CN103664882A - Dabigatran etexilate in crystal modification form, and preparation method and use of dabigatran etexilate - Google Patents
Dabigatran etexilate in crystal modification form, and preparation method and use of dabigatran etexilate Download PDFInfo
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- CN103664882A CN103664882A CN201210352147.8A CN201210352147A CN103664882A CN 103664882 A CN103664882 A CN 103664882A CN 201210352147 A CN201210352147 A CN 201210352147A CN 103664882 A CN103664882 A CN 103664882A
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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
- 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
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Abstract
The invention provides dabigatran etexilate in a crystal modification form A, and a preparation method and use of the dabigatran etexilate. The X-ray powder diffraction pattern of the dabigatran etexilate in the crystal modification form A is shown in figure 1. The dabigatran etexilate in the crystal modification form A can be easily prepared into a medicinal preparation, and shows high dissolution and releasing performance when forming the medicinal preparation as a poorly water-soluble medicament. In addition, the preparation method for the dabigatran etexilate in the crystal modification form A is easy to industrialize and high in production adaptability.
Description
Technical field
The present invention relates to dabigatran etcxilate of a kind of crystal modification form and its production and use.
Background technology
Dabigatran etcxilate (Dabigatran) is the novel anticoagulation medicine with various features of German Boehringer Ingelheim company exploitation.In April, 2008, first, in Germany and Britain's listing, commodity are called Pradaxa, for preventing and treating Acute Venous thrombus (VTE).This is the oral new drug of the anticoagulation of first listing over 50 years after warfarin, is another milestone in anticoagulation therapy field and potential lethality thrombus prevention field.U.S. food and Drug Administration approval Pradaxa capsule on October 19th, 2010 (dabigatran etcxilate) is preventing apoplectic and blood coagulation in having rhythm abnormality (atrial fibrillation) patient.
Dabigatran etcxilate, chemistry (Z)-3-(2-(((4-(N'-((hexyloxy) carbonyl) amidino) phenyl) amino) methyl)-1-methyl-N-(pyridine-2-yl)-1H-benzoglyoxaline-5-formamido-) ethyl propionate by name, molecular formula is suc as formula shown in I:
As everyone knows, solid chemical material can be divided into crystalline state, amorphous state and common crystalline form.The different existences of same solid pharmaceutical often have different physico-chemical properties, as solubleness and dissolution rate etc.The existence of medicine and polymorphous research have and important meaning guaranteeing stability and the safety and effectiveness in clinical use in pharmaceutical production storage process.The existence of medicine is relevant with drug molecular structure with crystal formation, and during simultaneously also with preparation, crystallization method is relevant.At present existing one piece of invention about dabigatran etcxilate crystal formation and preparation method thereof (WO2008059029A2).
Summary of the invention
One object of the present invention is to provide a kind of dabigatran etcxilate of crystal modification form, and it is superior in quality, and HLPC detects purity and reaches more than 99%.
Another object of the present invention is to provide the preparation method of the dabigatran etcxilate of above-mentioned crystal modification form, technique simple possible, favorable reproducibility.
A further object of the present invention is to provide the pharmaceutical applications of the pharmaceutical composition of the dabigatran etcxilate that contains crystal modification form and the dabigatran etcxilate of this crystal modification form.
For achieving the above object, the invention provides following technical scheme:
A dabigatran etcxilate of crystal modification form A, its X-ray powder diffraction pattern as shown in Figure 1.Further, the dabigatran etcxilate of described crystal modification form A has the constitutional features of the nmr spectrum shown in Fig. 2.
The preparation method who the present invention further provides the dabigatran etcxilate of described crystal modification form A, the method comprises the following steps:
(1) dabigatran etcxilate is dissolved in and in organic solvent A, makes solution;
(2) in the solution of step (1), add solvent B, stir crystallize out, and filter and collect crystal, obtain the dabigatran etcxilate of described crystal modification form A.
According to preparation method provided by the invention, wherein said organic solvent A can be one or more in alcohol, ketone, ether, oxygen heterocyclic ring, is preferably ketone, more preferably acetone.Described solvent B can be organic solvent C or water.Described organic solvent C can be one or more in alcohol, ketone, ether, oxygen heterocyclic ring and nitrile, is preferably one or more in alcohol, ether, oxygen heterocyclic ring and nitrile.Preferably, described solvent B is one or more in sherwood oil, water, Virahol, tetrahydrofuran (THF) and acetonitrile.Wherein, described solvent B is different from described organic solvent C.Preferably, the solubleness of dabigatran etcxilate in described solvent B lower than it solubleness in described organic solvent C.
Wherein, described alcohol can be one or more in methyl alcohol, ethanol, n-propyl alcohol, Virahol, propyl carbinol, the trimethyl carbinol and isopropylcarbinol; Described ketone can be acetone and/or butanone; Described ether can be sherwood oil; Described oxygen heterocyclic ring can be dioxane and/or tetrahydrofuran (THF).
According to preparation method provided by the invention, in step (1), with respect to 1 gram of dabigatran etcxilate, the consumption of described organic solvent A can be 10 ~ 100ml, is preferably 20 ~ 40ml.Preferably, described step (1) can also comprise and is heated at 30 ~ 80 ℃, dabigatran etcxilate be dissolved.
In described step (2), with respect to 1 gram of dabigatran etcxilate, the consumption of described solvent B can be 10 ~ 100ml, is preferably 20 ~ 40ml.
According to preparation method provided by the invention, preferably, described step (2) can also comprise after adding solvent B makes solution be cooled to-5 ~ 30 ℃, be preferably 5 ~ 20 ℃, or in step (2), the temperature of described solvent B is 5 ~ 30 ℃, is preferably 10 ~ 20 ℃.
According to preparation method provided by the invention, wherein, described step (1) can also comprise prepares dabigatran etcxilate in accordance with the following methods: by N-[[2-(((4-carbamimido-phenyl)-amino-methyl)-1-methyl isophthalic acid H-benzoglyoxaline-5-yl)-carbonyl]-N-(pyridine-2-yl)-Beta-alanine ethyl ester and the just own ester of chloroformic acid, in the solution of potassium carbonate of tetrahydrofuran (THF) and water, under normal temperature, react, after having reacted, separate organic layer, with anhydrous magnesium sulfate drying, filtration obtains the reaction soln that contains dabigatran etcxilate, and this reaction solution is concentrated into the dry dabigatran etcxilate that obtains.Above-mentioned preparation method can carry out according to bibliographical information, for example can be referring to, and CN1248251A.
In a kind of preferred embodiment of the present invention, the preparation method of the dabigatran etcxilate of described crystal modification form A is: at 30 ~ 80 ℃, dabigatran etcxilate 1g is dissolved in 10 ~ 50ml acetone and makes solution, the sherwood oil 10-100ml of-10 ~ 15 ℃ is added in this solution and stirs and separate out, filter, be dried, obtain the dabigatran etcxilate of crystal modification form A provided by the invention.
In another kind of preferred embodiment of the present invention, the preparation method of the dabigatran etcxilate of described crystal modification form A is: at 30 ~ 80 ℃, dabigatran etcxilate 1g is dissolved in 10 ~ 50ml acetone and makes solution, the water 10-100ml of 0 ~ 5 ℃ is added in this solution and stirs and separate out, filter, be dried, obtain the dabigatran etcxilate of crystal modification form A provided by the invention.
In another specific embodiments of the present invention, the preparation method of the dabigatran etcxilate of described crystal modification form A is: by N-[[2-(((4-carbamimido-phenyl)-amino-methyl)-1-methyl isophthalic acid H-benzoglyoxaline-5-yl)-carbonyl]-N-(pyridine-2-yl)-Beta-alanine ethyl ester and the just own ester of chloroformic acid be dissolved in reaction at normal temperatures in the solution of tetrahydrofuran (THF) that concentration of potassium carbonate is 80 grams per liters and water (volume ratio 5:1), after having reacted, separate organic layer, with anhydrous magnesium sulfate drying, filtering magnesium sulfate, obtains the reaction soln that contains dabigatran etcxilate.This reaction soln is concentrated into dry, then uses acetone solution, under stirring, add sherwood oil, crystallization, filters, and washing final vacuum is dry, obtains the dabigatran etcxilate of crystal modification form A provided by the invention.
Dabigatran etcxilate solid or its pharmaceutical composition of crystal modification form A prepared by the present invention, specific structural features is as follows:
1.X-ray powder diffraction detects
Instrument: Rigaku D/max2500 type X-ray diffractometer;
Target: Cu-K α radiation
2 θ sweep limit: 0-50 °;
Step angle: 0.04 ℃;
Computing time: 0.5 second;
Pipe is pressed: 40KV;
Pipe stream: 100mA;
Sweep velocity: 8 ℃/min;
Filter disc: graphite monochromator;
The X-ray powder diffraction detection display of dabigatran etcxilate solid of the present invention is crystal modification form, as shown in Figure 1.
2.
1h NMR detects
Instrument: BRUKER AV400 NMR;
Solvent: DMSO-d
6;
Dabigatran etcxilate solid of the present invention
1hNMR characteristic peak is: δ: 0.841-0.875 (t, 3H, CH
3), 1.095-1.130 (t, 3H, CH
3), 1.276-1.388 (6H, CH
2cH
2cH
2), 1.535-1.604 (m, 2H, CH
2), 2.656-2.691 (t, 2H, CH
2cO), 3.755 (s, 3H, CH
3n), 3.939-3.992 (m, 4H, 2CH
2o), 4.199-4.234 (t, 2H, CH
2), 4.577-4.590(d, 2H, CH
2n), 6.745-6.767(d, 2H, phenyl), 6.868-6.888(d, 1H, phenyl), 6.913-6.940(t, 1H, NH), 7.090-7.163 (m, 1H, pyridyl), 7.376-7.397(d, 1H, pyridyl), 7.463(s, 1H, phenyl), 7.509-7.513(d, 1H, phenyl), 7.529-7.552(dd, 1H, pyridyl), 7.776-7.798(d, 2H, phenyl), 8.371-8.386(dd, 1H, pyridyl), 8.9(br s, 2H, NH
2), as shown in Figure 2.
The present invention further provides a kind of pharmaceutical composition, the dabigatran etcxilate of the dabigatran etcxilate that this pharmaceutical composition comprises crystal modification form A of the present invention or the crystal modification form A that makes according to the inventive method, and one or more pharmaceutical excipients.Wherein said pharmaceutical composition is oral preparations or injection, preferred oral preparation.Such as tablet, capsule, granule, oral liquid etc.
According to pharmaceutical composition provided by the invention, wherein, described one or more pharmaceutical excipients comprise: thinner, disintegrating agent, solvent, stablizer, tackiness agent and lubricant etc.Wherein thinner includes but not limited to: starch, Microcrystalline Cellulose, sucrose, dextrin, lactose, Icing Sugar, glucose, low molecular dextran, sodium-chlor or N.F,USP MANNITOL etc.Described tackiness agent includes but not limited to: water, ethanol, starch slurry, syrup, gelatin, methylcellulose gum, Vltra tears, Xylo-Mucine, sodium alginate or polyvinylpyrrolidone etc.Described lubricant includes but not limited to: Magnesium Stearate, stearic acid, sodium stearyl fumarate etc.Described disintegrating agent includes but not limited to: starch, sodium starch glycolate, citric acid, sodium bicarbonate and low-substituted hydroxypropyl cellulose etc.Described stablizer comprises but is not limited to: BHA, BHT, vitamins C, metal chelator EDTA-2Na etc.
The application of the dabigatran etcxilate of the crystal modification form A that the present invention further provides the dabigatran etcxilate of crystal modification form A of the present invention or made according to the inventive method in the medicine for the preparation for the treatment of thrombus.The dabigatran etcxilate solid of the crystal modification form A that the present invention finds has purposes and the result for the treatment of identical with known dabigatran etcxilate solid chemical compound itself.
The positively effect that the dabigatran etcxilate of crystal modification form A provided by the invention has is:
1, the dabigatran etcxilate of described crystal modification form A is easier to make pharmaceutical preparation, improves the absorption of medicine.Known dabigatran etcxilate is poorly water soluble drugs, by comparison, and the dabigatran etcxilate of crystal modification form A of the present invention has better stripping to discharge behavior while making pharmaceutical preparation.The dabigatran etcxilate preparation method of crystal modification form A of the present invention is easy to industrialization simultaneously, produces strong adaptability.
2, the dabigatran etcxilate of the crystal modification form A that prepared by the present invention, demonstrating valuable characteristic aspect stripping and preparation preparation, has quality high, and solubleness is good, is beneficial to the advantages such as absorption.
Accompanying drawing explanation
Below, describe by reference to the accompanying drawings embodiment of the present invention in detail, wherein:
The X-ray powder diffraction of the dabigatran etcxilate of Fig. 1 crystal modification form provided by the invention A;
The dabigatran etcxilate of Fig. 2 crystal modification form provided by the invention A
1hNMR collection of illustrative plates.
Embodiment
Below in conjunction with embodiment, the present invention is further described in detail, the embodiment providing is only in order to illustrate the present invention, rather than in order to limit the scope of the invention.
Dabigatran etcxilate 1g is dissolved in 25ml acetone in room temperature, in the settled solution of gained, drips sherwood oil 25ml, stirring is separated out, and filters, dry, collects the dabigatran etcxilate powder 0.8g of crystal modification form A of the present invention, and it is 99.2% that HPLC measures content.Its X-ray powder diffraction as shown in Figure 1,
1hNMR collection of illustrative plates as shown in Figure 2.
Dabigatran etcxilate 1g is dissolved at 10 ℃ in 25ml acetone, in the settled solution of gained, drips sherwood oil 37.5ml, stirring is separated out, filter, be dried, collect the dabigatran etcxilate white powder 0.9g of crystal modification form A of the present invention, it is 99.0% that HPLC measures content.Its X-ray powder diffraction as shown in Figure 1,
1hNMR collection of illustrative plates as shown in Figure 2.
Dabigatran etcxilate 1g is dissolved in acetone 25ml in 0 ℃, in the settled solution of gained, drips sherwood oil 25ml, stirring is separated out, filter, be dried, collect the dabigatran etcxilate white powder 0.91g of crystal modification form A of the present invention, it is 99.5% that HPLC measures content.Its X-ray powder diffraction as shown in Figure 1,
1hNMR collection of illustrative plates as shown in Figure 2.
embodiment 4
Dabigatran etcxilate 1g is dissolved in acetone 25ml in room temperature, in the settled solution of gained, drips sherwood oil 50ml, stirring is separated out, filter, be dried, collect the dabigatran etcxilate white powder 0.93g of crystal modification form A of the present invention, it is 99.01% that HPLC measures content.Its X-ray powder diffraction as shown in Figure 1,
1hNMR collection of illustrative plates as shown in Figure 2.
Dabigatran etcxilate 1g is dissolved in acetone 25ml in room temperature, in the settled solution of gained, drips water 25ml, stirring is separated out, and filters, dry, collects the dabigatran etcxilate white powder 0.87g of crystal modification form A of the present invention, and it is 99.02% that HPLC measures content.Its X-ray powder diffraction as shown in Figure 1,
1hNMR collection of illustrative plates as shown in Figure 2.
Dabigatran etcxilate 1g is dissolved in acetone 25ml in room temperature, in the settled solution of gained, drips Virahol 5ml, stirring is separated out, and filters, dry, collects the dabigatran etcxilate white powder 0.68g of crystal modification form A of the present invention, and it is 99.32% that HPLC measures content.Its X-ray powder diffraction as shown in Figure 1,
1hNMR collection of illustrative plates as shown in Figure 2.
embodiment 7
Dabigatran etcxilate 1g is dissolved in acetone 25ml in room temperature, in the settled solution of gained, drips tetrahydrofuran (THF) 10ml, stirring is separated out, filter, be dried, collect the dabigatran etcxilate white powder 0.58g of crystal modification form A of the present invention, it is 99.12% that HPLC measures content.Its X-ray powder diffraction as shown in Figure 1,
1hNMR collection of illustrative plates as shown in Figure 2.
Dabigatran etcxilate 1g is dissolved in acetone 25ml in room temperature, in the settled solution of gained, drips acetonitrile 2ml, stirring is separated out, and filters, dry, collects the dabigatran etcxilate white powder 0.57g of crystal modification form A of the present invention, and it is 99.22% that HPLC measures content.Its X-ray powder diffraction as shown in Figure 1,
1hNMR collection of illustrative plates as shown in Figure 2.
By being dissolved in acetone 25ml under 30 ℃ of conditions of dabigatran etcxilate 1g heating, in the settled solution of gained, drip sherwood oil 25ml, stirring is separated out, filter, be dried, collect the dabigatran etcxilate white powder 0.78g of crystal modification form A of the present invention, it is 99.3% that HPLC measures content.Its X-ray powder diffraction as shown in Figure 1,
1hNMR collection of illustrative plates as shown in Figure 2.
embodiment 10
By being dissolved in acetone 20ml under 40 ℃ of conditions of dabigatran etcxilate 1g heating, in the settled solution of gained, drip sherwood oil 40ml, stirring is separated out, filter, be dried, collect the dabigatran etcxilate white powder 0.65g of crystal modification form A of the present invention, it is 99.10% that HPLC measures content.Its X-ray powder diffraction as shown in Figure 1,
1hNMR collection of illustrative plates as shown in Figure 2.
embodiment 11
By being dissolved in acetone 20ml under 50 ℃ of conditions of dabigatran etcxilate 1g heating, in the settled solution of gained, drip sherwood oil 40ml, stirring is separated out, filter, be dried, collect the dabigatran etcxilate white powder 0.55g of crystal modification form A of the present invention, it is 99.07% that HPLC measures content.Its X-ray powder diffraction as shown in Figure 1,
1hNMR collection of illustrative plates as shown in Figure 2.
embodiment 12
By being dissolved in acetone 20ml under 60 ℃ of conditions of dabigatran etcxilate 1g heating, in the settled solution of gained, drip sherwood oil 20ml, stirring is separated out, filter, be dried, collect the dabigatran etcxilate white powder 0.38g of crystal modification form A of the present invention, it is 99.05% that HPLC measures content.Its X-ray powder diffraction as shown in Figure 1,
1hNMR collection of illustrative plates as shown in Figure 2.
embodiment 13
By being dissolved in acetone 20ml under 70 ℃ of conditions of dabigatran etcxilate 1g heating, in the settled solution of gained, drip sherwood oil 20ml, stirring is separated out, filter, be dried, collect the dabigatran etcxilate white powder 0.32g of crystal modification form A of the present invention, it is 99.02% that HPLC measures content.Its X-ray powder diffraction as shown in Figure 1,
1hNMR collection of illustrative plates as shown in Figure 2.
embodiment 14
The present embodiment is for illustrating the preparation of the pharmaceutical composition of the dabigatran etcxilate that contains crystal modification form A of the present invention.
Prescription: 1000 capsules
The dabigatran etcxilate of crystal modification form A is crossed to 80 mesh sieves, and auxiliary material is crossed 60 mesh sieves.The dabigatran etcxilate, Microcrystalline Cellulose, pregelatinized Starch and the lactose that by recipe quantity, take crystal modification form A fully mix, and add 1%(weight/volume) hypromellose aqueous solution, softwood processed, sieves, and wet granular processed is dry in 55 ℃.Magnesium Stearate is added in above-mentioned particle, measures intermediate content, encapsulated, packing.
embodiment 15
The present embodiment is for illustrating the preparation of the pharmaceutical composition of the dabigatran etcxilate that contains crystal modification form A of the present invention.
Prescription: 1000
The dabigatran etcxilate of crystal modification form A is crossed to 80 mesh sieves, and auxiliary material is crossed 60 mesh sieves.The dabigatran etcxilate, Microcrystalline Cellulose and the lactose that by recipe quantity, take crystal modification form A fully mix, and add 1%(weight/volume) hypromellose aqueous solution, softwood processed, sieves, and wet granular processed is dry in 55 ℃.Polyvinylpolypyrrolidone and Magnesium Stearate are added in above-mentioned particle, measure intermediate content, compressing tablet, packing.
Because the present invention describes by conventional embodiment, the technician who is proficient in this technology can modify and equivalence change to it, and this is understood to include within the scope of the present invention.
Claims (10)
1. a dabigatran etcxilate of crystal modification form A, its X-ray powder diffraction pattern as shown in Figure 1.
2. the dabigatran etcxilate of crystal modification form A according to claim 1, wherein, the dabigatran etcxilate of described crystal modification form A has the constitutional features of nmr spectrum as shown in Figure 2.
3. according to the preparation method of the dabigatran etcxilate of crystal modification form A described in claim 1 or 2, the method comprises the following steps:
(1) dabigatran etcxilate is dissolved in and in organic solvent A, makes solution;
(2) in the solution of step (1), add solvent B, stir crystallize out, and filter and collect crystal, obtain the dabigatran etcxilate of described crystal modification form A.
4. preparation method according to claim 3, in step (1), described organic solvent A is one or more in alcohol, ketone, ether, oxygen heterocyclic ring, is preferably ketone, more preferably acetone; Described solvent B is organic solvent C or water, and described organic solvent C is one or more in alcohol, ketone, ether, oxygen heterocyclic ring and nitrile, is preferably one or more in alcohol, ether, oxygen heterocyclic ring and nitrile; Preferably, described solvent B is one or more in sherwood oil, water, Virahol, tetrahydrofuran (THF) and acetonitrile.
5. preparation method according to claim 4, wherein, described alcohol is one or more in methyl alcohol, ethanol, n-propyl alcohol, Virahol, propyl carbinol, the trimethyl carbinol and isopropylcarbinol; Described ketone is acetone and/or butanone; Described ether is sherwood oil; Described oxygen heterocyclic ring is dioxane and/or tetrahydrofuran (THF).
6. according to the preparation method described in any one in claim 3 to 5, in step (1), with respect to 1 gram of dabigatran etcxilate, the consumption of described organic solvent A is 10 ~ 100ml, is preferably 20 ~ 40ml; In step (2), with respect to 1 gram of dabigatran etcxilate, the consumption of described solvent B is 10 ~ 100ml, is preferably 20 ~ 40ml.
7. preparation method according to claim 3, wherein, described step (2) also comprises after adding solvent B makes solution be cooled to-5 ~ 30 ℃, be preferably 5 ~ 20 ℃, or in step (2), the temperature of described solvent B is 5 ~ 30 ℃, is preferably 10 ~ 20 ℃.
8. preparation method according to claim 3, wherein, described step (1) also comprises prepares dabigatran etcxilate in accordance with the following methods: by N-[[2-(((4-carbamimido-phenyl)-amino-methyl)-1-methyl isophthalic acid H-benzoglyoxaline-5-yl)-carbonyl]-N-(pyridine-2-yl)-Beta-alanine ethyl ester and the just own ester of chloroformic acid, in the solution of potassium carbonate of tetrahydrofuran (THF) and water, under normal temperature, react, after having reacted, separate organic layer, with anhydrous magnesium sulfate drying, filtration obtains the reaction soln that contains dabigatran etcxilate, and this reaction solution is concentrated into the dry dabigatran etcxilate that obtains.
9. a pharmaceutical composition, the dabigatran etcxilate of the dabigatran etcxilate that this pharmaceutical composition comprises the crystal modification form A described in claim 1 or 2 or the crystal modification form A making according to method described in any one in claim 3 to 8, and one or more pharmaceutical excipients.
10. the application of the dabigatran etcxilate of the dabigatran etcxilate of crystal modification form A or the crystal modification form A that makes according to method described in any one in claim 3 to 8 in the medicine for the preparation for the treatment of thrombus described in claim 1 or 2.
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CN106032376A (en) * | 2015-03-17 | 2016-10-19 | 天津药物研究院有限公司 | Dabigatran etexilate of crystal variant form C, preparation method and uses thereof |
CN106032375A (en) * | 2015-03-17 | 2016-10-19 | 天津药物研究院有限公司 | Dabigatran etexilate of crystal variant form F, preparation method and uses thereof |
CN106032374A (en) * | 2015-03-17 | 2016-10-19 | 天津药物研究院有限公司 | Dabigatran etexilate of crystal variant form D, preparation method and uses thereof |
CN106032372A (en) * | 2015-03-17 | 2016-10-19 | 天津药物研究院有限公司 | Dabigatran etexilate of crystal variant form E, preparation method and uses thereof |
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CN106032375A (en) * | 2015-03-17 | 2016-10-19 | 天津药物研究院有限公司 | Dabigatran etexilate of crystal variant form F, preparation method and uses thereof |
CN106032374A (en) * | 2015-03-17 | 2016-10-19 | 天津药物研究院有限公司 | Dabigatran etexilate of crystal variant form D, preparation method and uses thereof |
CN106032372A (en) * | 2015-03-17 | 2016-10-19 | 天津药物研究院有限公司 | Dabigatran etexilate of crystal variant form E, preparation method and uses thereof |
CN106032373A (en) * | 2015-03-17 | 2016-10-19 | 天津药物研究院有限公司 | Dabigatran etexilate of crystal variant form G, preparation method and uses thereof |
CN105418587A (en) * | 2015-11-30 | 2016-03-23 | 山东新华制药股份有限公司 | Refining method of pradaxa free alkali |
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