Novel tranexamic acid crystal form A and preparation method thereof

Abstract

The invention relates to a tranexamic acid crystal form A and a preparation method thereof. The tranexamic acid crystal form A has characteristic peaks at 6.8 degrees + / -0.2 degrees, 11.6 degrees + / -0.2 degrees, 15.5 degrees + / -0.2 degrees, 17.2 degrees + / -0.2 degrees, 17.5 degrees + / -0.2 degrees, 19.2 degrees + / -0.2 degrees and 23.6 degrees + / -0.2 degrees under Cu-K alpha radiation and X-ray powder diffraction represented by the angle of 2 theta. The crystal form product does not contain cis-4-aminomethylcyclohexanecarboxylic acid impurities, and has the advantages of high purity, high purity and the like. The compound has the advantages of high optical purity, low hygroscopicity, good stability and the like.

Description

TECHNICAL FIELD

[0001] The present application relates to a crystal form of a compound and a preparation method thereof, in particular to a crystal form of tranexamic acid and a preparation method thereof, and belongs to the technical field of pharmaceutical chemistry. BACKGROUND

[0002] Tranexamic acid (TXA), also known as trans-4-(aminomethyl)cyclohexanecarboxylic acid, aminomethylcyclohexane carboxylic acid, hemostatic ring acid and coagulation acid, is a synthetic amino acid antifibrinolytic drug that can competitively inhibit the binding of fibrin lysine and plasmin to achieve the effect of inhibiting fibrinolysis. It can also protect platelets by reducing the degradation of platelet membrane glycoprotein receptors by plasmin, thereby producing hemostatic effect. It is mainly used in clinical practice for various bleeding caused by fibrinolysis, which can significantly improve the bleeding symptoms of patients undergoing artificial abortion surgery, and the effect is safe and reliable. In addition, tranexamic acid also has the effects of removing spots and repairing skin.

[0003] The molecular structure of tranexamic acid is as follows:

[0004]

[0005] It is trans-4-aminomethylcyclohexanecarboxylic acid. Due to the influence of the synthesis process and the structure of the itself, the existing tranexamic acid product is more likely to contain cis-4-aminomethylcyclohexanecarboxylic acid impurities. The present inventors have surprisingly found that a specific new crystalline form of tranexamic acid, tranexamic acid Form A, can improve the above-mentioned defects of the existing tranexamic acid product, thereby completing the present application. SUMMARY

[0006] The present application provides a tranexamic acid Form A, which has characteristic diffraction peaks at the following 2θ positions in the X-ray powder diffraction spectrum using Cu-Kα radiation: 10.6°±0.2°, 19.5°±0.2°, 21.4°±0.2°, 28.0°±0.2°, 32.3°±0.2°.

[0007] Further, the X-ray powder diffraction spectrum of the tranexamic acid Form A also has characteristic diffraction peaks at the following 2θ positions: 17.6°±0.2°, 18.0°±0.2°, 24.2°±0.2°, 25.6°±0.2°, 28.8°±0.2°.

[0008] Still further, the X-ray powder diffraction spectrum of the tranexamic acid Form A also has characteristic diffraction peaks at the following 2θ positions: 15.0°±0.2°, 15.5°±0.2°, 18.8°±0.2°, 30.4°±0.2°, 31.2°±0.2°.

[0009] Further, the tranexamic acid crystal form A has an X-ray powder diffraction pattern substantially as shown in Figure 1

[0010] The present application also provides a preparation method of the tranexamic acid crystal form A, which comprises the following steps:

[0011] (a) heating a solvent to 50-85℃, adding crude tranexamic acid, and dissolving to obtain a clear solution, wherein the solvent is selected from the group consisting of n-propanol, isopropanol, n-butanol, 2-butanol, tert-butanol or a mixture of any two or three thereof, preferably tert-butanol;

[0012] (b) cooling the tranexamic acid solution obtained in step a) to precipitate the tranexamic acid crystal form A, wherein the cooling temperature is preferably -5℃-0℃.

[0013] (c) separating and drying the tranexamic acid crystal form A obtained in step b).

[0014] The tranexamic acid crystal form A of the present application has the advantages of high optical purity, no cis-4-aminomethylcyclohexanecarboxylic acid impurity, low hygroscopicity, good stability and the like, and is of great significance for improving the quality of drugs.

[0015] The HPLC analysis method used in the present application is as follows:

[0016] Test sample solution: take the product, dissolve and dilute with water to prepare a solution containing about 10mg per 1mL.

[0017] Control solution: accurately take 1mL of the test sample solution, place it in a 200mL volumetric flask, dilute to the mark with water, and shake well.

[0018] Chromatographic conditions: octadecylsilane-bonded silica gel as the filler, 0.23% sodium dodecyl sulfate solution (take sodium dihydrogen phosphate 18.3g, dissolve in 800mL of water, add triethylamine 8.3mL, mix well, then add sodium dodecyl sulfate 2.3g, shake to dissolve, adjust the pH value to 2.5 with phosphoric acid, and add water to 1000mL, shake well) - methanol (60:40) as the mobile phase, detection wavelength is 220nm, injection volume is 20μL.

[0019] Determination method: accurately take the test sample solution and the control solution, respectively inject into the liquid chromatograph, and record the chromatogram to 3 times the retention time of the main peak. BRIEF DESCRIPTION OF DRAWINGS

[0020] Figure 1 X-ray powder diffraction spectrum of the tranexamic acid crystal form A of the present application;

[0021] Figure 2 X-ray powder diffraction detection report data table screenshot of the tranexamic acid crystal form A of the present application; ​

[0022] Figure 3 Appearance of the block crystal of the tranexamic acid crystal form A prepared in Example 2 of the present application;

[0023] Figure 4 Appearance of the tranexamic acid crystal form A at the end of the precipitation in the preparation of Example 2 of the present application. DETAILED DESCRIPTION

[0024] The present application is further illustrated in detail by the following examples. However, the examples are not intended to limit the present application.

[0025] Preparation of the crude tranexamic acid in Example 1

[0026] Preparation method: The crude tranexamic acid prepared according to the method disclosed in CN1524847A has a cis-isomer content of about 0.18%.

[0027] Preparation of the tranexamic acid crystal form A in Example 2

[0028] Preparation method: 1.0 kg of the crude tranexamic acid prepared in Example 1 was added into 10 L of t-butyl alcohol, heated to reflux (about 83°C), and stirred to dissolve into a clear and transparent solution. The solution was slowly cooled to room temperature, stirred for 30 minutes, and then cooled to -5°C to 0°C using an ice-salt bath. A large amount of solid was precipitated, and the mixture was stirred for 2 hours. The solid was filtered and washed with an appropriate amount of ethanol. The filter cake was dried to obtain 890 g of the tranexamic acid crystal form A; yield 89%, and HPLC detection of cis-isomer (cis-4-aminomethylcyclohexanecarboxylic acid): none detected. The obtained tranexamic acid crystal form A was white block crystal, as shown in the attached Figure 3 、 4 .

[0029] The X-ray powder diffraction data of the tranexamic acid crystal form A were measured using Cu-Kα radiation, and the specific data are shown in Table 1 below:

[0030] Table 1 X-ray powder diffraction data of the tranexamic acid crystal form A

[0031]

[0032] The X-ray powder diffraction spectrum of the tranexamic acid crystal form A is shown in the attached Figure 1 , and the screenshot of the detection report data table is shown in the attached Figure 2 .

[0033] Preparation of the tranexamic acid crystal form A in Example 3

[0034] Preparation method: take the crude tranexamic acid 10.0 kg prepared in example 1, add 100 L of tert-butyl alcohol, heat to reflux, stir to dissolve to a clear transparent solution. Slowly drop to room temperature, stir for 50 minutes, then cool to -5~0℃ with ice salt bath, a large amount of solid is precipitated, keep stirring for 3 hours, filter and rinse with appropriate amount of ethanol, dry the filter cake to obtain tranexamic acid crystal form A 865 g; yield 86.5%, cis-isomer (cis-4-aminomethylcyclohexanecarboxylic acid) HPLC: not detected; its XRPD diffraction data are consistent with those of example 2.

[0035] Example 4 Preparation of tranexamic acid crystal form A

[0036] Preparation method: take the crude tranexamic acid 1.0 kg prepared in example 1, add 50 L of tert-butyl alcohol, 50 L of n-butyl alcohol, heat to about 80℃, stir to dissolve to a clear transparent solution. Slowly drop to room temperature, stir for 30 minutes, then cool to -5~0℃ with ice salt bath, a large amount of solid is precipitated, keep stirring for 2 hours, filter and rinse with appropriate amount of ethanol, dry the filter cake to obtain tranexamic acid crystal form A 823 g; yield 82.3%, cis-isomer HPLC: not detected; its XRPD diffraction data are consistent with those of example 2.

[0037] Example 5 Preparation of tranexamic acid crystal form A

[0038] Preparation method: take the crude tranexamic acid 10.0 g prepared in example 1, add 80 ml of isopropyl alcohol, heat to about 80℃, stir to dissolve to a clear transparent solution. Slowly drop to room temperature, then cool to -5~0℃ with ice salt bath, a large amount of solid is precipitated, keep stirring for 2 hours, filter and rinse with appropriate amount of ethanol, dry the filter cake to obtain tranexamic acid crystal form A 8.6 g, its XRPD diffraction data are consistent with those of example 2, cis-isomer HPLC: not detected.

[0039] Example 6 Preparation of tranexamic acid crystal form A

[0040] Preparation method: take the crude tranexamic acid 10.0 g prepared in example 1, add 130 ml of 2-butanol, heat to about 80℃, stir to dissolve to a clear transparent solution. Slowly drop to room temperature, then cool to -5~0℃ with ice salt bath, a large amount of solid is precipitated, keep stirring for 2 hours, filter and rinse with appropriate amount of ethanol, dry the filter cake to obtain tranexamic acid crystal form A 8.1 g, its XRPD diffraction data are consistent with those of example 2, cis-isomer HPLC: not detected.

[0041] Example 7 Preparation of tranexamic acid crystal form A

[0042] Preparation method: take the crude tranexamic acid 10.0 g prepared in example 1, add 110 ml of n-propanol, heat to about 60 °C, stir to dissolve to a clear transparent solution. Slowly drop to room temperature, and then cool to -5 °C to 0 °C with ice salt bath, a large amount of solid precipitates, keep stirring for 2 hours, filter and rinse with appropriate amount of ethanol, and dry to obtain 8.3 g of tranexamic acid crystal form A, and the XRPD diffraction data thereof are consistent with those of example 2, and the cis-isomer HPLC: not detected.

[0043] Example 8 Preparation of tranexamic acid crystal form A

[0044] Preparation method: take the crude tranexamic acid 10.0 g prepared in example 1, add 110 ml of n-propanol, heat to about 60 °C, stir to dissolve to a clear transparent solution. Slowly drop to room temperature, and then cool to -5 °C to 0 °C with ice salt bath, a large amount of solid precipitates, keep stirring for 2 hours, filter and rinse with appropriate amount of ethanol, and dry to obtain 8.3 g of tranexamic acid crystal form A, and the XRPD diffraction data thereof are consistent with those of example 2, and the cis-isomer HPLC: not detected.

[0045] Test example 1 Comparative study on hygroscopicity of tranexamic acid crystal form A of the application and existing tranexamic acid product

[0046] Take samples of the commercially available tranexamic acid and the tranexamic acid crystal form A prepared in example 1 of the application, respectively, and store them under high humidity conditions for a period of time, and then test the water content changes of the three tranexamic acid products by Karl Fischer method, and the data results are shown in Table 2 below:

[0047] Table 2 Comparison of hygroscopicity of tranexamic acid crystal form A of the application and existing tranexamic acid product

[0048]

[0049] The above data show that the commercially available product with an original water content of 0.1% increases to 3.8% after being placed in a high humidity environment for a period of time, while the tranexamic acid crystal form A of the application has little change in water content before and after being placed under the same conditions, has small hygroscopicity, has better stability, and has good process controllability when used for preparation production; at the same time, compared with the existing tranexamic acid product, the tranexamic acid crystal form A of the application can avoid the weight change caused by high hygroscopicity, and is more conducive to ensuring the accuracy of the drug content during preparation production and dispensing process.

[0050] Test example 2 Comparative study on stability of tranexamic acid crystal form A of the application and existing tranexamic acid product

[0051] Take the commercially available product of tranexamic acid and the sample of tranexamic acid crystal form A of Example 1 of the present application, and carry out chemical stability investigation in parallel, the investigation conditions are respectively placing at high temperature (60℃), high humidity (92.5%), strong light irradiation (4500Lx) for 10 days, and the investigation indexes are the content of tranexamic acid and the content of cis isomer, and the results are shown in Table 3 below.

[0052] Table 3 Stability comparison of tranexamic acid crystal form A of the present application and commercially available product of tranexamic acid

[0053]

[0054] It can be seen from the above table that after placing under various conditions for 10 days, the amount of cis isomer impurity produced by the tranexamic acid crystal form A of the present application is very small, and its content is significantly lower than that of the commercially available product, which shows that the tranexamic acid crystal form A of the present application has more excellent chemical stability.

Claims

1. A crystalline form A of tranexamic acid, characterized in that, X-ray powder diffraction pattern using Cu-Ka radiation having characteristic diffraction peaks at the following 2Θ positions: 10.6°±0.2°, 19.5°±0.2°, 21.4°±0.2°, 28.0°±0.2°, 32.3°±0.2°.

2. The tranexamic acid crystalline Form A of claim 1, characterized by, X-ray powder diffraction pattern using Cu-Ka radiation having characteristic diffraction peaks at the following 2Θ positions: 17.6°±0.2°, 18.0°±0.2°, 24.2°±0.2°, 25.6°±0.2°, 28.8°±0.2°.

3. The tranexamic acid crystalline Form A of claim 2, characterized by, X-ray powder diffraction pattern using Cu-Ka radiation having characteristic diffraction peaks at the following 2Θ positions: 15.0°±0.2°, 15.5°±0.2°, 18.8°±0.2°, 30.4°±0.2°, 31.2°±0.2°.

4. The tranexamic acid crystalline Form A of claim 3, characterized by, X-ray powder diffraction pattern using Cu-Ka radiation having characteristic diffraction peaks at the following 2Θ positions: 15.0°±0.2°, 15.5°±0.2°, 18.8°±0.2°, 30.4°±0.2°, 31.2°±0.2°.

5. The process for preparing the crystalline Form A of tranexamic acid according to any one of claims 1 to 4, characterized in that, The preparation steps are as follows: (a) heating a solvent selected from the group consisting of n-propanol, isopropanol, n-butanol, 2-butanol, t-butanol or a mixture of any two or three of the foregoing to a temperature of 50-85°C, adding the crude tranexamic acid, and dissolving to obtain a clear solution; (b) cooling the solution of tranexamic acid obtained in step a) to precipitate tranexamic acid Form A; (c) isolating and drying the tranexamic acid Form A obtained in step b).

6. The production method according to claim 5, wherein The solvent in step (a) is t-butanol.

7. The production method according to claim 5, wherein The cooling temperature in step (b) is -5°C to 0°C.

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