CN103965164A - Dabigatran etexilate mesylate crystals VI and preparation method thereof - Google Patents
Dabigatran etexilate mesylate crystals VI and preparation method thereof Download PDFInfo
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- 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
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Abstract
The invention relates to dabigatran etexilate mesylate crystals VI and a preparation method thereof. The crystals are defined by using characteristic peaks of an X-ray powder diffraction pattern at a diffraction angle of 2 theta degrees and DSC (differential scanning calorimetry). The preparation method comprises the steps of adding a dabigatran etexilate mesylate solid in amorphous form or any one known crystal form into dimethyl sulfoxide to form 200g/L-300g/L of suspension liquid, completely dissolving the solid at 30-45 DEG C, and dropwise adding a solvent with the usage amount being 8-12 times the volume of the solvent into a mixed solution; performing suction filtration to form suspension liquid, and drying the dabigatran etexilate mesylate crystals into the constant weight. The preparation method provided by the invention has the advantages of simple process and short time, and prepared products have the advantages of high purity, high solubility, good thermodynamic stability and the like.
Description
Technical field
The invention belongs to drug crystallization technical field, particularly a kind of new methylsulfonic acid dabigatran crystalline esters its preparation method.
Background technology
Dabigatran etcxilate (dabigatran etexilate) is a kind of two prodrug, is converted in vivo the dabigatran (dabigatran) with anticoagulant active.In order to improve the water-soluble of medicine, conventionally make the form of dabigatran etcxilate additive salt.The medicinal ingredients of current commercially available capsule is methylsulfonic acid dabigatran etcxilate (dabigatran etexilate mesylate).The chinesization formal name used at school of methylsulfonic acid dabigatran etcxilate is 3-[[[2-[[[4-[[[(hexyloxy) carbonyl] amino] formamino] phenyl] amino] methyl]-1-methyl isophthalic acid H-benzoglyoxaline-5-yl] carbonyl] (pyridine-2-yl) amino] ethyl propionate mesylate, English chemistry ethyl3-[[[2-[[[4-[[[(hexyloxy by name) carbonyl] amino] iminomethyl] phenyl] amino] methyl]-1-methyl-1H-benzimidazol-5-yl] carbonyl] (pyridin-2-yl) amino] propionatemethanesulfonate, molecular formula is C
34h
41n
7o
5cH
4o
3s, molecular weight is 723.86.The structural formula of dabigatran, dabigatran etcxilate, methylsulfonic acid dabigatran etcxilate is as follows respectively.
Dabigatran (dabigatran) is first disclosed as in WO98/37075, after developed by German Boehringer Ingelheim company (Boehringer Ingelheim), in April, 2008 first in Germany and Britain's listing, trade(brand)name Pradaxa, medicinal ingredients is methylsulfonic acid dabigatran etcxilate.This medicine is the brand-new oral direct anticoagulation medicine of first listing over 50 years after warfarin, within 2008, gets permission the prevention for full hip or total knee replacement surgery posterior vein thrombus in European Union.After this medicine is oral, discharge in vivo dabigatran, be combined with the scleroproein specific site of zymoplasm, stop Fibrinogen to be cracked into scleroproein, thus final step and the thrombosis of blocking-up blood coagulation waterfall network.In October, 2010, FDA ratifies again the generation of methylsulfonic acid dabigatran etcxilate capsule for the pre-preventing thrombosis of NVAF patient and cerebral apoplexy.The listing of methylsulfonic acid dabigatran etcxilate, is an important breakthrough in anticoagulant treatment field and potential lethality thrombus prevention field, has milestone significance.
Over more than 50 year, atrial fibrillation anticoagulant therapy can only rely on warfarin.But warfarin exists, and treatment window is narrow, bleeding risk is higher, need frequent monitoring coagulation function and adjust drug dose, have congenital " short slabs " such as interactions with multiple food medicine.Compared with the vitamin K antagons such as warfarin, methylsulfonic acid dabigatran etcxilate not only has effective, measurable and consistent anticoagulation and good stroke prevention effect, and it is lower to have bleeding risk, without advantages such as routine monitorings, the possibility of drug drug interaction is lower, and does not interact with food.Along with this medicine comes out in China, dabigatran etcxilate will, for nearly ten million atrial fibrillation patients of China is aspect prevention palsy and systemic embolism, provide new treatment means.
Active pharmaceutical ingredient is except meeting certain requirement in stability, water absorbability, solubility, and its crystal modification form also should have strict control.Same medicine, due to the difference of physical field envrionment conditions in crystallisation process, can generate the diverse crystal product of internal structure (being the arrangement mode of Molecule in Crystal), is called polymorphism.Medicine polymorphic generally shows as the existence form of medicine material under solid state.A kind of medicine can exist by multiple crystal-form substances state, the different crystal forms of same medicine, and dissolving in vivo may be different with absorption, thereby can exert an influence to the stripping of preparation and release.To the polymorphous research of medicine, can find that there is and be beneficial to the pharmaceutically-active medicine advantage crystal formation of performance, simultaneously determine preparation process according to the feature of crystal formation, effectively ensure to produce batch between pharmacokinetics etc.Therefore need to illustrate as far as possible the heteromorphism of the active substance existing with crystal habit.If there are the different polymorphic variant forms of active substance, must guarantee that the crystal modification form of this material can not change in medicine preparation subsequently.Otherwise this renewable usefulness for medicine has harmful effect.
The additive salt that dabigatran etcxilate and multiple mineral acid and organic acid form has multiple crystal formation.Patent WO2008043759A1 and WO2011110876A1 disclose the preparation method of the different crystal forms of DHB salt, benzene sulfonate, hydrochloride, fumarate, oxalate, phosphoric acid salt, salicylate etc. salt.
The crystal of methylsulfonic acid dabigatran etcxilate has multiple crystal formation, has following crystal formation and unformed in the report of patent documentation:
Patent ZL200480024952.1 discloses crystal formation I, crystal form II and the semihydrate of methylsulfonic acid dabigatran etcxilate;
Patent ZL201110249228.0 discloses the monohydrate of methylsulfonic acid dabigatran etcxilate;
Patent WO2012027543A1 discloses methylsulfonic acid dabigatran etcxilate crystal form A, B, C, D, G, H, III and amorphous;
Patent WO2011110876A1 discloses methylsulfonic acid dabigatran etcxilate form IV.
Although the report of existing above-mentioned multiple crystal formation, but still be necessary that research is conveniently easy to get, thermodynamic stability is good, be convenient to industrialized methylsulfonic acid dabigatran etcxilate new crystal, to ensure bulk drug and preparation thereof the stability in preparation and storage, improve drug quality and the clinical efficacy of methylsulfonic acid dabigatran etcxilate.
Summary of the invention
The object of the invention is on the basis of existing technology, provide that a kind of purity is high, solubleness is high, the new crystal of methylsulfonic acid dabigatran etcxilate of good stability.
The preparation method that technique that another object of the present invention is to provide a kind of above-mentioned methylsulfonic acid dabigatran crystalline esters is simple, with low cost, be suitable for suitability for industrialized production.
Object of the present invention can reach by following measures:
The invention discloses a kind of crystal of methylsulfonic acid dabigatran etcxilate, i.e. crystal VI, the X-ray powder diffraction of this crystal is 4.4 ± 0.2,9.0 ± 0.2 at diffraction angle 2 θ, 11.0 ± 0.2,13.5 ± 0.2,17.8 ± 0.2, there is characteristic peak at 18.1 ± 0.2,22.3 ± 0.2 degree places, referred to as VI crystal formation.
In a kind of preferred version, the X-ray powder diffraction of this VI crystal formation is 4.4 ± 0.2,9.0 ± 0.2 at diffraction angle 2 θ, 9.3 ± 0.2,9.5 ± 0.2,11.0 ± 0.2,13.5 ± 0.2,14.0 ± 0.2,17.8 ± 0.2,18.1 ± 0.2,22.3 ± 0.2,22.9 ± 0.2,26.8 ± 0.2, there is characteristic peak at 27.3 ± 0.2,32.1 ± 0.2 degree places.
In a kind of preferred version, this VI crystal formation has following X-ray diffracting spectrum:
Further, this VI crystal formation has substantially powder x-ray diffraction collection of illustrative plates as shown in Figure 1.
Furtherly, the demonstration of dsc analysis result, this VI crystal formation only has an endotherm(ic)peak, at 180 ± 2 DEG C, specifically as shown in Figure 2.
Furtherly, the infrared spectra of this VI crystal formation is presented at 3255 ± 2cm
-1, 1732 ± 2cm
-1, 1643 ± 2cm
-1, 1581 ± 2cm
-1, 1531 ± 2cm
-1, 1369 ± 2cm
-1, 1319 ± 2cm
-1, 1199 ± 2cm
-1, 1161 ± 2cm
-1, 1045 ± 2cm
-1, 941 ± 2cm
-1, 829 ± 2cm
-1, 783 ± 2cm
-1there is absorption peak at place, specifically as shown in Figure 3.
Furtherly, the Raman spectrum of this VI crystal formation is presented at 1734 ± 2cm
-1, 1666 ± 2cm
-1, 1587 ± 2cm
-1, 1531 ± 2cm
-1, 1386 ± 2cm
-1, 1344 ± 2cm
-1, 1243 ± 2cm
-1, 1207 ± 2cm
-1, 1163 ± 2cm
-1, 1099 ± 2cm
-1, 1047 ± 2cm
-1, 994 ± 2cm
-1, 864 ± 2cm
-1, 756 ± 2cm
-1, 635 ± 2cm
-1, 618 ± 2cm
-1, 602 ± 2cm
-1, 558 ± 2cm
-1, 414 ± 2cm
-1, 349 ± 2cm
-1, 250 ± 2cm
-1there is scattering peak at place, specifically as shown in Figure 4.
The present invention also provides a kind of preparation method of above-mentioned VI crystal formation, specifically comprises the steps:
A) methylsulfonic acid dabigatran etcxilate crude product is added in good solvent, be configured to the suspension of 200～300g/L;
B) solid is dissolved completely at 30～45 DEG C;
C) in mixing solutions, slowly add dissolved agent, dissolved agent consumption is 8～12 times of solvent volume;
D) suspension that suction filtration forms;
E) dry methylsulfonic acid dabigatran etcxilate crystal product is to constant weight.
In above-mentioned preparation method,
Described methylsulfonic acid dabigatran etcxilate crude product is unformed or known arbitrary crystal formation pressed powder, HPLC purity >=95%.
In above-mentioned preparation method, one or several mixture in good solvent selection ethylene glycol, propyl carbinol, isopropylcarbinol, methyl-sulphoxide, dimethyl formamide.In above-mentioned preparation method, dissolved agent is selected from one or more the mixture in ethyl acetate, propyl acetate, methyl acetate, butylacetate, methyl-formiate, ethyl formate, propyl formate.
In above-mentioned preparation method, dissolved agent adopts the mode slowly adding to add, and general employing drips, and its drop rate is 5%～20% of per minute dropping dissolved agent volume.
In above-mentioned preparation method, drying conditions is to carry out under 30 DEG C-45 DEG C, the condition of normal pressure.
The present invention also comprises a kind of pharmaceutical composition, and its crystal VI taking methylsulfonic acid dabigatran etcxilate of the present invention, as active substance or main active substances, is aided with pharmaceutically acceptable auxiliary material, makes pharmaceutical preparation, and particularly solid orally ingestible, as capsule, tablet etc.; Wherein the pharmaceutically acceptable auxiliary material of indication includes but not limited to disintegrating agent, tackiness agent, pH adjusting agent, solubility promoter, antisticking agent, solvent, carrier, dispersion agent, wetting agent, defoamer etc., can adopt existing universal method to be prepared into various concrete preparations.This pharmaceutical composition is mainly used in prevention and the treatment of acute and chronic thrombotic disease.
Compared with prior art, the preparation method of methylsulfonic acid dabigatran crystalline esters VI provided by the invention have technique simple, consuming time short, be suitable for the advantages such as technology production, it is high that the methylsulfonic acid dabigatran crystalline esters VI that method provided by the invention is prepared simultaneously has purity, and solubleness is high, the advantage of good stability.
Brief description of the drawings
Fig. 1: the X-ray powder diffraction pattern of methylsulfonic acid dabigatran crystalline esters VI;
Fig. 2: the dsc analysis figure of methylsulfonic acid dabigatran crystalline esters VI;
Fig. 3: the infrared spectrogram of methylsulfonic acid dabigatran crystalline esters VI;
Fig. 4: the Raman spectrogram of methylsulfonic acid dabigatran crystalline esters VI;
Fig. 5: the stability study X-ray powder diffraction pattern of methylsulfonic acid dabigatran crystalline esters VI;
Fig. 6: the stability study dsc analysis figure of methylsulfonic acid dabigatran crystalline esters VI.
In figure, be respectively the dsc analysis figure of 16 weeks, 9 weeks, 4 weeks, 3 weeks, 1 week and 1 day from top to bottom.
Embodiment
Below in conjunction with drawings and Examples, the present invention is further detailed explanation.
Methylsulfonic acid dabigatran etcxilate crude product for embodiment can be indefiniteness or known arbitrary crystal formation, preferably purity >=95%, its concrete preparation method is with reference to described in the documents such as WO98/37075, WO2008043759A1, WO2011110876A1, WO2012027543A1, ZL200480024952.1, ZL201110249228.0.
The condition determination of X-ray powder diffraction: at strength of current 100mA, voltage 40kV, 0.02 ° of step-length, under 8 °/min of sweep velocity, is used x-ray powder diffraction instrument Rigaku D/MAX2500 to measure, and the measuring error of diffraction angle 2 θ is ± 0.2.
DSC test condition: at 25-220 DEG C, temperature rise rate is under 10K/min, is used poor formula heat scanner METTLERTOLEDO to measure.
IR test condition: pressing potassium bromide troche.
Raman spectrum test condition: spectral measurement ranges 150-1900cm
-1.
Method for detecting purity: chromatographic column: Symmetry shield RP18,250*4.6mm, 5 μ m; Mobile phase A: take 3.85g ammonium acetate, add 900ml water dissolution, and adjust PH to 4.8 with acetic acid, final water is quantitatively diluted to 1000ml.Mobile phase B: acetonitrile; Flow velocity: 1ml/min; Column temperature: 40 DEG C; Detect wavelength: 292nm; Sampling volume: 10 μ L, working time: 45 minutes; Test fluid: sample thief 40.0mg, accurately weighed, put in 25ml volumetric flask, use sample diluting liquid acetonitrile: water (1:1) dissolves, and is quantitatively diluted to scale, shakes up, and to obtain final product.
Gradient condition is as follows:
| Time (minute) | Mobile phase A (%) | Mobile phase B (%) |
| 0 | 80 | 20 |
| 40 | 20 | 80 |
| 45 | 20 | 80 |
The measuring method of solubleness: isothermal dynamic method; Reference: " Crystallization " third edition, author: J.W.Mullin, press: world book publishing company, date of publication: 1970-1-1.
Embodiment 1:
Dry methylsulfonic acid dabigatran etcxilate 0.2066g is added in 1mL dimethyl sulfoxide (DMSO) and forms suspension, under agitation this suspension is heated to 40 DEG C, solid is all dissolved, steady temperature, in 10 minutes, to the ethyl acetate that drips 10mL in solution, obtain suspension, vacuum filtration magma, product is dried to constant weight under 35 DEG C, normal pressure, obtains VI crystal formation methylsulfonic acid dabigatran etcxilate.
The HPLC purity of the present embodiment gained crystal is 99.21%.
The X-ray powder diffraction of the crystal that the present embodiment makes is as shown in Figure 1: it is mainly in diffraction angle 2 θ=4.44,8.96,11.00,13.50, there is characteristic peak at 17.80,18.10,22.32 degree places, and more fully characteristic peak is that diffraction angle 2 θ are 4.4 ± 0.2,9.0 ± 0.2,9.3 ± 0.2,9.5 ± 0.2,11.0 ± 0.2,13.5 ± 0.2,14.0 ± 0.2,17.8 ± 0.2,18.1 ± 0.2,22.3 ± 0.2,22.9 ± 0.2,26.8 ± 0.2,27.3 ± 0.2,32.1 ± 0.2 degree.
The DSC collection of illustrative plates of the crystal that the present embodiment makes is as shown in Figure 2: locate to have respectively endotherm(ic)peak at 180 DEG C.
The infared spectrum of the crystal that the present embodiment makes is as shown in Figure 3: at 3255.3cm
-1, 1731.8cm
-1, 1643.1cm
-1, 1581.3cm
-1, 1531.2cm
-1, 1369.2cm
-1, 1319.1cm
-1, 1199.5cm
-1, 1160.9cm
-1, 1045.2cm
-1, 941.1cm
-1, 829.2cm
-1, 783.0cm
-1there is absorption peak at place.
The Raman collection of illustrative plates of the crystal that the present embodiment makes is as shown in Figure 4: 1734cm
-1, 1666cm
-1, 1587cm
-1, 1531cm
-1, 1386cm
-1, 1344cm
-1, 1243cm
-1, 1207cm
-1, 1163cm
-1, 1099cm
-1, 1047cm
-1, 994cm
-1, 864cm
-1, 756cm
-1, 635cm
-1, 618cm
-1, 602cm
-1, 558cm
-1, 414cm
-1, 349cm
-1, 250cm
-1there is scattering peak at place.
The present embodiment gained crystal product has higher solubleness in given test solvent, and result is as follows:
Different crystal product solubility synopsis
Stability study data presentation, the present embodiment gained crystal product has good stability, and normal temperature sealing is placed after 1 day, 1 week, 3 weeks, 4 weeks, 9 weeks, 16 weeks, and crystal form V I product crystal formation does not all change.Stability collection of illustrative plates is referring to accompanying drawing 5, accompanying drawing 6.
Embodiment 2:
Dry methylsulfonic acid dabigatran etcxilate 0.2015g is added in 0.7mL propyl carbinol and forms suspension, under agitation this suspension is heated to 40 DEG C, solid is all dissolved, steady temperature, in 10 minutes, to the propyl acetate that drips 7mL in solution, obtain suspension, vacuum filtration magma, product is dried to constant weight under 35 DEG C, normal pressure, obtains VI crystal formation methylsulfonic acid dabigatran etcxilate.
The HPLC purity of the present embodiment gained crystal is 99.17%, and characterization data is identical with embodiment 1.
Embodiment 3:
Dry methylsulfonic acid dabigatran etcxilate 0.2073g is added in 1mL isopropylcarbinol and forms suspension, under agitation this suspension is heated to 35 DEG C, solid is all dissolved, steady temperature, in 20 minutes, to the methyl acetate that drips 8mL in solution, obtain suspension, vacuum filtration magma, product is dried to constant weight under 35 DEG C, normal pressure, obtains VI crystal formation methylsulfonic acid dabigatran etcxilate.
The HPLC purity of the present embodiment gained crystal is 99.26%, and characterization data is identical with embodiment 1.
Embodiment 4:
Dry methylsulfonic acid dabigatran etcxilate 0.2035g is added in 1mL ethylene glycol and forms suspension, under agitation this suspension is heated to 30 DEG C, solid is all dissolved, steady temperature, in 10 minutes, to the ethyl acetate that drips 12mL in solution, obtain suspension, vacuum filtration magma, product is dried to constant weight under 35 DEG C, normal pressure, obtains VI crystal formation methylsulfonic acid dabigatran etcxilate.
The HPLC purity of the present embodiment gained crystal is 99.11%, and characterization data is identical with embodiment 1.
Embodiment 5:
Dry methylsulfonic acid dabigatran etcxilate 0.2054g is added in 0.7mL dimethyl formamide and forms suspension, under agitation this suspension is heated to 45 DEG C, solid is all dissolved, steady temperature, in 10 minutes, to the propyl acetate that drips 7mL in solution, obtain suspension, vacuum filtration magma, product is dried to constant weight under 35 DEG C, normal pressure, obtains VI crystal formation methylsulfonic acid dabigatran etcxilate.
The HPLC purity of the present embodiment gained crystal is 99.14%, and characterization data is identical with embodiment 1.
Embodiment 6:
Dry methylsulfonic acid dabigatran etcxilate 0.2073g is added to formation suspension in 1mL dimethyl sulfoxide (DMSO) and n-butanol mixed solvent (mass percent each 50%), under agitation this suspension is heated to 40 DEG C, solid is all dissolved, steady temperature, in 5 minutes, to the ethyl acetate that drips 10mL in solution, obtain suspension, vacuum filtration magma, product is dried to constant weight under 45 DEG C, normal pressure, obtains VI crystal formation methylsulfonic acid dabigatran etcxilate.
The HPLC purity of the present embodiment gained crystal is 99.36%, and characterization data is identical with embodiment 1.
Embodiment 7:
Dry methylsulfonic acid dabigatran etcxilate 10g is added in 50mL dimethyl sulfoxide (DMSO) and forms suspension, under agitation this suspension is heated to 35 DEG C, solid is all dissolved, steady temperature, in 10 minutes, to the methyl acetate that drips 500mL in solution, obtain suspension, vacuum filtration magma, product is dried to constant weight under 35 DEG C, normal pressure, obtains VI crystal formation methylsulfonic acid dabigatran etcxilate.
The HPLC purity of the present embodiment gained crystal is 99.33%, and characterization data is identical with embodiment 1.
Embodiment 8
Pharmaceutical formulation: in 1000 capsules
| Methylsulfonic acid dabigatran etcxilate crystal form V I | 172.95g (being equivalent to 150mg dabigatran etcxilate) |
| Sulfuric acid | 20g |
| Sodium pyrosulfate | 20g |
| Gum arabic | 10g |
| Microcrystalline Cellulose | 150g |
| Talcum powder | 35g |
| Hypromellose | 40g |
| Simethicone | 0.08g |
| Water | 200g |
| 96% ethanol | 90g |
| Virahol | 90mg |
Capsule preparation method thereof:
By prescription, sulfuric acid, sodium pyrosulfate and gum arabic are dissolved in the water, as tackiness agent, Microcrystalline Cellulose is made to the micropill of 0.5～0.8mm; Using the Simethicone of recipe quantity and wherein the talcum powder of hypromellose, the 5g of 5g with 96% dissolve with ethanol as coating liquid, bag barrier gown; Again the methylsulfonic acid dabigatran etcxilate of recipe quantity and remaining 35g hypromellose are dissolved in Virahol, the above-mentioned solution that contains methylsulfonic acid dabigatran etcxilate is sprayed on tartrate micropill, after being dried, mixes with remaining 30.00mg talcum powder, filling to No. 1 capsule, to obtain final product.
The methylsulfonic acid dabigatran etcxilate capsule onset of preparation is rapid according to the method described above, and in the hydrochloric acid soln of 0.01mol/L, 10 minutes dissolution rates can reach more than 95%, contribute to ensure the human bioavailability of this product
The X-ray powder diffraction of embodiment 1 crystal.
Open and methylsulfonic acid dabigatran etcxilate crystal formation of proposing of the present invention and preparation method thereof, those skilled in the art can be by using for reference content herein, and the links such as appropriate change raw material, processing parameter realize.Method of the present invention and product are described by preferred embodiment, person skilled obviously can, not departing from content of the present invention, spirit and scope method as herein described and product is changed or suitably change and combination, realize the technology of the present invention.Special needs to be pointed out is, all similar replacements and change apparent to those skilled in the artly, they are deemed to be included in spirit of the present invention, scope and content.
Claims (10)
1. the crystal VI of methylsulfonic acid dabigatran etcxilate, is characterized in that the X-ray powder diffraction of this crystal is 4.4 ± 0.2,9.0 ± 0.2 at diffraction angle 2 θ, 11.0 ± 0.2,13.5 ± 0.2,17.8 ± 0.2,18.1 ± 0.2, and there is characteristic peak at 22.3 ± 0.2 degree places.
2. the crystal VI of methylsulfonic acid dabigatran etcxilate according to claim 1, is characterized in that the X-ray powder diffraction of this crystal is 4.4 ± 0.2,9.0 ± 0.2 at diffraction angle 2 θ, 9.3 ± 0.2,9.5 ± 0.2,11.0 ± 0.2,13.5 ± 0.2,14.0 ± 0.2,17.8 ± 0.2,18.1 ± 0.2,22.3 ± 0.2,22.9 ± 0.2,26.8 ± 0.2, there is characteristic peak at 27.3 ± 0.2,32.1 ± 0.2 degree places.
3. the crystal VI of methylsulfonic acid dabigatran etcxilate according to claim 2, is characterized in that this crystal has following X-ray diffracting spectrum:
4. the crystal VI of methylsulfonic acid dabigatran etcxilate according to claim 3, is characterized in that this crystal has substantially powder x-ray diffraction collection of illustrative plates as shown in Figure 1.
5. the crystal VI of methylsulfonic acid dabigatran etcxilate according to claim 1, is characterized in that this crystal located DSC endotherm(ic)peak at 180 ± 2 DEG C.
6. the crystal VI of methylsulfonic acid dabigatran etcxilate according to claim 1, is characterized in that the infrared spectra 3255 ± 2cm of this crystal
-1, 1732 ± 2cm
-1, 1643 ± 2cm
-1, 1581 ± 2cm
-1, 1531 ± 2cm
-1, 1369 ± 2cm
-1, 1319 ± 2cm
-1, 1199 ± 2cm
-1, 1161 ± 2cm
-1, 1045 ± 2cm
-1, 941 ± 2cm
-1, 829 ± 2cm
-1, 783 ± 2cm
-1there is absorption peak at place.
7. the crystal VI of methylsulfonic acid dabigatran etcxilate according to claim 1, is characterized in that the Raman spectrum of this crystal is at 1734 ± 2cm
-1, 1666 ± 2cm
-1, 1587 ± 2cm
-1, 1531 ± 2cm
-1, 1386 ± 2cm
-1, 1344 ± 2cm
-1, 1243 ± 2cm
-1, 1207 ± 2cm
-1, 1163 ± 2cm
-1, 1099 ± 2cm
-1, 1047 ± 2cm
-1, 994 ± 2cm
-1, 864 ± 2cm
-1, 756 ± 2cm
-1, 635 ± 2cm
-1, 618 ± 2cm
-1, 602 ± 2cm
-1, 558 ± 2cm
-1, 414 ± 2cm
-1, 349 ± 2cm
-1, 250 ± 2cm
-1there is scattering peak at place.
8. a preparation method for the crystal VI of methylsulfonic acid dabigatran etcxilate described in any one in claim 1～7, is characterized in that comprising the steps:
A) methylsulfonic acid dabigatran etcxilate crude product is added in good solvent, be configured to the suspension of 200～300g/L;
B) solid is dissolved completely at 30～45 DEG C;
C) in mixing solutions, slowly add dissolved agent, dissolved agent consumption is 8～12 times of solvent volume;
D) suspension that suction filtration forms;
E) dry methylsulfonic acid dabigatran etcxilate crystal product is to constant weight.
9. preparation method according to claim 8, is characterized in that described methylsulfonic acid dabigatran etcxilate crude product is unformed or known arbitrary crystal formation pressed powder, its HPLC purity >=95%; One or several mixture in described good solvent selection ethylene glycol, propyl carbinol, isopropylcarbinol, methyl-sulphoxide, dimethyl formamide; Described dissolved agent is selected from one or more the mixture in ethyl acetate, propyl acetate, methyl acetate, butylacetate, methyl-formiate, ethyl formate, propyl formate; The slow drop rate of dissolved agent is 5%～20% of per minute dropping dissolved agent volume; Described drying conditions is that temperature is 30-45 DEG C, normal pressure.
10. a pharmaceutical composition, its crystal VI taking the methylsulfonic acid dabigatran etcxilate described in any one in claim 1～7, as active substance or main active substances, is aided with pharmaceutically acceptable auxiliary material, makes pharmaceutical preparation.
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105572275A (en) * | 2014-10-08 | 2016-05-11 | 华仁药业股份有限公司 | Dabigatran etexilate mesylate content detection method |
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