaks in the Differential Scanning Calorimetry (DSC) curve in the temperature ranges of 120 ℃ to 130 ℃ and 210 ℃ to 220 ℃ respectively with peak temperatures of 124.5 ℃ and 218.6 ℃ respectively.
In some embodiments, a Differential Scanning Calorimetry (DSC) curve of the tromethamine salt of daprodudostat is shown in figure 20.
The thermogravimetric analysis curve (TGA) of the tromethamine salt of Daprodustat has a weight loss of 3.0% to 3.5% in the range of 30 ℃ to 150 ℃. In some embodiments, the thermogravimetric analysis curve (TGA) of tromethamine salt of daprodudostat has a weight loss of 3.2% in the range of 30 ℃ to 150 ℃.
In some embodiments, the thermogravimetric analysis (TGA) of tromethamine salt of daprodudostat is as shown in figure 21.
According to the experimental study on the stability of influencing factors, the tromethamine salt of Daprodustat is found to be a stable crystal form, is stable under the conditions of high temperature, high humidity or illumination, and cannot generate crystal form transformation. According to the experimental results of the performance research of the tromethamine salt of Daprodustat, the tromethamine salt of Daprodustat is considered to be a crystal form with better water solubility compared with the known crystal form.
In another aspect, the present invention also provides a method for preparing said piperazine salt of Daprodustat and tromethamine salt of daprodudat.
A process for preparing said piperazine salt of dapprodustat or tromethamine salt of dapprodustat comprising: daprodustat and piperazine or tromethamine are suspended and stirred in a solvent, and then filtered, and the solvent is dried to obtain the piperazine salt of Daprodustat or the tromethamine salt of Daprodustat.
In the method, the molar ratio of Daprodustat to piperazine or tromethamine is 1.
In the method, the solvent is a ketone solvent, an ester solvent, or a combination thereof.
In the method, the mass-volume ratio of Daprodustat to the solvent is 4.0mg to 1ml.
The ketone solvent is at least one selected from acetone and butanone. In some embodiments, the ketone solvent is acetone, which is more advantageous for handling and obtaining the co-crystal.
The ester solvent is at least one selected from methyl formate, ethyl formate, butyl formate, methyl acetate, ethyl acetate and isopropyl acetate. In some embodiments, the ester solvent is ethyl acetate, which is more advantageous for handling and obtaining the co-crystals.
The temperature of the suspension stirring is 20-35 ℃.
The suspension stirring time is 4-72 h. In some embodiments, the suspension is stirred for a period of time ranging from 4h to 24h.
The eutectic and the salt have better stability, are beneficial to storage, transfer and operation in a production process, and can be prepared into a medicinal composition together with a pharmaceutically acceptable carrier.
The eutectic of Daprodustat and isoniazid and the eutectic of Daprodustat and 3-aminopyridine have relatively good performances in the aspects of dissolution rate, fluidity and the like, are favorable for storage, transfer and operation in a production process, and are suitable for being prepared into a medicinal composition with a pharmaceutically acceptable carrier.
In another aspect, the present invention also provides a composition.
A composition, comprising: at least one crystal form selected from the eutectic crystal and the salt and pharmaceutically acceptable auxiliary materials.
In some embodiments, the dapprodustat in the crystalline form of the co-crystal or salt is at least 80% by weight of the total dapprodustat in the composition, calculated on the mass of dapprodustat. In some embodiments, the Daprodustat in the crystalline form of the co-crystal or salt is at least 85% by weight of the total Daprodustat in the composition, calculated on the mass of Daprodustat. In some embodiments, dapprodustat in the crystalline form of the co-crystal or salt is at least 90% by weight of the total dapprodustat in the composition, calculated on the mass of dapprodustat. In some embodiments, the Daprodustat in the crystalline form of the co-crystal or salt is at least 95% by weight of the total Daprodustat in the composition, calculated on the mass of Daprodustat. In some embodiments, the Daprodustat in the crystalline form of the co-crystal or salt is at least 97% of the total weight of Daprodustat in the composition, by mass of Daprodustat. In some embodiments, the Daprodustat in the crystalline form of the co-crystal or salt is at least 99% by weight of the total Daprodustat in the composition, calculated on the mass of Daprodustat.
In some embodiments, the Daprodustat in the crystalline form of the co-crystal or salt is at least 10% by weight of the total Daprodustat in the composition, calculated on the mass of Daprodustat. In some embodiments, dapprodustat in the crystalline form of the co-crystal or salt is at least 5% by weight of the total dapprodustat in the composition, calculated on the mass of dapprodustat. In some embodiments, the Daprodustat in the crystalline form of the co-crystal or salt is at least 1% by weight of the total Daprodustat in the composition, calculated on the mass of Daprodustat. In some embodiments, the Daprodustat in the crystalline form of the co-crystal or salt is at least 0.5% by weight of the total Daprodustat in the composition, calculated on the mass of Daprodustat. In some embodiments, dapprodustat in the crystalline form of the co-crystal or salt is at least 5% to 10% by weight of the total dapprodustat in the composition, calculated on the mass of dapprodustat.
In some embodiments, in the composition, daprodustat in the crystalline form of the co-crystal or salt is at most 10% by weight of the total Daprodustat in the composition, calculated on the mass of Daprodustat. In some embodiments, daprodustat in the crystalline form of the co-crystal or salt is at most 6%, or at most 5%, or at most 3%, or at most 1%, or at most 0.5% of the total weight of daprodudstat in the composition, by mass of Daprodustat.
In some embodiments, in the composition, the crystalline form of the co-crystal or salt is at least 0.05% to 95%,0.1% to 95%,1% to 95%,5% to 95%, or 1% to 50% of the total mass of the composition, calculated as mass ratios. In some embodiments, the crystalline form of the co-crystal or salt in the composition is at least 0.5% to 5% of the total mass of the composition, calculated as mass ratio. In some embodiments, the crystalline form of the co-crystal or salt is at least 5% to 10% of the total mass of the composition, calculated as a mass ratio.
In some embodiments, a composition comprises the aforementioned co-crystal of daproductstat with isoniazid and a pharmaceutically acceptable excipient.
In some embodiments, a composition comprises the aforementioned co-crystal of daprodudstat with 3-aminopyridine and a pharmaceutically acceptable excipient.
The pharmaceutically acceptable auxiliary materials can comprise diluents, disintegrants, binders, lubricants and the like.
The crystal forms of the various cocrystals or salts can be used for preparing medicines for treating or improving ischemic diseases.
The composition can be used for preparing a medicament for treating or improving ischemic diseases.
Drawings
FIG. 1 shows an X-ray powder diffraction pattern (XRPD) of a co-crystal of Daprodustat and isoniazid;
FIG. 2 shows a Differential Scanning Calorimetry (DSC) curve of a co-crystal of Daprodustat and isoniazid;
FIG. 3 shows a thermogravimetric analysis (TGA) of a co-crystal of Daprodustat with isoniazid.
FIG. 4 shows an X-ray powder diffraction pattern (XRPD) of a co-crystal of Daprodustat and isonicotin;
FIG. 5 shows a Differential Scanning Calorimetry (DSC) curve of a co-crystal of Daprodustat with isonicotin;
FIG. 6 shows a thermogravimetric analysis (TGA) profile of a co-crystal of Daprodustat and isonicotine
FIG. 7 shows an X-ray powder diffraction pattern (XRPD) of a co-crystal of Daprodustat with propionamide;
FIG. 8 shows a Differential Scanning Calorimetry (DSC) curve of a co-crystal of Daprodustat with propionamide;
fig. 9 shows a thermogravimetric analysis (TGA) of a co-crystal of Daprodustat with propionamide.
FIG. 10 shows an X-ray powder diffraction pattern (XRPD) of a co-crystal of Daprodustat and urea;
FIG. 11 shows a Differential Scanning Calorimetry (DSC) curve of a eutectic of Daprodustat and urea;
fig. 12 shows a thermogravimetric analysis (TGA) of a co-crystal of Daprodustat and urea.
FIG. 13 shows an X-ray powder diffraction pattern (XRPD) of a co-crystal of Daprodustat and 3-aminopyridine.
FIG. 14 shows a Differential Scanning Calorimetry (DSC) curve of a co-crystal of Daprodustat with 3-aminopyridine;
FIG. 15 shows a thermogravimetric analysis (TGA) of a co-crystal of Daprodustat with 3-aminopyridine.
FIG. 16 shows an X-ray powder diffraction pattern (XRPD) of a piperazine salt of Daprodustat;
FIG. 17 shows a Differential Scanning Calorimetry (DSC) curve of a piperazine salt of Daprodustat;
FIG. 18 shows a thermogravimetric analysis (TGA) profile of the piperazine salt of Daprodustat.
FIG. 19 shows an X-ray powder diffraction pattern (XRPD) of tromethamine salt of Daprodustat;
FIG. 20 shows a Differential Scanning Calorimetry (DSC) curve of tromethamine salt of Daprodustat;
FIG. 21 shows a thermogravimetric analysis (TGA) of tromethamine salt of Daprodustat.
In the above drawings, 2Theta (. Degree.) represents 2 θ (degrees), temperature (. Degree.) represents Temperature (. Degree.C.), heat Flow (W/g) represents Heat flux (watts/gram), J/g represents joules/gram, and Weight represents Weight.
Detailed Description
In order to make the technical solutions of the present invention better understood by those skilled in the art, the present invention is further described in detail by further disclosing some non-limiting examples.
The reagents used in the present invention are either commercially available or can be prepared by the methods described herein.
In the present invention, mg means mg, mL means mL; rpm represents revolutions per minute; when referring to time, h represents hours, d represents days; RH means relative humidity.
In the present invention, unless otherwise specified, room temperature refers to ambient temperature, at 15-40 ℃, or 20-30 ℃, or 22-28 ℃.
Parameters of the instrument
All analyses below were performed at room temperature unless otherwise specified in the parameters.
X-ray powder diffraction (XRPD) study
PANALYTIC EMPYREAN X-RAY DIFFRACTOMETER ON THE Netherlands fitted with an automated 3X 15 zero background sample holderX-ray powder diffraction (XRPD) patterns were collected. The radiation source used was a source of radiation of (Cu, k α,1.540598;1.544426; the K alpha 2/K alpha 1 intensity ratio: 0.50 In which the voltage is set at 45KV and the current is set at 40ma.the beam divergence of the X-ray, i.e. the effective size of the X-ray confinement on the sample, is 6.6 mm.a theta-theta continuous scanning mode is used to obtain an effective 2theta range of 3 deg. -60 deg.. Taking a proper amount of sample at the position of the circular groove of the zero-background sample rack under the environmental condition (about 18-32 ℃), lightly pressing the sample by using a clean glass slide to obtain a flat plane, and fixing the zero-background sample rack. The sample was scanned at a scan step of 0.0167 ° in the range of 3-60 ° 2 θ ± 0.2 ° to produce a conventional XRPD pattern. The software used for Data collection was a Data Collector, and Data was analyzed and presented using Data Viewer and HighScore Plus.
Differential Scanning Calorimetry (DSC)
DSC measurements were performed in a TA instruments model Q2000 using a sealed tray apparatus. Samples (about 1-3 mg) were weighed in aluminum pans, capped with Tzero, precision recorded to one hundredth of a milligram, and transferred to the instrument for measurement. The instrument was purged with nitrogen at 50 mL/min. Data was collected between 30 ℃ and 300 ℃ at a heating rate of 10 ℃/min. The endothermic peak was plotted downward, and the data was analyzed and displayed using TA Universal Analysis.
Thermogravimetric analysis (TGA)
TGA data were collected on TA Instruments Q500. The temperature of the instrument was calibrated using certified nickel. Typically 8-12mg of sample is loaded onto a pre-weighed platinum crucible and heated from 30 ℃ to 300 ℃ at 10 ℃/min. A nitrogen purge of 60mL/min was maintained over the sample. In the TGA chart, the abscissa represents Temperature (deg.C) and the ordinate represents Weight loss in percentage (Weight (%)).
In the following examples, daprodustat, the starting material used, was tested for XRPD and DSC data substantially in accordance with CS1 as described in patent application WO 2019052133.
Example 1-1
Adding 78.7mg of Daprodustat and 27.4mg of isoniazid into a 5ml EP tube respectively, then adding 2.0ml of acetone, magnetically stirring at 200rpm at room temperature (25.0 ℃) until the acetone cannot be completely dissolved, suspending at room temperature for 24h, filtering, and vacuum-drying at 50 ℃ for 12h to obtain 69.1mg of eutectic crystal of Daprodustat and isoniazid; detection, X-ray powder diffraction, DSC, TGA results are shown in FIG. 1-FIG. 3.
Examples 1 to 2
39.3mg of Daprodustat and 13.7mg of isoniazid are respectively added into a 5ml EP tube, then 1.0ml of ethyl acetate is added, the mixture is magnetically stirred at the room temperature (25.0 ℃) under the condition of 200rpm and can not be completely dissolved, the mixture is suspended at the room temperature for 24h and filtered, and the mixture is dried in vacuum at the temperature of 50 ℃ for 12h to obtain the same eutectic 34.7mg of Daprodustat and isoniazid.
Example 2-1
Adding 78.7mg of Daprodustat and 24.4mg of isonicotin into a 5ml EP tube respectively, then adding 2.0ml of acetone, magnetically stirring at the room temperature (25.0 ℃) and 200rpm, enabling the acetone not to be completely dissolved, suspending at the room temperature for 24h, filtering, and drying in vacuum at 50 ℃ for 12h to obtain 65.3mg of eutectic of Daprodustat and isonicotin; detection, X-ray powder diffraction, DSC, TGA results are shown in FIGS. 4-6.
Examples 2 to 2
39.3mg of Daprodustat and 12.2mg of isonicotin are respectively added into a 5ml EP tube, then 1.0ml of ethyl acetate is added, magnetic stirring is carried out at the room temperature (25.0 ℃) and 200rpm, the mixture can not be completely dissolved, the mixture is suspended for 24h at the room temperature, filtration is carried out, and vacuum drying is carried out for 12h at the temperature of 50 ℃, thus obtaining 31.2mg of the same co-crystal of Daprodustat and isonicotin.
Example 3-1
Adding 78.7mg of Daprodustat and 14.6mg of propionamide into a 5ml EP tube respectively, then adding 2.0ml of acetone, magnetically stirring at the room temperature (25.0 ℃) of 200rpm, enabling the acetone not to be completely dissolved, suspending at the room temperature for 24 hours, filtering, and drying in vacuum at the temperature of 50 ℃ for 12 hours to obtain 47.5mg of eutectic of Daprodustat and propionamide; detection, X-ray powder diffraction, DSC, TGA results are shown in FIGS. 7-9.
Example 3-2
Daprodustat 39.3mg and propionamide 7.3mg were added to a 5ml EP tube, followed by addition of 1.0ml ethyl acetate, magnetic stirring at 200rpm at room temperature (25.0 ℃) and not complete dissolution, suspension at room temperature for 24 hours, filtration, and vacuum drying at 50 ℃ for 12 hours to obtain the same co-crystal of Daprodustat and propionamide 25.3mg.
Example 4-1
Adding 78.7mg of Daprodustat and 12.0mg of urea into a 5ml EP tube respectively, then adding 2.0ml of acetone, magnetically stirring at 200rpm at room temperature (25.0 ℃) until the acetone cannot be completely dissolved, suspending at room temperature for 24h, filtering, and vacuum-drying at 50 ℃ for 12h to obtain 63.7mg of a Daprodustat and urea eutectic product; detection, X-ray powder diffraction, DSC, TGA results are shown in FIG. 10-FIG. 12.
Example 4 to 2
39.3mg of Daprodustat and 6.0mg of urea were added to a 5ml EP tube, followed by addition of 1.0ml of ethyl acetate, magnetic stirring at 200rpm at room temperature (25.0 ℃) and failed to dissolve completely, suspension at room temperature for 24 hours, filtration, and vacuum drying at 50 ℃ for 12 hours to obtain 32.4mg of the same co-crystal of Daprodustat and urea.
Example 5-1
Adding 78.7mg of Daprodustat and 18.8mg of 3-aminopyridine into a 5ml EP tube respectively, then adding 2.0ml of acetone, magnetically stirring at the room temperature (25.0 ℃) and 200rpm, enabling the mixture not to be completely dissolved, suspending at the room temperature for 24 hours, filtering, and carrying out vacuum drying at the temperature of 50 ℃ for 12 hours to obtain 67.6mg of co-crystal of Daprodustat and 3-aminopyridine; detection, X-ray powder diffraction, DSC, TGA results are shown in FIG. 13-FIG. 15.
Examples 5 and 2
39.3mg of Daprodustat and 9.4mg of 3-aminopyridine were added to a 5ml EP tube, followed by addition of 1.0ml of ethyl acetate solvent, magnetic stirring at 200rpm at room temperature (25.0 ℃) and without complete dissolution, suspension at room temperature for 24 hours, filtration, and vacuum drying at 50 ℃ for 12 hours to obtain 31.8mg of the same co-crystal of Daprodustat and 3-aminopyridine.
Example 6-1
Adding 78.7mg of Daprodustat and 38.8mg of piperazine hexahydrate into a 5ml EP tube, adding 2.0ml of acetone, magnetically stirring at 200rpm at room temperature (25.0 ℃) for 24 hours at room temperature, filtering, and vacuum-drying at 50 ℃ for 12 hours to obtain the final product71.5mg of piperazine salt of Daprodustat; detection, X-ray powder diffraction, DSC, TGA results see fig. 16-fig. 18; nuclear magnetism:1H NMR(400MHz,DMSO)δ10.08(t,J=5.1Hz,1H),4.66(t,J=11.8Hz,2H),3.84(d,J=5.2Hz,4H),2.31(q,J=12.2Hz,4H),1.76(d,J=12.4Hz,4H),1.61(d,J=11.7Hz,2H),1.48(d,J=10.7Hz,4H),1.25(q,J=12.8Hz,4H),1.04-1.15(m,2H)。
example 6-2
39.3mg of Daprodustat and 19.4mg of piperazine hexahydrate were added to a 5ml EP tube, followed by addition of 1.0ml of ethyl acetate, and the mixture was magnetically stirred at 200rpm at room temperature (25.0 ℃) and was not completely dissolved, suspended at room temperature for 24 hours, filtered, and vacuum-dried at 50 ℃ for 12 hours to obtain 33.4mg of the same piperazine salt of Daprodustat.
Example 7-1
Adding 78.7mg of Daprodustat and 24.2mg of tromethamine into a 5ml EP tube respectively, then adding 2.0ml of acetone, magnetically stirring at 200rpm at room temperature (25.0 ℃) until the acetone cannot be completely dissolved, suspending at room temperature for 24h, filtering, and carrying out vacuum drying at 50 ℃ for 12h to obtain 65.3mg of the tromethamine salt of Daprodustat; detection, X-ray powder diffraction, DSC, TGA results see fig. 19-fig. 21; nuclear magnetic:1H NMR(400MHz,DMSO)δ10.06(s,1H),4.65(t,J=11.9Hz,2H),3.75(d,J=4.9Hz,2H),2.37–2.22(m,4H),1.76(d,J=12.4Hz,4H),1.61(d,J=11.9Hz,2H),1.49(d,J=10.7Hz,4H),1.25(q,J=12.7Hz,4H),1.11(dd,J=25.5,12.8Hz,2H)。
example 7-2
39.3mg of Daprodustat and 12.1mg of tromethamine were added to a 5ml EP tube, followed by 1.0ml of ethyl acetate, and the mixture was magnetically stirred at 200rpm at room temperature (25.0 ℃) and was not completely dissolved, suspended at room temperature for 24 hours, filtered, and vacuum-dried at 50 ℃ for 12 hours to obtain 29.5mg of the same Daprodustat tromethamine salt.
Example 8 stability testing
According to the guiding principle of the stability test of the bulk drugs, the influence factor test is carried out on each crystal form sample, including a high temperature test, a high humidity test and a strong light irradiation test, and the stability conditions of each crystal form under different conditions are investigated, wherein the specific test conditions are as follows:
light test (light U)V + VIS): respectively sampling appropriate amount of the extract, spreading in a weighing bottle, and exposing to visible light of 4500Lux + -500 Lux (VIS) and ultraviolet light of 1.7W x h/m2(UV) placing the mixture in a constant temperature and humidity chamber (25 ℃, RH 60% +/-5%), taking about 10mg of the sample at 5, 10 and 15 days respectively, and testing the crystal form condition by X-ray powder diffraction (XRPD);
high humidity test (high humidity 25 ℃ +92.5% RH): respectively taking a proper amount of samples, flatly spreading the samples in a weighing bottle, opening the bottle, placing the bottle in a constant temperature and humidity box with the temperature of 25 ℃ and RH being 92.5 +/-5 percent, then respectively taking samples of about 10mg in 5, 10 and 15 days, and testing the crystal form condition by adopting X-ray powder diffraction (XRPD);
high temperature test (high temperature 60 ℃ +75% RH): a proper amount of samples are respectively taken, laid in a weighing bottle, opened, placed in a constant temperature and humidity box with the temperature of 60 +/-5 ℃ and the RH of 75 +/-5 percent, then samples are respectively taken for 5, 10 and 15 days to obtain about 10mg, and the crystal form condition is tested by adopting X-ray powder diffraction (XRPD). The results of the measurements for each sample are shown in Table 1.
Table 1: results of stability experiments
From the results, it was found that each of the eutectic and salt crystal forms was relatively stable against high temperature, high humidity and light conditions.
Example 9 stability in Water investigation
10.0mg of the above-mentioned eutectic or salt and 2.0ml of purified water were added to a 5ml EP tube, and the temperature was set at 37.0 ℃ and magnetic stirring was carried out at 200rpm, so that a large amount of the solid was not dissolved. Maintaining the same temperature and magnetic stirring, suspending for a certain time of 2.0h and 12.0h respectively, and then sampling, filtering and detecting the crystal form condition of the sample. The results of the measurements for each sample are shown in Table 2.
Table 2: stability in purified water at 37.0 deg.C
According to the results, the various cocrystals and salts provided by the invention can be stably maintained in purified water at 37.0 ℃ for 12 hours, which shows that the cocrystals and salts are stable under the condition of purified water at 37.0 ℃.
Example 10 solubility test
1) A mass of sample was added to each 50ml round bottom flask, magnetic stirring was set at 250rpm at a block temperature of 25.0 deg.C, then purified water at 25.0 deg.C was added using 200. Mu.L and 1000. Mu.L pipette guns, 1000. Mu.L each time with 1000. Mu.L pipette gun (200. Mu.L purified water was added when the solid was about to dissolve completely), and after addition, the addition was continued for half an hour for undissolved water and then purified water was added continuously until complete dissolution. Finally, the total amount of purified water required to dissolve the sample solids was counted and the corresponding solubility was calculated. See table 3 for results for each sample.
Table 3: solubility behavior in purified water at 25.0 deg.C
2) A mass of sample was added to each 50ml round bottom flask, magnetic stirring was set at 250rpm at a block temperature of 37.0 deg.C, then different media at 37.0 deg.C were added using 200. Mu.L and 1000. Mu.L pipette guns, 1000. Mu.L each time was added using 1000. Mu.L pipette guns (200. Mu.L media was added when the solids were about to completely dissolve), the addition was followed by a half hour dwell time, and medium addition continued until complete dissolution had occurred with undissolved. Finally, the amount of total medium required to dissolve the sample solids was counted and the corresponding solubility calculated. See table 4 for each sample result.
pH 1.2 medium: 87ml of concentrated hydrochloric acid and 9.913L of purified water to 10L in volume;
pH 4.5 medium: preparing 29.9g of sodium acetate trihydrate or 18.0g of anhydrous sodium acetate, 18.5ml of concentrated glacial acetic acid and 9.9815L of purified water into 10L of the mixture, and obtaining the sodium acetate trihydrate or anhydrous sodium acetate;
pH6.8 medium: 68.05g of anhydrous potassium dihydrogen phosphate, 8.96g of sodium hydroxide and purified water are prepared into 10L of the mixture, and the potassium dihydrogen phosphate is obtained.
Table 4: solubility in various media at 37.0 DEG C
From the above results, it can be seen that: in purified water at 25.0 ℃, the co-crystal of Daprodustt and isoniazid, the co-crystal of Daprodustt and 3-aminopyridine, the piperazine salt of Daprodustt and the tromethamine salt of Daprodustt have better solubility compared with Daprodustt. The co-crystal of Daprodustat with isoniazid has better solubility than Daprodustat in different media at 37 ℃, in pH 6.8. According to the characteristics of each crystal form under multiple factors/conditions, the eutectic of Daprodustat and isoniazid is considered to be relatively optimal, the preparation of a pharmaceutical preparation is facilitated, the eutectic of Daprodustat and 3-aminopyridine, piperazine salt of Daprodustat and tromethamine salt of Daprodustat are relatively stable, and the solubility advantage of Daprodustat under some conditions is achieved; wherein, the tromethamine salt of Daprodustat has better solubility in a medium with pH6.8 compared with piperazine salt of Daprodustat, and is relatively beneficial to being applied to pharmaceutical preparations.
While the methods of the present invention have been described in terms of preferred embodiments, it will be apparent to those of ordinary skill in the art that variations and modifications of the methods and applications described herein, as well as other suitable variations and combinations of the techniques described herein, may be made and used without departing from the spirit and scope of the invention. Those skilled in the art can modify the process parameters appropriately to achieve the desired results with reference to the disclosure herein. It is specifically noted that all such substitutions and modifications will be apparent to those skilled in the art and are intended to be included within the present invention.
Claims (10)
1. A co-crystal of dapprodustat and isoniazid at a molar ratio of dapprodustat to isoniazid of 2, said co-crystal having an X-ray powder diffraction pattern with diffraction peaks at 5.5,8.1, 16.5 and 20.7 degrees 2 Θ.
2. The co-crystal of claim 1, wherein the X-ray powder diffraction pattern of the co-crystal has diffraction peaks at 5.5,8.1, 10.3, 12.4, 14.5, 16.5, 17.4, 19.3, 20.7, 22.2, 24.1, 24.8, 26.4, 27.0, and 27.7 degrees 2 Θ.
3. The co-crystal of claim 1 or 2 having endothermic peaks in a differential scanning calorimetry curve in the respective ranges of three temperatures, 100 ℃ to 150 ℃,150 ℃ to 190 ℃ and 190 ℃ to 210 ℃; and/or no significant weight loss at less than 150 ℃ in the thermogravimetric analysis curve thereof; or the X-ray powder diffraction pattern of the co-crystal is shown in figure 1.
4. A salt of dapprodustat, which salt is a tromethamine salt of dapprodustat, the molar ratio of dapprodustat to tromethamine being 1; and the X-ray powder diffraction pattern of the tromethamine salt of daprodudostat has diffraction peaks at 4.2,6.7,9.7, 14.1, 15.8, 16.3, 16.8, 18.2, 20.4, 21.0, 24.4, 25.9 and 26.7 degrees 2 theta.
5. The salt of claim 4, said tromethamine salt of Daprodustat having an X-ray powder diffraction pattern having diffraction peaks at 4.2,6.7,9.7, 10.5, 12.3, 14.1, 15.8, 16.3, 16.8, 18.2, 20.4, 21.0, 21.4, 21.7, 22.5, 23.6, 24.4, 25.9, 26.2, 26.7, 27.1, 29.4 and 31.7 degrees 2 θ; or an X-ray powder diffraction pattern of the tromethamine salt of Daprodustat is shown in FIG. 19.
6. The salt of claim 4 or 5, having endothermic peaks in differential scanning calorimetry curves for tromethamine salts of Daprodustat in the temperature ranges of 75 ℃ to 125 ℃ and 200 ℃ to 250 ℃, respectively; and/or said tromethamine salt of Daprodustat has a thermogravimetric analysis curve with a weight loss of 3.0% to 3.5% in the range of 30 ℃ to 150 ℃.
7. A method of preparing a co-crystal according to any one of claims 1 to 3 or a salt according to any one of claims 4 to 6, comprising: suspending Daprodustat and isoniazid or tromethamine in a solvent, stirring, filtering, drying and removing the solvent to obtain the eutectic crystal or salt; wherein the solvent is at least one of acetone, butanone, methyl formate, ethyl formate, butyl formate, methyl acetate, ethyl acetate and isopropyl acetate, and the feeding molar ratio of Daprodustat to isoniazid or tromethamine is 1.5-1.
8. The method of claim 7, wherein the mass to volume ratio of dapprodustat to solvent is 4.0mg to 1ml; and/or the temperature of the suspension stirring is 20-35 ℃; and/or the suspension stirring time is 4-72 h.
9. A composition comprising the co-crystal of any one of claims 1-3 or the salt of any one of claims 4-6, further comprising a pharmaceutically acceptable carrier; wherein Daprodustat in the co-crystal or salt is at least 80%, or at least 0.5%, or at most 10% by weight of the total weight of Daprodustat in the composition, calculated on the mass of Daprodustat.
10. The composition of claim 9, wherein the co-crystal or salt is at least 0.05% to 95% by mass of the total mass of the composition.
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