CN108794530A - A kind of the third phenol of tenofovir amidic-salt crystal form and its preparation method and application - Google Patents
A kind of the third phenol of tenofovir amidic-salt crystal form and its preparation method and application Download PDFInfo
- Publication number
- CN108794530A CN108794530A CN201710283169.6A CN201710283169A CN108794530A CN 108794530 A CN108794530 A CN 108794530A CN 201710283169 A CN201710283169 A CN 201710283169A CN 108794530 A CN108794530 A CN 108794530A
- Authority
- CN
- China
- Prior art keywords
- crystal form
- tenofovir
- phenol
- cooling
- amide
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
- 239000013078 crystal Substances 0.000 title claims abstract description 101
- 229960004556 tenofovir Drugs 0.000 title claims abstract description 70
- VCMJCVGFSROFHV-WZGZYPNHSA-N tenofovir disoproxil fumarate Chemical compound OC(=O)\C=C\C(O)=O.N1=CN=C2N(C[C@@H](C)OCP(=O)(OCOC(=O)OC(C)C)OCOC(=O)OC(C)C)C=NC2=C1N VCMJCVGFSROFHV-WZGZYPNHSA-N 0.000 title claims abstract description 47
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N Phenol Chemical compound OC1=CC=CC=C1 ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 title claims abstract description 34
- 238000002360 preparation method Methods 0.000 title claims abstract description 31
- 238000000634 powder X-ray diffraction Methods 0.000 claims abstract description 20
- 239000012535 impurity Substances 0.000 claims abstract description 11
- -1 tenofovir amide Chemical class 0.000 claims description 64
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 claims description 37
- 238000001816 cooling Methods 0.000 claims description 34
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical group CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 30
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 claims description 24
- 239000002904 solvent Substances 0.000 claims description 16
- 239000001530 fumaric acid Substances 0.000 claims description 15
- 238000000113 differential scanning calorimetry Methods 0.000 claims description 12
- 238000002411 thermogravimetry Methods 0.000 claims description 11
- LDEKQSIMHVQZJK-CAQYMETFSA-N tenofovir alafenamide Chemical compound O([P@@](=O)(CO[C@H](C)CN1C2=NC=NC(N)=C2N=C1)N[C@@H](C)C(=O)OC(C)C)C1=CC=CC=C1 LDEKQSIMHVQZJK-CAQYMETFSA-N 0.000 claims description 10
- 238000004128 high performance liquid chromatography Methods 0.000 claims description 8
- 238000000034 method Methods 0.000 claims description 7
- 238000001291 vacuum drying Methods 0.000 claims description 7
- ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-Butanone Chemical compound CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 claims description 6
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 6
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 6
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 6
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 4
- NTIZESTWPVYFNL-UHFFFAOYSA-N Methyl isobutyl ketone Chemical compound CC(C)CC(C)=O NTIZESTWPVYFNL-UHFFFAOYSA-N 0.000 claims description 4
- UIHCLUNTQKBZGK-UHFFFAOYSA-N Methyl isobutyl ketone Natural products CCC(C)C(C)=O UIHCLUNTQKBZGK-UHFFFAOYSA-N 0.000 claims description 4
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 claims description 4
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 4
- 208000002672 hepatitis B Diseases 0.000 claims description 4
- 229940043265 methyl isobutyl ketone Drugs 0.000 claims description 4
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 4
- 208000030507 AIDS Diseases 0.000 claims description 3
- 241000700721 Hepatitis B virus Species 0.000 claims description 3
- 239000000010 aprotic solvent Substances 0.000 claims description 3
- 238000001035 drying Methods 0.000 claims description 3
- 230000002265 prevention Effects 0.000 claims description 3
- 230000005855 radiation Effects 0.000 claims description 3
- JWUJQDFVADABEY-UHFFFAOYSA-N 2-methyltetrahydrofuran Chemical class CC1CCCO1 JWUJQDFVADABEY-UHFFFAOYSA-N 0.000 claims description 2
- 229910017488 Cu K Inorganic materials 0.000 claims description 2
- 229910017541 Cu-K Inorganic materials 0.000 claims description 2
- 241000700605 Viruses Species 0.000 claims description 2
- 230000002950 deficient Effects 0.000 claims description 2
- 239000008194 pharmaceutical composition Substances 0.000 claims description 2
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 2
- 238000000926 separation method Methods 0.000 claims description 2
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 2
- 239000003814 drug Substances 0.000 claims 4
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims 2
- 229940079593 drug Drugs 0.000 claims 2
- 229940093499 ethyl acetate Drugs 0.000 claims 1
- JMMWKPVZQRWMSS-UHFFFAOYSA-N isopropanol acetate Natural products CC(C)OC(C)=O JMMWKPVZQRWMSS-UHFFFAOYSA-N 0.000 claims 1
- 229940011051 isopropyl acetate Drugs 0.000 claims 1
- GWYFCOCPABKNJV-UHFFFAOYSA-N isovaleric acid Chemical compound CC(C)CC(O)=O GWYFCOCPABKNJV-UHFFFAOYSA-N 0.000 claims 1
- 229940032007 methylethyl ketone Drugs 0.000 claims 1
- 239000000126 substance Substances 0.000 description 7
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 6
- 238000006243 chemical reaction Methods 0.000 description 5
- 238000001228 spectrum Methods 0.000 description 5
- 238000012360 testing method Methods 0.000 description 5
- GFFGJBXGBJISGV-UHFFFAOYSA-N Adenine Chemical compound NC1=NC=NC2=C1N=CN2 GFFGJBXGBJISGV-UHFFFAOYSA-N 0.000 description 4
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 4
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 4
- 230000004927 fusion Effects 0.000 description 4
- 229910052760 oxygen Inorganic materials 0.000 description 4
- 239000001301 oxygen Substances 0.000 description 4
- 125000000951 phenoxy group Chemical group [H]C1=C([H])C([H])=C(O*)C([H])=C1[H] 0.000 description 4
- LFGREXWGYUGZLY-UHFFFAOYSA-N phosphoryl Chemical group [P]=O LFGREXWGYUGZLY-UHFFFAOYSA-N 0.000 description 4
- 239000000523 sample Substances 0.000 description 4
- 229960004946 tenofovir alafenamide Drugs 0.000 description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- 244000061458 Solanum melongena Species 0.000 description 3
- 235000002597 Solanum melongena Nutrition 0.000 description 3
- 238000013019 agitation Methods 0.000 description 3
- 230000000711 cancerogenic effect Effects 0.000 description 3
- 231100000315 carcinogenic Toxicity 0.000 description 3
- 238000005352 clarification Methods 0.000 description 3
- 239000012065 filter cake Substances 0.000 description 3
- 238000001914 filtration Methods 0.000 description 3
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 3
- 239000007787 solid Substances 0.000 description 3
- 238000003756 stirring Methods 0.000 description 3
- 238000010792 warming Methods 0.000 description 3
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 2
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 2
- 150000001408 amides Chemical class 0.000 description 2
- 238000004458 analytical method Methods 0.000 description 2
- 238000012512 characterization method Methods 0.000 description 2
- 238000002474 experimental method Methods 0.000 description 2
- 231100001244 hazardous air pollutant Toxicity 0.000 description 2
- 238000010438 heat treatment Methods 0.000 description 2
- 208000015181 infectious disease Diseases 0.000 description 2
- 238000011081 inoculation Methods 0.000 description 2
- 239000000203 mixture Substances 0.000 description 2
- 238000010606 normalization Methods 0.000 description 2
- 239000002777 nucleoside Substances 0.000 description 2
- 125000003835 nucleoside group Chemical group 0.000 description 2
- 125000003729 nucleotide group Chemical group 0.000 description 2
- 239000000843 powder Substances 0.000 description 2
- 230000001225 therapeutic effect Effects 0.000 description 2
- 239000003643 water by type Substances 0.000 description 2
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 1
- 238000005160 1H NMR spectroscopy Methods 0.000 description 1
- 238000004679 31P NMR spectroscopy Methods 0.000 description 1
- 241000208340 Araliaceae Species 0.000 description 1
- RYGMFSIKBFXOCR-UHFFFAOYSA-N Copper Chemical compound [Cu] RYGMFSIKBFXOCR-UHFFFAOYSA-N 0.000 description 1
- 238000005481 NMR spectroscopy Methods 0.000 description 1
- 235000005035 Panax pseudoginseng ssp. pseudoginseng Nutrition 0.000 description 1
- 235000003140 Panax quinquefolius Nutrition 0.000 description 1
- QOSMNYMQXIVWKY-UHFFFAOYSA-N Propyl levulinate Chemical compound CCCOC(=O)CCC(C)=O QOSMNYMQXIVWKY-UHFFFAOYSA-N 0.000 description 1
- 208000031320 Teratogenesis Diseases 0.000 description 1
- 238000002441 X-ray diffraction Methods 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 150000008064 anhydrides Chemical group 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 238000004587 chromatography analysis Methods 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 229910052802 copper Inorganic materials 0.000 description 1
- 239000010949 copper Substances 0.000 description 1
- 239000012043 crude product Substances 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 238000002330 electrospray ionisation mass spectrometry Methods 0.000 description 1
- 238000000921 elemental analysis Methods 0.000 description 1
- 238000010828 elution Methods 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 231100000025 genetic toxicology Toxicity 0.000 description 1
- 230000001738 genotoxic effect Effects 0.000 description 1
- 235000008434 ginseng Nutrition 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 238000005457 optimization Methods 0.000 description 1
- 230000008092 positive effect Effects 0.000 description 1
- 239000000651 prodrug Substances 0.000 description 1
- 229940002612 prodrug Drugs 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- QDQVXVRZVCTVHE-YFKPBYRVSA-N propan-2-yl (2s)-2-aminopropanoate Chemical compound CC(C)OC(=O)[C@H](C)N QDQVXVRZVCTVHE-YFKPBYRVSA-N 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 238000013094 purity test Methods 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 239000012488 sample solution Substances 0.000 description 1
- 238000012216 screening Methods 0.000 description 1
- 238000010583 slow cooling Methods 0.000 description 1
- 239000007921 spray Substances 0.000 description 1
- 238000013112 stability test Methods 0.000 description 1
- 238000003860 storage Methods 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
- C07F9/6561—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing systems of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring or ring system, with or without other non-condensed hetero rings
- C07F9/65616—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing systems of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring or ring system, with or without other non-condensed hetero rings containing the ring system having three or more than three double bonds between ring members or between ring members and non-ring members, e.g. purine or analogs
-
- 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
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Biochemistry (AREA)
- General Health & Medical Sciences (AREA)
- Molecular Biology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention discloses a kind of the third phenol of tenofovir amidic-salt crystal forms and its preparation method and application.The present invention provides a kind of crystal form first of tenofovir the third phenol amidic-salt shown in formula I, X-ray powder diffraction figure has characteristic peak at 5.17 ± 0.2 °, 7.30 ± 0.2 °, 10.30 ± 0.2 °, 10.91 ± 0.2 °, 11.13 ± 0.2 °, 18.55 ± 0.2 °, 19.42 ± 0.2 °, 21.14 ± 0.2 ° and 26.50 ± 0.2 ° of 2 θ values.The crystal form has the advantages that preparation is easy, removal diastereoisomer impurity ability is strong and stability is high.
Description
Technical field
The present invention relates to a kind of the third phenol of tenofovir amidic-salt crystal forms and its preparation method and application.
Background technology
The third phenol of tenofovir amide (tenofovir alafenamide) is the prodrug of tenofovir (tenofovir),
Entitled ((S)-((((R) -1- (6- amino -9H- purine -9- bases) propyl- 2- yls) oxygen) methyl) (phenoxy group) phosphoryl)-L- of chemistry
Alanine isopropyl ester.The third phenol of fumaric acid tenofovir amide (tenofovir alafenamide fumurate, TAF) has at present
Two kinds, i.e., the third phenol of tenofovir amide list fumarate (tenofovir alafenamide monofumurate) and replace promise good fortune
The third phenol of Wei amide hemifumarate (tenofovir alafenamide hemifumurate).Fumaric acid tenofovir the third phenol acyl
Amine clinically can be used for treating AIDS and hepatitis B as compound or folk prescription.
Document (Nucleosides, Nucleotides&Nucleic Acids, 2001,20 (4-7), 621-628) is reported
A kind of the third phenol of tenofovir amide list fumarate, chemistry entitled ((S)-((((R) -1- (6- amino -9H- purine -9-
Base) propyl- 2- yls) oxygen) methyl) (phenoxy group) phosphoryl)-l-Alanine isopropyl ester fumarate (1:1).Chinese patent application
CN105646584A discloses a series of tenofovirs the third phenol amide fumaric acid salt crystal form, including crystal form A, crystal form B, crystal form C, crystalline substance
Type D and crystal form α.Judge from specification, what CN105646584A was disclosed is the crystal form of tenofovir the third phenol amide list fumarate.
United States Patent (USP) US8754065B2 discloses a kind of crystal form of the third phenol of tenofovir amide hemifumarate, and chemistry is entitled ((S)-
((((R) -1- (6- amino -9H- purine -9- bases) propyl- 2- yls) oxygen) methyl) (phenoxy group) phosphoryl)-l-Alanine isopropyl ester
Fumarate (2:1).PCT Patent Application WO2017037608A1 discloses a kind of half fumaric acid crystal form of the third phenol of tenofovir amide
HL is that Isosorbide-5-Nitrae-dioxane solvent closes object, the crystal form is prepared by solvent of Isosorbide-5-Nitrae-dioxane.
But existing the third phenol of tenofovir amide list fumarate crystal form removes major impurity GS-7339 (tenofovirs
Third phenol amide diastereoisomer, chemical name ((R)-((((R) -1- (6- amino -9H- purine -9- bases) propyl- 2- yls) oxygen) first
Base) (phenoxy group) phosphoryl)-l-Alanine isopropyl ester) and ability it is weak；Tenofovir the third phenol amide that US8754065B2 is disclosed
Hemifumarate crystal form needs to be prepared by inoculation, and is inoculated with and needs to prepare high-purity seed and stringent control technique ginseng
Number, it is unfavorable with industrialized production；Isosorbide-5-Nitrae-dioxane is listed in 3 class carcinogenic substances of CMR (carcinogenic, teratogenesis, genotoxicity), in the U.S.
Hazardous air pollutants (HAP) are listed in, therefore half fumaric acid of the third phenol of tenofovir amide that WO2017037608A1 is disclosed is brilliant
Type HL has no medical usage.
So this field preparing richness easy, that removal diastereoisomer impurity ability is strong and stability is high there is an urgent need for a kind of
Horse acid tenofovir the third phenol amide crystal form.
Invention content
The technical problem to be solved by the present invention is in order to overcome existing the third phenol of fumaric acid tenofovir amide crystal form system
The shortcomings of standby cumbersome, removal diastereoisomer impurity ability is weak and (or) stability is relatively low, and a kind of tenofovir third is provided
Phenol amidic-salt crystal form and its preparation method and application.The crystal form has preparation simplicity, removal diastereoisomer impurity ability strong
The high advantage with stability.
The present invention provides a kind of crystal form first of tenofovir the third phenol amidic-salt shown in formula I, X-ray powder spreads out
Penetrate figure 5.17 ± 0.2 ° of 2 θ values, 7.30 ± 0.2 °, 10.30 ± 0.2 °, 10.91 ± 0.2 °, 11.13 ± 0.2 °, 18.55 ±
There is characteristic peak at 0.2 °, 19.42 ± 0.2 °, 21.14 ± 0.2 ° and 26.50 ± 0.2 °；The tenofovir third shown in formula I
Phenol amidic-salt is a kind of the third phenol of tenofovir amide hemifumarate.
1 radiation of Cu-K α can be used to measure for the X-ray powder diffraction figure of the crystal form first.The x-ray powder of the crystal form first
Diffraction pattern can be substantially as shown in.
Starting endothermic temperature in differential scanning calorimetry (DSC) figure of the crystal form first can be at 107 DEG C or so；The crystalline substance
Endothermic peak in the differential scanning calorimetry figure of type first can be at 113 DEG C or so；In the differential scanning calorimetry figure of the crystal form first
The heat of fusion of endothermic peak can be 90.82J/g.The differential scanning calorimetry figure of the crystal form first can also be shown basically as in Figure 2.
Thermogravimetric analysis (TGA) figure of the crystal form first can be in 30-100 DEG C of weightlessness 0.566%.The thermogravimetric of the crystal form first point
Analysis figure can also substantially as shown in Figure 3.
The present invention also provides a kind of preparation methods of the crystal form first comprising following step：
1) the third phenol of tenofovir amide, fumaric acid are dissolved in solvent appropriate；
2) the crystal form first is made to be precipitated, it is optional to add or be not added with crystal seed；
3) divide the isolated crystal form first；
4) the crystal form first of dry separation；
In the preparation method of the crystal form first, the third phenol of tenofovir amide can be sterling, or include
The crude product of the impurity such as its diastereoisomer GS-7339 is (for example, high performance liquid chromatography (HPLC) purity replaces promise not less than 70%
The third phenol of good fortune Wei amide (GS-7339 impurity contents are less than 30%), in another example HPLC purity is not less than 80% the third phenol of tenofovir
Amide (GS-7339 impurity contents are less than 20%), then for example HPLC purity is not less than 90% tenofovir the third phenol amide (GS-
10%) 7339 impurity contents are less than).
In the preparation method of the crystal form first, the temperature of the dissolving can be 65~75 DEG C, such as 70~75 DEG C, again
Such as 70 DEG C.
In the preparation method of the crystal form first, the solvent can be the recrystallisation solvent of routine, can be proton solvent,
Can be aprotic solvent or its mixture.The proton solvent, including but not limited to water and/or isopropanol.The non-matter
Sub- solvent, including but not limited to acetonitrile, tetrahydrofuran, 2- methyltetrahydrofurans, methyl tertiary butyl ether(MTBE), ethyl acetate, acetic acid are different
It is one or more in propyl ester, methyl ethyl ketone, methyl iso-butyl ketone (MIBK), heptane, toluene and dichloromethane.
In the preparation method of the crystal form first, the matter of the volume of the solvent and tenofovir the third phenol amide
The ratio of amount is, such as 5~15mL/g, in another example 10mL/g.
In the preparation method of the crystal form first, the molar ratio of tenofovir the third phenol amide and fumaric acid does not limit especially
It is fixed, generally 2.3:1 to 1.7:1, preferably 2.2:1 to 1.8:1, more preferable 2.1:1 to 1.9:1.
The preparation method of the crystal form first can carry out at any suitable temperature, for example, from about 0 DEG C to about 90
℃。
In the preparation method of the crystal form first, described " so that the crystal form first is precipitated, optional to add or be not added with crystal seed "
Method can be the Crystallization method of this field routine, such as " cooling that crystal form first is made to be precipitated but be added without crystal form first " or " cool down simultaneously
Crystal form first is added simultaneously, crystal form first is made to be precipitated ".
In the preparation method of the crystal form first, " cooling " can be primary cooling, target temperature can be 50~
65 DEG C (such as 55~60 DEG C), rate can be 10~20 DEG C/h (such as 15 DEG C/h).
In the preparation method of the crystal form first, " cooling " can also be to cool down three times；Cooling target for the first time
Temperature can be 50~65 DEG C (such as 55 DEG C~60 DEG C), and cooling rate can be 10~20 DEG C/h (such as 15 DEG C/h) for the first time,
Cooling for the first time holding time can be 2~3h；Second cooling target temperature can be 15~25 DEG C (such as 20 DEG C), second
The rate of secondary cooling can be 10~20 DEG C/h (such as 17.5 DEG C/h), and second of cooling holding time can be 2~3h；For the third time
Cooling target temperature can be 0~5 DEG C, and cooling the holding time of third time can be 1~2h.
In the preparation method of the crystal form first, the method for the drying can be the drying means of this field routine, example
Such as vacuum drying；The vacuum drying temperature can be 45~55 DEG C (such as 50 DEG C)；The vacuum drying time can
For 10~15h (such as 13h).
The present invention also provides the purposes of above-mentioned tenofovir the third phenol amide hemifumarate crystal form first.The third phenol of tenofovir
Amide hemifumarate crystal form first can be used as bulk pharmaceutical chemicals, be used to prepare various medical compositions, and being used clinically for HIV, (people exempts from
Epidemic disease defective virus) infection preventative and (or) therapeutic treatment, be used clinically for HBV (human hepatitis B virus) infection prevention
Property and (or) therapeutic treatment, and be used clinically for treatment AIDS and hepatitis B.
The present invention also provides a kind of pharmaceutical compositions, and it includes above-mentioned tenofovir the third phenol amide hemifumarate crystal forms
First and suitable pharmaceutic adjuvant.
Without prejudice to the field on the basis of common sense, above-mentioned each optimum condition can be combined arbitrarily each preferably to get the present invention
Example.
The commercially available acquisition of agents useful for same and raw material of the present invention is prepared according to known references method.For example, special with reference to the U.S.
Sharp US7390791 or document (Nucleosides, Nucleotides&Nucleic Acids, 2001,20 (4-7), 621-
628) tenofovir the third phenol amide is prepared.
The positive effect of tenofovir the third phenol amide hemifumarate crystal form first of present disclosure is：With for promise
Good fortune Wei the third phenol amide list fumarate is compared, and the major impurity GS-7339 in bulk pharmaceutical chemicals can be more effectively removed, to more have
Effect ground prepares the bulk pharmaceutical chemicals (table 1) of higher purity.
1 purification capacity of table compares
Note：HPLC normalization methods
Compared with tenofovir the third phenol amide hemifumarate crystal form that US8754065B2 is disclosed, tenofovir of the present invention
The preparation of third phenol amide hemifumarate crystal form first is since the optional crystal seed that is not added with is inoculated with, when avoiding crystal seed preparation, inoculation
Machine selects and inoculating process parameter optimization, therefore preparation method is more easy.In addition, the heat of fusion ratio of crystal form first of the present invention
The hemifumarate crystal form higher (90.82J/g that US8754065B2 is disclosed>72.71J/g).Stability of crystal form accelerated test is also demonstrate,proved
The real stability of the third phenol of tenofovir amide hemifumarate crystal form first of the present invention.With half fumaric acid of the third phenol of tenofovir amide
Crystal form HL is compared, and crystal form first of the present invention and preparation method thereof does not include the solvent of carcinogenic toxicity.
Description of the drawings
Fig. 1 is the X-ray powder diffraction figure of tenofovir the third phenol amide hemifumarate crystal form first.
Fig. 2 is differential scanning calorimetry (DSC) figure of tenofovir the third phenol amide hemifumarate crystal form first.
Fig. 3 is thermogravimetric analysis (TGA) figure of tenofovir the third phenol amide hemifumarate crystal form first.
Fig. 4 is the X-ray powder diffraction figure after tenofovir the third phenol amide hemifumarate crystal form first accelerated test four weeks.
Specific implementation mode
It is further illustrated the present invention below by the mode of embodiment, but does not therefore limit the present invention to the implementation
Among example range.In the following examples, the experimental methods for specific conditions are not specified, according to conventional methods and conditions, or according to commodity
Specification selects.
Analysis method and detecting instrument used in the embodiment of the present invention is as described below：
It is Waters e2695, detector 2998PDA-QDA that purity test, which uses HPLC normalization methods, instrument,；C18 chromatographies
Column：Micro- UniSil is received in Suzhou, 5 μm,4.6×250mm；Flow velocity：1ml/min；Detection：UV 260nm；Sample solution is used
Methanol is prepared；Mobile phase A：0.02% phosphoric acid (85%) is dissolved in water and acetonitrile (95:5), Mobile phase B：0.02% phosphoric acid (85%)
It is dissolved in water and acetonitrile (50:50), gradient elution：
| Time (min) | Mobile phase A (%) | Mobile phase B (%) |
| 0 | 100 | 0 |
| 5 | 100 | 0 |
| 7 | 70 | 30 |
| 32 | 70 | 30 |
| 40 | 0 | 100 |
| 50 | 0 | 100 |
| 55 | 100 | 0 |
| 60 | 100 | 0 |
The INOVA-400 of Nuclear Magnetic Resonance model Varian companies.Mass spectrograph model Waters companies
Micromass Q-Tof micro, electron spray ionisation (ESI), just ionize pattern.Elemental analyser is Thermo
SCIENTIFIC FLASH 2000Organic Elemental Analyzer。
The determining instrument of x-ray diffraction pattern (XRPD) is Bruker D8Advance X-ray powder diffraction instrument, is used
Copper K α radiation obtains the XRPD spectrums of sample.Experiment condition is as follows：Tube voltage 40KV, tube current 40mA, K α 1=1.5406A, scanning
3-45 ° of range, 8 °/min of sweep speed, 0.0197 ° of step-length.
It is Netzsch DSC 204F1 thermal analyzers that differential scanning calorimetry (DSC), which composes determining instrument,.Thermogravimetric analysis (TGA)
Spectrum determining instrument is Netzsch TG 209F1 thermal analyzers.
Due to the difference of determining instrument and the deviation of determination condition, there may be measure to miss for XRPD spectrums, DSC spectrums and TGA spectrums
Difference.When screening and determining various crystal structures, evaluated error should be taken into account.
Embodiment 1：The preparation of tenofovir the third phenol amide hemifumarate crystal form first
By the third phenol of tenofovir amide (500mg, 1.05mmol, GS-7339HPLC content 6.69%), fumaric acid (61mg,
It 0.52mmol) is added in 10ml eggplant type bottles with acetonitrile (5ml), magnetic agitation.70 DEG C are warming up to, reaction system dissolved clarification.In 1h
55 DEG C are cooled to, reaction system becomes cloudy, then 2h is stirred at 55 DEG C.Then, it is cooled to 20 DEG C in 2h, then is stirred at 20 DEG C
2h.Finally, it is cooled to 0-5 DEG C of stirring 1h.Filtering is washed filter cake with the acetonitrile (2ml) of precooling, is dried in vacuo (50 DEG C, 13h),
White solid is obtained, tenofovir the third phenol amide hemifumarate crystal form first (413mg, yield are confirmed as through X-ray powder diffraction
74%, GS-7339HPLC content 1.31%).
Embodiment 2：The preparation of tenofovir the third phenol amide hemifumarate crystal form first and characterization
By the third phenol of tenofovir amide (500mg, 1.05mmol, GS-7339HPLC content 0.13%), fumaric acid (61mg,
It 0.52mmol) is added in 10ml eggplant type bottles with acetonitrile (5ml), magnetic agitation.70 DEG C are warming up to, reaction system dissolved clarification.In 1h
60 DEG C are cooled to, addition crystal seed (prepared by 5mg, embodiment 1), reaction system becomes cloudy, then 2h is stirred at 60 DEG C.Then, in 2h
20 DEG C are inside cooled to, then stirs 1h at 20 DEG C.Finally, it is cooled to 0-5 DEG C of stirring 1h.Filtering, is washed with the acetonitrile (2ml) of precooling
Filter cake is dried in vacuo (50 DEG C, 12h), obtains white solid, and tenofovir the third phenol amide hemifumarate is confirmed as through following characterizations
Crystal form first (495mg, yield 88%, GS-7339HPLC contents 0%).
Elemental analysis (C23H31N6O7P) C, H, N, calculated value (%)：51.68,5.86,15.73, measured value (%),
51.24,5.78,15.29；1H NMR(400MHz,DMSO-d6) δ 8.18 (s, 1H), 8.13 (s, 1H), 7.26-7.30 (t, J=
8.0Hz, 4H), 7.09-7.13 (t, J=7.2Hz, 1H), 7.05-7.07 (d, J=8.0Hz, 2H), 6.66 (s, 1H), 5.61-
5.67 (t, J=11.2Hz, 1H), 4.81-4.88 (m, 1H), 4.28-4.31 (d, J=14.4Hz, 1H), 4.13-4.18 (dd, J
=6.4,14.4Hz, 1H), 3.93-3.96 (m, 1H), 3.86-3.91 (m, 2H), 3.75-3.80 (m, 1H), 1.13-1.15 (d,
J=6.0Hz, 9H), 1.07-1.08 (d, J=6.0Hz, 3H)；31P NMR(162MHz,DMSO-d6)δ22.15；13C NMR
(100MHz,DMSO-d6) δ 173.36,166.59,156.36,152.78,150.74,150.26,141.96,134.50,
129.91,124.78,121.01,118.86,76.05,68.36,65.37,49.55,47.40,21.85,21.81,20.79,
17.05；ESI-MS(m/z):477.15[M+H]+,499.17[M+Na]+。
X-ray powder diffraction (X-ray Powder Diffraction, XRPD) (Fig. 1)：In 5.17 ° of 2 θ values, 7.30 °,
There is characteristic peak (table 2) at 10.30 °, 10.91 °, 11.13 °, 18.55 °, 19.42 °, 21.14 °, 26.50 °.
The XRPD characteristic peaks of 2 tenofovir the third phenol amide hemifumarate crystal form first of table
Differential scanning calorimetry (Differential Scanning Calorimetry, DSC) (Fig. 2)：The third phenol of tenofovir
Amide hemifumarate crystal form first (2.750mg), heating rate are 10 DEG C/min, and temperature range is 20-250 DEG C.Starting heat absorption
Temperature has endothermic peak, heat of fusion 90.82J/g at 113 DEG C or so at 107 DEG C or so.Promise is replaced with what US8754065B2 was disclosed
Good fortune Wei the third phenol amide hemifumarate crystal form is compared, heat of fusion higher (90.82J/g>72.71J/g).
Thermogravimetric analysis (Thermogravimetric Analysis, TGA) (Fig. 3)：Half rich horse of the third phenol of tenofovir amide
Hydrochlorate crystal form first (15.6660mg), heating rate are 10 DEG C/min, and temperature range is 30-350 DEG C.It is lost in 30-100 DEG C of sample
Weigh 0.566%.Therefore, this product is anhydride.
Embodiment 3：The preparation of tenofovir the third phenol amide list fumarate
By the third phenol of tenofovir amide (114mg, 0.24mmol, GS-7339HPLC content 6.32%), fumaric acid (22mg,
It 0.22mmol) is added in 10ml eggplant type bottles with acetonitrile (3.2ml), magnetic agitation.70 DEG C are warming up to, reaction system dissolved clarification.Slowly
Cooling, when being down to about 55 DEG C, system becomes cloudy.Then slow cooling again, finally keeps 2h in ice bath.Filtering, with precooling
Acetonitrile (2ml) washs filter cake, is dried in vacuo (45 DEG C, 11h), obtains tenofovir the third phenol amide list fumarate, is white solid
(93mg, yield 66%, GS-7339HPLC contents 5.52%).
Embodiment 4：Tenofovir the third phenol amide hemifumarate crystal form first Accelerated stability test
Tenofovir the third phenol amide fumaric acid salt crystal form first sample prepared by embodiment 2 is relatively wet in 40 DEG C and 75%
Under degree, closed storage surrounding.X-ray powder diffraction (XRPD) is carried out to gained sample and measures (Fig. 4), in 5.19 ° of 2 θ values,
There is characteristic peak (table 3) at 7.34 °, 10.30 °, 10.95 °, 11.11 °, 18.55 °, 19.42 °, 21.13 °, 26.50 °.
XRPD characteristic peaks after 3 crystal form first accelerated test four weeks of table
The result shows that the X-ray powder diffraction figure of tenofovir the third phenol amide fumaric acid salt crystal form first accelerated test surrounding
Do not change.Therefore, the third phenol of tenofovir amide fumaric acid salt crystal form first accelerated test surrounding stable crystal form.
Claims (10)
1. a kind of crystal form first of tenofovir the third phenol amidic-salt shown in formula I, which is characterized in that its X-ray powder diffraction figure
5.17 ± 0.2 ° of 2 θ values, 7.30 ± 0.2 °, 10.30 ± 0.2 °, 10.91 ± 0.2 °, 11.13 ± 0.2 °, 18.55 ± 0.2 °,
There is characteristic peak at 19.42 ± 0.2 °, 21.14 ± 0.2 ° and 26.50 ± 0.2 °；
2. crystal form first as described in claim 1, which is characterized in that the X-ray powder diffraction figure of the crystal form first uses Cu-K α
1 radiation measures；
And/or the X-ray powder diffraction figure of the crystal form first is substantially as shown in；
And/or the starting endothermic temperature in the differential scanning calorimetry figure of the crystal form first is at 107 DEG C ± 2 DEG C；
And/or the thermogravimetric analysis figure of the crystal form first is substantially as shown in Figure 3.
3. crystal form first as described in claim 1, which is characterized in that the differential scanning calorimetry figure of the crystal form first is substantially such as
Shown in Fig. 2.
4. a kind of preparation method of crystal form first according to any one of claims 1 to 3, which is characterized in that it includes following
Step：
1) the third phenol of tenofovir amide, fumaric acid are dissolved in solvent；
2) the crystal form first is made to be precipitated；
3) divide the isolated crystal form first；
4) the crystal form first of dry separation；
5. preparation method as claimed in claim 4, which is characterized in that in step (1), the tenofovir the third phenol amide
HPLC purity is not less than 70%；
And/or in step (1), the impurity that the tenofovir the third phenol amide contains includes GS-7339；
And/or in step (1), the temperature of " dissolving " is 65~75 DEG C；
And/or in step (1), the solvent is proton solvent and/or aprotic solvent；
And/or in step (1), the ratio of the quality of the volume of the solvent and tenofovir the third phenol amide is 5~
15mL/g；
And/or in step (1), the molar ratio of the tenofovir the third phenol amide and the fumaric acid is 2.3:1 to 1.7:1；
And/or in step (2), the method for described " the crystal form first is made to be precipitated ", which is cooling, makes crystal form first be precipitated；
And/or in step (4), the method for the drying is vacuum drying.
6. preparation method as claimed in claim 5, which is characterized in that in step (1), the tenofovir the third phenol amide
HPLC purity is not less than 80%；
And/or in step (1), the temperature of " dissolving " is 70~75 DEG C；
And/or in step (1), the proton solvent is water and/or isopropanol；
And/or in step (1), the aprotic solvent is acetonitrile, tetrahydrofuran, 2- methyltetrahydrofurans, methyl tertbutyl
One kind in ether, ethyl acetate, isopropyl acetate, methyl ethyl ketone, methyl iso-butyl ketone (MIBK), heptane, toluene and dichloromethane or
It is a variety of；
And/or in step (1), the ratio of the quality of the volume of the solvent and tenofovir the third phenol amide is 5~
10mL/g；
And/or in step (1), the molar ratio of the tenofovir the third phenol amide and the fumaric acid is 2.2:1 to 1.8:1；
And/or in step (2), " cooling " is primary cooling or cools down three times；
And/or in step (4), the vacuum drying temperature is 45~55 DEG C；
And/or in step (4), the vacuum drying time is 10~15h.
7. preparation method as claimed in claim 6, which is characterized in that in step (1), the tenofovir the third phenol amide
HPLC purity is not less than 90%；
And/or in step (1), the molar ratio of the tenofovir the third phenol amide and the fumaric acid is 2.1:1 to 1.9:1；
And/or in step (2), the target temperature of " primary cooling " is 50~65 DEG C；
And/or in step (2), the rate of " primary cooling " is 10~20 DEG C/h；
And/or in step (2), in described " cooling down three times ", cooling target temperature is 50~65 DEG C for the first time；
And/or in step (2), in described " cooling down three times ", cooling rate is 10~20 DEG C/h for the first time；
And/or in step (2), in described " cooling down three times ", cooling for the first time holds time as 2~3h；
And/or in step (2), in described " cooling down three times ", second of cooling target temperature is 15~25 DEG C；
And/or in step (2), in described " cooling down three times ", second of cooling rate is 10~20 DEG C/h；
And/or in step (2), in described " cooling down three times ", second of cooling is held time as 2~3h；
And/or in step (2), in described " cooling down three times ", the cooling target temperature of third time is 0~5 DEG C；
And/or in step (2), in described " cooling down three times ", third time is cooling to hold time as 1~2h；
And/or in step (4), the vacuum drying temperature is 45~50 DEG C.
8. the application of crystal form first according to any one of claims 1 to 3 in medicine preparation, the drug is immune for people
Defective virus infects and/or the treatment and/or prevention of human hepatitis B virus infection.
9. the application of crystal form first according to any one of claims 1 to 3 in medicine preparation, the drug is used for AIDS
And/or the treatment and/or prevention of hepatitis B.
10. a kind of pharmaceutical composition, it includes crystal form first according to any one of claims 1 to 3 and pharmaceutic adjuvants.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201710283169.6A CN108794530A (en) | 2017-04-26 | 2017-04-26 | A kind of the third phenol of tenofovir amidic-salt crystal form and its preparation method and application |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201710283169.6A CN108794530A (en) | 2017-04-26 | 2017-04-26 | A kind of the third phenol of tenofovir amidic-salt crystal form and its preparation method and application |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN108794530A true CN108794530A (en) | 2018-11-13 |
Family
ID=64068839
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201710283169.6A Pending CN108794530A (en) | 2017-04-26 | 2017-04-26 | A kind of the third phenol of tenofovir amidic-salt crystal form and its preparation method and application |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN108794530A (en) |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN110452268A (en) * | 2019-08-21 | 2019-11-15 | 天地恒一制药股份有限公司 | A kind of preparation method of third phenol tenofovir, half fumaric acid monocrystalline |
| CN112782311A (en) * | 2020-12-30 | 2021-05-11 | 南京百泽医药科技有限公司 | HPLC (high performance liquid chromatography) determination method of L-isopropyl alanine in tenofovir disoproxil fumarate |
Citations (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1443189A (en) * | 2000-07-21 | 2003-09-17 | 吉里德科学公司 | Prodrugs of phosphonate nucleotide analogues and methods for selecting and making same |
| WO2013025788A1 (en) * | 2011-08-16 | 2013-02-21 | Gilead Sciences, Inc. | Tenofovir alafenamide hemifumarate |
| CN104558036A (en) * | 2014-12-11 | 2015-04-29 | 杭州和泽医药科技有限公司 | Tenofovir alafenamide hemi-fumarate crystal form and preparation method thereof |
| CN104926872A (en) * | 2015-05-12 | 2015-09-23 | 杭州和泽医药科技有限公司 | Tenofovir alafenamide semi-tartrate |
| CN105399771A (en) * | 2014-07-21 | 2016-03-16 | 连云港宏创药业有限公司 | Crystal form of tenofovir prodrug, preparation method and application of crystal form |
| CN105646584A (en) * | 2014-11-12 | 2016-06-08 | 四川海思科制药有限公司 | Novel crystal forms of Tenofovir alafenamide fumarate, preparation methods therefor and use of novel crystal forms of Tenofovir alafenamide fumarate |
| CN106478725A (en) * | 2016-10-14 | 2017-03-08 | 上海礼泰医药科技有限公司 | The preparation method and applications of high-purity phosphine the third tenofovir intermediate |
| CN107793451A (en) * | 2016-08-30 | 2018-03-13 | 江苏奥赛康药业股份有限公司 | Tenofovir Chinese mugwort draws phenol amine hemifumarate compound and its pharmaceutical composition |
-
2017
- 2017-04-26 CN CN201710283169.6A patent/CN108794530A/en active Pending
Patent Citations (9)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1443189A (en) * | 2000-07-21 | 2003-09-17 | 吉里德科学公司 | Prodrugs of phosphonate nucleotide analogues and methods for selecting and making same |
| WO2013025788A1 (en) * | 2011-08-16 | 2013-02-21 | Gilead Sciences, Inc. | Tenofovir alafenamide hemifumarate |
| CN103732594A (en) * | 2011-08-16 | 2014-04-16 | 吉联亚科学公司 | Tenofovir alafenamide hemifumarate |
| CN105399771A (en) * | 2014-07-21 | 2016-03-16 | 连云港宏创药业有限公司 | Crystal form of tenofovir prodrug, preparation method and application of crystal form |
| CN105646584A (en) * | 2014-11-12 | 2016-06-08 | 四川海思科制药有限公司 | Novel crystal forms of Tenofovir alafenamide fumarate, preparation methods therefor and use of novel crystal forms of Tenofovir alafenamide fumarate |
| CN104558036A (en) * | 2014-12-11 | 2015-04-29 | 杭州和泽医药科技有限公司 | Tenofovir alafenamide hemi-fumarate crystal form and preparation method thereof |
| CN104926872A (en) * | 2015-05-12 | 2015-09-23 | 杭州和泽医药科技有限公司 | Tenofovir alafenamide semi-tartrate |
| CN107793451A (en) * | 2016-08-30 | 2018-03-13 | 江苏奥赛康药业股份有限公司 | Tenofovir Chinese mugwort draws phenol amine hemifumarate compound and its pharmaceutical composition |
| CN106478725A (en) * | 2016-10-14 | 2017-03-08 | 上海礼泰医药科技有限公司 | The preparation method and applications of high-purity phosphine the third tenofovir intermediate |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN110452268A (en) * | 2019-08-21 | 2019-11-15 | 天地恒一制药股份有限公司 | A kind of preparation method of third phenol tenofovir, half fumaric acid monocrystalline |
| CN112782311A (en) * | 2020-12-30 | 2021-05-11 | 南京百泽医药科技有限公司 | HPLC (high performance liquid chromatography) determination method of L-isopropyl alanine in tenofovir disoproxil fumarate |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| JP7220154B2 (en) | Crystalline forms of amino lipids | |
| KR101470715B1 (en) | Polymorphs of Dasatinib, preparation methods and pharmaceutical compositions thereof | |
| EP3180343A1 (en) | Solid state forms of ibrutinib | |
| US10273262B2 (en) | Crystalline form A of obeticholic acid and preparation method thereof | |
| EP3218351B1 (en) | A method for the preparation, isolation and purification of pharmaceutically applicable forms of ahu-377 | |
| CN103764637A (en) | Solid state forms of cabazitaxel and processes for preparation thereof | |
| WO2017008773A1 (en) | Crystalline forms of obeticholic acid | |
| JP6378844B2 (en) | Method for preparing sixth crystalline form of sofosbuvir | |
| EA030142B1 (en) | Dasatinib salts | |
| CN109496210A (en) | His polymorphic and preparation method thereof of Baily department | |
| CN114746412A (en) | Novel crystal form of KD-025 and preparation method thereof | |
| CN108794530A (en) | A kind of the third phenol of tenofovir amidic-salt crystal form and its preparation method and application | |
| WO2017037608A1 (en) | Solid forms of tenofovir alafenamide and salts thereof, processes for its preparation and pharmaceutical compositions thereof | |
| CN107793451A (en) | Tenofovir Chinese mugwort draws phenol amine hemifumarate compound and its pharmaceutical composition | |
| KR20170018822A (en) | Lobaplatin crystal, preparation method and pharmaceutical application | |
| CN104926872B (en) | Tenofovir Chinese mugwort draws the tartrate of phenol amine half | |
| TWI808069B (en) | New solid forms of [(1s)-1-[(2s,4r,5r)-5-(5-amino-2-oxo-thiazolo[4,5-d]pyrimidin-3-yl)-4-hydroxy-tetrahydrofuran-2-yl]propyl] acetate | |
| CN107814802A (en) | A kind of new method for preparing citric acid tropsch imatinib medicinal crystal-form | |
| WO2015081566A1 (en) | Crystalline forms of trametinib and solvate thereof, preparation method therefor, pharmaceutical composition comprising same and use thereof | |
| CN107226826A (en) | Tenofovir Chinese mugwort draws phenol amine fumarate compound and its pharmaceutical composition | |
| EP2114910A1 (en) | A novel crystalline mycophenolate sodium polymorph and processes to manufacture same | |
| CN112409380A (en) | Preparation method and application of novel crystal form of bicarvir sodium | |
| CN104558034A (en) | Novel crystal form of tedizolid phosphate disodium salt and preparation method of novel crystal form | |
| CN108727417B (en) | Polycyclic compound sodium salt, and polycrystalline type, preparation method and application thereof | |
| US20150025040A1 (en) | Novel polymorphs of fosamprenavir calcium |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| WD01 | Invention patent application deemed withdrawn after publication |
Application publication date: 20181113 |
|
| WD01 | Invention patent application deemed withdrawn after publication |