Preparation method of dabigatran etexilate mesylate I crystal form

Abstract

The invention relates to the technical field of preparation of dabigatran etexilate mesylate crystal forms, in particular to a preparation method of a dabigatran etexilate mesylate I crystal form. The preparation method comprises the following steps: carrying out high-speed shearing or micronization on dabigatran etexilate mesylate; and then pulping or aging is carried out. According to the preparation method, the dabigatran etexilate mesylate semihydrate or the II crystal form or the mixed crystal can be directly subjected to crystal transformation, the dabigatran etexilate mesylate does not need to be dissociated again and then salified and crystallized, the operation is simple and convenient, and the working efficiency and the product yield are higher.

Description

Technical Field

[0001] The invention relates to the technical field of preparation of dabigatran etexilate mesylate crystal forms, and in particular to a method for preparing dabigatran etexilate mesylate I crystal form. Background Art

[0002] Dabigatran etexilate mesylate was developed by Boehringer Ingelheim of Germany and is the first new oral anticoagulant drug to be marketed in 50 years after warfarin.

[0003] Due to differences in physical environmental conditions during the crystallization process, a drug may produce products with different crystal forms, and different crystal forms may also transform into each other. Different crystal forms of the same drug may have different drug stability and physical and chemical properties, which in turn will affect the dissolution and release of the drug in the human body. Researching drug polymorphs, finding the dominant crystal form that is conducive to the drug's effect, and determining the process based on the characteristics of the crystal form can effectively ensure that the drug's raw materials or preparations do not undergo crystal form changes during production, transportation, storage, and use, thereby ensuring drug quality and clinical efficacy.

[0004] For the disclosed patent CN1845917A of dabigatran mesylate Boehringer Ingelheim, I crystal form, II crystal form and three kinds of crystal forms of hemihydrate of dabigatran mesylate have been reported, wherein the unique characteristic peak of I crystal form is 13.5 ± 0.1, 18.0 ± 0.1, and melting point is 180 ± 3 ℃. The unique characteristic peak of II crystal form is 12.4 ± 0.1, and melting point is 190 ± 3 ℃. The unique characteristic peak of hemihydrate is 3.9 ± 0.1, 7.6 ± 0.1, 8.2 ± 0.1, and melting point is 120 ± 5 ℃. FDA Drug Evaluation and Research Center (Center for Drug Evaluation and Research) has studied dabigatran capsules and found that the melting point of the used bulk drug of commercially available capsules is 180 ± 3 ℃. It can be seen from this that the raw material used in the capsules currently on the market is dabigatran etexilate mesylate I crystal form, which means that the active ingredient that exerts its pharmacological effect is dabigatran etexilate I crystal form.

[0005] However, in the process of production and storage, dabigatran mesylate I crystal form can be transformed to hemihydrate or II crystal form because of the reason of temperature and humidity, causing physicochemical property, bioavailability etc. to change, reducing drug efficacy, even having harmful effect on human body.Therefore, it is necessary to transform dabigatran mesylate hemihydrate or II crystal form into dabigatran mesylate I crystal form again and can be used for the preparation and use of preparation.The method that dabigatran mesylate hemihydrate or II crystal form is converted into dabigatran mesylate I crystal form reported at present mainly is that dabigatran mesylate is first dissociated to obtain dabigatran mesylate free alkali, then in the solution of dabigatran mesylate free alkali, methanesulfonic acid is added again and crystallization into salt is obtained dabigatran mesylate I crystal form.

[0006] For example, the method for preparing dabigatran etexilate mesylate I crystal form disclosed in patent CN1845917A is to add a methanesulfonic acid solution dissolved in acetone to an acetone solution of dabigatran etexilate at 30 ℃ to 36 ℃ for reaction, and the product is separated out by stage-wise cooling. The method needs to control the temperature and humidity in the reaction process, otherwise it is easy to generate II crystal form or hemihydrate.

[0007] The method for preparing dabigatran etcxilate mesylate I crystal form disclosed in patent CN104725360A is to heat and stir dabigatran etcxilate mesylate with esters or ether solvents, so that dabigatran etcxilate mesylate (containing a small amount of II crystal form or part of semihydrate) with lower I crystal form content is converted into dabigatran etcxilate mesylate with higher I crystal form content. The method still needs to start from dabigatran etcxilate free base, and salify to obtain dabigatran etcxilate mesylate again, and then redissolve and crystallize with esters or ether solvents, and the total yield is low, and the solvent residual and consistency evaluation of the product are challenged.

[0008] In view of this, the present invention is proposed. Summary of the invention

[0009] The object of the present invention is to provide a method for preparing dabigatran mesylate crystal form I. The embodiment of the present invention provides a new preparation method that can allow dabigatran mesylate hemihydrate or II crystal form or mixed crystal to directly undergo crystal transformation, and does not require dabigatran mesylate to be dissociated again and then salted and crystallized, which is simple and convenient to operate, and has higher work efficiency and product yield.

[0010] The present invention is achieved in that:

[0011] In a first aspect, the present invention provides a method for preparing a crystalline form I of dabigatran etexilate mesylate, comprising: high-speed shearing or micronizing dabigatran etexilate mesylate;

[0012] Then it is beaten or aged.

[0013] In an optional embodiment, the preparation method is selected from any one of the following methods:

[0014] (1) high-speed shearing is carried out after described dabigatran mesylate and solvent are mixed, and then beating or ageing is carried out;

[0015] (2) The dabigatran etexilate mesylate is micronized and then mixed with a solvent, followed by pulping or aging.

[0016] In an optional embodiment, the high-speed shearing conditions include: a speed greater than 3000 rpm and a temperature less than 35°C;

[0017] Preferably, the speed is 3000-20000 rpm; the temperature is 10-34°C;

[0018] Preferably, the time is 5-15 minutes.

[0019] In an optional embodiment, the D50 of the micronized dabigatran etexilate mesylate is less than 5 μm; preferably 2-4 μm;

[0020] Preferably, the conditions for micronization include: a pulverization pressure of 0.2-1.0 MPa.

[0021] In an optional embodiment, the beating conditions include: temperature below 35° C.; rotation speed of 100-500 rpm;

[0022] Preferably, the beating conditions include: temperature of 10-34°C; rotation speed of 100-300 rpm;

[0023] Preferably, the beating time is more than 10 hours, preferably 15-20 hours.

[0024] In an optional embodiment, the aging conditions include: temperature below 35° C.; standing time greater than 10 hours;

[0025] Preferably, the temperature is 10-34°C and the standing time is 15-20 hours.

[0026] In an optional embodiment, the solvent is selected from ketone solvents, preferably acetone;

[0027] Preferably, the amount of the solvent used is 10-30 times the mass of the dabigatran etexilate mesylate.

[0028] In an optional embodiment, the method further comprises filtering and drying after pulping or aging; the moisture content of the dried material is less than 0.3%;

[0029] Preferably, the drying conditions include: a temperature of 40-50°C and a vacuum degree of less than -0.08MPa;

[0030] Preferably, the dabigatran mesylate is dabigatran mesylate hemihydrate or dabigatran mesylate II crystal form or mixed crystal.

[0031] In an optional embodiment, the preparation method is selected from any one of the following methods:

[0032] (1) mixing the dabigatran etexilate mesylate and a solvent, shearing at high speed, and then beating, wherein the speed of the high-speed shearing is greater than 3000 rpm and the temperature is lower than 35° C.; the beating conditions include: the temperature is lower than 35° C.; the rotation speed is 100-500 rpm;

[0033] (2) mixing the dabigatran etexilate mesylate and a solvent, and then subjecting them to high-speed shearing, and then aging, wherein the speed of the high-speed shearing is greater than 3000 rpm and the temperature is lower than 35° C.; the aging conditions include: the temperature is lower than 35° C.; and the standing time is greater than 10 hours;

[0034] (3) micronizing the dabigatran etexilate mesylate, and then mixing with a solvent for pulping; the D50 of the micronized dabigatran etexilate mesylate is less than 5 μm; the pulping conditions include: a temperature below 35° C.; and a rotation speed of 100-500 rpm.

[0035] The present invention has the following beneficial effects: (1) The preparation method of the embodiment of the present invention can directly transform dabigatran mesylate hemihydrate or dabigatran mesylate II crystal form or mixed crystal, and then obtain dabigatran mesylate I crystal form by simple filtration and drying. It is not necessary to dissociate dabigatran mesylate again and then form salts and crystallize, the operation is simple and convenient, and the work efficiency and product yield are higher.

[0036] (2) In the embodiment of the present invention, dabigatran etexilate mesylate hemihydrate or dabigatran etexilate mesylate II crystal form or mixed crystal is formed into a suspension in acetone to complete the transformation to I crystal form, without introducing a new solvent, thereby ensuring the consistency of the product with the original research. BRIEF DESCRIPTION OF THE DRAWINGS

[0037] In order to more clearly illustrate the technical solutions of the embodiments of the present invention, the drawings required for use in the embodiments are briefly introduced below. It should be understood that the following drawings only show certain embodiments of the present invention and therefore should not be regarded as limiting the scope. For ordinary technicians in this field, other related drawings can be obtained based on these drawings without creative work.

[0038] Figure 1 It is the X-ray diffraction pattern of dabigatran etcxilate mesylate hemihydrate used in Examples 1-3 of the present invention and Comparative Examples 1 and 4-5;

[0039] Figure 2It is the X-ray diffraction pattern of the dabigatran etexilate mesylate II crystal form used in Examples 4-6 of the present invention and Comparative Example 2;

[0040] Figure 3 It is the X-ray diffraction pattern of the dabigatran etexilate mesylate mixed crystal used in Example 7 of the present invention and Comparative Example 3;

[0041] Figure 4 The X-ray diffraction pattern of the dabigatran etexilate mesylate I crystal form provided in Example 1 of the present invention;

[0042] Figure 5 The DSC figure of the dabigatran mesylate I crystal form provided by Example 1 of the present invention;

[0043] Figure 6 The X-ray diffraction pattern of the dabigatran etexilate mesylate I crystal form provided in Example 2 of the present invention;

[0044] Figure 7 The DSC figure of the dabigatran etexilate mesylate I crystal form provided for Example 2 of the present invention;

[0045] Figure 8 The X-ray diffraction pattern of the dabigatran etexilate mesylate I crystal form provided in Example 3 of the present invention;

[0046] Fig. 9 The DSC figure of the dabigatran etexilate mesylate I crystal form provided by Example 3 of the present invention;

[0047] Fig.10 The X-ray diffraction pattern of the dabigatran etexilate mesylate I crystal form provided by Example 4 of the present invention;

[0048] Fig.11 The DSC figure of the dabigatran etexilate mesylate I crystal form provided by Example 4 of the present invention;

[0049] Fig.12 The X-ray diffraction pattern of the dabigatran etexilate mesylate I crystal form provided in Example 5 of the present invention;

[0050] Fig.13 The DSC figure of the dabigatran etexilate mesylate I crystal form provided by Example 5 of the present invention;

[0051] Fig.14 The X-ray diffraction pattern of the dabigatran etexilate mesylate I crystal form provided by Example 6 of the present invention;

[0052] Fig.15 The DSC figure of the dabigatran etexilate mesylate I crystal form provided for Example 6 of the present invention;

[0053] Fig.16The X-ray diffraction pattern of the dabigatran etexilate mesylate I crystal form provided in Example 7 of the present invention;

[0054] Fig.17 The DSC figure of the dabigatran etexilate mesylate I crystal form provided for Example 7 of the present invention;

[0055] Fig.18 The X-ray diffraction pattern of the dabigatran etexilate mesylate I crystal form provided in Comparative Example 1 of the present invention;

[0056] Fig.19 The DSC diagram of the dabigatran etexilate mesylate I crystal form provided in Comparative Example 1 of the present invention;

[0057] Fig. 20 The X-ray diffraction pattern of the dabigatran etexilate mesylate I crystal form provided in Comparative Example 2 of the present invention;

[0058] Fig.21 The DSC diagram of the dabigatran etexilate mesylate I crystal form provided for Comparative Example 2 of the present invention;

[0059] Fig. 22 The X-ray diffraction pattern of dabigatran etexilate mesylate mixed crystals provided in Comparative Example 3 of the present invention;

[0060] Fig.23 The DSC diagram of dabigatran etexilate mesylate mixed crystal provided in Comparative Example 3 of the present invention;

[0061] Fig.24 The X-ray diffraction pattern of dabigatran etexilate mesylate mixed crystals provided in Comparative Example 4 of the present invention;

[0062] Fig.25 The DSC diagram of dabigatran etexilate mesylate mixed crystal provided in Comparative Example 4 of the present invention;

[0063] Fig.26 The X-ray diffraction pattern of dabigatran etexilate mesylate mixed crystals provided in Comparative Example 5 of the present invention;

[0064] Fig. 27 The DSC diagram of dabigatran etexilate mesylate mixed crystals provided in Comparative Example 5 of the present invention. DETAILED DESCRIPTION

[0065] In order to make the purpose, technical scheme and advantages of the embodiments of the present invention clearer, the technical scheme in the embodiments of the present invention will be described clearly and completely below. If the specific conditions are not specified in the embodiments, they are carried out according to conventional conditions or conditions recommended by the manufacturer. If the manufacturer of the reagents or instruments used is not specified, they are all conventional products that can be purchased commercially.

[0066] The known crystal forms of dabigatran etexilate mesylate include three crystal forms: crystal form I, crystal form II and hemihydrate. The melting point of crystal form I is 180±3°C, the melting point of crystal form II is 190±3°C, and the melting point of hemihydrate is 120±5°C. The characteristic peaks of X-ray diffraction 2θ angle of Form I are 4.40, 8.94, 9.23, 9.55, 10.55, 10.95, 12.73, 13.46, 13.95, 14.26, 15.17, 15.93, 16.46, 17.66, 18.07, 18.6, 19.89, 20.28, 20.54, 21.12, 22.06, 22.85, 24.12, 25.10, 25.99, 26.52, 26.83, 27.16, 27.64, 28.09, 29.08, 29.26, 29.94, 31.88, 34.37, 36.21, 38.26, 39.47, and 39.98. The characteristic peaks of X-ray diffraction 2θ angle of Form II are 4.30, 8.72, 9.68, 11.15, 12.42, 13.59, 13.95, 15.11, 15.97, 16.52, 17.45, 17.86, 18.45, 19.22, 19.89, 21.46, 21.98, 22.48, 23.75, 25.29, 28.17, and 28.59. The characteristic peaks of the hemihydrate at 2θ angles in X-ray diffraction are 3.90, 4.40, 5.64, 7.57, 8.25, 8.77, 9.34, 10.69, 11.33, 11.66, 11.96, 13.04, 14.54, 15.16, 16.56, 17.27, 17.78, 18.75, 19.41, 19.95, 20.38, 20. 84, 21.21, 22.22, 22.46, 23.05, 23.40, 23.85, 24.44, 25.30, 25.63, 26.22, 26.52, 27.06, 27.45, 29.27, 30.78, 32.32, 32.59, 34.31, 34.91, 36.04, 37.00, 37.84, 38.13. Among them, the characteristic peaks specific to Form I are 13.5±0.1 and 18.0±0.1, the characteristic peak specific to Form II is 12.4±0.1, and the characteristic peaks specific to hemihydrate are 3.9±0.1, 7.6±0.1, and 8.2±0.1.

[0067] It was also found that the crystal forms can be transformed into each other. For example, the crystal form I of dabigatran etexilate may be transformed into the crystal form I of dabigatran etexilate, and the crystal form I of dabigatran etexilate is the real active ingredient. Therefore, the crystal form I of dabigatran etexilate is required to be transformed into the crystal form I of dabigatran etexilate.

[0068] However, the preparation of the existing dabigatran mesylate I crystal form has the following problems: (1) the existing process for preparing dabigatran mesylate I crystal form requires the control of temperature and humidity in the reaction and post-treatment process. Due to the presence of water, the I crystal form will be converted to a hemihydrate or II crystal form. (2) the existing process for converting dabigatran mesylate hemihydrate into I crystal form requires the finished product to be dissociated and then re-salted and crystallized, which has cumbersome operation steps, large yield loss, and a large amount of additional saline wastewater and waste solvents, which is difficult to handle and pollutes the environment. (3) the method of using ester or ether solvents to redissolve dabigatran mesylate hemihydrate or II crystal form into I crystal form is only suitable for dabigatran mesylate containing a small amount of hemihydrate and II crystal form, and the yield is low. It adds new solvent types, which is not conducive to controlling the solvent residue of the product and maintaining the consistency with the original research product.

[0069] Therefore, in order to overcome the above technical problems, the embodiment of the present invention provides a novel method for preparing dabigatran mesylate I crystal form, comprising: high-speed shearing or micronizing dabigatran mesylate; and then beating or aging.

[0070] The dabigatran mesylate is subjected to high-speed shearing or micronization to make the dabigatran mesylate have a smaller particle size, and then slurrying and aging are performed to achieve crystal transformation to obtain the desired dabigatran mesylate I crystal form.

[0071] Specifically, any one of the following methods is selected:

[0072] (1) high-speed shearing is carried out after described dabigatran mesylate and solvent are mixed, and then beating or ageing is carried out;

[0073] (2) The dabigatran etexilate mesylate is micronized and then mixed with a solvent, followed by pulping or aging.

[0074] Wherein, dabigatran mesylate is dabigatran mesylate hemihydrate or dabigatran mesylate II crystal form or mixed crystal. That is to say, the preparation method of the embodiment of the present invention can realize crystal transformation.

[0075] The solvent used in the above (1) and (2) is selected from ketone solvents, preferably acetone; and its consumption is 10-30 times of the mass of the dabigatran mesylate, for example, any value between 10-30 times, such as 10 times, 15 times, 20 times, 25 times and 30 times.

[0076] The embodiment of the present invention adopts a specific solvent to enable the suspension of dabigatran mesylate and a solvent mixture to be sheared at high speed to make dabigatran mesylate crystallization, or the dabigatran mesylate after micronization and the solvent form a suspension to then make it crystallization, and no harmful toxic substances are introduced, and no new solvent needs to be introduced, thereby maintaining the consistency of the product and the original research. If the solvent adopts an ester solvent or an alcohol solvent, a genotoxic substance may be formed.

[0077] Further, the conditions of high-speed shearing include: a speed greater than 3000 rpm, a temperature lower than 35°C; and maintaining the temperature lower than 35°C during the entire process of crystal transformation to prevent the formation of Form II. Preferably, the speed is 3000-20000 rpm; the temperature is 10-34°C; and the time is 5-15 minutes.

[0078] The above conditions can effectively shear the suspension of dabigatran etexilate mesylate and solvent, which is conducive to subsequent beating or aging to achieve crystal transformation. If the rotation speed is too low, the suspension cannot be effectively sheared, and crystal transformation cannot be achieved subsequently.

[0079] Furthermore, the D50 of the dabigatran etexilate mesylate after micronization is less than 5 μm, preferably 2-4 μm. The D50 of the dabigatran etexilate mesylate after micronization is controlled so that subsequent beating or aging can achieve crystal transformation. If the particle size of the micronized particles is too large, crystal transformation cannot be achieved.

[0080] Wherein, the conditions of micronization in the embodiment of the present invention include: the crushing pressure is 0.2-1.0MPa. However, it is understood that other conditions may also be adopted, as long as the D50 of the final dabigatran mesylate meets the requirements.

[0081] The conditions for beating include: temperature below 35°C; rotation speed of 100-500 rpm; preferably, temperature of 10-34°C; rotation speed of 100-300 rpm; beating time of more than 10 hours, preferably 15-20 hours.

[0082] The aging conditions include: temperature below 35°C; standing time greater than 10 hours; preferably, the temperature is 10-34°C; and the standing time is 15-20 hours.

[0083] The above-mentioned aging or beating conditions can be beneficial to the realization of crystal transformation.

[0084] Specifically, the embodiments of the present invention illustrate that the methods that can be used are as follows:

[0085] (1) mixing the dabigatran etexilate mesylate and a solvent, shearing at high speed, and then beating, wherein the speed of the high-speed shearing is greater than 3000 rpm and the temperature is lower than 35° C.; the beating conditions include: the temperature is lower than 35° C.; the rotation speed is 100-500 rpm;

[0086] (2) mixing the dabigatran etexilate mesylate and a solvent, and then subjecting them to high-speed shearing, and then aging, wherein the speed of the high-speed shearing is greater than 3000 rpm and the temperature is lower than 35° C.; the aging conditions include: the temperature is lower than 35° C.; and the standing time is greater than 10 hours;

[0087] (3) micronizing the dabigatran etexilate mesylate, and then mixing with a solvent for pulping; the D50 of the micronized dabigatran etexilate mesylate is less than 5 μm; the pulping conditions include: a temperature below 35° C.; and a rotation speed of 100-500 rpm.

[0088] Then, after beating or aging, filtering is performed to form a filter cake, and the filter cake is dried, and the moisture content of the dried material is less than 0.3%. The dried product provided by the embodiment of the present invention is the dabigatran mesylate I crystal form, and its moisture content is less than 0.3%, which ensures that the product will not be converted into a hemihydrate or other crystal forms during storage and use, and the quality is more stable.

[0089] The drying method or drying conditions used in the embodiment of the present invention can be adjusted according to actual conditions. For example, the drying conditions include: a temperature of 40-50° C. and a vacuum degree of less than -0.08 MPa.

[0090] The preparation method provided by the embodiment of the present invention directly transforms the dabigatran mesylate hemihydrate or II crystal form through beating or aging by a high-speed shearing or micronization method, and subsequently obtains the dabigatran mesylate I crystal form by simple filtration and drying. It is not necessary to dissociate dabigatran mesylate again and then form salts and crystallize, the operation is simple and convenient, and the working efficiency and product yield are higher.

[0091] The features and performance of the present invention are further described in detail below in conjunction with the embodiments.

[0092] Example 1

[0093] The embodiment of the present invention provides a method for preparing dabigatran mesylate I crystal form, comprising:

[0094] Dabigatran etexilate mesylate hemihydrate (70.0 g) (its X-ray diffraction pattern is shown in Figure 1) is placed in high-speed shearing machine, adds 1050g acetone, rotating speed 5000 rev / min shears 10 minutes.Feed liquid is transferred in the reactor, is incubated at 32 ℃, 150 rev / min, stirs 17 hours.Filter and use 140g acetone drip washing filter cake.In 50 ℃, vacuum tightness is less than-0.08MPa drying, obtains dabigatran mesylate I crystal form 65.4g, weight yield 93.4%, moisture 0.14%.

[0095] The X-ray diffraction of dabigatran etexilate mesylate I crystal form prepared in this example is shown in Table 1 and Figure 4 shown.

[0096] Table 1 X-ray diffraction of the dried material

[0097]

[0098]

[0099] According to Table 1 and Figure 4 It can be seen that the dry material provided in the embodiment of the present invention contains 2θ characteristic peaks of 13.480 and 18.033 specific to the X-ray diffraction of dabigatran mesylate I crystal, but does not contain 2θ characteristic peak 12.4±0.1 specific to the dabigatran mesylate II crystal, nor does it contain characteristic peaks of 3.9±0.1, 7.6±0.1, and 8.2±0.1 specific to the hemihydrate, indicating that the dabigatran mesylate I crystal is prepared in this embodiment.

[0100] The DSC of dabigatran etexilate mesylate I crystal form prepared in this example is as follows Figure 5 As shown, the melting point is 181.47°C.

[0101] Example 2

[0102] The embodiment of the present invention provides a method for preparing dabigatran mesylate I crystal form, comprising:

[0103] Dabigatran etcxilate mesylate hemihydrate (470.0g) is placed in high-speed shearing machine, add 7050g acetone, rotating speed 3500 rev / min shearing 20 minutes.Feed liquid is transferred in the reactor, insulation 30 ℃ standing ageing 17 hours.Filter and use 940g acetone drip washing filter cake.In 50 ℃, vacuum is less than-0.08MPa drying, obtains dabigatran mesylate I crystal form 446.2g, weight yield 94.9%, moisture 0.17%.

[0104] The X-ray diffraction pattern of the dabigatran etexilate mesylate I crystal prepared in this example is as follows: Figure 6 As shown. Figure 6It can be seen that the material provided in the embodiment of the present invention contains 2θ characteristic peaks of 13.506 and 18.072 specific to the X-ray diffraction of dabigatran etexilate mesylate I crystal, but does not contain 2θ characteristic peak 12.4±0.1 specific to the dabigatran etexilate II crystal, nor does it contain characteristic peaks of 3.9±0.1, 7.6±0.1, and 8.2±0.1 specific to the hemihydrate, indicating that the dabigatran etexilate mesylate I crystal is prepared in this embodiment.

[0105] The DSC of dabigatran etexilate mesylate I crystal form prepared in this example is as follows Figure 7 As shown, the melting point is 182.11°C.

[0106] Example 3

[0107] The embodiment of the present invention provides a method for preparing dabigatran mesylate I crystal form, comprising:

[0108] Dabigatran etexilate mesylate hemihydrate (1000 g) was placed in a micronizer, and the feed pressure was set to 0.4 MPa and the crushing pressure was set to 0.4 MPa. After micronization, 950 g of solid was obtained. The particle size was D50: 3.19 μm.

[0109] Get the solid 50g after the micropowder, add 750g acetone, be incubated at 30 ℃, stir 15 hours at 200 rev / min.Filter and use 100g acetone drip filter cake.At 50 ℃, vacuum degree is less than-0.08MPa dry filter cake, obtain 46.1g of dabigatran mesylate I crystal form, weight yield 92.2%, moisture 0.11%.

[0110] The X-ray diffraction pattern of the dabigatran etexilate mesylate I crystal prepared in this example is as follows: Figure 8 As shown, the spectrum contains 2θ characteristic peaks 13.430 and 17.934 specific to the X-ray diffraction of dabigatran mesylate I crystal, but does not contain 2θ characteristic peak 12.4±0.1 specific to the dabigatran mesylate II crystal, nor does it contain characteristic peaks 3.9±0.1, 7.6±0.1, and 8.2±0.1 specific to the hemihydrate, indicating that the dabigatran mesylate I crystal is prepared in this embodiment.

[0111] The DSC of dabigatran etexilate mesylate I crystal form prepared in this example is as follows Fig. 9 As shown, the melting point is 182.35°C.

[0112] Example 4

[0113] The embodiment of the present invention provides a method for preparing dabigatran mesylate I crystal form, comprising:

[0114] Dabigatran etexilate mesylate II crystal form (70.0 g) (its X-ray diffraction pattern see Figure 2) is placed in high-speed shearing machine, adds 700g acetone, rotating speed 3000 rev / min shears 15 minutes.Feed liquid is transferred in the reactor, is incubated at 25 ℃, 100 rev / mins, stirs 17 hours.Filter and use 140g acetone drip washing filter cake.In 40 ℃, vacuum is less than-0.08MPa drying, obtains dabigatran mesylate I crystal form 62.3g, weight yield 89.0%, moisture 0.15%.

[0115] The X-ray diffraction pattern of the dabigatran etexilate mesylate I crystal prepared in this example is as follows: Fig.10 As shown. Fig.10 It can be seen that the material provided in the embodiment of the present invention contains 2θ characteristic peaks of 13.506 and 18.072 specific to the X-ray diffraction of dabigatran etexilate mesylate I crystal, but does not contain 2θ characteristic peak 12.4±0.1 specific to the dabigatran etexilate II crystal, nor does it contain characteristic peaks of 3.9±0.1, 7.6±0.1, and 8.2±0.1 specific to the hemihydrate, indicating that the dabigatran etexilate mesylate I crystal is prepared in this embodiment.

[0116] The DSC of dabigatran etexilate mesylate I crystal form prepared in this example is as follows Fig.11 As shown, the melting point is 182.84°C.

[0117] Example 5

[0118] The embodiment of the present invention provides a method for preparing dabigatran mesylate I crystal form, comprising:

[0119] Dabigatran mesylate II crystal form (70.0g) is placed in high-speed shearing machine, add 2100g acetone, rotating speed 4500 rev / min shearing 15 minutes.Feed liquid is transferred in the reactor, is incubated 34 ℃, 200 rev / min, stirs 10 hours.Filter and use 200g acetone drip washing filter cake.In 45 ℃, vacuum is less than-0.08MPa drying, obtains dabigatran mesylate I crystal form 62.0g, weight yield 88.6%, moisture 0.10%.

[0120] The X-ray diffraction pattern of the dabigatran etexilate mesylate I crystal prepared in this example is as follows: Fig.12 As shown. Fig.12 It can be seen that the material provided in the embodiment of the present invention contains 2θ characteristic peaks of 13.506 and 18.072 specific to the X-ray diffraction of dabigatran etexilate mesylate I crystal, but does not contain 2θ characteristic peak 12.4±0.1 specific to the dabigatran etexilate II crystal, nor does it contain characteristic peaks of 3.9±0.1, 7.6±0.1, and 8.2±0.1 specific to the hemihydrate, indicating that the dabigatran etexilate mesylate I crystal is prepared in this embodiment.

[0121] The DSC of dabigatran etexilate mesylate I crystal form prepared in this example is as follows Fig.13 As shown, the melting point is 182.77°C.

[0122] Example 6

[0123] The embodiment of the present invention provides a method for preparing dabigatran mesylate I crystal form, comprising:

[0124] Dabigatran etexilate mesylate II crystal form (800 g) was placed in a micronizer, and the feed pressure was set to 0.1 MPa and the crushing pressure was set to 0.2 MPa. After micronization, 750 g of solid was obtained. The particle size was D50: 2.31 μm.

[0125] Get the solid 50g after the micropowder, add 750g acetone, be incubated at 25 ℃, stir 17 hours at 150 rev / min.Filter and use 150g acetone drip filter cake.At 50 ℃, vacuum degree is less than-0.08MPa dry filter cake, obtain 45.0g of dabigatran mesylate I crystal form, weight yield 90.0%, moisture 0.11%.

[0126] The X-ray diffraction pattern of the dabigatran etexilate mesylate I crystal prepared in this example is as follows: Fig.14 As shown. Fig.14 It can be seen that the material provided in the embodiment of the present invention contains 2θ characteristic peaks of 13.506 and 18.072 specific to the X-ray diffraction of dabigatran etexilate mesylate I crystal, but does not contain 2θ characteristic peak 12.4±0.1 specific to the dabigatran etexilate II crystal, nor does it contain characteristic peaks of 3.9±0.1, 7.6±0.1, and 8.2±0.1 specific to the hemihydrate, indicating that the dabigatran etexilate mesylate I crystal is prepared in this embodiment.

[0127] The DSC of dabigatran etexilate mesylate I crystal form prepared in this example is as follows Fig.15 As shown, the melting point is 182.47°C.

[0128] Example 7

[0129] The embodiment of the present invention provides a method for preparing dabigatran mesylate I crystal form, comprising:

[0130] Dabigatran etexilate mesylate mixed crystals (100 g) (X-ray diffraction pattern see Figure 3 ) is placed in high-speed shearing machine, adds 1500g butanone, rotating speed 5000 rev / min shears 15 minutes.Feed liquid is transferred in the reactor, is incubated at 32 ℃, 200 rev / min, stirs 18 hours.Filter and use 200g acetone drip washing filter cake.In 50 ℃, vacuum is less than-0.08MPa drying, obtains dabigatran mesylate I crystal form 93.5g, weight yield 93.5%, moisture 0.09%.

[0131] The X-ray diffraction pattern of the dabigatran etexilate mesylate I crystal prepared in this example is as follows: Fig.16 shown.

[0132] according to Fig.16 It can be seen that the dry material provided in the embodiment of the present invention contains 2θ characteristic peaks of 13.480 and 18.033 specific to the X-ray diffraction of dabigatran mesylate I crystal, but does not contain 2θ characteristic peak 12.4±0.1 specific to the dabigatran mesylate II crystal, nor does it contain characteristic peaks of 3.9±0.1, 7.6±0.1, and 8.2±0.1 specific to the hemihydrate, indicating that the dabigatran mesylate I crystal is prepared in this embodiment.

[0133] The DSC of dabigatran etexilate mesylate I crystal form prepared in this example is as follows Fig.17 As shown, the melting point is 182.77°C.

[0134] Comparative Example 1

[0135] The dabigatran etexilate mesylate I crystal form was prepared according to patent CN1845917A.

[0136] Dabigatran etcxilate mesylate hemihydrate (100.0g) is joined in 500mL ethyl acetate, stir and be cooled to 10 ℃.Add potassium carbonate (19.0g), insulated and stirred 1 hour.Add 500mL water, continue insulated and stirred 1 hour after separating out solid.Filter and use 100mL water rinse filter cake, obtain dabigatran etcxilate free alkali wet product 122.7g.Add 500mL water and stir 2 hours, filter and use 100mL water rinse filter cake.In 50 ℃, vacuum is less than-0.08MPa dry filter cake, obtains dabigatran etcxilate free alkali 80.3g.

[0137] Dabigatran etcxilate free alkali is joined in 444g acetone, stir and be warming up to 40 ℃ of dissolvings.Be cooled to 30 ℃, drip the acetone (64g) solution of methanesulfonic acid (12.0g), insulate and stir 1 hour at 26 ℃ after adding.Be cooled to 17 ℃~23 ℃ and continue stirring 1 hour.Filter, at 50 ℃, vacuum is less than-0.08MPa dry filter cake, obtains dabigatran mesylate I crystal form 84.9g, weight yield 84.9%, moisture 0.24%.

[0138] The X-ray diffraction of dabigatran etexilate mesylate prepared in this comparative example is as follows: Fig.18 As shown. Fig.18It can be seen that the material provided in the embodiment of the present invention contains 2θ characteristic peaks of 13.506 and 18.072 specific to the X-ray diffraction of dabigatran etexilate mesylate I crystal, but does not contain 2θ characteristic peak 12.4±0.1 specific to the dabigatran etexilate II crystal, nor does it contain characteristic peaks of 3.9±0.1, 7.6±0.1, and 8.2±0.1 specific to the hemihydrate, indicating that the comparative example prepared dabigatran etexilate mesylate I crystal.

[0139] The DSC of dabigatran etexilate mesylate I crystal prepared in this comparative example is as follows Fig.19 As shown, the melting point is 181.76°C.

[0140] Comparative Example 2

[0141] The dabigatran etexilate mesylate I crystal form was prepared according to patent CN104725360A.

[0142] Dabigatran etexilate mesylate II crystal form (100.0g) is joined in 500mL ethyl acetate, stir and be cooled to 10 ℃.Add potassium carbonate (19.0g), insulated and stirred 1 hour.Add 500mL water, continue insulated and stirred 1 hour after separating out solid.Filter and use 100mL water rinse filter cake, obtain dabigatran etexilate free alkali wet product 124.4g.Add 500mL water and stir 2 hours, filter and use 100mL water rinse filter cake.In 50 ℃, vacuum is less than-0.08MPa dry filter cake, obtains dabigatran etexilate free alkali 81.6g.

[0143] Dabigatran etcxilate free alkali is joined in 1600mL acetone, stirred and warmed up to 30 ℃ of dissolvings.Be cooled to 25 ℃, drip acetone (180mL) solution of methanesulfonic acid (12.2g), after adding, incubate and stir 1 hour at 25 ℃.Be cooled to 10 ℃ and continue stirring 1.5 hours.Filter, obtain dabigatran mesylate wet product 116.2g, filter cake is joined in ethyl acetate (2400mL), is warming up to 45 ℃ and incubate and stir 5 hours, is cooled to 0 ℃, stirred 1 hour.Filter, at 30 ℃, vacuum is less than-0.08MPa dry filter cake, obtains dabigatran mesylate I crystal form 80.6g, weight yield 80.6%, moisture 0.21%.

[0144] The X-ray diffraction of dabigatran etexilate mesylate prepared in this comparative example is as follows: Fig. 20 As shown. Fig. 20It can be seen that the material provided in the embodiment of the present invention contains 2θ characteristic peaks of 13.506 and 18.072 specific to the X-ray diffraction of dabigatran etexilate mesylate I crystal, but does not contain 2θ characteristic peak 12.4±0.1 specific to the dabigatran etexilate II crystal, nor does it contain characteristic peaks of 3.9±0.1, 7.6±0.1, and 8.2±0.1 specific to the hemihydrate, indicating that the comparative example prepared dabigatran etexilate mesylate I crystal.

[0145] The DSC of dabigatran etexilate mesylate I crystal prepared in this comparative example is as follows Fig.21 As shown, the melting point is 181.54°C.

[0146] The comparison results of Examples 1 to 7 with Comparative Examples 1 and 2 show that the method of the present invention for directly converting dabigatran mesylate hemihydrate or II crystal form or mixed crystal into dabigatran mesylate I crystal form does not require dissociation and re-salting, is simple and convenient to operate, and has higher work efficiency and product yield.

[0147] Comparative Example 3

[0148] The dabigatran etexilate mesylate I crystal form was prepared according to patent CN104725360A.

[0149] Dabigatran etcxilate mixed crystal (100g) is placed in a reactor, 3000mL of ethyl acetate is added, the mixture is heated to 45°C and insulated with stirring for 5 hours, then cooled to 0°C and stirred for 1 hour. Filter, and dry the filter cake at 30°C with a vacuum degree less than -0.08MPa to obtain 89.9g of dabigatran etcxilate, with a weight yield of 89.9% and a moisture content of 0.47%.

[0150] The X-ray diffraction of dabigatran etexilate mesylate prepared in this comparative example is as follows: Fig. 22 As shown. Fig. 22 It can be seen that the material provided in the embodiment of the present invention contains 2θ characteristic peaks 13.506 and 18.072 unique to the X-ray diffraction of dabigatran etexilate mesylate I crystal form, and also contains characteristic peaks 3.9±0.1, 7.6±0.1, and 8.2±0.1 unique to the hemihydrate, indicating that the mixed crystal of dabigatran etexilate mesylate is prepared in this comparative example.

[0151] The dabigatran etexilate mesylate DSC prepared in this comparative example is as follows Fig.23 As shown, there are absorption peaks at 130°C and 182°C.

[0152] Comparison of the results of Examples 1 to 7 with Comparative Example 3 shows that the preparation method provided in the embodiments of the present invention can directly convert dabigatran etexilate mesylate containing a large amount of hemihydrate or II crystal form or mixed crystal into I crystal form, but the preparation method in the prior art cannot achieve the crystal conversion of mixed crystals containing a large amount of other crystal forms, and is only suitable for crystal conversion with less other crystal forms.

[0153] Comparative Example 4

[0154] The embodiment of the present invention provides a method for preparing dabigatran mesylate I crystal form, comprising:

[0155] Dabigatran etcxilate mesylate hemihydrate (100.0g) is placed in high-speed shearing machine, adds 1500g acetone, and 2900 rev / mins of rotating speeds are sheared 20 minutes.Feed liquid is transferred in the reactor, and 30 ℃ of insulations are left standstill for ageing 17 hours.Filter and use 200g acetone drip washing filter cake.In 50 ℃, vacuum is less than-0.08MPa drying, obtains dabigatran etcxilate mesylate 92.6g, yield 92.6%, moisture 0.38%.

[0156] The X-ray diffraction of dabigatran etexilate mesylate prepared in this comparative example is as follows: Fig.24 As shown. Fig.24 It can be seen that the material provided in the embodiment of the present invention contains 2θ characteristic peaks 13.506 and 18.072 unique to the X-ray diffraction of dabigatran etexilate mesylate I crystal form, and also contains characteristic peaks 3.9±0.1, 7.6±0.1, and 8.2±0.1 unique to the hemihydrate, indicating that the mixed crystal of dabigatran etexilate mesylate is prepared in this comparative example.

[0157] The dabigatran etexilate mesylate DSC prepared in this comparative example is as follows Fig.25 As shown, there are absorption peaks at 130°C and 182°C.

[0158] Comparative Example 5

[0159] The embodiment of the present invention provides a method for preparing dabigatran mesylate I crystal form, comprising:

[0160] Dabigatran etexilate mesylate hemihydrate (1000 g) was placed in a micronizer, and the feed pressure was set to 0.4 MPa and the crushing pressure was set to 0.1 MPa. After micronization, 917 g of solid was obtained. The particle size was D50: 5.83 μm.

[0161] Get the solid 50g after micro powder, add 750g acetone, 30 ℃ 200 rev / min stirring 15 hours. Filter and use 100g acetone rinse filter cake. At 50 ℃, vacuum degree is less than-0.08MPa dry filter cake, obtain dabigatran etcxilate mesylate 45.9g, weight yield 91.8%, moisture 0.42%.

[0162] The X-ray diffraction of dabigatran etexilate mesylate prepared in this comparative example is as follows: Fig.26 As shown. Fig.26It can be seen that the material provided in the embodiment of the present invention contains 2θ characteristic peaks 13.506 and 18.072 unique to the X-ray diffraction of dabigatran etexilate mesylate I crystal, and also contains characteristic peaks 3.9±0.1, 7.6±0.1, and 8.2±0.1 unique to the hemihydrate, indicating that the mixed crystals of dabigatran etexilate mesylate are prepared in this embodiment.

[0163] The dabigatran etexilate mesylate DSC prepared in this comparative example is as follows Fig. 27 As shown, there are absorption peaks at 130°C and 182°C.

[0164] The above description is only a preferred embodiment of the present invention and is not intended to limit the present invention. For those skilled in the art, the present invention may have various modifications and variations. Any modification, equivalent replacement, improvement, etc. made within the spirit and principle of the present invention shall be included in the protection scope of the present invention.

Claims

1. A method for preparing a dabigatran mesylate I crystal form, characterized in that, include: High-speed shearing or micronization of dabigatran etexilate mesylate; Then it is beaten or aged.

2. the preparation method of dabigatran mesylate I crystal form according to claim 1, is characterized in that, The preparation method is selected from any one of the following methods: (1) high-speed shearing is carried out after described dabigatran mesylate and solvent are mixed, and then beating or ageing is carried out; (2) The dabigatran etexilate mesylate is micronized and then mixed with a solvent, followed by pulping or aging.

3. according to the preparation method of the dabigatran mesylate I crystal form according to claim 1 and 2, it is characterized in that, The conditions for high-speed shearing include: speed greater than 3000 rpm and temperature less than 35°C; Preferably, the speed is 3000-20000 rpm; the temperature is 10-34°C; Preferably, the time is 5-15 minutes.

4. according to the preparation method of the dabigatran mesylate I crystal form according to claim 1 and 2, it is characterized in that, The D50 of the micronized dabigatran etexilate mesylate is less than 5 μm; preferably 2-4 μm; Preferably, the conditions for micronization include: a pulverization pressure of 0.2-1.0 MPa.

5. according to the preparation method of the dabigatran mesylate I crystal form according to claim 1 and 2, it is characterized in that, The conditions for beating include: temperature below 35°C; rotation speed of 100-500 rpm; Preferably, the beating conditions include: temperature of 10-34°C; rotation speed of 100-300 rpm; Preferably, the beating time is more than 10 hours, preferably 15-20 hours.

6. according to the preparation method of the dabigatran mesylate I crystal form according to claim 1 and 2, it is characterized in that, The aging conditions include: temperature below 35°C; standing time greater than 10 hours; Preferably, the temperature is 10-34°C and the standing time is 15-20 hours.

7. the preparation method of dabigatran mesylate I crystal form according to claim 2, is characterized in that, The solvent is selected from ketone solvents, preferably acetone; Preferably, the amount of the solvent used is 10-30 times the mass of the dabigatran etexilate mesylate.

8. the preparation method of dabigatran mesylate I crystal form according to claim 1, is characterized in that, It also includes filtering and drying after beating or aging; the moisture content of the dried material is less than 0.3%; Preferably, the drying conditions include: a temperature of 40-50°C and a vacuum degree of less than -0.08MPa; Preferably, the dabigatran mesylate is dabigatran mesylate hemihydrate or dabigatran mesylate II crystal form or mixed crystal.

9. the preparation method of dabigatran mesylate I crystal form according to claim 1, is characterized in that, The preparation method is selected from any one of the following methods: (1) mixing the dabigatran etexilate mesylate and a solvent, shearing at high speed, and then beating, wherein the speed of the high-speed shearing is greater than 3000 rpm and the temperature is lower than 35° C.; the beating conditions include: the temperature is lower than 35° C.; the rotation speed is 100-500 rpm; (2) mixing the dabigatran etexilate mesylate and a solvent, and then subjecting them to high-speed shearing, and then aging, wherein the speed of the high-speed shearing is greater than 3000 rpm and the temperature is lower than 35° C.; the aging conditions include: the temperature is lower than 35° C.; and the standing time is greater than 10 hours; (3) micronizing the dabigatran etexilate mesylate, and then mixing with a solvent for pulping; the D50 of the micronized dabigatran etexilate mesylate is less than 5 μm; the pulping conditions include: a temperature below 35° C.; and a rotation speed of 100-500 rpm.

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