KR102147600B1 - The polymorph of a novel dabigatran etexilate hemi-salt and the manufacturing method thereof - Google Patents

Abstract

The present inventors of the present invention provide dabigatran etexilate hemi-edisylate, a new dabigatran etexilate salt with improved low water solubility and thermal stability of the currently available dabigatran etexilate methanesulfonate, a coagulation inhibitor as a polymorph thereof, and a pharmaceutical composition for the treatment of stroke and systemic embolism in patients with non-membrane atrial fibrillation.

Description

A novel polymorph of dabigatran etexylate hemiedecylate and its manufacturing method {THE POLYMORPH OF A NOVEL DABIGATRAN ETEXILATE HEMI-SALT AND THE MANUFACTURING METHOD THEREOF}

The present invention relates to a novel polymorph of dabigatran etexylate hemiedecylate and a preparation method thereof.

Dabigatran etexilate shown in Chemical Formula 1 is known as WO 98/37075 as an oral direct thrombin inhibitor for reducing stroke and systemic embolism in patients with non-valvular atrial fibrillation. , It is useful for the prevention of thromboembolism in patients who have undergone total knee or hip replacement surgery, and is particularly suitable for preventing stroke in patients with atrial fibrillation. Dabigatran etecylate is ethyl 3-[(2-[4-(hexyloxycarbonylamino-imino-methyl)-phenylamino]-methyl-1-methyl-1H-benzimidazole-5-carbonyl )-Pyridin-2-yl-amino]-propionate. Dabigatran etexylate is administered in the form of a methanesulfonate salt known in W0 2005/028468, but can also be used as a pharmaceutically acceptable acid and salt. And, according to the publication in W0 2005/028468, it is reported that dabigatran etexylate methanesulfonate has two anhydrides and one hemihydrate crystal form. Among them, the anhydrous crystalline form 2 is the final stable thermodynamically stable polymorph, and the currently marketed and administered polymorphic form is form 2. And in domestic patents 10-2016-0026468 and 10-2015-0082985, dabigatran etexylate hemisuccinate and salts in the form of mucates have been published.

From what has been reported to be a very low water solubility as Darby teksil rate sulfonate is 0.00466 mg / mL thereof may be accommodated in the Tran (https: //www.drugbank.ca/salts/DBSALT000035). In addition, it was confirmed that it was not easy during formulation and storage due to poor thermal stability.

In general, the criterion for selecting a pharmaceutical excellent salt is due to the most important physicochemical properties required by the drug. Choose the one that is thermodynamically most stable, choose the one that is optimized for the manufacture of pharmaceutical raw materials and final products, or choose the solubility of the drug and To improve the dissolution rate or to change the pharmacokinetic properties, etc., the selection of the optimized crystalline form may vary depending on the purpose.

In addition, the discovery of new polymorphs and solvates of pharmaceutical products promotes the desired processing properties, such as ease of handling, ease of processing, storage stability and ease of purification, or conversion to other polymorphic forms, resulting in materials having the desired intermediate crystalline form. Can provide. For these reasons there is a need for additional polymorphs of dabigatran etexylate or salts thereof.

Therefore, the present invention has made efforts to solve the problem of low water solubility and stability of dabigatran ethoxylate methanesulfonate currently on the market.As a result, the water solubility and stability of Formula 2 are remarkably improved. It is to provide a polymorph of edecylate and a method for preparing the same.

The crystal structure through single crystal x-ray diffraction analysis, powder X-ray diffraction data (PXRD), thermogravimetric analysis (TGA) data, temperature differential scanning calorimetry (DSC) data, and hot-stage microscopy HSM ) By confirming the new polymorph of dabigatran etexylate hemiedecylate through analysis, the present invention was completed. In the present invention, the monohydrate of the polymorph of dabigatran etexylate hemiedecylate is referred to as crystalline form 1 and the rest of the anhydride as crystalline form 2.

Accordingly, an object of the present invention is to provide a polymorph of dabigatran etexylate characterized by crystalline hemiedecylate.

Another object of the present invention is to provide a method for preparing a polymorph of dabigatran etexylate hemiedecylate of the present invention described above.

Other objects and advantages of the present invention will become more apparent by the following detailed description, claims and drawings.

According to an aspect of the present invention, according to single crystal X-ray diffraction crystal structure data (Siemens SMART CCD-based Bruker X8 APEX X-ray diffractometer, Mo-Kα irradiation (0.71073 Å)), dabigatran etexylate hemie The decylate crystal form 1 is as follows.

Experimental formula: C ₃₆ H ₄₇ N ₇ O ₁₁ S ₂ H ₂ O, Chemical formula Weight: 829.42, Crystalline: Triclinic, Space group: P-1, a = 7.7793(4), b = 8.7050 (5), c = 28.3967(15), α = 84.172 (2)°β = 88.831 (1)°γ = 69.599(3)° cell volume: 1792.83 (17), Z = 2. Final discrepancy factor It provides a dabigatran etexilate hemiedecylate crystal form 1, characterized in that it has a crystal structure of 3%. To compare this, the dabigatran etexilate hemiedecylate crystal structure data of the present invention is shown in Table 1 below.

Parameter What is Dabigatran Ethoxylate
Hemiedecylate Crystal type 1 Molecular formula C ₃₆ H ₄₇ N ₇ O ₁₁ S ₂ H ₂ O Molecular Weight 829.42 Crystal system Triclinic (triclinic system) Space group P a, Å 7.7793 (4) b, Å 8.7050 (5) c, Å 28.3967 (15) α (˚) 84.172 (2) β (˚) 88.831 (1) γ (˚) 69.599 (2) Cell volume (Å ³ ) 1792.83 (17) Z 2

And in the crystal structure shown in Fig. 1, in the form of dabigatran etexilate hemiedecylate crystal type 1, the H of OH of edicilic acid moves to the amide N of dabigatran etexilate, It has a shape, and it can indicate that the water molecule is a hemiedecylate monohydrate bonded through a hydrogen bond with the N of the aromatic ring and the O of the edecyllic acid with dabigatran.

In addition, a unit cell having a crystal structure of type 1 crystal of dabigatran etexilate hemiedecylate may be shown through [FIG. 2].

Powder X-ray diffraction pattern with characteristic peaks at 2θ diffraction angles 12.272±0.2, 12.435±0.2, 13.716±0.2, 17.216±0.2, 18.227±0.2, 18.468±0.2, 24.718±0.2 in powder X-ray diffraction (PXRD) analysis It provides a dabigatran etexylate hemiedecylate crystal form 1, characterized in that it has. For example, the intensity and peak position of the powder X-ray diffraction of an embodiment of the dabigatran etexylate hemiedecylate crystal 1 type according to the present invention may be as shown in Table 2 below.

In the thermogravimetric (TGA) analysis, it provides a dabigatran etexilate hemiedecylate crystal form 1, characterized in that the thermogravimetric decrease due to moisture at 100°C is from 2.1% to 2.5%.

In the differential scanning calorimetry (DSC) analysis using a sealed fan, it has a dehydration peak with an endothermic start temperature of 109.17℃±3℃ and an endothermic temperature of 144.40℃±3℃, and an endothermic start temperature of 183.37℃±3℃ and an endothermic temperature of 188.41℃±3℃ It provides a crystal form 1 of dabigatran etexilate hemiedecylate crystal showing a melting point peak of °C.

In addition, dabigatran etexilate hemiedecylate crystal type 1, which is dehydrated in the heating-cooling-heating method of temperature differential scanning calorimetry shown in Fig. 5, is polymorphic transformed into anhydride crystal type 2 do.

Dabigatran etexilate hemiedecyl, which has a rectangular crystal form in the hot-stage microscopy HSM shown in [Fig. 6] and undergoes polymorphic conversion to form 2 of a long and thin dendritic anhydride at 123°C or higher. Provides rate determination type 1.

The dabigatran etexilate hemiedecylate crystal form 1 of the present invention is a single crystal X-ray analysis (SXD), powder X-ray diffraction (PXRD) analysis, thermogravimetric (TGA) analysis, heating state (HSM) microscopic analysis and It is a novel crystalline polymorph with a characteristic crystal structure in differential scanning calorimetry (DSC) analysis and a moisture content of 2.1% to 2.5%.

In powder X-ray diffraction (PXRD) analysis, 2θ diffraction angles 6.658±0.2, 10.232±0.2, 11.028±0.2, 11.979±0.2, 14.776±0.2, 16.678±0.2, 17.176±0.2, 18.101±0.2, 19.34±0.2, 19.96±0.2 Dabigatran etexylate hemie, characterized by having a powder X-ray diffraction pattern with characteristic peaks at 0.2, 20.411±0.2, 20.964±0.2, 22.323±0.2, 23.082±0.2, 24.216±0.2, and 25.583±0.2. Provides decylate crystal form 2. For example, the intensity and peak positions of the powder X-ray diffraction of the embodiment of the dabigatran etexilate hemiedecylate crystal type 2 according to the present invention may be as shown in Table 3 below.

In the thermogravimetric (TGA) analysis, dabigatran etexylate hemiedecylate crystal form 2, characterized in that the anhydride does not show a decrease in thermoweight due to moisture at 100°C.

In the differential scanning calorimetry (DSC) analysis using a sealed fan, dabigatran etexylate hemiedecylate crystal form 2 showing a melting point peak of 184.42°C±3°C and 189.73°C±3°C of endothermic start temperature is provided.

In addition, in the heating-cooling-heating method of the temperature differential scanning calorimetry shown in [Fig. 5], the thermodynamically stable dabigatran etexilate hemiedecylate crystal type 2 is dehydrated and polymorphic transformation Provides.

Thermodynamically stable dabigatran etexylate in which crystal 1 form, which is a rectangular crystal form, becomes polymorphic to an anhydride in a long and thin dendritic form above 123°C in a hot-stage microscopy HSM shown in FIG. 6 Provides hemiedecylate crystal form 2

The dabigatran etexilate hemiedecylate crystal form 1 of the present invention is a single crystal X-ray analysis (SXD), powder X-ray diffraction (PXRD) analysis, thermogravimetric (TGA) analysis, heating state (HSM) microscopic analysis and It is a novel crystalline polymorph with a characteristic crystal structure in differential scanning calorimetry (DSC) analysis and a moisture content of 2.1% to 2.5%.

The dabigatran etexilate hemiedecylate crystal form 2 of the present invention is characterized in powder X-ray diffraction (PXRD) analysis, thermogravimetric (TGA) analysis, heating state (HSM) microscopic analysis, and differential scanning calorimetry (DSC) analysis. It is a novel crystalline polymorph with a natural crystal structure and a moisture content of 1% or less.

The values reported in relation to the DSC thermogram may show a difference of ±3℃, which means that the temperature observed through DSC may have a deviation of ±3℃ depending on the heating rate, sample preparation method, and type of equipment used. Because it can.

In relation to the DSC thermogram, the reported dehydration peak values can generally show a wide difference of ±11℃, which means that the temperature observed through the DSC ranges from ±11℃ depending on the heating rate, sample preparation method, and type of equipment used. Because it can have a deviation of.

The most rational method for identifying and determining the polymorph of dabigatran etexylate hemiedecylate of the present invention is based on a unit cell based on crystal structure data by single crystal X-ray diffraction (SXD) analysis, and powder X It is based on the characteristic 2θ diffraction angle of the result of line diffraction (PXRD) analysis, and is specified by the measurement results of thermogravimetric (TGA) and temperature differential scanning calorimeter (DSC).

Dabigatran ethoxylate hemiedecylate according to the present invention can be prepared by reacting dabigatran ethoxylate and edecylic acid in an organic solvent as shown in Scheme 1 below.

[Scheme 1]

Specifically, the manufacturing method of the present invention comprises (1) dabigatran etexylate and edecylic acid of Formula 1 as a polar protic solvent, a polar aprotic solvent, and a mixed solvent thereof. Precipitating crystals through reaction crystallization in a solvent selected from the group consisting of, and (2) filtering dabigatran etexilate hemiedecylate precipitated from the solution in which the reaction of step 1 is completed under reduced pressure. In the preparation method of the present invention, an anti-solvent may be additionally added to the solution of step 1.

More specifically, (i) after dissolving dabigatran ethoxylate and edecylic acid of Formula 1 in a solvent selected from the group consisting of a polar protic solvent, a polar aprotic solvent, and a mixed solvent thereof, reaction crystallization is performed. And then separating the solid to prepare a crystalline edecylate salt, or (ii) in a solvent selected from the group consisting of a polar protic solvent, a polar aprotic solvent, and a mixed solvent thereof. After dissolving by reacting tran etexilate and edecylic acid, an anti-solvent is added thereto to precipitate a solid, and then the solid is separated to prepare a crystalline edecylate salt, (iii) dabigatran etexilate In the step of vacuum drying the hemiedecylate crystal form 1, crystal form 2 can be obtained.

Edecyllic acid may be used in an amount of 0.4 to 1.5 equivalents based on 1 equivalent of dabigatran etexylate, and preferably 0.5 to 1.0 equivalents.

In the above, as the polar protic solvent and the anti-solvent, a solvent selected from the group consisting of methyl alcohol, ethyl alcohol, isopropyl alcohol, n-butyl alcohol, sec-butyl alcohol, t-butyl alcohol and a mixed solvent thereof, or A mixed solvent of this solvent and water can be used. Polar aprotic solvents and anti-solvents include acetone, methyl ethyl ketone, methyl isobutyl ketone, tetrahydrofuran, dimethyl sulfoxide, dimethylformamide, dimethylacetamide, ethyl acetate, acetonitrile, methylene chloride, chloroform, diethyl A solvent selected from the group consisting of ether, methyl t-butyl ether, isopropyl acetate, isopropyl ether, n-hexane and n-heptane, and a mixed solvent thereof, or a mixed solvent of this solvent and water may be used.

The polymorph of dabigatran etexylate hemiedecylate of the present invention can be used as a therapeutically active substance.

The novel dabigatran etexylate hemiedecylate crystal types 1 and 2 can be directly used as thrombin inhibitors. The present invention provides a pharmaceutical composition for inhibiting blood coagulation comprising crystals 1 and 2 of the dabigatran etexilate hemiedecylate of Formula 2 as an active ingredient.

The dabigatran etexylate hemiedecylate of the present invention is useful for preventing thromboembolism in patients who have undergone hip replacement surgery, and is particularly suitable for preventing nozolosis in patients with atrial fibrillation.

The pharmaceutical composition of the present invention includes one or more pharmaceutically acceptable fillers, extenders, binders, wetting agents, disintegrants, surfactants, etc., along with the active ingredient dabigatran etexilate hemiedecylate crystal forms 1 and 2 It contains a diluent or excipient or carrier.

The pharmaceutical composition of the present invention can be administered orally or parenterally, and can be formulated in the form of a general pharmaceutical formulation. Orally, it may be administered by oral, sublingual, or the like, and parenterally through intravenous, intramuscular, or subcutaneous routes.

As the formulation for oral administration, capsules, tablets, powders, granules, pills, syrups, dispersions, suspensions or films may be used. One or more excipients may be used for solid preparations such as tablets and powders. As a diluent, microcrystalline cellulose, lactose, mannitol, calcium phosphate, etc. may be used, and as a binder, hydroxypropylcellulose, microcrystalline cellulose, ethylcellulose, hydroxypropylmethylcellulose, and the like may be used. As a disintegrant, starch, croscarmellose sodium, etc. may be used, and lubricants such as magnesium stearate, palmitic acid, and polyethylene glycol may also be used. In addition, the surface of the formulation can be coated with a coating agent such as Opadry®II Y-30-10671-A or Opadry II 32K-18425. Oral liquid formulations include suspensions, emulsions, and syrups. In addition to water and liquid paraffin, which are commonly used simple diluents, various excipients such as wetting agents, sweetening agents, fragrances, preservatives, and the like may be included.

Preparations for parenteral administration include sterilized aqueous solutions, non-aqueous solutions, suspensions, emulsions, freeze-dried preparations, and the like. As a solvent for preparing non-aqueous liquids and suspensions, propylene glycol, polyethylene glycol, vegetable oils such as olive oil, injectable esters such as ethyl oleate, and the like may be used. As a base for the suppository, witepsol, macrogol, tween61, cacao butter, laurinji, glycerol, gelatin, and the like can be used.

The features and advantages of the present invention are summarized as follows:

(a) The present invention provides dabigatran etexylate hemiedecylate crystal forms 1 and 2, a method for preparing the same, and uses thereof.

(b) The dabigatran etexylate hemiedecylate crystals 1 and 2 are suitable for exhibiting excellent medicinal effects.

(c) The dabigatran etexylate hemiedecylate crystal types 1 and 2 of the present invention can be used pharmaceutically for direct thrombin inhibitor and blood coagulation inhibition.

FIG. 1 shows a molecule of a crystal structure verified through a single crystal X-ray diffraction (SXD) analysis of a dabigatran etexylate hemiedecylate crystal type 1 prepared according to an embodiment of the present invention.
FIG. 2 shows a unit cell of a crystal structure verified through single crystal X-ray diffraction (SXD) analysis of the dabigatran etexilate hemiedecylate crystal type 1 prepared according to an embodiment of the present invention.
3 shows a powder X-ray diffraction pattern of the dabigatran etexilate hemiedecylate crystal type 1 prepared according to an embodiment of the present invention.
FIG. 4 shows the results of thermogravimetric (TGA) and temperature differential scanning calorimetry (DSC) analysis of dabigatran etexylate hemiedecylate crystal type 1 prepared according to an embodiment of the present invention.
5 is a dehydration analysis of dabigatran etexylate hemiedecylate crystal type 1 prepared according to an embodiment of the present invention through a heating-cooling-heating method in temperature differential scanning calorimetry (DSC) analysis in a sealed fan It shows the results of the fire and melting point peaks.
Figure 6 shows the result of polymorphism conversion of the rhodabigatran etexylate hemiedecylate crystal type 1 prepared according to an embodiment of the present invention to crystal type 2 through a heated state microscope (HSM).
7 shows a powder X-ray diffraction pattern of the dabigatran etexilate hemiedecylate crystal type 2 prepared according to an embodiment of the present invention.
FIG. 8 shows the results of thermogravimetric (TGA) and temperature differential scanning calorimetry (DSC) analysis of dabigatran etexilate hemiedecylate crystal type 2 prepared according to an embodiment of the present invention.

The present invention will be described in more detail through the following examples. These examples are only for describing the present invention in more detail, and it will be apparent to those of ordinary skill in the art that the scope of the present invention is not limited by these examples according to the gist of the present invention. .

[ Example 1] using reaction crystallization What is Dabigatran Ethoxylate Hemiedecylate Crystal type 1 manufacturing

10 g of dabigatran etexylate tetrahydrate is dissolved in 300 ml of acetone at room temperature, and 2 g of edecylic acid dihydrate is dissolved in 6 ml of methanol. The two solutions are mixed and stirred for 5 hours at 200 rpm at room temperature to precipitate crystals. The precipitated crystals were filtered under reduced pressure and vacuum-dried at 40 degrees for 16 hours to prepare dabigatran etexylate hemiedecylate crystal type 1.

[ Example 2] Crystallization Used What is Dabigatran Ethoxylate Hemiedecylate Crystal 1 Produce

10 g of dabigatran etexylate tetrahydrate was dissolved in 100 ml of methylene chloride. Thereafter, 2 g of edecylic acid dihydrate is dissolved in 6 ml of methanol. The two solutions were mixed and stirred at 200 rpm for 1 hour, and then 100 ml of acetone was added and further stirred for 5 hours. Thereafter, when crystals were precipitated, it was filtered under reduced pressure and vacuum-dried at 40° C. for 16 hours to prepare dabigatran etexilate hemiedecylate crystal 1.

[ Example 3] Solid state at 45 degrees Polymorphism Method What is Dabigatran Ethoxylate Hemiedecylate Crystal 2 Produce

The dabigatran etexilate hemiedecylate crystal form 1 prepared in Examples 1 and 2 was vacuum-dried at 45 degrees for 70 hours to prepare the dabigatran etexilate hemiedecylate crystal form 2.

[ Example 4] Solid state at 50 degrees Polymorphism Method What is Dabigatran Ethoxylate Hemiedecylate Crystal 2 Produce

The dabigatran etexilate hemiedecylate crystal form 1 prepared in Examples 1 and 2 was vacuum-dried at 50 degrees for 40 hours to prepare the dabigatran etexilate hemiedecylate crystal form 2.

[ Example 5] Solid state at 60 degrees Polymorphism Method What is Dabigatran Ethoxylate Hemiedecylate Crystal 2 Produce

The dabigatran etexilate hemiedecylate crystal Form 1 prepared in Examples 1 and 2 was vacuum-dried at 60 degrees for 20 hours to prepare the dabigatran etexilate hemiedecylate crystal Form 2.

[ Experimental example 1) single crystal X-ray diffraction ( SXD )

Siemens SMART CCD-based Bruker X8 APEX X-ray diffractometer (Karlsruhe, Germany) with graphite monochromatic Mo-Kα radiation (λ=0.7137 Å) and 3 kW for SXD analysis (see Table 1 and FIGS. 1 and 2) was used. I did. Crystals were placed on glass fibers using hydrocarbon oil, and the values were obtained at -135±1℃. And the software for the crystal packing plot was Diamond 3.1 (Crystal Impact GbR, Brandenberg Germany).

[ Experimental example 2) powder X-ray diffraction ( PXRD )

PXRD analysis (see Fig. 3, Fig. 7) was performed on an X-ray powder diffractometer (D8 Advance) using Cu Kα radiation. The instrument was equipped with tube power, and the amount of current was set at 45 kV and 40 mA. The divergence and scattering slits were set to 1°, and the light receiving slits were set to 0.2 mm. A θ-2θ continuous scan of 3° minutes (0.4 sec/0.02° interval) from 5 to 35°2θ was used.

[ Experimental example 3] Thermal weight Analysis method( TGA )

Using a TGA Q50 obtained from TA company, measurement (see Figs. 4 and 8) was performed using a TGA fan at a scan rate of 10°C/min from 30°C to 300°C under nitrogen purification.

[ Experimental example 4] Temperature differential scanning Calorimetry ( DSC )

DSC Q20 obtained from TA company was used to perform DSC measurements (see Figs. 4 and 8) in a closed pan at a scan rate of 10°C/min from 30°C to 250°C under nitrogen purification. And in order to use the heating-cooling-heating method, DSC measurement in a sealed fan at a scan rate of 10℃/min from the primary heating 30℃ to 160℃, cooling 160℃ to 30℃, and secondary heating 30℃ to 220℃. Through (see Fig. 5), the polymorphism was observed.

[ Experimental example 5] Solubility test

The aqueous solubility and gastrointestinal tract pH 1.2, 4.0, 6.8 of dabigatran etexylate hemiedecylate and polymorphs thereof and dabigatran etexylate methanesulfonate, a novel salt of the present invention prepared in Examples 1 and 3 The solubility was compared and analyzed [Table 4].

Distilled water pH 1.2 pH 4 pH 6.8 Methanesulfonate 0.0052 mg/mL 0.124 mg/mL 0.0078 mg/mL 0.0048 mg/mL Hemiedecylate crystal form 1 1.25 mg/mL 2.15 mg/mL 1.48 mg/mL 1.21 mg/mL Hemiedecylate
Crystal type 2 0.85 mg/mL 1.52 mg/mL 1.02 mg/mL 0.88 mg/mL

As a result, it was confirmed that the water solubility and gastrointestinal pH solubility of the novel dabigatran etexilate hemiedecylate and the polymorph of the present invention were increased by up to 240 times or more compared to the dabigatran etexilate methanesulfonate. . Therefore, it was predicted that the novel dabigatran etexilate hemiedecylate and the polymorph according to the present invention would be easy to improve the absorption rate and bioavailability of dabigatran.

[ Experimental example 6] Thermal stability exam

In order to compare the thermal stability of the novel dabigatran etexilate hemiedecylate and the polymorph of the present invention with dabigatran etexilate methanesulfonate, a thermal stability test was conducted at 60 degrees for 2 weeks [Table 5].

Early 1 week 2 weeks Methanesulfonate 99.75% 98.12% 96.54% Hemiedecylate crystal form 1 99.84% 99.82% 99.83% Hemiedecylate crystal form 2 99.78% 99.75% 99.75%

As a result, the purity of dabigatran etexilate methanesulfonate decreases to 96.54% after 2 weeks at 60 degrees, while the novel dabigatran ethoxylate hemiedecylate of the present invention has a purity of 2 weeks at 60 degrees. It was confirmed that the stability was improved as there was no change in

As described above, specific parts of the present invention have been described in detail, and it is obvious that these specific techniques are only preferred embodiments, and the scope of the present invention is not limited thereto for those of ordinary skill in the art. Therefore, it will be said that the substantial scope of the present invention is defined by the appended claims and their equivalents.

Claims (5)

delete Powder X-ray diffraction pattern with characteristic peaks at 2θ diffraction angles 12.272±0.2, 17.216±0.2, 18.227±0.2, 18.468±0.2 and 24.718±0.2 in powder X-ray diffraction (PXRD) analysis, and thermogravimetric (TGA) In the analysis, the thermal weight reduction before 100°C is characterized by 2.1% to 2.5%, and in the differential scanning calorimetry (DSC) analysis using a sealed fan, the endothermic start temperature of 109.17℃±3℃ and the endothermic temperature of 144.40℃±3℃ Dabigatran ethoxylate hemiedecylate crystal type 1 characterized by a monohydrate having a dehydration peak and a melting point peak of an endothermic initiation temperature of 183.37℃±3℃ and an endothermic temperature of 188.41℃±3℃. The method of claim 2, wherein the empirical formula: C ₃₆ H ₄₇ N ₇ O ₁₁ S ₂ H ₂ O, chemical formula weight: 829.42, crystal system: triclinic, space group: P-1, a = 7.7793 ( 4), b = 8.7050(5), c = 28.3967(15), α = 84.172 (2)°β = 88.831 (1)°γ = 69.599(3)° cell volume: 1792.83 (17), Z = 2. Dabigatran etexylate hemiedecylate crystal type 1, characterized in that it has a crystal structure with a final discrepancy factor of 3%. Powder with characteristic peaks at 2θ diffraction angles 11.028±0.2, 17.176±0.2, 19.34±0.2, 19.96±0.2, 20.411±0.2, 20.964±0.2, 22.323±0.2 and 23.082±0.2 in powder X-ray diffraction (PXRD) analysis. It has an X-ray diffraction pattern, characterized in that the thermogravimetric (TGA) analysis does not show a decrease in thermal weight before 100°C, and the endothermic start temperature is 184.42°C±3°C and Dabigatran etexylate hemiedecylate crystal form 2 characterized by an anhydride with an endothermic temperature of 189.73℃±3℃. delete

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