CN108864049A - 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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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 tetrahydrofuran 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 method of 8 kinds of crystal forms of dabigatran etcxilate mesylate is disclosed in WO2012027543, being respectively adopted will reach
Than add group ester mesylate placed in the environment of relative humidity 100% 30 days (crystal form A), with water process (crystal form B), with to different
Propyltoluene recrystallization (crystal form C) recrystallizes (crystal form D) with dimethyl sulfoxide, places 1 month (crystal form in normal heptane environment
G), with pyridine recrystallization (crystal form H), in 2- methyltetrahydrofuran crystallization (or with cyclohexanone, amylalcohol, ethyl acetoacetate, two
Glyme recrystallization) (crystal form I), in 2- butanol crystallization (or with ethyl alcohol and 2- methyltetrahydrofuran, ethyl alcohol and acetic acid second
Ester, butanol and ethyl acetate, ethyl alcohol and isobutyl ketone recrystallization) (crystal form III) etc..Above method is the problem is that use acetone
There are security risks for industrial production, with cymene, dimethyl sulfoxide, normal heptane, pyridine, 2- methyltetrahydrofuran, second
Ethyl acetoacetic acid ethyl ester, 2- butanol etc. make solvent and all there is high production cost, and solvent easily remains, is not industrialized production Conventional solvents
Problem.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：It takes 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.
Specially：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：It takes 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.
Specially：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：It takes 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.
Specially：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 following advantages 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 characteristic diffraction peak 4.54 ± 0.2,3.76 ± 0.2,22.16 ± 0.2,18.16 ± 0.2,17.76 ± 0.2；Infrared spectroscopy
Figure 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；Fusing point is 176-183 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
The tetrahydrofuran of 2~15 times of amounts (w/v) is added, is stirred, cool down stirring and crystallizing, filtering, and tetrahydrofuran washing is added, and it is dry,
To obtain the final product.
3. the pharmaceutical composition containing dabigatran etcxilate mesylate crystal form described in claim 1.
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