CN104974137A - New crystal forms of dabigatran etexilate mesylate and preparation method thereof - Google Patents

New crystal forms of dabigatran etexilate mesylate and preparation method thereof Download PDF

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CN104974137A
CN104974137A CN201410135794.2A CN201410135794A CN104974137A CN 104974137 A CN104974137 A CN 104974137A CN 201410135794 A CN201410135794 A CN 201410135794A CN 104974137 A CN104974137 A CN 104974137A
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dabigatran etcxilate
etcxilate mesylate
add
white powder
detect
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刘文铮
高禹哲
王国成
刘金平
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Jiangsu Tasly Diyi Pharmaceutical Co Ltd
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Jiangsu Tasly Diyi Pharmaceutical Co Ltd
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Priority to CN201810787701.2A priority Critical patent/CN108864049A/en
Priority to CN201810787722.4A priority patent/CN108947966A/en
Priority to CN201410135794.2A priority patent/CN104974137A/en
Priority to PCT/CN2015/074956 priority patent/WO2015149638A1/en
Publication of CN104974137A publication Critical patent/CN104974137A/en
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    • 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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Abstract

The invention provides four new crystal forms of dabigatran etexilate mesylate and a preparation method of the four new crystal forms. The preparation method comprises the following steps: dissolving dabigatran etexilate mesylate in dichloromethane; then adding a second organic solvent for re-crystallizing; and further dissolving dabigatran etexilate mesylate in ethanol, heating for dissolving, and distilling off ethanol.

Description

Dabigatran etcxilate mesylate new crystal and preparation method thereof
Technical field
The invention belongs to pharmaceutical field, relate to the crystal formation of medical compounds, particularly a kind of new crystal formation and preparation method thereof of anticoagulation medicine dabigatran etcxilate mesylate.
Background technology
Dabigatran etcxilate mesylate (Dabigatran etexilate mesylate) is a kind of novel direct thrombin inhibitor, is the prodrug of dabigatran, belongs to the thrombin inhibitors of non-peptide class.Oral after gastrointestinal absorption, be converted into the dabigatran with direct anticoagulant active in vivo.Dabigatran is incorporated into the scleroproein specific binding site of zymoplasm, stops Fibrinogen to be cracked into scleroproein, thus has blocked final step and the thrombosis of blood coagulation network.Dabigatran can dissociate from scleroproein zymoplasm combination, plays reversible anticoagulation.Its chemical structure is as follows:
Due to the pharmacologically active of dabigatran etcxilate mesylate uniqueness, researchist has carried out extensive research to its crystal formation, new crystal formation is constantly found, such as, disclose the preparation method of dabigatran etcxilate mesylate 2 kinds of crystal formations in WO2005028468: crystal formation I and crystal form II all adopt acetone to be solvent, just recrystallization temperature is different, and crystal form II also can be obtained by the method adding crystal seed.Disclose the preparation method of dabigatran etcxilate mesylate a kind of crystal formation in WO2011110876, the method take ethyl acetate as solvent, obtained form IV.
The preparation method of dabigatran etcxilate mesylate 8 kinds of crystal formations is disclosed in WO2012027543, adopt respectively and dabigatran etcxilate mesylate is placed 30 days (crystal form A) in the environment of relative humidity 100%, with water treatment (crystal form B), with cymene recrystallization (crystal C), with dimethyl sulfoxide (DMSO) recrystallization (crystal formation D), 1 month (crystal formation G) is placed in normal heptane environment, with pyridine recrystallization (crystal formation H), in 2-methyltetrahydrofuran, crystallization is (or with pimelinketone, amylalcohol, methyl aceto acetate, diglyme recrystallization) (crystal formation I), in 2-butanols, crystallization is (or with ethanol and 2-methyltetrahydrofuran, ethanol and ethyl acetate, butanols and ethyl acetate, ethanol and isobutyl ketone recrystallization) (crystal form II I) etc.Above method Problems existing there is potential safety hazard by acetone industrial production, making solvent with cymene, dimethyl sulfoxide (DMSO), normal heptane, pyridine, 2-methyltetrahydrofuran, methyl aceto acetate, 2-butanols etc., all to there is production cost high, solvent easily residual, be not the problem of suitability for industrialized production Conventional solvents.Therefore be necessary to find a kind of crystal formation that is stable, that easily prepare as medicinal application.
Summary of the invention
In order to solve the problem, the invention provides the crystal formation that four kinds of dabigatran etcxilate mesylates are new, and the preparation method of these new crystal.
Dabigatran etcxilate mesylate of the present invention can adopt either method of the prior art to be prepared.
The first dabigatran etcxilate mesylate new crystal (crystal formation 1) provided by the present invention, its powder x-ray diffraction figure, has characteristic diffraction peak to spend 2 θ represented 4.44 ± 0.2,18.04 ± 0.2,13.48 ± 0.2,22.02 ± 0.2,17.58 ± 0.2.Its concrete powder x-ray diffraction data are as table 1, and its powder x-ray diffraction figure is shown in Fig. 1.
Table 1 crystal formation 1 powder x-ray diffraction figure characteristic peak parameter
Sequence number 2θ D value Relative intensity I/I 0
1 4.44 19.8851 100
2 8.94 9.8834 11
3 9.54 9.2631 4
4 10.96 8.0659 8
5 13.48 6.5632 19
6 13.98 6.3295 5
7 15.96 5.5485 4
8 16.48 5.3746 5
9 17.58 5.0407 15
10 18.04 4.9132 21
11 19.94 4.4491 10
12 21.08 4.2110 11
13 22.02 4.0333 19
14 22.82 3.8937 14
15 25.28 3.5201 7
16 26.80 3.3238 12
17 29.22 3.0538 6
18 32.00 2.7945 6
Crystal formation 1 fusing point is 175-179 DEG C.
Crystal formation 1 infrared spectrogram 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 charateristic avsorption band.Its infrared spectrogram is shown in Fig. 2.
This crystal formation is adopted and is prepared with the following method: get dabigatran etcxilate mesylate and be placed in reaction flask, add the methylene dichloride of 2 ~ 15 times amount (weightmeasurement ratio, w/v), stirring heating makes it dissolve, add 2 ~ 15 times amount (weightmeasurement ratios, w/v) ethyl acetate, stirs, cooling stirring and crystallizing, filter, with ethyl acetate washing, dry, to obtain final product.
Be specially: get dabigatran etcxilate mesylate and be placed in reaction flask, add the methylene dichloride of 2 ~ 15 times amount (w/v), be heated with stirring to backflow, add the ethyl acetate of 2 ~ 15 times amount (w/v), stir 5 ~ 15 minutes, cool to 5-15 DEG C of stirring and crystallizing 1 hour.Filter, with ethyl acetate washing, dry, to obtain final product.
The second dabigatran etcxilate mesylate new crystal (crystal formation 2) provided by the present invention, its powder x-ray diffraction figure, has characteristic diffraction peak to spend 2 θ represented 3.78 ± 0.2,23.78 ± 0.2,7.52 ± 0.2,8.18 ± 0.2,17.72 ± 0.2,19.88 ± 0.2.Its concrete powder x-ray diffraction data are as table 2, and its powder x-ray diffraction figure is shown in Fig. 3.
Table 2 crystal formation 2 powder x-ray diffraction figure characteristic peak parameter
Sequence number 2θ D value Relative intensity I/I 0
1 3.78 23.3555 100
2 7.52 11.7462 5
3 8.18 10.7998 5
4 8.70 10.1555 3
5 9.28 9.5220 2
6 10.60 8.3390 2
7 11.26 7.8517 1
8 12.96 6.8253 1
9 14.46 6.1205 3
10 14.98 5.9092 1
11 16.46 5.3810 4
12 17.16 5.1631 3
13 17.72 5.0012 5
14 18.66 4.7513 1
15 19.30 4.5952 2
16 19.88 4.4624 5
17 20.28 4.3753 3
18 21.14 4.1992 5
19 22.10 4.0189 3
20 23.00 3.8636 2
21 23.78 3.7386 6
22 24.42 3.6421 4
23 25.18 3.5338 1
24 26.48 3.3632 2
25 27.42 3.2500 2
26 29.24 3.0517 2
Crystal formation 2 fusing point is 129-133 DEG C.
Crystal formation 2 infrared spectrogram 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 charateristic avsorption band.Its infrared spectrogram is shown in Fig. 4.
This crystal formation is adopted and is prepared with the following method: get dabigatran etcxilate mesylate and be placed in reaction flask, add the methylene dichloride of 2 ~ 15 times amount (weightmeasurement ratio, w/v), stirring heating makes it dissolve, add 2 ~ 15 times amount (weightmeasurement ratios, w/v) acetone, stirs, cooling stirring and crystallizing, filter, with washing with acetone, dry, to obtain final product.
Be specially: get dabigatran etcxilate mesylate and be placed in reaction flask, add the methylene dichloride of 2 ~ 15 times amount (w/v), be heated with stirring to backflow, add the acetone of 2 ~ 15 times amount (w/v), stir 5 ~ 15 minutes, cool to 5-15 DEG C of stirring and crystallizing 1 hour.Filter, with washing with acetone, dry, to obtain final product.
The third dabigatran etcxilate mesylate new crystal (crystal formation 3) provided by the present invention, its powder x-ray diffraction figure, has characteristic diffraction peak to spend 2 θ represented 4.54 ± 0.2,3.76 ± 0.2,22.16 ± 0.2,18.16 ± 0.2,17.76 ± 0.2.Its concrete powder x-ray diffraction data are as table 3, and its powder x-ray diffraction figure is shown in Fig. 5.
Table 3 crystal formation 3 powder x-ray diffraction figure characteristic peak parameter
Sequence number 2θ D value Relative intensity I/I 0
1 3.76 23.4797 62
2 4.54 19.4473 100
3 7.48 11.8089 5
4 8.18 10.7998 6
5 9.06 9.7527 11
6 9.34 9.4610 9
7 9.68 9.1294 6
8 10.60 8.3390 7
9 11.06 7.9932 14
10 13.58 6.5151 18
11 14.46 6.1205 10
12 16.38 5.4071 12
13 17.76 4.9900 28
14 18.16 4.8810 30
15 18.74 4.7312 13
16 19.90 4.4579 23
17 21.12 4.2031 22
18 22.16 4.0081 32
19 22.96 3.8703 26
20 23.82 3.7324 17
21 24.38 3.6480 16
22 25.18 3.5338 14
23 26.46 3.3657 16
24 26.92 3.3092 16
25 28.28 3.1531 13
26 29.28 3.0477 12
Crystal formation 3 fusing point is 176-183 DEG C.
Crystal formation 3 infrared spectrogram 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 charateristic avsorption band.Its infrared spectrogram is shown in Fig. 6.
This crystal formation is adopted and is prepared with the following method: get dabigatran etcxilate mesylate and be placed in reaction flask, add the methylene dichloride of 2 ~ 15 times amount (weightmeasurement ratio, w/v), stirring heating makes it dissolve, add 2 ~ 15 times amount (weightmeasurement ratios, w/v) tetrahydrofuran (THF), stirs, cooling stirring and crystallizing, filter, with tetrahydrofuran (THF) washing, dry, to obtain final product.
Be specially: get dabigatran etcxilate mesylate and be placed in reaction flask, add the methylene dichloride of 2 ~ 15 times amount (w/v), be heated with stirring to backflow, add the tetrahydrofuran (THF) of 2 ~ 15 times amount (w/v), stir 5 ~ 15 minutes, cool to 5-15 DEG C of stirring and crystallizing 1 hour.Filter, with tetrahydrofuran (THF) washing, dry, to obtain final product.
4th kind of dabigatran etcxilate mesylate new crystal (crystal formation 4) provided by the present invention, its powder x-ray diffraction figure, has characteristic diffraction peak to spend 2 θ represented 4.46 ± 0.2,21.60 ± 0.2,17.92 ± 0.2,19.96 ± 0.2,19.28 ± 0.2,28.20 ± 0.2.Its concrete powder x-ray diffraction data are as table 4, and its powder x-ray diffraction figure is shown in Fig. 7.
Table 4 crystal formation 4 powder x-ray diffraction figure characteristic peak parameter
Sequence number 2θ D value Relative intensity I/I 0
1 4.46 19.7960 100
2 8.78 10.0631 8
3 9.78 9.0363 6
4 11.28 7.8378 7
5 12.44 7.1094 16
6 13.58 6.5151 8
7 13.98 6.3295 13
8 15.20 5.8241 12
9 16.06 5.5142 15
10 16.56 5.3488 11
11 17.38 5.0982 9
12 17.92 4.9458 39
13 18.54 4.7818 22
14 19.28 4.5999 33
15 19.96 4.4447 38
16 21.60 4.1108 43
17 22.14 4.0117 18
18 22.58 3.9345 24
19 23.46 3.7889 24
20 23.84 3.7293 24
21 24.48 3.6333 13
22 25.34 3.5119 18
23 26.04 3.4190 13
24 26.60 3.3483 14
25 26.90 3.3117 14
26 27.40 3.2524 17
27 28.20 3.1619 33
28 28.64 3.1143 18
29 36.74 2.4442 8
Crystal formation 4 fusing point is 183-190 DEG C.
Crystal formation 4 infrared spectrogram 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 charateristic avsorption band.Its infrared spectrogram is shown in Fig. 8.
This crystal formation is adopted and is prepared with the following method: dabigatran etcxilate mesylate is dissolved in heated and stirred 10-20 minute in the ethanol of 3 ~ 20 times (w/v), steams ethanol, dry, to obtain final product.
The present invention also provides pharmaceutical composition, particularly solid composite medicament containing any one dabigatran etcxilate mesylate new crystal of the present invention.
Pharmaceutically active substance in pharmaceutical composition of the present invention is any one dabigatran etcxilate mesylate new crystal of the present invention, its in the formulation shared weight percent can be 0.01-99.99%, all the other are medicine acceptable carrier.
The present invention is solid port drug administration preparation compositions preferably, as tablet, and capsule, granule, pill, dry powder doses etc.
Pharmaceutical composition of the present invention in use according to the situation determination usage and dosage of patient, as can daily 1-3 time.
Compared to the prior art crystal formation of the present invention has the following advantages:
Compared with the prior art, because methylene dichloride is large to dabigatran etcxilate mesylate solubleness, refining solvent consumption is little, adds another kind of organic solvent and product yield is increased substantially; The mixture of methylene dichloride and other organic solvent is higher to the dissolve organic contaminants degree in dabigatran etcxilate mesylate, and product purity is increased substantially.With the dabigatran etcxilate Mesylate Form that method of the present invention is obtained, purity and stability etc. are all better than prior art.In addition, crystal formation 4 is through Ethanol Treatment, and solvability is better compared with other crystal formation.4 kinds of crystal formations are all stable in illumination, high temperature, high humidity and accelerated test, do not have considerable change.
Below by way of experimental data, beneficial effect of the present invention is described:
One, dissolubility test
1, dabigatran etcxilate Mesylate Form 1 dissolubility test, respectively with ethanol, water, methylene dichloride, acetone, ethyl acetate, tetrahydrofuran (THF), 0.1M HCl and 0.1M NaOH for solvent, measure its solubleness, the results are shown in Table 5.
Table 5 dabigatran etcxilate Mesylate Form 1 dissolubility test result
2, dabigatran etcxilate Mesylate Form 2 dissolubility test, respectively with ethanol, water, methylene dichloride, acetone, ethyl acetate, tetrahydrofuran (THF), 0.1M HCl and 0.1M NaOH for solvent, measure its solubleness, the results are shown in Table 6.
Table 6 dabigatran etcxilate Mesylate Form 2 dissolubility test result
3, dabigatran etcxilate Mesylate Form 3 dissolubility test, respectively with ethanol, water, methylene dichloride, acetone, ethyl acetate, tetrahydrofuran (THF), 0.1M HCl and 0.1M NaOH for solvent, the results are shown in Table 7.
Table 7 dabigatran etcxilate Mesylate Form 3 dissolubility test result
4, dabigatran etcxilate Mesylate Form 4 dissolubility test, respectively with ethanol, water, methylene dichloride, acetone, ethyl acetate, tetrahydrofuran (THF), 0.1M HCl and 0.1M NaOH for solvent, measure its solubleness, the results are shown in Table 8.
Table 8 dabigatran etcxilate Mesylate Form 4 dissolubility test result
Two, stability test
1, the stability of dabigatran etcxilate Mesylate Form 1
1.1 rayed tests
Get under dabigatran etcxilate Mesylate Form 1 is placed in the condition of light intensity 4500 ± 500Lx and irradiate, detect in sampling in 5,10 days, the results are shown in Table 9.
Table 9 dabigatran etcxilate Mesylate Form 1 strong illumination test-results
Time (my god) Appearance luster Weight loss on drying (%) Content (%) Related substance
0 day White powder 0.27 99.97 Do not detect
5 days White powder 0.28 99.92 Do not detect
10 days White powder 0.30 99.87 Do not detect
1.2 high temperature test
Getting dabigatran etcxilate Mesylate Form 1 puts in 60 DEG C of thermostat containers, detects, the results are shown in Table 10 in sampling in 5,10 days.
Table 10 dabigatran etcxilate Mesylate Form 1 high temperature test result
Time (my god) Appearance luster Weight loss on drying (%) Content (%) Related substance
0 day White powder 0.27 99.97 Do not detect
5 days White powder 0.30 99.65 Do not detect
10 days White powder 0.29 99.72 Do not detect
1.3 high wet tests
Dabigatran etcxilate Mesylate Form 1 is placed in 25 DEG C of thermostat containers (relative humidity is 75 ± 5%), detects in sampling in 5,10 days.The results are shown in Table 11.
Table 11 dabigatran etcxilate Mesylate Form 1 high humidity test-results
Time (my god) Appearance luster Moisture absorption weightening finish (%) Content (%) Related substance
0 day White powder 0 99.97 Do not detect
5 days White powder 0.39 99.77 Do not detect
10 days White powder 0.57 99.62 Do not detect
1.4 accelerated test
Dabigatran etcxilate Mesylate Form 1 polythene film bag sealing, be placed in temperature 40 ± 2 DEG C, relative humidity, under 75 ± 5% conditions, is placed 6 months, respectively at the 1st, sampling detection at 2,3,6 months the end of month, the results are shown in Table 12.
Table 12 dabigatran etcxilate Mesylate Form 1 accelerated test result
Test period Appearance luster Content (%) Related substance
0 month White powder 99.97 Do not detect
January White powder 99.85 Do not detect
February White powder 99.74 Do not detect
March White powder 99.96 Do not detect
June White powder 99.67 Do not detect
Result shows: dabigatran etcxilate Mesylate Form 1 is in strong illumination, high temperature, high humidity and accelerated test conditional stability, and appearance luster, weight loss on drying, content and related substance do not have considerable change, under conditions of high humidity slightly moisture absorption weightening finish.
2, the stability of dabigatran etcxilate Mesylate Form 2
2.1 rayed tests
Get under dabigatran etcxilate Mesylate Form 2 is placed in the condition of light intensity 4500 ± 500Lx and irradiate, in sampling inspection in 5,10 days.The results are shown in Table 13.
Table 13 dabigatran etcxilate Mesylate Form 2 thing strong illumination test-results
Time (my god) Appearance luster Weight loss on drying (%) Content (%) Related substance
0 day White powder 0.32 99.95 Do not detect
5 days White powder 0.35 99.93 Do not detect
10 days White powder 0.29 99.90 Do not detect
2.2 high temperature test
Getting dabigatran etcxilate Mesylate Form 2 thing puts in 60 DEG C of thermostat containers, detects, the results are shown in Table 14 in sampling in 5,10 days.
Table 14 dabigatran etcxilate Mesylate Form 2 high temperature test result
Time (my god) Appearance luster Weight loss on drying (%) Content (%) Related substance
0 day White powder 0.35 99.95 Do not detect
5 days White powder 0.37 99.77 Do not detect
10 days White powder 0.29 99.65 Do not detect
2.3 high wet tests
Dabigatran etcxilate Mesylate Form 2 is placed in 25 DEG C of thermostat containers (relative humidity is 75 ± 5%), detects in sampling in 5,10 days.The results are shown in Table 15.
Table 15 dabigatran etcxilate Mesylate Form 2 high humidity test-results
Time (my god) Appearance luster Moisture absorption weightening finish (%) Content (%) Related substance
0 day White powder 0 99.95 Do not detect
5 days White powder 0.32 99.73 Do not detect
10 days White powder 0.57 99.68 Do not detect
2.4 accelerated test
Dabigatran etcxilate Mesylate Form 2 polythene film bag sealing, be placed in temperature 40 ± 2 DEG C, relative humidity, under 75 ± 5% conditions, is placed 6 months, respectively at the 1st, sampling detection at 2,3,6 months the end of month, the results are shown in Table 16.
Table 16 dabigatran etcxilate Mesylate Form 2 accelerated test result
Test period Appearance luster Content (%) Related substance
0 month White powder 99.95 Do not detect
January White powder 99.78 Do not detect
February White powder 99.85 Do not detect
March White powder 99.78 Do not detect
June White powder 99.83 Do not detect
Result shows: dabigatran etcxilate Mesylate Form 2 is in strong illumination, high temperature, high humidity and accelerated test conditional stability, and appearance luster, weight loss on drying, content and related substance do not have considerable change, under conditions of high humidity slightly moisture absorption weightening finish.
3, the stability of dabigatran etcxilate Mesylate Form 3
3.1 rayed tests
Get under dabigatran etcxilate Mesylate Form 3 is placed in the condition of light intensity 4500 ± 500Lx and irradiate, detect in sampling in 5,10 days.The results are shown in Table 17.
Table 17 dabigatran etcxilate Mesylate Form 3 strong illumination test-results
Time (my god) Appearance luster Weight loss on drying (%) Content (%) Related substance
0 day White powder 0.28 99.90 Do not detect
5 days White powder 0.30 99.91 Do not detect
10 days White powder 0.35 99.86 Do not detect
3.2 high temperature test
Getting dabigatran etcxilate Mesylate Form 3 puts in 60 DEG C of thermostat containers, detects, the results are shown in Table 18 in sampling in 5,10 days.
Table 18 dabigatran etcxilate Mesylate Form 3 high temperature test stability result
Time (my god) Appearance luster Weight loss on drying (%) Content (%) Related substance
0 day White powder 0.28 99.90 Do not detect
5 days White powder 0.32 99.78 Do not detect
10 days White powder 0.33 99.68 Do not detect
3.3 high wet tests
Dabigatran etcxilate Mesylate Form 3 is placed in 25 DEG C of thermostat containers (relative humidity is 75 ± 5%), detects in sampling in 5,10 days.The results are shown in Table 19.
Table 19 dabigatran etcxilate Mesylate Form 3 high humidity test stability result
Time (my god) Appearance luster Moisture absorption weightening finish (%) Content (%) Related substance
0 day White powder 0 99.90 Do not detect
5 days White powder 0.36 99.88 Do not detect
10 days White powder 0.57 99.73 Do not detect
3.4 accelerated test
Dabigatran etcxilate Mesylate Form 3 polythene film bag sealing, be placed in temperature 40 ± 2 DEG C, relative humidity, under 75 ± 5% conditions, is placed 6 months, respectively at the 1st, sampling detection at 2,3,6 months the end of month, the results are shown in Table 20.
Table 20 dabigatran etcxilate Mesylate Form 3 accelerated test result
Test period Appearance luster Content (%) Related substance
0 month White powder 99.90 Do not detect
January White powder 99.89 Do not detect
February White powder 99.89 Do not detect
March White powder 99.95 Do not detect
June White powder 99.73 Do not detect
Result shows: dabigatran etcxilate Mesylate Form 3 is in strong illumination, high temperature, high humidity and accelerated test conditional stability, and appearance luster, weight loss on drying, content and related substance do not have considerable change, under conditions of high humidity slightly moisture absorption weightening finish.
4, the stability of dabigatran etcxilate Mesylate Form 4
4.1 rayed tests
Get under dabigatran etcxilate Mesylate Form 4 is placed in the condition of light intensity 4500 ± 500Lx and irradiate, detect in sampling in 5,10 days.The results are shown in Table 21.
Table 21 dabigatran etcxilate Mesylate Form semi-finals rayed test-results
Time (my god) Appearance luster Weight loss on drying (%) Content (%) Related substance
0 day White powder 0.31 99.93 Do not detect
5 days White powder 0.35 99.97 Do not detect
10 days White powder 0.37 99.89 Do not detect
4.2 high temperature test
Getting dabigatran etcxilate Mesylate Form 4 puts in 60 DEG C of thermostat containers, detects, the results are shown in Table 22 in sampling in 5,10 days.
Table 22 dabigatran etcxilate Mesylate Form 4 high temperature test stability result
Time (my god) Appearance luster Weight loss on drying (%) Content (%) Related substance
0 day White powder 0.31 99.93 Do not detect
5 days White powder 0.33 99.89 Do not detect
10 days White powder 0.36 99.67 Do not detect
4.3 high wet tests
Dabigatran etcxilate Mesylate Form 4 is placed in 25 DEG C of thermostat containers (relative humidity is 75 ± 5%), detects in sampling in 5,10 days.The results are shown in Table 23.
Table 23 dabigatran etcxilate Mesylate Form 4 high humidity test stability result
Time (my god) Appearance luster Moisture absorption weightening finish (%) Content (%) Related substance
0 day White powder 0 99.93 Do not detect
5 days White powder 0.39 99.86 Do not detect
10 days White powder 0.67 99.63 Do not detect
4.4 accelerated test
Dabigatran etcxilate Mesylate Form 4 polythene film bag sealing, be placed in temperature 40 ± 2 DEG C, relative humidity, under 75 ± 5% conditions, is placed 6 months, respectively at the 1st, sampling detection at 2,3,6 months the end of month, the results are shown in Table 24.
Table 24 dabigatran etcxilate Mesylate Form 4 accelerated test result
Test period Appearance luster Content (%) Related substance
0 month White powder 99.93 Do not detect
January White powder 99.68 Do not detect
February White powder 99.91 Do not detect
March White powder 99.90 Do not detect
June White powder 99.75 Do not detect
Result shows: dabigatran etcxilate Mesylate Form 4 is in strong illumination, high temperature, high humidity and accelerated test conditional stability, and appearance luster, weight loss on drying, content and related substance do not have considerable change, under conditions of high humidity slightly moisture absorption weightening finish.
Below the method in is conventionally prepared two kinds of dabigatran etcxilate Mesylate Form, and carries out the contrast of stability with crystal formation prepared by the present invention:
5, the stability of dabigatran etcxilate Mesylate Form I
Dabigatran etcxilate Mesylate Form I is prepared according to the method in patent WO2005028468.
5.1 rayed tests
Get under dabigatran etcxilate Mesylate Form I is placed in the condition of light intensity 4500 ± 500Lx and irradiate, detect in sampling in 5,10 days.The results are shown in Table 25.
Table 25 dabigatran etcxilate Mesylate Form I strong illumination test-results
Time (my god) Appearance luster Weight loss on drying (%) Content (%) Related substance (%))
0 day White powder 0.31 99.97 Do not detect
5 days White powder 0.35 99.95 Do not detect
10 days White powder 0.37 99.89 Do not detect
5.2 high temperature test
Getting dabigatran etcxilate Mesylate Form I puts in 60 DEG C of thermostat containers, detects, the results are shown in Table 26 in sampling in 5,10 days.
Table 26 dabigatran etcxilate Mesylate Form I high temperature test stability result
Time (my god) Appearance luster Weight loss on drying (%) Content (%) Related substance
0 day White powder 0.31 99.97 Do not detect
5 days White powder 0.35 99.90 0.02
10 days White powder 0.34 99.88 0.03
5.3 high wet tests
Dabigatran etcxilate Mesylate Form I is placed in 25 DEG C of thermostat containers (relative humidity is 75 ± 5%), detects in sampling in 5,10 days.The results are shown in Table 27.
Table 27 dabigatran etcxilate Mesylate Form I high humidity test stability result
Time (my god) Appearance luster Moisture absorption weightening finish (%) Content (%) Related substance
0 day White powder 0 99.97 Do not detect
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 Form I polythene film bag seals, and is placed in temperature 40 ± 2 DEG C, and relative humidity, under 75 ± 5% conditions, is placed 6 months, and respectively at the 1st, sampling at 2,3,6 months the end of month detects, and the results are shown in Table 28.
Table 28 dabigatran etcxilate Mesylate Form I accelerated test result
Test period Appearance luster Content (%) Related substance
0 month White powder 99.97 Do not detect
January White powder 99.87 Do not detect
February White powder 99.95 0.01
March White powder 99.98 0.03
June White powder 99.89 0.07
Result shows: dabigatran etcxilate Mesylate Form I is stable under strong illumination condition, and appearance luster, weight loss on drying, content and related substance do not have considerable change; And under high temperature, high humidity and accelerated test condition, appearance luster, weight loss on drying, content do not have considerable change, but related substance slightly increases, under conditions of high humidity slightly moisture absorption weightening finish.
6, the stability of dabigatran etcxilate Mesylate Form III
Dabigatran etcxilate Mesylate Form III is prepared according to the method in patent WO2012027543.
6.1 rayed tests
Get under dabigatran etcxilate Mesylate Form III is placed in the condition of light intensity 4500 ± 500Lx and irradiate, detect in sampling in 5,10 days.The results are shown in Table 29.
Table 29 dabigatran etcxilate Mesylate Form III strong illumination test-results
Time (my god) Appearance luster Weight loss on drying (%) Content (%) Related substance
0 day White powder 0.29 99.92 Do not detect
5 days White powder 0.32 99.87 Do not detect
10 days White powder 0.33 99.73 Do not detect
6.2 high temperature test
Getting dabigatran etcxilate Mesylate Form III puts in 60 DEG C of thermostat containers, detects, the results are shown in Table 30 in sampling in 5,10 days.
Table 30 dabigatran etcxilate Mesylate Form III high temperature test stability result
Time (my god) Appearance luster Weight loss on drying (%) Content (%) Related substance
0 day White powder 0.29 99.92 Do not detect
5 days White powder 0.30 99.89 0.01
10 days White powder 0.31 99.67 0.04
6.3 high wet tests
Dabigatran etcxilate Mesylate Form III is placed in 25 DEG C of thermostat containers (relative humidity is 75 ± 5%), detects in sampling in 5,10 days.The results are shown in Table 31.
Table 31 dabigatran etcxilate Mesylate Form III high humidity test stability result
Time (my god) Appearance luster Moisture absorption weightening finish (%) Content (%) Related substance
0 day White powder 0 99.92 Do not detect
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 Form III polythene film bag seals, and is placed in temperature 40 ± 2 DEG C, and relative humidity, under 75 ± 5% conditions, is placed 6 months, and respectively at the 1st, sampling at 2,3,6 months the end of month detects, and the results are shown in Table 32.
Table 32 dabigatran etcxilate Mesylate Form III accelerated test result
Test period Appearance luster Content (%) Related substance
0 month White powder 99.92 Do not detect
January White powder 99.78 0.01
February White powder 99.90 0.01
March White powder 99.94 0.02
June White powder 99.83 0.07
Result shows: dabigatran etcxilate Mesylate Form III is stable under strong illumination condition, and appearance luster, weight loss on drying, content and related substance do not have considerable change; And under high temperature, high humidity and accelerated test condition, appearance luster, weight loss on drying, content do not have considerable change, but related substance slightly increases, under conditions of high humidity slightly moisture absorption weightening finish.
From above stability test, the dabigatran etcxilate Mesylate Form prepared by the inventive method has the advantages such as good stability, and strong illumination, high temperature, high humidity and accelerated test condition are all stable, and related substance has no increase.And the crystal formation I that prior art obtains and crystal form II I related substance under high temperature, high humidity and accelerated test condition slightly increases.
Accompanying drawing explanation
Fig. 1, crystal formation 1 powder x-ray diffraction figure
Fig. 2, crystal formation 1 infrared spectrogram
Fig. 3, crystal formation 2 powder x-ray diffraction figure
Fig. 4, crystal formation 2 infrared spectrogram
Fig. 5, crystal formation 3 powder x-ray diffraction figure
Fig. 6, crystal formation 3 infrared spectrogram
Fig. 7, crystal formation 4 powder x-ray diffraction figure
Fig. 8, crystal formation 4 infrared spectrogram
Embodiment
The present invention is further illustrated below by embodiment.Method in embodiments of the invention is only used for the present invention is described, instead of limitation of the present invention.
The preparation of embodiment 1 dabigatran etcxilate Mesylate Form 1
Get dabigatran etcxilate mesylate 20g and be placed in reaction flask, add methylene dichloride 40ml, be stirred and heated to and make it dissolve, add ethyl acetate 40ml, stir 15 minutes, cool to 10-15 DEG C of stirring and crystallizing 1 hour.Filter, ethyl acetate is washed, dry, obtains dabigatran etcxilate Mesylate Form 118.4g, yield 92%.
The preparation of embodiment 2 dabigatran etcxilate Mesylate Form 1
Get dabigatran etcxilate mesylate 5g and be placed in reaction flask, add methylene dichloride 75ml, stirring heating makes it dissolve, and adds ethyl acetate 75ml, stirs 15 minutes, cools to 10-15 DEG C of stirring and crystallizing 1.5 hours.Filter, ethyl acetate is washed, dry, obtains dabigatran etcxilate Mesylate Form 14.1g, yield 82.0%.
The preparation of embodiment 3 dabigatran etcxilate Mesylate Form 1
Get dabigatran etcxilate mesylate 10g and be placed in reaction flask, add methylene dichloride 80ml, stirring heating makes it dissolve, and adds ethyl acetate 100ml, stirs 10 minutes, cools to 10-15 DEG C of stirring and crystallizing 1 hour.Filter, ethyl acetate is washed, dry, obtains dabigatran etcxilate Mesylate Form 19.50g, yield 95.0%.
The preparation of embodiment 4 dabigatran etcxilate Mesylate Form 2
Get dabigatran etcxilate mesylate 5g and be placed in reaction flask, add methylene dichloride 10ml, stirring heating makes it dissolve, and adds acetone 10ml, stirs 5 minutes, cools to 10-15 DEG C of stirring and crystallizing 1.5 hours.Filter, washing with acetone, dry, obtain dabigatran etcxilate Mesylate Form 24.5g, yield 90.0%.
The preparation of embodiment 5 dabigatran etcxilate Mesylate Form 2
Get dabigatran etcxilate mesylate 20g and be placed in reaction flask, add methylene dichloride 300m, stirring heating makes it dissolve, and adds acetone 300ml, stirs 15 minutes, cools to 10-15 DEG C of stirring and crystallizing 1 hour.Filter, washing with acetone, dry, obtain dabigatran etcxilate Mesylate Form 218.7g, yield 93.5%.
The preparation of embodiment 6 dabigatran etcxilate Mesylate Form 2
Get dabigatran etcxilate mesylate 10g and be placed in reaction flask, add methylene dichloride 100ml, stirring heating makes it dissolve, and adds acetone 150ml, stirs 15 minutes, cools to 10-15 DEG C of stirring and crystallizing 1 hour.Filter, washing with acetone, dry, obtain dabigatran etcxilate Mesylate Form 29.3g, yield 93.0%.
The preparation of embodiment 7 dabigatran etcxilate Mesylate Form 3
Get dabigatran etcxilate mesylate 20g and be placed in reaction flask, add methylene dichloride 40ml, stirring heating makes it dissolve, and adds tetrahydrofuran (THF) 40ml, stirs 15 minutes, cools to 10-15 DEG C of stirring and crystallizing 0.5 hour.Filter, tetrahydrofuran (THF) washs, dry, obtains dabigatran etcxilate Mesylate Form 318g, yield 90%.
The preparation of embodiment 8 dabigatran etcxilate Mesylate Form 3
Get dabigatran etcxilate mesylate 20g and be placed in reaction flask, add methylene dichloride 300ml, stirring heating makes it dissolve, and adds tetrahydrofuran (THF) 300ml, stirs 15 minutes, cools to 10-15 DEG C of stirring and crystallizing 1.5 hours.Filter, tetrahydrofuran (THF) washs, dry, obtains dabigatran etcxilate Mesylate Form 317.2g, yield 86%.
The preparation of embodiment 9 dabigatran etcxilate Mesylate Form 3
Get dabigatran etcxilate mesylate 10g and be placed in reaction flask, add methylene dichloride 80ml, stirring heating makes it dissolve, and adds tetrahydrofuran (THF) 100ml, stirs 15 minutes, cools to 10-15 DEG C of stirring and crystallizing 1 hour.Filter, tetrahydrofuran (THF) washs, dry, obtains dabigatran etcxilate Mesylate Form 39.3g, yield 93%.
The preparation of embodiment 10 dabigatran etcxilate Mesylate Form 4
Get dabigatran etcxilate mesylate 5g and be placed in reaction flask, add ethanol 15ml, stirring heating makes it all dissolve, and decompression steams ethanol, dry, obtains dabigatran etcxilate Mesylate Form 44.9g, yield 98%.
The preparation of embodiment 11 dabigatran etcxilate Mesylate Form 4
Get dabigatran etcxilate mesylate 20g and be placed in reaction flask, add ethanol 400ml, stirring heating makes it all dissolve, and decompression steams ethanol, dry, obtains dabigatran etcxilate Mesylate Form 419.2g, yield 97%.
The preparation of the capsule medicine composition of embodiment 12 containing dabigatran etcxilate Mesylate Form 1
1, prescription
2, the preparation method of capsule
Dabigatran etcxilate Mesylate Form 1, lactose, Microcrystalline Cellulose, W-Gum, sodium starch glycolate add in efficient wet nodulizer and mix, and add 2% polyvinylpyrrolidone ethanolic soln (80%) and granulate.Wet granular is dry in fluidized-bed, through the whole grain of 18 mesh sieve.Add in dry particle after Magnesium Stearate suitably mixes and incapsulate.
The preparation of the capsule medicine composition of embodiment 13 containing dabigatran etcxilate Mesylate Form 2
1, prescription
2, the preparation method of capsule
Dabigatran etcxilate Mesylate Form 2, lactose, Microcrystalline Cellulose, W-Gum, sodium starch glycolate add in efficient wet nodulizer and mix, and add 2% polyvinylpyrrolidone ethanolic soln (80%) and granulate.Wet granular is dry in fluidized-bed, through the whole grain of 18 mesh sieve.Add in dry particle after Magnesium Stearate suitably mixes and incapsulate.
The preparation of the capsule medicine composition of embodiment 14 containing dabigatran etcxilate Mesylate Form 3
1, prescription
2, the preparation method of capsule
Dabigatran etcxilate Mesylate Form 3, lactose, Microcrystalline Cellulose, W-Gum, sodium starch glycolate add in efficient wet nodulizer and mix, and add 2% polyvinylpyrrolidone ethanolic soln (80%) and granulate.Wet granular is dry in fluidized-bed, through the whole grain of 18 mesh sieve.Add in dry particle after Magnesium Stearate suitably mixes and incapsulate.
The preparation of the capsule medicine composition of embodiment 15 containing dabigatran etcxilate Mesylate Form 4
1, prescription
2, the preparation method of capsule
Dabigatran etcxilate Mesylate Form 4, lactose, Microcrystalline Cellulose, W-Gum, sodium starch glycolate add in efficient wet nodulizer and mix, and add 2% polyvinylpyrrolidone ethanolic soln (80%) and granulate.Wet granular is dry in fluidized-bed, through the whole grain of 18 mesh sieve.Add in dry particle after Magnesium Stearate suitably mixes and incapsulate.

Claims (9)

1. a new crystal for dabigatran etcxilate mesylate, is characterized in that, its powder x-ray diffraction figure, has characteristic diffraction peak to spend 2 θ represented 4.44 ± 0.2,18.04 ± 0.2,13.48 ± 0.2,22.02 ± 0.2,17.58 ± 0.2; Infrared spectrogram 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 charateristic avsorption band; Fusing point is 175-179 DEG C.
2. the preparation method of the new crystal of dabigatran etcxilate mesylate as claimed in claim 1, it is characterized in that, dabigatran etcxilate mesylate is placed in reaction flask, add the methylene dichloride of 2 ~ 15 times amount (w/v), stirring heating makes it dissolve, and then add the ethyl acetate of 2 ~ 15 times amount (w/v), stir, cooling stirring and crystallizing, filter, add ethyl acetate washing, dry, to obtain final product.
3. a new crystal for dabigatran etcxilate mesylate, is characterized in that, its powder x-ray diffraction figure, has characteristic diffraction peak to spend 2 θ represented 3.78 ± 0.2,23.78 ± 0.2,7.52 ± 0.2,8.18 ± 0.2,17.72 ± 0.2,19.88 ± 0.2; 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 charateristic avsorption band; Fusing point is 129-133 DEG C.
4. the preparation method of the new crystal of dabigatran etcxilate mesylate as claimed in claim 3, it is characterized in that, dabigatran etcxilate mesylate is placed in reaction flask, add the methylene dichloride of 2 ~ 15 times amount (w/v), stirring heating makes it dissolve, and then add the acetone of 2 ~ 15 times amount (w/v), stir, cooling stirring and crystallizing, filter, add washing with acetone, dry, to obtain final product.
5. a new crystal for dabigatran etcxilate mesylate, is characterized in that, its powder x-ray diffraction figure, has characteristic diffraction peak to spend 2 θ represented 4.54 ± 0.2,3.76 ± 0.2,22.16 ± 0.2,18.16 ± 0.2,17.76 ± 0.2; Infrared spectrogram 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 charateristic avsorption band; Fusing point is 176-183 DEG C.
6. the preparation method of the new crystal of dabigatran etcxilate mesylate as claimed in claim 5, it is characterized in that, dabigatran etcxilate mesylate is placed in reaction flask, add the methylene dichloride of 2 ~ 15 times amount (w/v), stirring heating makes it dissolve, and then add the tetrahydrofuran (THF) of 2 ~ 15 times amount (w/v), stir, cooling stirring and crystallizing, filter, add tetrahydrofuran (THF) washing, dry, to obtain final product.
7. the new crystal of a dabigatran etcxilate mesylate, it is characterized in that, its powder x-ray diffraction figure, has characteristic diffraction peak to spend 2 θ represented 4.46 ± 0.2,21.60 ± 0.2,17.92 ± 0.2,19.96 ± 0.2,19.28 ± 0.2,28.20 ± 0.2; Infrared spectrogram 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 charateristic avsorption band; Fusing point is 183-190 DEG C.
8. the preparation method of the new crystal of dabigatran etcxilate mesylate as claimed in claim 7, is characterized in that, dabigatran etcxilate mesylate is dissolved in heated and stirred 10-20 minute in the ethanol of 3 ~ 20 times (w/v), steams ethanol, dry, to obtain final product.
9. the pharmaceutical composition containing claim 1,3,5,7 any one dabigatran etcxilate Mesylate Form.
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Publication number Priority date Publication date Assignee Title
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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Inventor after: Liu Wenzheng

Inventor after: Gao Yuzhe

Inventor after: Wang Guocheng

Inventor after: Liu Jinping

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Application publication date: 20151014