CN108947966A - Dabigatran etcxilate mesylate novel crystal forms and preparation method thereof - Google Patents
Dabigatran etcxilate mesylate novel crystal forms and preparation method thereof Download PDFInfo
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- CN108947966A CN108947966A CN201810787722.4A CN201810787722A CN108947966A CN 108947966 A CN108947966 A CN 108947966A CN 201810787722 A CN201810787722 A CN 201810787722A CN 108947966 A CN108947966 A CN 108947966A
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- crystal form
- dabigatran etcxilate
- etcxilate mesylate
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- 239000013078 crystal Substances 0.000 title claims abstract description 173
- 229960003850 dabigatran Drugs 0.000 title claims abstract description 145
- YBSJFWOBGCMAKL-UHFFFAOYSA-N dabigatran Chemical compound N=1C2=CC(C(=O)N(CCC(O)=O)C=3N=CC=CC=3)=CC=C2N(C)C=1CNC1=CC=C(C(N)=N)C=C1 YBSJFWOBGCMAKL-UHFFFAOYSA-N 0.000 title claims abstract description 145
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 title claims abstract description 142
- 238000002360 preparation method Methods 0.000 title claims abstract description 29
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims abstract description 69
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims abstract description 54
- 238000003756 stirring Methods 0.000 claims description 34
- 238000010521 absorption reaction Methods 0.000 claims description 18
- 238000006243 chemical reaction Methods 0.000 claims description 18
- 238000000634 powder X-ray diffraction Methods 0.000 claims description 17
- 238000001914 filtration Methods 0.000 claims description 16
- 238000010438 heat treatment Methods 0.000 claims description 15
- -1 ester mesylate Chemical class 0.000 claims description 10
- 238000005406 washing Methods 0.000 claims description 10
- 239000008194 pharmaceutical composition Substances 0.000 claims description 4
- 238000000034 method Methods 0.000 abstract description 18
- 239000000843 powder Substances 0.000 description 72
- 238000012360 testing method Methods 0.000 description 64
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 42
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical group CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 41
- 239000000126 substance Substances 0.000 description 32
- 239000002932 luster Substances 0.000 description 29
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 28
- 238000001514 detection method Methods 0.000 description 23
- 235000019441 ethanol Nutrition 0.000 description 18
- 238000001035 drying Methods 0.000 description 16
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 14
- 239000002775 capsule Substances 0.000 description 13
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 12
- 239000002904 solvent Substances 0.000 description 10
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 8
- 239000000203 mixture Substances 0.000 description 7
- 239000004698 Polyethylene Substances 0.000 description 6
- BTANRVKWQNVYAZ-UHFFFAOYSA-N butan-2-ol Chemical compound CCC(C)O BTANRVKWQNVYAZ-UHFFFAOYSA-N 0.000 description 6
- 239000003814 drug Substances 0.000 description 6
- 238000002474 experimental method Methods 0.000 description 6
- 229920000573 polyethylene Polymers 0.000 description 6
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 5
- 229920002261 Corn starch Polymers 0.000 description 4
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 4
- 102000009123 Fibrin Human genes 0.000 description 4
- 108010073385 Fibrin Proteins 0.000 description 4
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 4
- 229920000168 Microcrystalline cellulose Polymers 0.000 description 4
- 229920002472 Starch Polymers 0.000 description 4
- 239000008120 corn starch Substances 0.000 description 4
- 229940099112 cornstarch Drugs 0.000 description 4
- 238000005469 granulation Methods 0.000 description 4
- 230000003179 granulation Effects 0.000 description 4
- 238000005286 illumination Methods 0.000 description 4
- 239000008101 lactose Substances 0.000 description 4
- 229960001375 lactose Drugs 0.000 description 4
- 235000019359 magnesium stearate Nutrition 0.000 description 4
- 235000019813 microcrystalline cellulose Nutrition 0.000 description 4
- 239000008108 microcrystalline cellulose Substances 0.000 description 4
- 229940016286 microcrystalline cellulose Drugs 0.000 description 4
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 4
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 4
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 4
- 238000001144 powder X-ray diffraction data Methods 0.000 description 4
- 238000001953 recrystallisation Methods 0.000 description 4
- 239000011734 sodium Substances 0.000 description 4
- 229910052708 sodium Inorganic materials 0.000 description 4
- 229940083542 sodium Drugs 0.000 description 4
- 239000008107 starch Substances 0.000 description 4
- 235000019698 starch Nutrition 0.000 description 4
- BWGVNKXGVNDBDI-UHFFFAOYSA-N Fibrin monomer Chemical compound CNC(=O)CNC(=O)CN BWGVNKXGVNDBDI-UHFFFAOYSA-N 0.000 description 3
- 238000002425 crystallisation Methods 0.000 description 3
- 230000008025 crystallization Effects 0.000 description 3
- 229950003499 fibrin Drugs 0.000 description 3
- 238000010992 reflux Methods 0.000 description 3
- JWUJQDFVADABEY-UHFFFAOYSA-N 2-methyltetrahydrofuran Chemical compound CC1CCCO1 JWUJQDFVADABEY-UHFFFAOYSA-N 0.000 description 2
- 238000004566 IR spectroscopy Methods 0.000 description 2
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
- 238000004458 analytical method Methods 0.000 description 2
- 230000010100 anticoagulation Effects 0.000 description 2
- 230000023555 blood coagulation Effects 0.000 description 2
- JHIVVAPYMSGYDF-UHFFFAOYSA-N cyclohexanone Chemical compound O=C1CCCCC1 JHIVVAPYMSGYDF-UHFFFAOYSA-N 0.000 description 2
- 229930007927 cymene Natural products 0.000 description 2
- 230000006837 decompression Effects 0.000 description 2
- XYIBRDXRRQCHLP-UHFFFAOYSA-N ethyl acetoacetate Chemical compound CCOC(=O)CC(C)=O XYIBRDXRRQCHLP-UHFFFAOYSA-N 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- 239000003960 organic solvent Substances 0.000 description 2
- HFPZCAJZSCWRBC-UHFFFAOYSA-N p-cymene Chemical compound CC(C)C1=CC=C(C)C=C1 HFPZCAJZSCWRBC-UHFFFAOYSA-N 0.000 description 2
- 239000007787 solid Substances 0.000 description 2
- 238000013112 stability test Methods 0.000 description 2
- PTTPXKJBFFKCEK-UHFFFAOYSA-N 2-Methyl-4-heptanone Chemical compound CC(C)CC(=O)CC(C)C PTTPXKJBFFKCEK-UHFFFAOYSA-N 0.000 description 1
- DKPFZGUDAPQIHT-UHFFFAOYSA-N Butyl acetate Natural products CCCCOC(C)=O DKPFZGUDAPQIHT-UHFFFAOYSA-N 0.000 description 1
- 108010049003 Fibrinogen Proteins 0.000 description 1
- 102000008946 Fibrinogen Human genes 0.000 description 1
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 description 1
- 101000712605 Theromyzon tessulatum Theromin Proteins 0.000 description 1
- 229940122388 Thrombin inhibitor Drugs 0.000 description 1
- 208000007536 Thrombosis Diseases 0.000 description 1
- 239000013543 active substance Substances 0.000 description 1
- 239000003146 anticoagulant agent Substances 0.000 description 1
- 229940127219 anticoagulant drug Drugs 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 239000002131 composite material Substances 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- KSGXQBZTULBEEQ-UHFFFAOYSA-N dabigatran etexilate Chemical compound C1=CC(C(N)=NC(=O)OCCCCCC)=CC=C1NCC1=NC2=CC(C(=O)N(CCC(=O)OCC)C=3N=CC=CC=3)=CC=C2N1C KSGXQBZTULBEEQ-UHFFFAOYSA-N 0.000 description 1
- 229960004951 dabigatran etexilate mesylate Drugs 0.000 description 1
- SBZXBUIDTXKZTM-UHFFFAOYSA-N diglyme Chemical compound COCCOCCOC SBZXBUIDTXKZTM-UHFFFAOYSA-N 0.000 description 1
- 239000003937 drug carrier Substances 0.000 description 1
- 239000002532 enzyme inhibitor Substances 0.000 description 1
- 229940125532 enzyme inhibitor Drugs 0.000 description 1
- DXVYLFHTJZWTRF-UHFFFAOYSA-N ethyl iso-butyl ketone Natural products CCC(=O)CC(C)C DXVYLFHTJZWTRF-UHFFFAOYSA-N 0.000 description 1
- 229940012952 fibrinogen Drugs 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- 230000002496 gastric effect Effects 0.000 description 1
- 239000008187 granular material Substances 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 239000012535 impurity Substances 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 238000009776 industrial production Methods 0.000 description 1
- 238000007689 inspection Methods 0.000 description 1
- 239000008183 oral pharmaceutical preparation Substances 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 239000006187 pill Substances 0.000 description 1
- 108090000765 processed proteins & peptides Proteins 0.000 description 1
- 102000004196 processed proteins & peptides Human genes 0.000 description 1
- 229940002612 prodrug Drugs 0.000 description 1
- 239000000651 prodrug Substances 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- RDRCCJPEJDWSRJ-UHFFFAOYSA-N pyridine;1h-pyrrole Chemical compound C=1C=CNC=1.C1=CC=NC=C1 RDRCCJPEJDWSRJ-UHFFFAOYSA-N 0.000 description 1
- 238000007670 refining Methods 0.000 description 1
- 230000002441 reversible effect Effects 0.000 description 1
- 230000006641 stabilisation Effects 0.000 description 1
- 238000011105 stabilization Methods 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- 239000003868 thrombin inhibitor Substances 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
- A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- 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
- A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C303/00—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides
- C07C303/32—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides of salts of sulfonic acids
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C309/00—Sulfonic acids; Halides, esters, or anhydrides thereof
- C07C309/01—Sulfonic acids
- C07C309/02—Sulfonic acids having sulfo groups bound to acyclic carbon atoms
- C07C309/03—Sulfonic acids having sulfo groups bound to acyclic carbon atoms of an acyclic saturated carbon skeleton
- C07C309/04—Sulfonic acids having sulfo groups bound to acyclic carbon atoms of an acyclic saturated carbon skeleton containing only one sulfo group
-
- 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
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- General Health & Medical Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Medicinal Chemistry (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Hematology (AREA)
- Diabetes (AREA)
- Engineering & Computer Science (AREA)
- Epidemiology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The present invention provides the preparation methods of a kind of dabigatran etcxilate mesylate novel crystal forms and this novel crystal forms.This method includes that dabigatran etcxilate mesylate is dissolved in methylene chloride, then adds the step of acetone is recrystallized.
Description
Technical field
The invention belongs to pharmaceutical fields, are related to the crystal form of medical compounds, in particular to a kind of anticoagulation medicine Da Bijia
The new crystal form and preparation method thereof of group's ester mesylate.
Background technique
Dabigatran etcxilate mesylate (Dabigatran etexilate mesylate) is a kind of novel direct blood coagulation
Enzyme inhibitor is the pro-drug of dabigatran, belongs to the thrombin inhibitor of non-peptides.It takes orally after gastrointestinal absorption, in vivo
It is converted into the dabigatran with direct anticoagulant active.Dabigatran is incorporated into the fibrin specific bond position of fibrin ferment
Point prevents fibrinogen from being cracked into fibrin, to block the final step and thrombosis of blood coagulation network.Da Bijia
Group can dissociate from fibrin fibrin ferment combination, play reversible anticoagulation.Its chemical structure is as follows:
Due to the unique pharmacological activity of dabigatran etcxilate mesylate, researcher has carried out extensive research to its crystal form,
New crystal form is constantly found, such as the preparation side of 2 kinds of crystal forms of dabigatran etcxilate mesylate is disclosed in WO2005028468
Method: it is solvent that crystal form I and crystal form II, which is all made of acetone, and only crystallization temperature is different, and crystal form II can also be by being added crystal seed
Method obtains.The preparation method of a kind of crystal form of dabigatran etcxilate mesylate is disclosed in WO2011110876, this method is with second
Acetoacetic ester is solvent, and crystal form IV is made.The preparation side of 8 kinds of crystal forms of dabigatran etcxilate mesylate is disclosed in WO2012027543
Method is respectively adopted and dabigatran etcxilate mesylate is placed to 30 days (crystal form A) in the environment of relative humidity 100%, at water
It manages (crystal form B), recrystallize (crystal form D) with cymene recrystallization (crystal form C), with dimethyl sulfoxide, in normal heptane environment
It is middle place 1 month (crystal form G), with pyridine recrystallization (crystal form H), in 2- methyltetrahydrofuran crystallization (or with cyclohexanone, penta
Alcohol, ethyl acetoacetate, diethylene glycol dimethyl ether recrystallization) (crystal form I), in 2- butanol crystallization (or with ethyl alcohol and 2- methyl four
Hydrogen furans, ethyl alcohol and ethyl acetate, butanol and ethyl acetate, ethyl alcohol and isobutyl ketone recrystallization) (crystal form III) etc..With top
Method is the problem is that with acetone industrial production, there are security risks, with cymene, dimethyl sulfoxide, normal heptane, pyrrole
Pyridine, 2- methyltetrahydrofuran, ethyl acetoacetate, 2- butanol etc. make solvent and all there is high production cost, and solvent easily remains, is not
The problem of industrialized production Conventional solvents.It is therefore desirable to find a kind of stabilization, be easy the crystal form of preparation as medicinal application.
Summary of the invention
To solve the above-mentioned problems, the present invention provides the new crystal form of four kinds of dabigatran etcxilate mesylates and these
The preparation method of novel crystal forms.
Dabigatran etcxilate mesylate of the present invention can be used either method in the prior art and be prepared.
The first dabigatran etcxilate mesylate novel crystal forms (crystal form 1) provided by the present invention, powder x-ray diffraction
Figure, 2 θ being expressed in degrees have feature 4.44 ± 0.2,18.04 ± 0.2,13.48 ± 0.2,22.02 ± 0.2,17.58 ± 0.2
Diffraction maximum.Its specific powder x-ray diffraction data such as table 1, powder x-ray diffraction figure are shown in Fig. 1.
1 crystal form of table, 1 powder x-ray diffraction figure characteristic peak parameter
1 fusing point of crystal form is 175-179 DEG C.
1 infrared spectrogram of crystal form shows, 3272.98,2956.67,2931.60,2860.24,1731.96,
1645.17、1608.52、1587.31、1537.16、1469.66、1434.94、1371.29、1330.79、1238.21、
1205.43、1163.00、1045.35、829.33、781.12、746.40、557.39、530.39cm-1There is characteristic absorption peak.Its
Infrared spectrogram is shown in Fig. 2
The crystal form is prepared with the following method: being taken dabigatran etcxilate mesylate to be placed in a reaction flask, is added 2~15
The methylene chloride of (w/v, w/v) is measured again, and agitating and heating makes it dissolve, and 2~15 times of amounts (w/v, w/v) are added
Ethyl acetate, stirring, cool down stirring and crystallizing, and filtering is washed with ethyl acetate, it is dry to get.
Specifically: it takes dabigatran etcxilate mesylate to be placed in a reaction flask, the methylene chloride of 2~15 times of amounts (w/v) is added,
It is heated with stirring to reflux, the ethyl acetate of 2~15 times of amounts (w/v) is added, is stirred 5~15 minutes, 5-15 DEG C of stirring analysis is cooled to
It is 1 hour brilliant.Filtering, is washed with ethyl acetate, it is dry to get.
Second of dabigatran etcxilate mesylate novel crystal forms (crystal form 2) provided by the present invention, powder x-ray diffraction
Figure, 2 θ being expressed in degrees 3.78 ± 0.2,23.78 ± 0.2,7.52 ± 0.2,8.18 ± 0.2,17.72 ± 0.2,19.88 ±
0.2 has characteristic diffraction peak.Its specific powder x-ray diffraction data such as table 2, powder x-ray diffraction figure are shown in Fig. 3.
2 crystal form of table, 2 powder x-ray diffraction figure characteristic peak parameter
2 fusing point of crystal form is 129-133 DEG C.
2 infrared spectrogram of crystal form shows, 3307.69,2954.74,2933.53,1737.74,1650.95,
1608.52、1587.31、1573.81、1537.16、1469.66、1434.94、1377.08、1325.01、1240.14、
1209.28、1180.35、1037.63、835.12、779.19、551.60、522.67cm-1There is characteristic absorption peak.Its infrared spectroscopy
Figure is shown in Fig. 4.
The crystal form is prepared with the following method: being taken dabigatran etcxilate mesylate to be placed in a reaction flask, is added 2~15
The methylene chloride of (w/v, w/v) is measured again, and agitating and heating makes it dissolve, and 2~15 times of amounts (w/v, w/v) are added
Acetone, stirring, cool down stirring and crystallizing, filtering, with acetone washing, it is dry to get.
Specifically: it takes dabigatran etcxilate mesylate to be placed in a reaction flask, the methylene chloride of 2~15 times of amounts (w/v) is added,
It is heated with stirring to reflux, the acetone of 2~15 times of amounts (w/v) is added, stirs 5~15 minutes, it is small to cool to 5-15 DEG C of stirring and crystallizing 1
When.Filtering, with acetone washing, it is dry to get.
The third dabigatran etcxilate mesylate novel crystal forms (crystal form 3) provided by the present invention, powder x-ray diffraction
Figure, 2 θ being expressed in degrees have feature to spread out 4.54 ± 0.2,3.76 ± 0.2,22.16 ± 0.2,18.16 ± 0.2,17.76 ± 0.2
Penetrate peak.Its specific powder x-ray diffraction data such as table 3, powder x-ray diffraction figure are shown in Fig. 5.
3 crystal form of table, 3 powder x-ray diffraction figure characteristic peak parameter
3 fusing point of crystal form is 176-183 DEG C.
3 infrared spectrogram of crystal form shows, 3286.48,2956.67,2931.60,2860.24,1731.96,
1650.95、1608.52、1587.31、1537.16、1469.66、1434.94、1371.29、1330.79、1238.21、
1205.43、1163.00、1045.35、831.26、781.12、746.40、557.39、530.39cm-1There is characteristic absorption peak.Its
Infrared spectrogram is shown in Fig. 6
The crystal form is prepared with the following method: being taken dabigatran etcxilate mesylate to be placed in a reaction flask, is added 2~15
The methylene chloride of (w/v, w/v) is measured again, and agitating and heating makes it dissolve, and 2~15 times of amounts (w/v, w/v) are added
Tetrahydrofuran, stirring, cool down stirring and crystallizing, and filtering is washed with tetrahydrofuran, it is dry to get.
Specifically: it takes dabigatran etcxilate mesylate to be placed in a reaction flask, the methylene chloride of 2~15 times of amounts (w/v) is added,
It is heated with stirring to reflux, the tetrahydrofuran of 2~15 times of amounts (w/v) is added, is stirred 5~15 minutes, 5-15 DEG C of stirring analysis is cooled to
It is 1 hour brilliant.Filtering, is washed with tetrahydrofuran, it is dry to get.
4th kind of dabigatran etcxilate mesylate novel crystal forms (crystal form 4) provided by the present invention, powder x-ray diffraction
Figure, 2 θ being expressed in degrees have in 4.46+0.2,21.60+0.2,17.92+0.2,19.96+0.2,19.28+0.2,28.20+0.2
Characteristic diffraction peak.Its specific powder x-ray diffraction data such as table 4, powder x-ray diffraction figure are shown in Fig. 7.
4 crystal form of table, 4 powder x-ray diffraction figure characteristic peak parameter
4 fusing point of crystal form is 183-190 DEG C.
4 infrared spectrogram of crystal form shows, 3309.62,2956.67,2931.60,2860.24,1731.96,
1652.88、1608.52、1589.23、1537.16、1469.66、1377.08、1328.86、1244.00、1207.36、
1166.85、1041.49、833.19、769.54、744.47、551.60、532.32cm-1There is characteristic absorption peak.Its infrared spectroscopy
Figure is shown in Fig. 8
The crystal form is prepared with the following method: dabigatran etcxilate mesylate is dissolved in the ethyl alcohol of 3~20 times (w/v)
Middle heating stirring 10-20 minutes, steam ethyl alcohol, it is dry to get.
It is special the present invention also provides the pharmaceutical composition containing any dabigatran etcxilate mesylate novel crystal forms of the present invention
It is not solid composite medicament.
Pharmaceutically active substance in pharmaceutical composition of the invention is any dabigatran etcxilate mesylate of the present invention
Novel crystal forms, shared weight percent can be 0.01-99.99% in the formulation, remaining is pharmaceutically acceptable carrier.
Currently preferred is solid oral pharmaceutical preparation composition, such as tablet, capsule, granule, pill, dry powder
Agent etc..
Pharmaceutical composition of the invention determines usage and dosage according to the patient's condition when in use, such as can daily 1-3
It is secondary.
Compared to the prior art crystal form of the invention has the advantage that
Compared with the prior art, since methylene chloride is big to dabigatran etcxilate mesylate solubility, refining solvent dosage
Small, another organic solvent, which is added, increases substantially product yield；The mixture of methylene chloride and other organic solvents is to reaching
Than adding the organic impurities solubility in group ester mesylate higher, increase substantially product purity.With method system of the invention
The dabigatran etcxilate mesylate crystal form obtained, purity and stability etc. are superior to the prior art.In addition, crystal form 4 is by ethyl alcohol
Reason, dissolubility is more preferable compared with other crystal forms.4 kinds of crystal forms are stable in illumination, high temperature, high humidity and accelerated test, not bright
Aobvious variation.
Illustrate beneficial effects of the present invention below by way of experimental data:
One, dissolubility test
1,1 dissolubility test of dabigatran etcxilate mesylate crystal form, respectively with ethyl alcohol, water, methylene chloride, acetone, acetic acid
Ethyl ester, tetrahydrofuran, 0.1M HCl and 0.1M NaOH are solvent, measure its solubility, the results are shown in Table 5.
5 dabigatran etcxilate mesylate crystal form of table, 1 solubility test result
2,2 dissolubility test of dabigatran etcxilate mesylate crystal form, respectively with ethyl alcohol, water, methylene chloride, acetone, acetic acid
Ethyl ester, tetrahydrofuran, 0.1M HCl and 0.1M NaOH are solvent, measure its solubility, the results are shown in Table 6.
6 dabigatran etcxilate mesylate crystal form of table, 2 solubility test result
3,3 dissolubility test of dabigatran etcxilate mesylate crystal form, respectively with ethyl alcohol, water, methylene chloride, acetone, acetic acid
Ethyl ester, tetrahydrofuran, 0.1M HCl and 0.1M NaOH are solvent, the results are shown in Table 7.
7 dabigatran etcxilate mesylate crystal form of table, 3 solubility test result
4,4 dissolubility test of dabigatran etcxilate mesylate crystal form, respectively with ethyl alcohol, water, methylene chloride, acetone, acetic acid
Ethyl ester, tetrahydrofuran, 0.1M HCl and 0.1M NaOH are solvent, measure its solubility, the results are shown in Table 8.
8 dabigatran etcxilate mesylate crystal form of table, 4 solubility test result
Two, stability test
1, the stability of dabigatran etcxilate mesylate crystal form 1
1.1 smooth exposure experiments
It irradiates under conditions of taking dabigatran etcxilate mesylate crystal form 1 to be placed in 4500 ± 500Lx of luminous intensity, was taken in 5,10 days
Sample detection, the results are shown in Table 9.
9 dabigatran etcxilate mesylate crystal form of table, 1 bright light test result
| Time (day) | Appearance luster | Loss on drying (%) | Content (%) | Related substance |
| 0 day | White powder | 0.27 | 99.97 | It is not detected |
| 5 days | White powder | 0.28 | 99.92 | It is not detected |
| 10 days | White powder | 0.30 | 99.87 | It is not detected |
1.2 hot test
It takes dabigatran etcxilate mesylate crystal form 1 to set in 60 DEG C of insulating boxs, in 5,10 days sample detections, the results are shown in Table 10.
10 dabigatran etcxilate mesylate crystal form of table, 1 high temperature test result
| Time (day) | Appearance luster | Loss on drying (%) | Content (%) | Related substance |
| 0 day | White powder | 0.27 | 99.97 | It is not detected |
| 5 days | White powder | 0.30 | 99.65 | It is not detected |
| 10 days | White powder | 0.29 | 99.72 | It is not detected |
1.3 high humidity test
Dabigatran etcxilate mesylate crystal form 1 is placed in 25 DEG C of insulating boxs (relative humidity is 75 ± 5%), in 5,10 days
Sample detection.It the results are shown in Table 11.
11 dabigatran etcxilate mesylate crystal form of table, 1 high humidity test result
| Time (day) | Appearance luster | (%) is increased weight in moisture absorption | Content (%) | Related substance |
| 0 day | White powder | 0 | 99.97 | It is not detected |
| 5 days | White powder | 0.39 | 99.77 | It is not detected |
| 10 days | White powder | 0.57 | 99.62 | It is not detected |
1.4 accelerated test
Dabigatran etcxilate mesylate crystal form 1 seal with polyethylene film bag, is placed in 40 ± 2 DEG C of temperature, relative humidity exists
Under the conditions of 75 ± 5%, places 6 months, respectively at the 1st, 2,3,6 month the end of month sample detection, the results are shown in Table 12.
12 dabigatran etcxilate mesylate crystal form of table, 1 accelerated test result
| Test period | Appearance luster | Content (%) | Related substance |
| 0 month | White powder | 99.97 | It is not detected |
| January | White powder | 99.85 | It is not detected |
| 2 months | White powder | 99.74 | It is not detected |
| March | White powder | 99.96 | It is not detected |
| June | White powder | 99.67 | It is not detected |
The result shows that: dabigatran etcxilate mesylate crystal form 1 is steady under strong light irradiation, high temperature, high humidity and accelerated test conditions
Fixed, appearance luster, loss on drying, content and related substance do not have significant change, and slightly moisture absorption is increased weight under conditions of high humidity.
2, the stability of dabigatran etcxilate mesylate crystal form 2
2.1 smooth exposure experiments
It irradiates under conditions of taking dabigatran etcxilate mesylate crystal form 2 to be placed in 4500 ± 500Lx of luminous intensity, was taken in 5,10 days
Sample inspection.It the results are shown in Table 13.
13 dabigatran etcxilate mesylate crystal form of table, 2 object bright light test result
| Time (day) | Appearance luster | Loss on drying (%) | Content (%) | Related substance |
| 0 day | White powder | 0.32 | 99.95 | It is not detected |
| 5 days | White powder | 0.35 | 99.93 | It is not detected |
| 10 days | White powder | 0.29 | 99.90 | It is not detected |
2.2 hot test
It takes 2 object of dabigatran etcxilate mesylate crystal form to set in 60 DEG C of insulating boxs, in 5,10 days sample detections, the results are shown in Table
14。
14 dabigatran etcxilate mesylate crystal form of table, 2 high temperature test result
| Time (day) | Appearance luster | Loss on drying (%) | Content (%) | Related substance |
| 0 day | White powder | 0.35 | 99.95 | It is not detected |
| 5 days | White powder | 0.37 | 99.77 | It is not detected |
| 10 days | White powder | 0.29 | 99.65 | It is not detected |
2.3 high humidity test
Dabigatran etcxilate mesylate crystal form 2 is placed in 25 DEG C of insulating boxs (relative humidity is 75 ± 5%), in 5,10 days
Sample detection.It the results are shown in Table 15.
15 dabigatran etcxilate mesylate crystal form of table, 2 high humility test result
| Time (day) | Appearance luster | (%) is increased weight in moisture absorption | Content (%) | Related substance |
| 0 day | White powder | 0 | 99.95 | It is not detected |
| 5 days | White powder | 0.32 | 99.73 | It is not detected |
| 10 days | White powder | 0.57 | 99.68 | It is not detected |
2.4 accelerated test
Dabigatran etcxilate mesylate crystal form 2 seal with polyethylene film bag, is placed in 40 ± 2 DEG C of temperature, relative humidity exists
Under the conditions of 75 ± 5%, places 6 months, respectively at the 1st, 2,3,6 month the end of month sample detection, the results are shown in Table 16.
16 dabigatran etcxilate mesylate crystal form of table, 2 accelerated test result
The result shows that: dabigatran etcxilate mesylate crystal form 2 is steady under strong light irradiation, high temperature, high humidity and accelerated test conditions
Fixed, appearance luster, loss on drying, content and related substance do not have significant change, and slightly moisture absorption is increased weight under conditions of high humidity.
3, the stability of dabigatran etcxilate mesylate crystal form 3
3.1 smooth exposure experiments
It irradiates under conditions of taking dabigatran etcxilate mesylate crystal form 3 to be placed in 4500 ± 500Lx of luminous intensity, was taken in 5,10 days
Sample detection.It the results are shown in Table 17.
17 dabigatran etcxilate mesylate crystal form of table, 3 bright light test result
| Time (day) | Appearance luster | Loss on drying (%) | Content (%) | Related substance |
| 0 day | White powder | 0.28 | 99.90 | It is not detected |
| 5 days | White powder | 0.30 | 99.91 | It is not detected |
| 10 days | White powder | 0.35 | 99.86 | It is not detected |
3.2 hot test
It takes dabigatran etcxilate mesylate crystal form 3 to set in 60 DEG C of insulating boxs, in 5,10 days sample detections, the results are shown in Table 18.
18 dabigatran etcxilate mesylate crystal form of table, 3 hot test stability result
| Time (day) | Appearance luster | Loss on drying (%) | Content (%) | Related substance |
| 0 day | White powder | 0.28 | 99.90 | It is not detected |
| 5 days | White powder | 0.32 | 99.78 | It is not detected |
| 10 days | White powder | 0.33 | 99.68 | It is not detected |
3.3 high humidity test
Dabigatran etcxilate mesylate crystal form 3 is placed in 25 DEG C of insulating boxs (relative humidity is 75 ± 5%), in 5,10 days
Sample detection.It the results are shown in Table 19.
19 dabigatran etcxilate mesylate crystal form of table, 3 high humility tests stability result
| Time (day) | Appearance luster | (%) is increased weight in moisture absorption | Content (%) | Related substance |
| 0 day | White powder | 0 | 99.90 | It is not detected |
| 5 days | White powder | 0.36 | 99.88 | It is not detected |
| 10 days | White powder | 0.57 | 99.73 | It is not detected |
3.4 accelerated test
Dabigatran etcxilate mesylate crystal form 3 seal with polyethylene film bag, is placed in 40 ± 2 DEG C of temperature, relative humidity exists
Under the conditions of 75 ± 5%, places 6 months, respectively at the 1st, 2,3,6 month the end of month sample detection, the results are shown in Table 20.
20 dabigatran etcxilate mesylate crystal form of table, 3 accelerated test result
| Test period | Appearance luster | Content (%) | Related substance |
| 0 month | White powder | 99.90 | It is not detected |
| January | White powder | 99.89 | It is not detected |
| 2 months | White powder | 99.89 | It is not detected |
| March | White powder | 99.95 | It is not detected |
| June | White powder | 99.73 | It is not detected |
The result shows that: dabigatran etcxilate mesylate crystal form 3 is steady under strong light irradiation, high temperature, high humidity and accelerated test conditions
Fixed, appearance luster, loss on drying, content and related substance do not have significant change, and slightly moisture absorption is increased weight under conditions of high humidity.
4, the stability of dabigatran etcxilate mesylate crystal form 4
4.1 smooth exposure experiments
It irradiates under conditions of taking dabigatran etcxilate mesylate crystal form 4 to be placed in 4500 ± 500Lx of luminous intensity, was taken in 5,10 days
Sample detection.It the results are shown in Table 21.
21 dabigatran etcxilate mesylate crystal form semi-finals light of table irradiates test result
4.2 hot test
It takes dabigatran etcxilate mesylate crystal form 4 to set in 60 DEG C of insulating boxs, in 5,10 days sample detections, the results are shown in Table 22.
22 dabigatran etcxilate mesylate crystal form of table, 4 hot test stability result
| Time (day) | Appearance luster | Loss on drying (%) | Content (%) | Related substance |
| 0 day | White powder | 0.31 | 99.93 | It is not detected |
| 5 days | White powder | 0.33 | 99.89 | It is not detected |
| 10 days | White powder | 0.36 | 99.67 | It is not detected |
4.3 high humidity test
Dabigatran etcxilate mesylate crystal form 4 is placed in 25 DEG C of insulating boxs (relative humidity is 75 ± 5%), in 5,10 days
Sample detection.It the results are shown in Table 23.
23 dabigatran etcxilate mesylate crystal form of table, 4 high humility tests stability result
| Time (day) | Appearance luster | (%) is increased weight in moisture absorption | Content (%) | Related substance |
| 0 day | White powder | 0 | 99.93 | It is not detected |
| 5 days | White powder | 0.39 | 99.86 | It is not detected |
| 10 days | White powder | 0.67 | 99.63 | It is not detected |
4.4 accelerated test
Dabigatran etcxilate mesylate crystal form 4 seal with polyethylene film bag, is placed in 40 ± 2 DEG C of temperature, relative humidity exists
Under the conditions of 75 ± 5%, places 6 months, respectively at the 1st, 2,3,6 month the end of month sample detection, the results are shown in Table 24.
24 dabigatran etcxilate mesylate crystal form of table, 4 accelerated test result
| Test period | Appearance luster | Content (%) | Related substance |
| 0 month | White powder | 99.93 | It is not detected |
| January | White powder | 99.68 | It is not detected |
| 2 months | White powder | 99.91 | It is not detected |
| March | White powder | 99.90 | It is not detected |
| June | White powder | 99.75 | It is not detected |
The result shows that: dabigatran etcxilate mesylate crystal form 4 is steady under strong light irradiation, high temperature, high humidity and accelerated test conditions
Fixed, appearance luster, loss on drying, content and related substance do not have significant change, and slightly moisture absorption is increased weight under conditions of high humidity.
Two kinds of dabigatran etcxilate mesylate crystal forms will be prepared according to method in the prior art below, and will be made with the present invention
Standby crystal form carries out the comparison of stability:
5, the stability of dabigatran etcxilate mesylate crystal form I
Dabigatran etcxilate mesylate crystal form I is prepared according to the method in patent WO2005028468.
5.1 smooth exposure experiments
It irradiates under conditions of taking dabigatran etcxilate mesylate crystal form I to be placed in 4500 ± 500Lx of luminous intensity, was taken in 5,10 days
Sample detection.It the results are shown in Table 25.
25 dabigatran etcxilate mesylate crystal form I bright light test result of table
| Time (day) | Appearance luster | Loss on drying (%) | Content (%) | Related substance (%)) |
| 0 day | White powder | 0.31 | 99.97 | It is not detected |
| 5 days | White powder | 0.35 | 99.95 | It is not detected |
| 10 days | White powder | 0.37 | 99.89 | It is not detected |
5.2 hot test
It takes dabigatran etcxilate mesylate crystal form I to set in 60 DEG C of insulating boxs, in 5,10 days sample detections, the results are shown in Table 26.
26 dabigatran etcxilate mesylate crystal form I hot test stability result of table
| Time (day) | Appearance luster | Loss on drying (%) | Content (%) | Related substance |
| 0 day | White powder | 0.31 | 99.97 | It is not detected |
| 5 days | White powder | 0.35 | 99.90 | 0.02 |
| 10 days | White powder | 0.34 | 99.88 | 0.03 |
5.3 high humidity test
Dabigatran etcxilate mesylate crystal form I is placed in 25 DEG C of insulating boxs (relative humidity is 75 ± 5%), in 5,10 days
Sample detection.It the results are shown in Table 27.
27 dabigatran etcxilate mesylate crystal form I high humility of table tests stability result
| Time (day) | Appearance luster | (%) is increased weight in moisture absorption | Content (%) | Related substance |
| 0 day | White powder | 0 | 99.97 | It is not detected |
| 5 days | White powder | 0.35 | 99.59 | 0.03 |
| 10 days | White powder | 0.57 | 99.88 | 0.06 |
5.4 accelerated test
Dabigatran etcxilate mesylate crystal form I seal with polyethylene film bag, is placed in 40 ± 2 DEG C of temperature, relative humidity exists
Under the conditions of 75 ± 5%, places 6 months, respectively at the 1st, 2,3,6 month the end of month sample detection, the results are shown in Table 28.
28 dabigatran etcxilate mesylate crystal form I accelerated test result of table
The result shows that: dabigatran etcxilate mesylate crystal form I stablizes under the conditions of strong illumination, appearance luster, dry mistake
Weight, content and related substance do not have significant change；And under the conditions of high temperature, high humidity and accelerated test, appearance luster, dry mistake
Weight, content do not have significant change, but related substance is increased slightly, and slightly moisture absorption is increased weight under conditions of high humidity.
6, the stability of dabigatran etcxilate mesylate crystal form III
Dabigatran etcxilate mesylate crystal form III is prepared according to the method in patent WO2012027543.
6.1 smooth exposure experiments
It is irradiated under conditions of taking dabigatran etcxilate mesylate crystal form III to be placed in 4500 ± 500Lx of luminous intensity, in 5,10 days
Sample detection.It the results are shown in Table 29.
29 dabigatran etcxilate mesylate crystal form III bright light test result of table
| Time (day) | Appearance luster | Loss on drying (%) | Content (%) | Related substance |
| 0 day | White powder | 0.29 | 99.92 | It is not detected |
| 5 days | White powder | 0.32 | 99.87 | It is not detected |
| 10 days | White powder | 0.33 | 99.73 | It is not detected |
6.2 hot test
It takes dabigatran etcxilate mesylate crystal form III to set in 60 DEG C of insulating boxs, in 5,10 days sample detections, the results are shown in Table
30。
30 dabigatran etcxilate mesylate crystal form III hot test stability result of table
| Time (day) | Appearance luster | Loss on drying (%) | Content (%) | Related substance |
| 0 day | White powder | 0.29 | 99.92 | It is not detected |
| 5 days | White powder | 0.30 | 99.89 | 0.01 |
| 10 days | White powder | 0.31 | 99.67 | 0.04 |
6.3 high humidity test
Dabigatran etcxilate mesylate crystal form III is placed in 25 DEG C of insulating boxs (relative humidity is 75 ± 5%), in 5,10
Its sample detection.It the results are shown in Table 31.
31 dabigatran etcxilate mesylate crystal form III high humility of table tests stability result
| Time (day) | Appearance luster | (%) is increased weight in moisture absorption | Content (%) | Related substance |
| 0 day | White powder | 0 | 99.92 | It is not detected |
| 5 days | White powder | 0.35 | 99.96 | 0.02 |
| 10 days | White powder | 0.57 | 99.73 | 0.05 |
6.4 accelerated test
Dabigatran etcxilate mesylate crystal form III seal with polyethylene film bag, is placed in 40 ± 2 DEG C of temperature, relative humidity
Under the conditions of 75 ± 5%, places 6 months, respectively at the 1st, 2,3,6 month the end of month sample detection, the results are shown in Table 32.
32 dabigatran etcxilate mesylate crystal form III accelerated test result of table
| Test period | Appearance luster | Content (%) | Related substance |
| 0 month | White powder | 99.92 | It is not detected |
| January | White powder | 99.78 | 0.01 |
| 2 months | White powder | 99.90 | 0.01 |
| March | White powder | 99.94 | 0.02 |
| June | White powder | 99.83 | 0.07 |
The result shows that: dabigatran etcxilate mesylate crystal form III stablizes under the conditions of strong illumination, appearance luster, drying
Weightless, content and related substance do not have significant change；And under the conditions of high temperature, high humidity and accelerated test, appearance luster, dry mistake
Weight, content do not have significant change, but related substance is increased slightly, and slightly moisture absorption is increased weight under conditions of high humidity.
By the above stability test it is found that the dabigatran etcxilate mesylate crystal form tool being prepared by the method for the invention
Have the advantages that stability is good, no matter strong illumination, high temperature, high humidity and accelerated test condition it is all stable, related substance has no increase.
And the crystal form I and crystal form III that the prior art obtains related substance under the conditions of high temperature, high humidity and accelerated test are increased slightly.
Detailed description of the invention
Fig. 1,1 powder x-ray diffraction figure of crystal form
Fig. 2,1 infrared spectrogram of crystal form
Fig. 3,2 powder x-ray diffraction figure of crystal form
Fig. 4,2 infrared spectrogram of crystal form
Fig. 5,3 powder x-ray diffraction figure of crystal form
Fig. 6,3 infrared spectrogram of crystal form
Fig. 7,4 powder x-ray diffraction figure of crystal form
Fig. 8,4 infrared spectrogram of crystal form
Specific embodiment
The present invention is further illustrated below by embodiment.Method in the embodiment of the present invention is only used for illustrating
The present invention, rather than limiting the invention.
The preparation of 1 dabigatran etcxilate mesylate crystal form 1 of embodiment
It takes dabigatran etcxilate mesylate 20g to be placed in a reaction flask, methylene chloride 40ml is added, being stirred and heated to keeps its molten
Ethyl acetate 40ml is added in solution, stirs 15 minutes, cools to 10-15 DEG C of stirring and crystallizing 1 hour.Filtering, ethyl acetate washing,
It is dry, obtain 1 18.4g of dabigatran etcxilate mesylate crystal form, yield 92%.
The preparation of 2 dabigatran etcxilate mesylate crystal form 1 of embodiment
It taking dabigatran etcxilate mesylate 5g to be placed in a reaction flask, methylene chloride 75ml is added, agitating and heating makes it dissolve,
Ethyl acetate 75ml is added, stirs 15 minutes, cools to 10-15 DEG C of stirring and crystallizing 1.5 hours.Filtering, ethyl acetate washing, does
It is dry, obtain 1 4.1g of dabigatran etcxilate mesylate crystal form, yield 82.0%.
The preparation of 3 dabigatran etcxilate mesylate crystal form 1 of embodiment
It takes dabigatran etcxilate mesylate 10g to be placed in a reaction flask, methylene chloride 80ml is added, agitating and heating keeps its molten
Ethyl acetate 100ml is added in solution, stirs 10 minutes, cools to 10-15 DEG C of stirring and crystallizing 1 hour.Filtering, ethyl acetate washing,
It is dry, obtain 1 9.50g of dabigatran etcxilate mesylate crystal form, yield 95.0%.
The preparation of 4 dabigatran etcxilate mesylate crystal form 2 of embodiment
It taking dabigatran etcxilate mesylate 5g to be placed in a reaction flask, methylene chloride 10ml is added, agitating and heating makes it dissolve,
Acetone 10ml is added, stirs 5 minutes, cools to 10-15 DEG C of stirring and crystallizing 1.5 hours.Filtering, acetone washing is dry, obtain up to than
Add crowd 2 4.5g of ester Mesylate Form, yield 90.0%.
The preparation of 5 dabigatran etcxilate mesylate crystal form 2 of embodiment
It takes dabigatran etcxilate mesylate 20g to be placed in a reaction flask, methylene chloride 300m is added, agitating and heating keeps its molten
Acetone 300ml is added in solution, stirs 15 minutes, cools to 10-15 DEG C of stirring and crystallizing 1 hour.Filtering, acetone washing is dry, obtains
2 18.7g of dabigatran etcxilate mesylate crystal form, yield 93.5%.
The preparation of 6 dabigatran etcxilate mesylate crystal form 2 of embodiment
It takes dabigatran etcxilate mesylate 10g to be placed in a reaction flask, methylene chloride 100ml is added, agitating and heating keeps its molten
Acetone 150ml is added in solution, stirs 15 minutes, cools to 10-15 DEG C of stirring and crystallizing 1 hour.Filtering, acetone washing is dry, obtains
2 9.3g of dabigatran etcxilate mesylate crystal form, yield 93.0%.
The preparation of 7 dabigatran etcxilate mesylate crystal form 3 of embodiment
It takes dabigatran etcxilate mesylate 20g to be placed in a reaction flask, methylene chloride 40ml is added, agitating and heating keeps its molten
Tetrahydrofuran 40ml is added in solution, stirs 15 minutes, cools to 10-15 DEG C of stirring and crystallizing 0.5 hour.Filtering, tetrahydrofuran are washed
It washs, it is dry, obtain 3 18g of dabigatran etcxilate mesylate crystal form, yield 90%.
The preparation of 8 dabigatran etcxilate mesylate crystal form 3 of embodiment
It takes dabigatran etcxilate mesylate 20g to be placed in a reaction flask, methylene chloride 300ml is added, agitating and heating keeps its molten
Tetrahydrofuran 300ml is added in solution, stirs 15 minutes, cools to 10-15 DEG C of stirring and crystallizing 1.5 hours.Filtering, tetrahydrofuran are washed
It washs, it is dry, obtain 3 17.2g of dabigatran etcxilate mesylate crystal form, yield 86%.
The preparation of 9 dabigatran etcxilate mesylate crystal form 3 of embodiment
It takes dabigatran etcxilate mesylate 10g to be placed in a reaction flask, methylene chloride 80ml is added, agitating and heating keeps its molten
Tetrahydrofuran 100ml is added in solution, stirs 15 minutes, cools to 10-15 DEG C of stirring and crystallizing 1 hour.Filtering, tetrahydrofuran washing,
It is dry, obtain 3 9.3g of dabigatran etcxilate mesylate crystal form, yield 93%.
The preparation of 10 dabigatran etcxilate mesylate crystal form 4 of embodiment
It taking dabigatran etcxilate mesylate 5g to be placed in a reaction flask, ethyl alcohol 15ml is added, agitating and heating dissolves it all,
Decompression steams ethyl alcohol, dry, obtains 4 4.9g of dabigatran etcxilate mesylate crystal form, yield 98%.
The preparation of 11 dabigatran etcxilate mesylate crystal form 4 of embodiment
It takes dabigatran etcxilate mesylate 20g to be placed in a reaction flask, ethyl alcohol 400ml is added, agitating and heating keeps it all molten
Solution, decompression steam ethyl alcohol, dry, obtain 4 19.2g of dabigatran etcxilate mesylate crystal form, yield 97%.
The preparation of capsule medicine composition of the embodiment 12 containing dabigatran etcxilate mesylate crystal form 1
1, prescription
Specification 75mg
2, the preparation method of capsule
Dabigatran etcxilate mesylate crystal form 1, lactose, microcrystalline cellulose, cornstarch, sodium carboxymethyl starch are added efficient
It is mixed in wet granulator, 2% polyvinylpyrrolidone ethanol solution (80%) granulation is added.Wet granular is done in a fluidized bed
It is dry, through 18 mesh sieves.It is added in dry particl after magnesium stearate properly mixes and is packed into capsule.
The preparation of capsule medicine composition of the embodiment 13 containing dabigatran etcxilate mesylate crystal form 2
1, prescription
Specification 110mg
2, the preparation method of capsule
Dabigatran etcxilate mesylate crystal form 2, lactose, microcrystalline cellulose, cornstarch, sodium carboxymethyl starch are added efficient
It is mixed in wet granulator, 2% polyvinylpyrrolidone ethanol solution (80%) granulation is added.Wet granular is done in a fluidized bed
It is dry, through 18 mesh sieves.It is added in dry particl after magnesium stearate properly mixes and is packed into capsule.
The preparation of capsule medicine composition of the embodiment 14 containing dabigatran etcxilate mesylate crystal form 3
1, prescription
Specification 110mg
2, the preparation method of capsule
Dabigatran etcxilate mesylate crystal form 3, lactose, microcrystalline cellulose, cornstarch, sodium carboxymethyl starch are added efficient
It is mixed in wet granulator, 2% polyvinylpyrrolidone ethanol solution (80%) granulation is added.Wet granular is done in a fluidized bed
It is dry, through 18 mesh sieves.It is added in dry particl after magnesium stearate properly mixes and is packed into capsule.
The preparation of capsule medicine composition of the embodiment 15 containing dabigatran etcxilate mesylate crystal form 4
1, prescription
Specification 150mg
2, the preparation method of capsule
Dabigatran etcxilate mesylate crystal form 4, lactose, microcrystalline cellulose, cornstarch, sodium carboxymethyl starch are added efficient
It is mixed in wet granulator, 2% polyvinylpyrrolidone ethanol solution (80%) granulation is added.Wet granular is done in a fluidized bed
It is dry, through 18 mesh sieves.It is added in dry particl after magnesium stearate properly mixes and is packed into capsule.
Claims (3)
1. a kind of novel crystal forms of dabigatran etcxilate mesylate, which is characterized in that its powder x-ray diffraction figure is expressed in degrees
2 θ have feature diffraction 3.78 ± 0.2,23.78 ± 0.2,7.52 ± 0.2,8.18 ± 0.2,17.72 ± 0.2,19.88 ± 0.2
Peak；Infrared spectrogram 3307.69,2954.74,2933.53,1737.74,1650.95,1608.52,1587.31,
1573.81、1537.16、1469.66、1434.94、1377.08、1325.01、1240.14、1209.28、1180.35、
1037.63、835.12、779.19、551.60、522.67cm-1There is characteristic absorption peak；Fusing point is 129-133 DEG C.
2. the preparation method of the novel crystal forms of dabigatran etcxilate mesylate as described in claim 1, which is characterized in that will up to than
Add group ester mesylate to be placed in a reaction flask, the methylene chloride of 2~15 times of amounts (w/v) is added, agitating and heating makes it dissolve, then
Add the acetone of 2~15 times of amounts (w/v), stir, cool down stirring and crystallizing, filtering, is added acetone washing, it is dry to get.
3. the pharmaceutical composition containing dabigatran etcxilate mesylate crystal form described in claim 1.
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| CN201810787722.4A Pending CN108947966A (en) | 2014-04-04 | 2014-04-04 | Dabigatran etcxilate mesylate novel crystal forms and preparation method thereof |
| CN201410135794.2A Pending CN104974137A (en) | 2014-04-04 | 2014-04-04 | Dabigatran etexilate mesylate new crystal form and preparation method thereof |
| CN201810787701.2A Pending CN108864049A (en) | 2014-04-04 | 2014-04-04 | Dabigatran etcxilate mesylate novel crystal forms and preparation method thereof |
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| CN201810787701.2A Pending CN108864049A (en) | 2014-04-04 | 2014-04-04 | Dabigatran etcxilate mesylate novel crystal forms and preparation method thereof |
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| CN107778291A (en) * | 2016-08-31 | 2018-03-09 | 亚宝药业集团股份有限公司 | A kind of preparation method of dabigatran etexilate methanesulfonate crystal formation II |
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| CN1845917A (en) * | 2003-08-29 | 2006-10-11 | 贝林格尔·英格海姆国际有限公司 | 3-[(2-{[4-(Hexyloxycarbonylamino-imino-methyl)-phenylamino]-methyl}-1-methyl-1 H-benzimidazole-5-carbonyl)-pyridine -2-yl-amino]-propionate ethyl-mesylate and its use as medicine |
| WO2012027543A1 (en) * | 2010-08-25 | 2012-03-01 | Teva Pharmaceuticals Usa, Inc. | Solid state forms of dabigatran etexilate, dabigatran etexilate mesylate and processes for preparation thereof |
| CN102391250A (en) * | 2011-08-29 | 2012-03-28 | 石药集团欧意药业有限公司 | Dabigatran compound and preparation method and medicinal composition thereof |
| WO2012077136A2 (en) * | 2010-12-06 | 2012-06-14 | Msn Laboratories Limited | Process for the preparation of benzimidazole derivatives and its salts |
| CN102858762A (en) * | 2010-02-02 | 2013-01-02 | 埃吉斯药物股份公开有限公司 | Novel salts for the preparation of pharmaceutical compositions |
| WO2013124385A2 (en) * | 2012-02-23 | 2013-08-29 | Esteve Química, S.A. | Solid forms of dabigatran etexilate mesylate and processes for their preparation |
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| DE102005020002A1 (en) * | 2005-04-27 | 2006-11-02 | Boehringer Ingelheim Pharma Gmbh & Co. Kg | Physiologically acceptable salts of 3 - [(2 - {[4- (hexyloxycarbonylamino-imino-methyl) -phenyl-amino] -methyl} -1-methyl-1H-benzimidazole-5-carbonyl) -pyridin-2-yl-amino] - propionate |
| DE102005025728A1 (en) * | 2005-06-04 | 2006-12-07 | Boehringer Ingelheim Pharma Gmbh & Co. Kg | Polymorphs of 3 - [(2 - {[4- (hexyloxycarbonylamino-imino-methyl) -phenyl-amino] -methyl} -1-methyl-1H-benzimidazole-5-carbonyl) -pyridin-2-yl-amino] -propionic acid ethyl ester |
| EP2074112A1 (en) * | 2006-10-10 | 2009-07-01 | Boehringer Ingelheim International GmbH | Physiologically acceptable salts of 3-[(2-{[4-(hexyloxycarbonylamino-imino-methyl)-phenylamino]-methyl}-1-methyl-1h-benzimidazol-5-carbonyl)-pyridin-2-yl-amino]-propionic acid ethyl ester |
| EP2522662A1 (en) * | 2011-05-11 | 2012-11-14 | Medichem, S.A. | Dabigatran etexilate and related substances, processes and compositions, and use of the substances as reference standards and markers |
| WO2014009966A2 (en) * | 2012-07-12 | 2014-01-16 | Rao Davuluri Ramamohan | An improved process for the preparation of dabigatran etexilate mesylate and its intermediates thereof |
| WO2014041559A2 (en) * | 2012-08-27 | 2014-03-20 | Glenmark Pharmaceuticals Limited; Glenmark Generics Limited | Process for the preparation of dabigatran etexilate and intermediates thereof |
| CA2886094A1 (en) * | 2012-09-28 | 2014-04-03 | Ranbaxy Laboratories Limited | Process for the preparation of dabigatran etexilate or pharmaceutically acceptable salt thereof |
| CN103288800B (en) * | 2013-06-03 | 2016-03-30 | 华仁药业股份有限公司 | Dabigatran etcxilate benzene sulfonate and its preparation method and application |
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2014
- 2014-04-04 CN CN201810787722.4A patent/CN108947966A/en active Pending
- 2014-04-04 CN CN201410135794.2A patent/CN104974137A/en active Pending
- 2014-04-04 CN CN201810787701.2A patent/CN108864049A/en active Pending
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2015
- 2015-03-24 WO PCT/CN2015/074956 patent/WO2015149638A1/en active Application Filing
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| CN1845917A (en) * | 2003-08-29 | 2006-10-11 | 贝林格尔·英格海姆国际有限公司 | 3-[(2-{[4-(Hexyloxycarbonylamino-imino-methyl)-phenylamino]-methyl}-1-methyl-1 H-benzimidazole-5-carbonyl)-pyridine -2-yl-amino]-propionate ethyl-mesylate and its use as medicine |
| CN102858762A (en) * | 2010-02-02 | 2013-01-02 | 埃吉斯药物股份公开有限公司 | Novel salts for the preparation of pharmaceutical compositions |
| WO2012027543A1 (en) * | 2010-08-25 | 2012-03-01 | Teva Pharmaceuticals Usa, Inc. | Solid state forms of dabigatran etexilate, dabigatran etexilate mesylate and processes for preparation thereof |
| WO2012077136A2 (en) * | 2010-12-06 | 2012-06-14 | Msn Laboratories Limited | Process for the preparation of benzimidazole derivatives and its salts |
| CN102391250A (en) * | 2011-08-29 | 2012-03-28 | 石药集团欧意药业有限公司 | Dabigatran compound and preparation method and medicinal composition thereof |
| WO2013124385A2 (en) * | 2012-02-23 | 2013-08-29 | Esteve Química, S.A. | Solid forms of dabigatran etexilate mesylate and processes for their preparation |
Also Published As
| Publication number | Publication date |
|---|---|
| WO2015149638A1 (en) | 2015-10-08 |
| CN108864049A (en) | 2018-11-23 |
| CN104974137A (en) | 2015-10-14 |
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Application publication date: 20181207 |