Preparation method of dabigatran etexilate mesylate crystal form I

Abstract

The invention discloses a preparation method of a dabigatran etexilate mesylate crystal form I. The preparation method comprises the following steps: mixing dabigatran etexilate with a first solvent at a first temperature, then filtering, and taking filtrate to prepare a first solution; mixing methanesulfonic acid and a second solvent to prepare a second solution; mixing the first solution and the second solution at a second temperature, crystallizing, filtering, washing, taking a filter cake, and drying; wherein the first solvent comprises acetone; the second solvent comprises a mixed solution of acetone and ethyl acetate. The preparation method disclosed by the invention can be used for effectively inhibiting conversion from the crystal form I to the crystal form II of the dabigatran etexilate mesylate, and is short in process, simple and convenient to operate and short in required crystallization time.

Description

Technical Field

[0001] The present invention relates to the field of chemical medicine, and particularly relates to a preparation method of dabigatran etexilate mesylate crystal form I. Background Art

[0002] Dabigatran etexilate mesylate is a direct thrombin inhibitor developed by Boehringer Ingelheim GmbH and applied clinically, and is a novel oral anticoagulant. The mechanism of action of dabigatran etexilate mesylate is to reversibly and strongly competitively bind to the fibrin-specific binding site of thrombin, so that the formation of fibrin is blocked, thereby inhibiting the formation of thrombus.

[0003] Dabigatran etexilate mesylate is a prodrug of dabigatran, which is metabolized in vivo to be converted into active dabigatran. Compared with warfarin, dabigatran etexilate mesylate does not need to frequently monitor the coagulation function and adjust the dosage during the treatment process, has few drug interactions, and is not affected by eating, thereby improving the medication compliance of patients.

[0004] The chemical name of dabigatran etexilate mesylate is ethyl 3-[[[2-[[[4-[[[(hexyloxy)carbonyl]amino]iminomethyl]phenyl]amino]methyl]-1-methyl-1H-benzimidazol-5-yl]carbonyl](pyridin-2-yl)amino]propionate mesylate, and its structural formula is shown as follows:

[0005] Research reports show that dabigatran etexilate mesylate has two crystal forms, namely crystal form I and crystal form II, wherein the melting point of crystal form I is 180±3°C, and the melting point of crystal form II is 190±3°C. Since the melting point of crystal form I is lower than that of crystal form II, crystal form I is a metastable crystal form and crystal form II is a stable crystal form. According to the traditional preparation method of dabigatran etexilate mesylate crystal form I, it is very easy to have mixed crystals of crystal form II, and it is difficult to stably obtain a relatively pure crystal form I sample, and it is difficult to achieve stable and controllable quality, thereby affecting its drug stability and physical and chemical properties, and may lead to differences in the bioavailability of the final drug, affecting the medication safety of patients.

[0006] A traditional technology discloses a preparation method of dabigatran etexilate mesylate, which adopts the method of fractional crystallization in different solvents. Although crystal form I can be prepared, this method is relatively cumbersome and is not conducive to large-scale production.

[0007] Another traditional technology discloses a preparation method of dabigatran etexilate mesylate, which inhibits the conversion of crystal form I to crystal form II by dissolving dabigatran etexilate in acetone and then adding ethyl acetate for crystallization. However, it requires a longer crystallization time during the crystallization process of industrial scale-up production, and there is still a possibility of converting to crystal form II, and this process has certain risks. Summary of the Invention

[0008] Based on this, the present invention provides a method for preparing dabigatran etexilate mesylate crystal form I, which can effectively inhibit the transformation of dabigatran etexilate mesylate crystal form I into crystal form II, and has a short process, simple operation and short crystallization time required.

[0009] The present invention is achieved through the following technical solutions.

[0010] A method for preparing dabigatran etexilate mesylate crystal form I includes the following steps: Mix dabigatran etexilate with a first solvent at a first temperature, then filter, take the filtrate to prepare a first solution; Mix methanesulfonic acid with a second solvent to prepare a second solution; Mix the first solution and the second solution at a second temperature to crystallize, then filter, wash, and take the filter cake to dry; Wherein, the first solvent includes acetone; the second solvent includes a mixed solution of acetone and ethyl acetate.

[0011] In one embodiment, the mass-volume ratio of dabigatran etexilate to the first solvent is 1 g:(5 mL to 20 mL).

[0012] In one embodiment, the first temperature is selected from 30°C to 50°C.

[0013] In one embodiment, the first temperature is selected from 30°C to 40°C.

[0014] In one embodiment, the mass-volume ratio of dabigatran etexilate to the second solvent is 1 g:(5 mL to 30 mL).

[0015] In one embodiment, the second temperature is selected from -5°C to 15°C.

[0016] In one embodiment, the second temperature is selected from 0°C to 5°C.

[0017] In one embodiment, in the second solvent, the volume ratio of acetone to ethyl acetate is 1:(0.5 to 1.3).

[0018] In one embodiment, in the second solvent, the volume ratio of acetone to ethyl acetate is 1:(0.9 to 1.1).

[0019] In one embodiment, the way of mixing the first solution and the second solution is to drop the first solution into the second solution.

[0020] Compared with the prior art, the method for preparing dabigatran etexilate mesylate crystal form I of the present invention has the following beneficial effects: In the present invention, dabigatran etexilate is first dissolved in acetone, and methanesulfonic acid is dissolved in a mixed solution of acetone and ethyl acetate. Then, the two are mixed, which can effectively inhibit the transformation of crystal form I to crystal form II. Finally, the obtained crystal form I of dabigatran etexilate mesylate has a high yield and high purity.

[0021] Furthermore, the preparation method of the present invention has short process steps, is easy to operate, and requires a short crystallization time, and can realize industrial scale-up production. BRIEF DESCRIPTION OF THE DRAWINGS Attached Figure 1 is the structural formula of crystal form I of dabigatran etexilate mesylate. EMBODIMENTS

[0022] For ease of understanding the present invention, the present invention will be described more fully hereinafter with reference to the relevant embodiments. Preferred embodiments of the present invention are given in the examples. However, the present invention can be implemented in many different forms and is not limited to the embodiments described herein. On the contrary, these embodiments are provided so that the understanding of the disclosure of the present invention is more thorough and comprehensive.

[0023] Unless otherwise specified, the following terms and phrases used herein are intended to have the following meanings. A particular term or phrase should not be considered indeterminate or unclear without a special definition, but should be understood in its ordinary meaning. When a trade name appears herein, it is intended to refer to the corresponding commodity or its active ingredient.

[0024] The solvents used in the present invention are commercially available.

[0025] "Crystal form" or "crystalline form" refers to a solid having a highly regular chemical structure, including but not limited to, single-component or multi-component crystals, and / or polymorphs, solvates, hydrates, clathrates, co-crystals, salts, solvates of salts, hydrates of salts of a compound. The crystalline form of a substance can be obtained by many methods known in the art. Such methods include but are not limited to, melt crystallization, melt cooling, solvent crystallization, crystallization in a confined space, such as in nanopores or capillaries, crystallization on a surface or template, such as on a polymer, crystallization in the presence of an additive such as a co-crystallization countermolecule, desolvation, dehydration, rapid evaporation, rapid cooling, slow cooling, vapor diffusion, sublimation, reaction crystallization, anti-solvent addition, grinding, and solvent-drop grinding, etc.

[0026] "Solvent" refers to a substance (typically a liquid) that can completely or partially dissolve another substance (typically a solid). Solvents used in the implementation of the present invention include, but are not limited to, water, acetic acid, acetone, acetonitrile, benzene, chloroform, carbon tetrachloride, dichloromethane, dimethyl sulfoxide, 1,4-dioxane, ethanol, ethyl acetate, butanol, tert-butanol, N,N-dimethylacetamide, N,N-dimethylformamide, formamide, formic acid, heptane, hexane, isopropanol, methanol, methyl ethyl ketone, 1-methyl-2-pyrrolidone, mesitylene, nitromethane, polyethylene glycol, propanol, 2-propanone, pyridine, tetrahydrofuran, toluene, xylene, their mixtures, and so on.

[0027] Crystal forms or amorphous forms can be identified by a variety of technical means, such as X-ray powder diffraction (XRPD), infrared absorption spectroscopy (IR), melting point method, differential scanning calorimetry (DSC), thermogravimetric analysis (TGA), nuclear magnetic resonance method, Raman spectroscopy, single crystal X-ray diffraction, solution calorimetry, scanning electron microscopy (SEM), quantitative analysis, solubility, and dissolution rate, etc.

[0028] X-ray powder diffraction (XRPD) can detect information such as changes in crystal form, crystallinity, and crystal structure state, and is a commonly used means for identifying crystal forms. The peak positions in the XRPD pattern mainly depend on the crystal form structure and are relatively insensitive to experimental details, while the relative peak heights depend on many factors related to sample preparation and instrument geometry. The measurement of 2θ in the XRPD pattern can have experimental errors, and there may be slight differences in the measurement of 2θ in the XRPD patterns between different instruments and different samples. Therefore, the numerical values of the 2θ cannot be regarded as absolute.

[0029] Solids with the same chemical composition often form polymorphs or variants with different crystal structures under different thermodynamic conditions, and this phenomenon is called polymorphism or polyphasic phenomenon. When the temperature and pressure conditions change, mutual transformation occurs between the variants, and this phenomenon is called crystal form transformation. The crystal form or amorphous form of the compounds of the present invention can undergo crystal form transformation under appropriate conditions.

[0030] In the context of the present invention, the 2θ values in the X-ray powder diffraction pattern are all in degrees (°).

[0031] In the present invention, "room temperature" generally refers to 22°C to 28°C if not otherwise specified.

[0032] The term "substantially as shown" means that at least 50%, or at least 60%, or at least 70%, or at least 80%, or at least 90%, or at least 95%, or at least 99% of the peaks in the X-ray powder diffraction pattern are shown in the figure.

[0033] In the context of the present invention, when the words "about" or "approximately" are used or whether they are used or not, it means within 10% of a given value or range, suitably within 5%, especially within 1%. Alternatively, for a person of ordinary skill in the art, the term "about" or "approximately" means within the acceptable standard error range of the average value. Whenever a number with a value of N is disclosed, any number within the value of N + / - 1%, N + / - 2%, N + / - 3%, N + / - 5%, N + / - 7%, N + / - 8% or N + / - 10% will be explicitly disclosed, where "+ / -" means plus or minus.

[0034] The terms "first" and "second" in the present invention are only used for descriptive purposes and cannot be construed as indicating or implying relative importance or implicitly specifying the quantity of the indicated technical features. Thus, the features defined with "first" and "second" may explicitly or implicitly include at least one of such features. In the description of the invention, the meaning of "a plurality" is at least two, such as two, three, etc., unless otherwise specifically defined. In the description of the present invention, the meaning of "several" is at least one, such as one, two, etc., unless otherwise specifically defined.

[0035] The terms "preferably", "more preferably", etc. in the present invention refer to embodiments of the present invention that can provide certain beneficial effects in certain cases. However, in the same or other cases, other embodiments may also be preferred. In addition, the description of one or more preferred embodiments does not imply that other embodiments are not available, nor is it intended to exclude other embodiments from the scope of the present invention.

[0036] When a numerical range is disclosed herein, the above range is considered continuous and includes the minimum and maximum values of the range, as well as every value therebetween. Further, when the range refers to integers, every integer between the minimum and maximum values of the range is included. In addition, when multiple ranges are provided to describe features or characteristics, the ranges can be combined. In other words, unless otherwise specified, all ranges disclosed herein should be understood to include any and all sub-ranges subsumed therein.

[0037] Unless otherwise specified, all percentages, fractions and ratios are calculated based on the total mass of the composition of the present invention. Unless otherwise specified, all masses of the listed ingredients are given for the content of the active substance, and thus they do not include solvents or by-products that may be contained in commercially available materials. The term "mass percentage content" herein can be represented by the symbol "%". Unless otherwise specified, all molecular weights herein are weight-average molecular weights expressed in daltons.

[0038] In this text, "including", "comprising", "containing", "having" or other variants are intended to cover non-closed inclusion, and no distinction is made among these terms. The term "comprising" means that other steps and components can be added without affecting the final result. The compositions and methods / processes of the present invention comprise, consist of, and consist essentially of the essential elements and limitations described herein, as well as any additional or optional components, ingredients, steps, or limitations described herein. In this text, no distinction is made among the terms "efficacy", "performance", "effect", and "efficiency".

[0039] The weight of the relevant components mentioned in the specification of the embodiments of the present invention not only can refer to the specific content of each component, but also can represent the proportional relationship of the weights among the components. Therefore, as long as the content of the relevant components in the specification of the embodiments of the present invention is scaled up or down in proportion, it is within the scope disclosed in the specification of the embodiments of the present invention. Specifically, the weight mentioned in the specification of the embodiments of the present invention can be mass units well-known in the chemical engineering field such as μg, mg, g, kg, etc.

[0040] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by those of ordinary skill in the technical field to which the present invention belongs. The terms used in the specification of the present invention are only for the purpose of describing specific embodiments, and are not intended to limit the present invention. The term "and / or" used herein includes any and all combinations of one or more of the related listed items.

[0041] The present invention provides a method for preparing dabigatran etexilate polymorph I, comprising the following steps: Mix dabigatran etexilate with a first solvent at a first temperature, then filter, take the filtrate, and prepare a first solution; Mix methanesulfonic acid with a second solvent to prepare a second solution; Mix the first solution and the second solution at a second temperature to crystallize, then filter, wash, and take the filter cake to dry; Wherein, the first solvent includes acetone; the second solvent includes a mixture of acetone and ethyl acetate.

[0042] In a specific example, the mass-to-volume ratio of dabigatran etexilate to the first solvent is 1 g:(5 mL - 20 mL).

[0043] Understandably, in the present invention, the mass-to-volume ratio of dabigatran etexilate to the first solvent includes, but is not limited to, 1 g:5 mL, 1 g:6 mL, 1 g:7 mL, 1 g:8 mL, 1 g:9 mL, 1 g:10 mL, 1 g:11 mL, 1 g:12 mL, 1 g:13 mL, 1 g:14 mL, 1 g:15 mL, 1 g:16 mL, 1 g:17 mL, 1 g:18 mL, 1 g:19 mL, 1 g:20 mL.

[0044] In a preferred example, the mass-to-volume ratio of dabigatran etexilate to the first solvent is 1 g:(7 mL - 12 mL).

[0045] In a specific example, the first temperature is selected from 30°C to 50°C.

[0046] Understandably, in the present invention, the first temperature includes, but is not limited to, 30°C, 31°C, 32°C, 33°C, 34°C, 35°C, 36°C, 37°C, 38°C, 39°C, 40°C, 42°C, 44°C, 46°C, 48°C, 50°C.

[0047] In a preferred example, the first temperature is selected from 30°C to 40°C.

[0048] In a specific example, the mass-to-volume ratio of dabigatran etexilate to the second solvent is 1 g:(5 mL - 30 mL).

[0049] Understandably, in the present invention, the mass-to-volume ratio of dabigatran etexilate to the second solvent includes, but is not limited to, 1 g:5 mL, 1 g:6 mL, 1 g:7 mL, 1 g:8 mL, 1 g:9 mL, 1 g:10 mL, 1 g:11 mL, 1 g:12 mL, 1 g:13 mL, 1 g:14 mL, 1 g:15 mL, 1 g:16 mL, 1 g:17 mL, 1 g:18 mL, 1 g:19 mL, 1 g:20 mL, 1 g:21 mL, 1 g:22 mL, 1 g:23 mL, 1 g:24 mL, 1 g:25 mL, 1 g:26 mL, 1 g:27 mL, 1 g:28 mL, 1 g:29 mL, 1 g:30 mL.

[0050] In a preferred example, the mass-to-volume ratio of dabigatran etexilate to the second solvent is 1 g:(10 mL - 15 mL).

[0051] In a specific example, the second temperature is selected from -5°C to 15°C.

[0052] Understandably, in the present invention, the second temperature is selected from -5°C, -4°C, -3°C, -2°C, -1°C, 0°C, 1°C, 2°C, 3°C, 4°C, 5°C, 7°C, 9°C, 11°C, 13°C, 15°C.

[0053] In a preferred example, the second temperature is selected from 0°C to 5°C.

[0054] In a specific example, in the second solvent, the volume ratio of acetone to ethyl acetate is 1:(0.5 - 1.3).

[0055] Understandably, in the present invention, in the second solvent, the volume ratio of acetone to ethyl acetate is 1:0.5, 1:0.6, 1:0.7, 1:0.8, 1:0.9, 1:1, 1:1.1, 1:1.2, 1:1.3.

[0056] In a preferred example, in the second solvent, the volume ratio of acetone to ethyl acetate is 1:(0.9 - 1.1).

[0057] In a more preferred example, in the second solvent, the volume ratio of acetone to ethyl acetate is 1:1.

[0058] In a specific example, the mass - to - volume ratio of mesylate to the second solvent is 1 g:(80 mL - 120 mL).

[0059] In a preferred example, the mass - to - volume ratio of mesylate to the second solvent is 1 g:(90 mL - 110 mL).

[0060] In a more preferred example, the mass - to - volume ratio of mesylate to the second solvent is 1 g:100 mL.

[0061] In a specific example, the first solution and the second solution are mixed by dropping the first solution into the second solution.

[0062] In a specific example, the duration required for crystallization is 0.5 h - 1 h.

[0063] In a specific example, after crystallization, it is kept warm and stirred at 0°C - 5°C for 2 hours - 3 hours and then filtered.

[0064] In a specific example, the detergent used for washing is acetone.

[0065] In a specific example, the drying is vacuum drying. More specifically, the temperature of vacuum drying is 35°C - 40°C.

[0066] In a more specific example, the preparation method of dabigatran etexilate mesylate polymorph I includes the following steps: Weigh dabigatran etexilate into a reaction flask, add acetone thereto, heat up to 30°C - 50°C and stir to dissolve, filter, collect the filtrate, and prepare the first solution; Weigh methanesulfonic acid into a reaction flask, add a mixed solution of acetone and ethyl acetate with a volume ratio of 1:(0.5 - 1.3) thereto, stir to dissolve at 0°C - 5°C, and prepare the second solution; Dropwise add the first solution to the second solution at 0°C - 5°C, which takes 0.5 - 1 hour. After crystallization, keep stirring at 0°C - 5°C for 2 - 3 hours and then filter. Take the filter cake, wash it with acetone, and then vacuum dry the filter cake at 35°C - 40°C to obtain the product.

[0067] The present application will be described in detail below through examples, but this does not mean any adverse limitations to the present application. The present application has been described in detail herein, and its specific embodiments have also been disclosed. For those skilled in the art, various changes and improvements to the specific embodiments of the present application will be obvious without departing from the spirit and scope of the present application.

[0068] Unless otherwise specified, the raw materials used in the present invention are all commercially available.

[0069] The crystal form detection results of the present invention were collected on a Bruker D2 type X-ray powder diffractometer. The method parameters of the X-ray powder diffraction of the present invention are as follows: X-ray source: Cu(Å): 1.54184; Voltage: 30 kilovolts (kV); Current: 10 milliamperes (mA); Scanning range: from 3.0 to 50.0 degrees.

[0070] Weigh 5 g of dabigatran etexilate into a reaction flask, add 50 mL of acetone thereto, heat up to 35°C and stir to dissolve, filter, and collect the filtrate. Weigh 0.75 g of methanesulfonic acid into a reaction flask, add a mixed solution of 75 mL of acetone and ethyl acetate (ratio 1:1) thereto, stir to dissolve at 0 - 5°C, dropwise add the acetone solution of dabigatran etexilate thereto, which takes 0.5 - 1 hour. After crystallization, keep stirring at 0 - 5°C for 2 - 3 hours and then filter. Wash the filter cake with acetone and then vacuum dry the filter cake at 35 - 40°C to obtain the crystalline form I sample of dabigatran mesylate, with a yield of 96% and a purity of 99.81%.

[0071] The crystal form detection data thereof is shown in Table 1.

[0072] Table 1 Crystal form detection data 2θ d value 4.52 19.35 9.02 9.63 9.35 9.4 9.59 9.12 11.08 7.86 12.72 6.88 13.64 6.39 14.18 6.18 16.49 5.3 17.68 4.69 18.72 4.67 20.36 4.28 20.06 4.11 21.88 4.01 22.39 3.82 24.13 3.61 26.88 3.23 28.23 3.04 29.14 3.01 32.27 2.68 34.01 2.55

[0073] Under room temperature conditions, weigh 1 g of the dabigatran etexilate mesylate polymorph I sample, add it to the corresponding solvent, stir at the corresponding temperature, and sample and test the sample polymorph after 1 day and 3 days respectively. The selection of the solvent system and temperature and the results are shown in Table 2.

[0074] Table 2 Results of the investigation on polymorph stability solvent temperature stirring time crystal form stirring time crystal form acetone 35℃ 1 day Crystal Form II 3 days Crystal Form II acetone:ethyl acetate = 1:0.5 35℃ 1 day Crystal Form I 3 days Crystal Form II acetone:ethyl acetate = 1:1 35℃ 1 day Crystal Form I 3 days Crystal Form II acetone:ethyl acetate = 1:2 35℃ 1 day Crystal Form I 3 days Crystal Form II acetone:ethyl acetate = 1:3 35℃ 1 day Crystal Form I 3 days Crystal Form II acetone 5℃ 1 day Crystal Form I 3 days Crystal Form II acetone:ethyl acetate = 1:0.5 5℃ 1 day Crystal Form I 3 days Crystal Form I acetone:ethyl acetate = 1:1 5℃ 1 day Crystal Form I 3 days Crystal Form I acetone:ethyl acetate = 1:2 5℃ 1 day Crystal Form I 3 days Crystal Form I acetone:ethyl acetate = 1:3 5℃ 1 day Crystal Form I 3 days Crystal Form I As can be seen from the data in Table 2, under the condition of higher temperature (35 °C), polymorph I will turn into polymorph II after 3 days in acetone and the mixed solution of acetone and ethyl acetate; under the condition of lower temperature (5 °C), polymorph I remains polymorph I after 1 day in pure acetone and will turn into polymorph II after 3 days, while in the mixed solution of acetone and ethyl acetate, it remains polymorph I after 3 days. Thus, it can be obtained that choosing to crystallize in a system of low temperature and a mixed solvent of acetone and ethyl acetate can better ensure the stability of dabigatran etexilate mesylate polymorph I.

[0075] In the description of this specification, the description with reference to terms such as "one embodiment", "some embodiments", "example", "specific example", or "some examples" means that the specific features, structures, materials, or characteristics described in connection with the embodiment or example are included in at least one embodiment or example of the present invention. In this specification, the schematic representations of the above terms do not necessarily refer to the same embodiment or example. Moreover, the specific features, structures, materials, or characteristics described can be combined in any one or more embodiments or examples in a suitable manner. In addition, without contradiction, those skilled in the art can combine and combine the different embodiments or examples described in this specification and the features of different embodiments or examples.

[0076] Although the embodiments of the present invention have been shown and described above, it can be understood that the above embodiments are exemplary and should not be construed as limiting the present invention. Those of ordinary skill in the art can make changes, modifications, substitutions, and variations to the above embodiments within the scope of the present invention.

Claims

1. A preparation method of dabigatran etexilate mesylate polymorph I, characterized in that, It includes the following steps: Mix dabigatran etexilate with a first solvent at a first temperature, then filter, take the filtrate, and prepare a first solution; Mix methanesulfonic acid with a second solvent to prepare a second solution; Mix the first solution with the second solution at a second temperature, crystallize, then filter, wash, and take the filter cake to dry; Wherein, the first solvent includes acetone; the second solvent includes a mixture of acetone and ethyl acetate.

2. The preparation method of dabigatran etexilate mesylate polymorph I according to claim 1, wherein, The mass-volume ratio of the dabigatran etexilate to the first solvent is 1 g:(5 mL - 20 mL).

3. The preparation method of dabigatran etexilate mesylate polymorph I according to claim 1, characterized in that, The first temperature is selected from 30°C to 50°C.

4. The preparation method of dabigatran etexilate mesylate polymorph I according to claim 3, characterized in that, The first temperature is selected from 30°C to 40°C.

5. The preparation method of dabigatran etexilate mesylate polymorph I according to claim 1, characterized in that, The mass-volume ratio of the dabigatran etexilate to the second solvent is 1 g:(5 mL - 30 mL).

6. The preparation method of dabigatran etexilate mesylate polymorph I according to claim 1, characterized in that, The second temperature is selected from -5°C to 15°C.

7. The preparation method of dabigatran etexilate mesylate polymorph I according to claim 6, wherein, The second temperature is selected from 0°C to 5°C.

8. The preparation method of dabigatran etexilate mesylate polymorph I according to any one of claims 1 to 7, characterized in that, In the second solvent, the volume ratio of the acetone to the ethyl acetate is 1:(0.5 - 1.3).

9. The preparation method of dabigatran etexilate mesylate polymorph I according to claim 8, wherein, In the second solvent, the volume ratio of the acetone to the ethyl acetate is 1:(0.9 - 1.1).

10. The preparation method of dabigatran etexilate mesylate polymorph I according to any one of claims 1 to 7, characterized in that, The mixing method of the first solution and the second solution is to drop the first solution into the second solution.

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