New crystal form of nafamostat mesylate and preparation method thereof

Abstract

The invention provides a nafamostat mesylate new crystal form and a preparation method thereof, and belongs to the technical field of medicine crystal forms. An X-ray diffraction pattern of the new crystal form of nafamostat mesylate has characteristic diffraction peaks at the following 2 theta angles: 10.56 degrees, 12.02 degrees, 14.97 degrees, 15.95 degrees, 16.27 degrees, 16.95 degrees, 17.68 degrees, 18.35 degrees, 18.71 degrees, 19.22 degrees, 19.78 degrees, 20.42 degrees, 20.84 degrees, 21.74 degrees, 21.98 degrees, 22.55 degrees, 23.09 degrees, 23.72 degrees, 24.05 degrees, 24.25 degrees, 24.88 degrees, 25.78 degrees, 26.27 degrees, 27.30 degrees, 28.01 degrees, 28.84 degrees, 29.02 degrees, 29.81 degrees, 30.60 degrees, 30.96 degrees, 32.28 degrees, 32.98 degrees, 33.39 degrees, the new crystal form of nafamostat mesylate and the preparation method provided by the invention have the advantages of high purity, good stability, controllable process and easiness in repetition.

Description

Technical Field

[0001] The present invention relates to the technical field of drug crystal forms, and in particular to a new crystal form of nafamostat mesylate and a preparation method thereof. Background Art

[0002] The chemical name of nafamostat mesylate is 6-amidino-2-naphthyl-4-guanidinobenzoate dimethanesulfonate, and its molecular formula is C 21 H 25 N5O8S2, whose structural formula is shown in Formula 1, is a synthetic serine protease inhibitor. It was first launched in Japan in 1986 and is used to treat acute pancreatitis, acute exacerbation of chronic pancreatitis, postoperative acute pancreatitis, acute pancreatitis after pancreatography, and improvement of acute symptoms of traumatic pancreatitis. In 1987, it was proposed to be used as an anticoagulant in hemodialysis.

[0003]

[0004] Formula 1 Drug polymorphism is a common phenomenon in drug research and development, and is also an important factor affecting drug quality. Different crystal forms of the same drug have an important impact on the physicochemical properties, formulation dissolution and efficacy of the drug. The crystal form research of raw materials is receiving more and more attention, and has become an indispensable content in drug research and drug quality control. There are fewer studies on the crystal forms of nafamostat mesylate, and the patent named nafamostat mesylate A crystal form and its preparation method and use discloses the crystalline form of nafamostat mesylate, and the new crystal form is named as crystal form A. The above-mentioned technical scheme claims that the preparation method is simple, and the conditions are easier to control in industrial production. But it is still necessary to conduct in-depth exploratory research to develop new crystal forms and preparation methods thereof with high purity, good stability, controllable process and easy repetition. Summary of the invention

[0005] In view of this, the present invention provides a new crystal form of nafamostat mesylate and a preparation method thereof, which has the advantages of high purity, good stability, controllable process and easy repeatability.

[0006] To achieve the above object, the present invention provides a new crystal form of nafamostat mesylate, wherein the X-ray diffraction pattern of the new crystal form of nafamostat mesylate has characteristic diffraction peaks at the following 2θ angles: 10.56°, 12.02°, 14.97°, 15.95°, 16.27°, 16.95°, 17.68°, 18.35°, 18.71°, 19.22°, 19.78°, 20.42°, 20.84°, 21.74°, 21.98°, 22. .55°, 23.09°, 23.72°, 24.05°, 24.25°, 24.88°, 25.78°, 26.27°, 27.30°, 28.01°, 28.84°, 29.02°, 29.81°, 30.60°, 30.96°, 32.28°, 32.98°, 33.39°, 33.78°, 34.35°, 35.92°, 36.41°, 39.09°, with an error of ±0.2°.

[0007] Optionally, the relative intensity of the X-ray powder diffraction pattern of nafamostat mesylate at the following diffraction 2θ angles is as follows: .

[0008] Optionally, the X-ray powder diffraction pattern of the new crystal form of nafamostat mesylate is as follows: Figure 1 shown.

[0009] Optionally, the new crystal form of nafamostat mesylate has endothermic peaks at 261.1±2°C and 345.7°C±2°C.

[0010] Optionally, the infrared spectrum of the new crystal form of nafamostat mesylate is at 3436.22 cm -1 、3180.95 cm -1 、1741.34 cm -1 、1630.90 cm -1 、1494.31 cm -1 and 1212.24 cm -1 There are characteristic peaks.

[0011] Optionally, the new crystal form of nafamostat mesylate does not contain a crystallization solvent.

[0012] Optionally, the crystallization solvent is crystallization water.

[0013] In order to achieve the above-mentioned object, the present invention also provides a method for preparing a new crystal form of nafamostat mesylate, comprising the following steps: mixing a crude product of nafamostat mesylate, water and an organic solvent, stirring and dissolving, adding methanesulfonic acid and medicinal charcoal and stirring, filtering to obtain a filtrate, adding acetone to the filtrate, cooling and crystallizing, filtering, and drying to obtain the new crystal form of nafamostat mesylate.

[0014] Optionally, the organic solvent is one or a mixture of two or more of ethanol, acetonitrile, dimethyl sulfoxide, tetrahydrofuran and acetone.

[0015] Optionally, the mass volume ratio of the crude nafamostat mesylate, water and organic solvent is 1g:5~10ml:4~8ml.

[0016] Optionally, the stirring temperature after adding methanesulfonic acid and medicinal charcoal is 25-30° C. and the stirring time is 1-3 h.

[0017] Optionally, the temperature of the cooling crystallization is 5-15° C. and the time is 1-2 h.

[0018] The above technical solution of the present invention includes at least the following beneficial effects: The present invention provides a new crystal form of nafamostat mesylate and a preparation method thereof. The method for preparing the new crystal form of nafamostat mesylate of the present invention is simple, reduces the amount of reaction solvent, reduces crystallization time, and improves reaction yield. And the obtained new crystal form of nafamostat mesylate has high purity and high melting point, better stability compared with the existing crystal form of nafamostat mesylate, meets the solvent limit requirement, and has higher quality. The crystal form of nafamostat mesylate obtained by the present invention is conducive to storage and quality control at room temperature as a drug raw material, and can also effectively extend the shelf life of the drug. The present invention realizes that the new crystal form of nafamostat mesylate has the advantages of high purity, good product stability, easy repetition, controllable process and simple operation, and is suitable for industrial production. BRIEF DESCRIPTION OF THE DRAWINGS

[0019] Figure 1 The X-ray powder diffraction pattern of nafamostat mesylate in the embodiment of the present invention; Figure 2 The X-ray powder diffraction data of nafamostat mesylate in the embodiment of the present invention is shown; Figure 3 The differential scanning calorimetry diagram of nafamostat mesylate in the embodiment of the present invention; Figure 4 It is the infrared spectrum of nafamostat mesylate in the embodiment of the present invention; Figure 5 It is the nuclear magnetic hydrogen spectrum of nafamostat mesylate in the embodiment of the present invention; Figure 6 It is the NMR carbon spectrum of nafamostat mesylate in the embodiment of the present invention.

[0020] Figure 7 The X-ray powder diffraction pattern of nafamostat mesylate stability test for one month in the present invention; Figure 8The X-ray powder diffraction pattern of nafamostat mesylate stability test for 2 months in the present invention; Fig. 9 The X-ray powder diffraction pattern of the nafamostat mesylate stability test for 3 months in the present invention; Fig.10 The figure is the X-ray powder diffraction pattern of the nafamostat mesylate stability test for 6 months in the present invention. DETAILED DESCRIPTION

[0021] To make the purpose, technical solution and advantages of the embodiments of the present invention clearer, the following will be combined with the appended drawings of the embodiments of the present invention. Figures 1 to 9 , the technical scheme of the embodiment of the present invention is clearly and completely described. Obviously, the described embodiment is a part of the embodiment of the present invention, not all of the embodiments. Based on the described embodiment of the present invention, all other embodiments obtained by ordinary technicians in this field belong to the scope of protection of the present invention.

[0022] Example 1 Add 100 g of crude nafamostat mesylate to the reactor, then add 650 mL of water and 520 mL of acetone, stir to dissolve, then add 2 g of methanesulfonic acid and 20 g of medicinal charcoal, stir at 25 ° C for 2 hours, filter, add 3 L of acetone to the filtrate, cool to 10 ° C for crystallization for 1.5 h, filter, wash the filter cake with 0.4 L of acetone, and dry it in vacuo at 60 ° C to obtain 96 g of nafamostat mesylate with a product purity of 99.8%.

[0023] Example 2 Add 100 g of crude nafamostat mesylate to the reactor, then add 700 mL of water and 600 mL of ethanol, stir to dissolve, then add 2 g of methanesulfonic acid and 20 g of medicinal charcoal, stir at 30 ° C for 2 hours, filter, add 3 L of acetone to the filtrate, cool to 15 ° C for crystallization for 2 hours, filter, wash the filter cake with 0.4 L of acetone, and dry in vacuo at 60 ° C to obtain 95 g of nafamostat mesylate with a product purity of 99.8%.

[0024] The nafamostat mesylate prepared in Example 1 was tested, and the X-ray powder diffraction pattern was shown in Figure 1 , X-ray powder diffraction data are shown in Figure 2 ; Differential scanning calorimetry diagram see Figure 3 ; Infrared spectrum see Figure 4 ; H NMR spectrum see Figure 5 , data attribution see Table 1; NMR carbon spectrum see Figure 6 , data attribution see Table 2.

[0025] Table 1 Nafamostat mesylate 1 H-NMR spectral data assignment

[0026] Table 2 Nafamostat mesylate 13 C-NMR spectral data assignment

[0027] Combining Table 1, Table 2 and Figure 5 , Figure 6 The structure of the new crystal form is consistent with that of the existing nafamostat mesylate, that is, the prepared product is nafamostat mesylate. Figure 1~Figure 4 It can be seen that the present invention provides a new crystal form of nafamostat mesylate.

[0028] Stability test: The stability of nafamostat mesylate prepared by the preparation method of Example 1 was tested by an accelerated test at 40° C. and RH 75% according to the pharmacopoeia method. The experimental results are shown in Table 3.

[0029] Table 3 Stability of the new crystalline form of nafamostat mesylate prepared in Example 1

[0030] Combine Table 3 with Figure 1 and Figures 7 to 10 The new crystalline form of nafamostat mesylate prepared in Example 1 has good stability after 1 month, 2 months, 3 months and 6 months of accelerated stability experiments, and its appearance, melting point and purity are basically consistent with those at 0 month. The crystalline form has not changed after 1 month, 2 months, 3 months and 6 months of accelerated stability experiments, that is, the new crystalline form of nafamostat mesylate prepared by the present invention has good stability.

[0031] The above are preferred embodiments of the present invention. It should be pointed out that, for ordinary technicians in this technical field, several improvements and modifications can be made without departing from the principles of the present invention. These improvements and modifications should also be regarded as within the scope of protection of the present invention.

Claims

1. A new crystal form of nafamostat mesylate, characterized in that: The X-ray diffraction spectrum of the new crystalline form of nafamostat mesylate has characteristic diffraction peaks at the following 2θ angles: 10.56°, 12.02°, 14.97°, 15.95°, 16.27°, 16.95°, 17.68°, 18.35°, 18.71°, 19.22°, 19.78°, 20.42°, 20.84°, 21.74°, 21.98°, 22.55°, 23.09°, 24.70°, 25.91°, 26.80°, 27.71°, 28.67°, 29.81°, 30. 3.72°, 24.05°, 24.25°, 24.88°, 25.78°, 26.27°, 27.30°, 28.01°, 28.84°, 29.02°, 29.81°, 30.60°, 30.96°, 32.28°, 32.98°, 33.39°, 33.78°, 34.35°, 35.92°, 36.41°, 39.09°, with an error of ±0.2°.

2. The new crystal form of nafamostat mesylate according to claim 1, characterized in that The relative intensities of the X-ray powder diffraction pattern of nafamostat mesylate at the following diffraction 2θ angles are as follows: 。 3. The new crystal form of nafamostat mesylate according to claim 1, characterized in that The X-ray powder diffraction pattern of the new crystal form of nafamostat mesylate is shown in FIG1 .

4. The new crystal form of nafamostat mesylate according to claim 1, characterized in that The new crystal form of nafamostat mesylate has endothermic peaks at 261.1±2°C and 345.7°C±2°C.

5. The new crystal form of nafamostat mesylate according to claim 1, characterized in that, The infrared spectrum of the new crystalline form of nafamostat mesylate is at 3436.22 cm -1 、3180.95 cm -1 、1741.34 cm -1 、1630.90 cm -1 、1494.31cm -1 and 1212.24 cm -1 There are characteristic peaks.

6. A method for preparing the new crystal form of nafamostat mesylate as described in any one of claims 1 to 5, characterized in that: The method comprises the following steps: mixing a crude product of nafamostat mesylate, water and an organic solvent, stirring and dissolving, adding methanesulfonic acid and medicinal charcoal and stirring, filtering to obtain a filtrate, adding acetone to the filtrate, cooling and crystallizing, filtering, and drying to obtain a new crystal form of nafamostat mesylate.

7. The method for preparing the new crystal form of nafamostat mesylate according to claim 6, wherein: The organic solvent is one or a mixture of two or more of ethanol, acetonitrile, dimethyl sulfoxide, tetrahydrofuran and acetone.

8. The method for preparing the new crystal form of nafamostat mesylate according to claim 6, wherein: The mass volume ratio of the crude nafamostat mesylate, water and organic solvent is 1 g: (5-10) ml: (4-8) ml.

9. The method for preparing the new crystal form of nafamostat mesylate according to claim 6, characterized in that: The stirring temperature after adding methanesulfonic acid and medicinal charcoal is 25-30° C. and the stirring time is 1-3 hours.

10. The method for preparing the new crystal form of nafamostat mesylate according to claim 6, characterized in that: The temperature of the cooling crystallization is 5-15°C and the time is 1-2h.

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