Tranexamic acid crystal as well as preparation method and application thereof

Abstract

The invention belongs to the technical field of pharmaceutical chemistry, and provides a tranexamic acid crystal and a preparation method and application thereof, the tranexamic acid crystal has characteristic peaks in an X-ray powder diffraction pattern under Cu-K alpha radiation when diffraction angles 2 theta are 10.52 + / -0.2 degrees, 17.54 + / -0.2 degrees, 17.90 + / -0.2 degrees, 20.86 + / -0.2 degrees and 21.24 + / -0.2 degrees. The tranexamic acid crystal is of a novel crystal structure, is high in purity and good in stability, can simultaneously meet EP11.0, USP-NF2025 and tranexamic acid quality standards of the current edition of Chinese Pharmacopoeia, can be kept stable under severe conditions of high temperature, high humidity, strong acid, strong alkali, illumination, oxidation and the like, and is convenient to produce and store. The preparation method of the tranexamic acid crystal is simple to operate, the used crystallization reagent is safe, the production cost is low, and industrial production is easy.

Description

Technical Field

[0001] The invention belongs to the technical field of pharmaceutical chemistry, and particularly relates to a tranexamic acid crystal, a preparation method and an application thereof. Background Art

[0002] Tranexamic acid, also known as tranexamic acid, tranexamic acid, and hemostatic acid, is a lysine derivative and an antifibrinolytic drug. It can strongly adsorb to the lysine binding site (LBS) of the fibrin affinity site on plasmin and plasminogen, inhibiting the binding of plasmin and plasminogen to fibrin, thereby inhibiting the decomposition of fibrin caused by plasmin and exerting a hemostatic effect. The structural formula of tranexamic acid is The molecular formula is C8H 15 NO2, molecular weight is 157.21, American Chemical Service registration number is 1197-18-8.

[0003] Studies have shown that in addition to its anti-fibrinolytic effect, tranexamic acid can also competitively inhibit tyrosinase and reduce melanin formation; it can inhibit the number of mast cells, reduce the secretion of plasmin and fibroblast growth factor, reduce angiogenesis, and has a good effect on melasma of different stages and types. The clinical efficacy and long-term oral safety of tranexamic acid have gradually been recognized, and it has become a first-line drug for the treatment of melasma, with oral administration being the most commonly used. The "Chinese Expert Consensus on the Diagnosis and Treatment of Chloasma (2021 Edition)" points out that tranexamic acid is a systemic drug for the clinical treatment of melasma. The clinical treatment plan in the "Clinical Treatment and Long-term Management of Chloasma" (Group Standard 2024 Edition) points out that the clinical efficacy and long-term oral safety of tranexamic acid have gradually been recognized, and it has become a first-line drug for the treatment of melasma. The "Expert Consensus on the Prevention and Treatment of Post-inflammatory Pigmentation (2024 Edition)" lists commonly used oral medications for the treatment of post-inflammatory hyperpigmentation (PIH) and recommends tranexamic acid.

[0004] Tranexamic acid is gaining more and more attention from scientists as a hemostatic and whitening freckle-removing drug. Therefore, conducting research on the physical and chemical properties, crystal form, in vivo and in vitro release, in vivo metabolism, and bioavailability of tranexamic acid is of great significance for the research of tranexamic acid oral preparations.

[0005] The European Pharmacopoeia (EP11.0) stipulates that the limits for the drug substance specification for tranexamic acid are: Impurity A ≤ 0.05%, Impurity B (Z-isomer) ≤ 0.15%, Impurity C (Cycloolefin) ≤ 0.05%, Impurity D (Aminomethylbenzoic Acid) ≤ 0.05%, Impurity E ≤ 0.05%, Impurity F ≤ 0.05%, and the maximum unknown individual impurity ≤ 0.05%, and the total impurities ≤ 0.2%. The United States Pharmacopoeia (USP-NF2025) stipulates that the limits for the drug substance specification for tranexamic acid are: Impurity A ≤ 0.1%, Impurity B (Z-isomer) ≤ 0.2%, Impurity C (Cycloolefin) ≤ 0.1%, Impurity D (Aminomethylbenzoic Acid) ≤ 0.1%, the maximum unknown individual impurity ≤ 0.05%, and the total impurities ≤ 0.2%. The Japanese Pharmacopoeia (JP18) specifies the following substance limits for tranexamic acid: Impurity C (cycloolefin) ≤ 0.1%, Impurity D (aminomethylbenzoic acid) ≤ 0.1%, Impurity B (Z-isomer) ≤ 0.2%, Other maximum unknown individual impurities ≤ 0.1%, and Total impurities ≤ 0.5%. The Chinese Pharmacopoeia (CP2020, Part II) specifies the following substance limits for tranexamic acid: Impurity C (cycloolefin) ≤ 0.1%, Impurity D (aminomethylbenzoic acid) ≤ 0.1%, Impurity B (Z-isomer) ≤ 0.2%, Other maximum unknown individual impurities ≤ 0.1%, and Total impurities ≤ 0.5%. By comparison, the order of strictness of the substance controls for tranexamic acid raw material quality standards is EP11.0 > USP-NF2025 > JP18 > CP2020. Transexamic acid products exported to the EU must comply with EP11.0.

[0006]

[0007]

[0008] Sun Jialiang disclosed a method for synthesizing tranexamic acid in "Research on Synthesis Technology of Tranexamic Acid API" (China Practical Medicine, 2011, 6(17)), which mentioned that the reaction solution was obtained after pressurized hydrogenation, filtered, the filter cake was washed with pure water, the filtrate and washings were combined, an appropriate amount of activated carbon was added, the mixture was boiled for decolorization, filtered, concentrated, 92-95% ethanol was added for crystallization, cooled, filtered, the crystals were washed with ethanol, filtered and dried to obtain tranexamic acid with a total yield of 55-65%. The yield of this crystallization method is low, and the use of activated carbon for decolorization in pure water has limited effect on decolorization and impurity removal due to the high solubility of some impurities in pure water.

[0009] CN115784915A discloses an improved method for synthesizing tranexamic acid, wherein the step of refining tranexamic acid comprises: recrystallizing crude tranexamic acid twice with water to obtain refined tranexamic acid; the results of related substance detection of the refined tranexamic acid in Examples 1-7 are as follows: impurity C (cycloolefin) is 0.027-0.091%, impurity D (aminophenyl oxadiazine) is 0.033-0.072%, impurity B is 0.041-0.163%, and other individual impurities are ≤0.091%; the refined tranexamic acid prepared by this method does not meet the EP11.0 and USP-NF2025 edition tranexamic acid raw material quality standards.

[0010] In the synthesis method of tranexamic acid disclosed in CN116730856A, high-purity tranexamic acid is obtained by electrodialysis, but other purification devices are required, which places high demands on the purification equipment. In addition, it is disclosed that during the hydrogenation process of tranexamic acid synthesis, the hydrogenation of aminocyclic acid will produce a deaminated impurity (4-methylcyclohexylcarboxylic acid). The solubility of this impurity in water is poor, and tranexamic acid recrystallizes in an aqueous system. Therefore, it is difficult to remove this impurity by subsequent recrystallization. In the prior art, this impurity is mostly made to comply with the provisions of EP11.0 or USP-NF2025 tranexamic acid raw materials by multiple recrystallization with water. The process is cumbersome and a large amount of wastewater is generated.

[0011] The production method of tranexamic acid (tranexamic acid) disclosed in CN1524847A comprises the following steps: hydrogenation reduction of an aminomethylbenzoic acid sulfate solution to obtain aminomethylbenzoic acid (a mixed solution of cis and trans isomers), adding barium carbonate to the mixed solution to remove sulfate groups, adding barium hydroxide to the filtrate for high-temperature conversion, introducing carbon dioxide at the end of the high-temperature conversion to precipitate a barium salt to remove barium ions, and concentrating and crystallizing the filtrate or adding a solvent for crystallization to obtain tranexamic acid. The crude tranexamic acid solution obtained by this method contains a high content of 4-methylcyclohexylcarboxylic acid, a key impurity generated during the hydrogenation process, which affects the recrystallization effect. Moreover, the impurity-enriched recrystallization mother liquor cannot be directly used, resulting in insufficient purity of the final product.

[0012] CN117820144A discloses a method for synthesizing tranexamic acid, comprising the following steps: uniformly mixing a platinum-carbon catalyst, aminomethylbenzoic acid, water, and concentrated sulfuric acid in a hydrogenation kettle, replacing the atmosphere in the hydrogenation kettle with hydrogen, hydrogenating at 20-25° C., filtering to obtain a hydrogenation reaction liquid, then adding barium hydroxide, treating the reaction liquid in the hydrogenation kettle at high temperature and high pressure to convert the configuration, neutralizing the reaction liquid with sulfuric acid solution, cooling, and filtering to obtain a mother liquor; passing the mother liquor obtained by neutralization with sulfuric acid through a first carbon column adsorption tank, cooling and crystallizing the decolorized liquid; dissolving the crystals in water and passing the mother liquor through a second carbon column adsorption tank, cooling and crystallizing the decolorized liquid; dissolving the crystals in water and passing the mother liquor through a third carbon column adsorption tank, cooling and crystallizing the decolorized liquid, filtering and drying to obtain refined tranexamic acid. The refining and purification method is complex and has a low yield. In addition, the contents of other individual impurities in the refined tranexamic acid products obtained in Examples 1-6 are greater than 0.05%, and the contents of impurity C and impurity D in Examples 4 and 5 are greater than 0.05%. The products do not meet the quality standards for tranexamic acid in EP11.0 and USP-NF2025.

[0013] In summary, the current tranexamic acid bulk drug purification method is mostly pure water multiple recrystallization, with ethanol crystallization, resulting in tranexamic acid because of its large solubility in water, low yield, and easy inclusion of trace impurities in the crystallization process; In addition, due to the presence of water-insoluble trace impurities (such as 4-methylcyclohexylcarboxylic acid) in tranexamic acid to be refined, although the tranexamic acid refined product obtained by the simple pure water recrystallization method meets the quality requirements of "Chinese Pharmacopoeia" and "Japanese Pharmacopoeia", it is difficult to meet the quality requirements of EP11.0 and USP-NF2025. Moreover, the stability of the tranexamic acid refined product prepared by the prior art is insufficient, and the research on its stable crystal form is still blank. Therefore, the development of high stability, highly purified tranexamic acid new crystal form and preparation method thereof is a problem demanding urgent solution in this area. Summary of the Invention

[0014] In view of the deficiencies in the prior art, the present invention aims to provide a tranexamic acid crystal and a preparation method and application thereof. The tranexamic acid crystal has high purity and excellent stability, can simultaneously meet the tranexamic acid quality standards of EP11.0, USP-NF2025 and the current edition of the Chinese Pharmacopoeia, and has a simple preparation method and broad application prospects.

[0015] In order to achieve the purpose of the invention, the present invention adopts the following technical solutions:

[0016] In a first aspect, the present invention provides a tranexamic acid crystal, wherein the tranexamic acid crystal has characteristic peaks at diffraction angles 2θ of 10.52±0.2°, 17.54±0.2°, 17.90±0.2°, 20.86±0.2° and 21.24±0.2° in an X-ray powder diffraction pattern under Cu-Kα radiation.

[0017] The following are preferred technical solutions of the present invention, but are not intended to limit the technical solutions provided by the present invention. Through the following preferred technical solutions, the objectives and beneficial effects of the present invention can be better achieved and realized.

[0018] Preferably, the X-ray powder diffraction pattern of the tranexamic acid crystals under Cu-Kα radiation has characteristic peaks at diffraction angles 2θ of 10.52±0.2°, 17.54±0.2°, 17.90±0.2°, 19.44±0.2°, 20.86±0.2°, 21.24±0.2°, 27.96±0.2° and 28.68±0.2°.

[0019] The tranexamic acid crystals provided by the present invention have a specific new crystal structure and high purity, and can simultaneously meet the tranexamic acid quality standards of EP11.0, USP-NF2025, and the current edition of the Chinese Pharmacopoeia. Furthermore, the tranexamic acid crystals have good stability and can remain stable under harsh conditions such as high temperature, high humidity, strong acid, alkali, light, and strong oxidation, making them easy to produce and store. They can fully meet the stability requirements in applications such as pharmaceutical preparations and have broad application prospects. The preparation process of the tranexamic acid crystals is simple to operate, the reagents used are safe, the production cost is low, and they are easy to industrialize.

[0020] As a preferred technical solution of the present invention, the characteristic peaks and relative peak intensities (I / I0) expressed by the diffraction angle 2θ in the X-ray powder diffraction pattern of the tranexamic acid crystals under Cu-Kα radiation are as follows:

[0021] 2θ Relative peak intensity 10.52±0.2° 15.8±0.1％ 17.54±0.2° 17.5±0.1％ 17.90±0.2° 22.6±0.1％ 19.44±0.2° 15.1±0.1％ 20.86±0.2° 35.4±0.1％ 21.24±0.2° 100％ 27.96±0.2° 13.9±0.1％ 28.68±0.2° 11.8±0.1％

[0022] Preferably, in the X-ray powder diffraction pattern of the tranexamic acid crystals under Cu-Kα radiation, the characteristic peaks and relative peak intensities (I / I0) expressed as diffraction angles 2θ are as follows:

[0023] 2θ Relative peak intensity 10.52±0.2° 15.8％ 17.54±0.2° 17.5％ 17.90±0.2° 22.6％ 19.44±0.2° 15.1％ 20.86±0.2° 35.4％ 21.24±0.2° 100.0％ 27.96±0.2° 13.9％ 28.68±0.2° 11.8％

[0024] As a preferred technical solution of the present invention, the characteristic peaks and interplanar spacing (d value) of the tranexamic acid crystals in the X-ray powder diffraction pattern under Cu-Kα radiation are as follows:

[0025]

[0026] Further preferably, in the X-ray powder diffraction pattern of the tranexamic acid crystals under Cu-Kα radiation, the characteristic peaks represented by the diffraction angle 2θ and the interplanar spacing (d value) are as follows:

[0027]

[0028] Exemplarily, in the X-ray powder diffraction test of the tranexamic acid crystal under Cu-Kα radiation, λ is

[0029] As a preferred technical solution of the present invention, the infrared absorption spectrum of the tranexamic acid crystal has an absorption peak at the following wavenumbers: 2933±2cm -1 , 2607±2cm -1 , 2206±2cm -1 , 1645±2cm -1 , 1539±2cm -1 , 1450±2cm -1 , 1381±2cm -1 , 1327±2cm -1 , 1278±2cm -1 , 1224±2cm -1 , 1193±2cm -1 , 1161±2cm -1 , 1089±2cm -1 , 1029±2cm -1 , 1008±2cm -1 , 975±2cm -1 , 918±2cm -1 , 840±2cm -1 , 767±2cm -1 , 700±2cm -1 , 553±2cm -1 , 524±2cm -1 , 472±2cm -1 , 412±2cm -1 .

[0030] Illustratively, the infrared absorption spectrum of the tranexamic acid crystals is tested using KBr pellets.

[0031] As a preferred technical solution of the present invention, the differential scanning calorimetry (DSC) spectrum of the tranexamic acid crystals has an endothermic peak at 297-303°C (300±3°C), and the position of the endothermic peak can be 297.5°C, 298°C, 298.5°C, 299°C, 299.5°C, 300°C, 300.5°C, 301°C, 301.5°C, 302°C or 302.5°C, as well as specific point values between the above point values. Due to space limitations and for the sake of simplicity, the present invention no longer exhaustively enumerates the specific point values included in the range.

[0032] Exemplarily, the heating rate in the DSC analysis of the tranexamic acid crystals is 10° C. / min.

[0033] As a preferred technical solution of the present invention, the purity (content) of the tranexamic acid crystals is ≥99%, for example, it can be 99.1%, 99.2%, 99.3%, 99.4%, 99.5%, 99.6%, 99.7%, 99.8%, 99.9%, 99.95% or 99.99%, as well as specific point values between the above point values. Due to space limitations and for the sake of simplicity, the present invention no longer exhaustively enumerates the specific point values included in the range.

[0034] In a second aspect, the present invention provides a method for preparing the tranexamic acid crystals as described in the first aspect, the preparation method comprising:

[0035] Providing a tranexamic acid solution, the tranexamic acid solution comprises a combination of a crude tranexamic acid product and a crystallization solvent, wherein the crystallization solvent is a mixture of an alcohol solvent and water, and the volume percentage of the alcohol solvent in the crystallization solvent is 10-50%;

[0036] The tranexamic acid solution is subjected to crystallization treatment to obtain the tranexamic acid solution crystals.

[0037] In the present invention, the tranexamic acid crystals are obtained by crystallizing a crude tranexamic acid product in a specific crystallization solvent, which has the advantages of simple operation, safe crystallization solvent, low production cost, and easy industrial scale production.

[0038] The volume percentage of the alcohol solvent in the crystallization solvent is 10-50%, for example, it can be 12%, 15%, 18%, 20%, 22%, 25%, 28%, 30%, 32%, 35%, 38%, 40%, 42%, 45% or 48%, as well as specific values between the above points. Due to space limitations and for the sake of simplicity, the present invention does not exhaustively enumerate the specific values included in the range.

[0039] Preferably, the alcohol solvent comprises methanol and / or ethanol.

[0040] Preferably, the volume of the recrystallization solvent is 10-100 mL, for example, 20 mL, 30 mL, 40 mL, 50 mL, 60 mL, 70 mL, 80 mL, 90 mL or 95 mL, and specific values between the above values. Due to space limitations and for simplicity, the present invention no longer exhaustively enumerates the specific values included in the range.

[0041] Preferably, the purity of the crude tranexamic acid (mass content of tranexamic acid) is 95-99%, for example, it can be 95.2%, 95.5%, 96%, 96.5%, 97%, 97.5%, 97.8%, 98%, 98.2%, 98.5% or 98.8%, as well as specific values between the above points. Due to space limitations and for simplicity, the present invention no longer exhaustively enumerates the specific values included in the range.

[0042] Preferably, the tranexamic acid solution further comprises activated carbon, and the crystallization treatment further comprises a filtration step.

[0043] As a preferred technical solution of the present invention, activated carbon is used to perform adsorption decolorization and purification treatment on the crude tranexamic acid, thereby obtaining tranexamic acid crystals of higher purity; before the crystallization treatment, the activated carbon (activated carbon that has completed adsorption decolorization) is removed by filtration.

[0044] Preferably, the preparation method of the tranexamic acid solution comprises: mixing crude tranexamic acid, a crystallization solvent and activated carbon, dissolving the crude tranexamic acid and then filtering to obtain the tranexamic acid solution.

[0045] Preferably, based on the mass of the crude tranexamic acid as 100%, the mass of the activated carbon is 0.1-5%, for example, it can be 0.2%, 0.5%, 0.8%, 1%, 1.2%, 1.5%, 1.8%, 2%, 2.2%, 2.5%, 2.8%, 3%, 3.2%, 3.5%, 3.8%, 4%, 4.2%, 4.5% or 4.8%, as well as specific point values between the above point values. Due to space limitations and for simplicity, the present invention no longer exhaustively enumerates the specific point values included in the range.

[0046] Preferably, the crude tranexamic acid product is fully dissolved by heating, and the heating temperature is 50-100°C, for example, 452°C, 55°C, 58°C, 60°C, 62°C, 65°C, 68°C, 70°C, 72°C, 75°C, 78°C, 80°C, 82°C, 85°C, 88°C, 90°C, 92°C, 95°C or 98°C, as well as specific point values between the above point values. Due to space limitations and for simplicity, the present invention no longer exhaustively enumerates the specific point values included in the range.

[0047] Preferably, the temperature of the crystallization treatment is 0-40°C, for example, it can be 2°C, 5°C, 8°C, 10°C, 12°C, 15°C, 18°C, 20°C, 22°C, 25°C, 28°C, 30°C, 35°C or 38°C, as well as specific point values between the above point values. Due to space limitations and for the sake of simplicity, the present invention no longer exhaustively lists the specific point values included in the range.

[0048] Preferably, the crystallization treatment time is ≥12h, for example, it can be 15h, 18h, 20h, 24h, 28h, 30h, 32h, 36h, 40h, 44h, 48h, 50h, 52h, 56h, 60h, 64h, 68h, 70h, 72h, 76h, 80h, 84h, 88h or 92h, as well as specific point values between the above point values. Due to space limitations and for the sake of simplicity, the present invention no longer exhaustively lists the specific point values included in the range, and 12-84h is further preferred.

[0049] Preferably, the crystallization treatment further includes the steps of solid-liquid separation, washing and drying.

[0050] Preferably, the solid-liquid separation method comprises filtration.

[0051] Preferably, the washing solvent used in the washing comprises an alcohol solvent, more preferably methanol and / or ethanol.

[0052] Preferably, the drying method includes drying under reduced pressure.

[0053] Preferably, the drying temperature is 40-60°C, for example, it can be 42°C, 45°C, 46°C, 48°C, 50°C, 52°C, 55°C, 56°C or 58°C, as well as specific point values between the above point values. Due to space limitations and for the sake of simplicity, the present invention no longer exhaustively lists the specific point values included in the range.

[0054] As a preferred technical solution of the present invention, the preparation method of the tranexamic acid crystals comprises the following steps:

[0055] (1) mixing crude tranexamic acid, a crystallization solvent, and activated carbon, dissolving them at 50-100° C., and then filtering to obtain a tranexamic acid solution;

[0056] Based on the mass of the crude tranexamic acid product as 1g, the volume of the crystallization solvent is 10-100mL, and the mass of the activated carbon is 0.001-0.05g;

[0057] The crystallization solvent is a mixture of an alcohol solvent and water, the volume percentage of the alcohol solvent in the crystallization solvent is 10-50%, and the alcohol solvent includes methanol and / or ethanol;

[0058] (2) The tranexamic acid solution is allowed to stand at 0-40° C. for crystallization for ≥12 h, followed by solid-liquid separation, and the solid is collected, washed, and dried to obtain the tranexamic acid crystals.

[0059] In a third aspect, the present invention provides a use of the tranexamic acid crystals as described in the first aspect in the preparation of pharmaceutical preparations or cosmetics.

[0060] Compared with the prior art, the present invention has the following beneficial effects:

[0061] (1) The tranexamic acid crystals provided by the present invention are a new crystal structure with the characteristics of high purity and good stability. The purity is ≥99%, which can simultaneously meet the tranexamic acid quality standards of EP11.0, USP-NF2025 and the current edition of the Chinese Pharmacopoeia. They can remain stable under harsh conditions such as high temperature, high humidity, strong acid, alkali, light, and strong oxidation, are easy to produce and store, can meet the technical requirements of high stability in applications such as pharmaceutical preparations, and have broad application prospects.

[0062] (2) The preparation method of tranexamic acid crystals provided by the present invention is simple to operate, the crystallization reagents used are safe, the production cost is low, and it is easy to industrialize production. BRIEF DESCRIPTION OF THE DRAWINGS

[0063] Figure 1 The X-ray powder diffraction pattern of the tranexamic acid crystals provided in Example 1;

[0064] Figure 2 The DSC test pattern of the tranexamic acid crystal provided in Example 1;

[0065] Figure 3 The infrared absorption spectrogram of the tranexamic acid crystals provided in Example 1;

[0066] Figure 4 The HPLC test pattern of the tranexamic acid crystal provided for Example 1;

[0067] Figure 5 The X-ray powder diffraction pattern of the tranexamic acid reference substance provided for Comparative Example 1;

[0068] Figure 6 The X-ray powder diffraction pattern of the tranexamic acid crystals provided in Comparative Example 2;

[0069] Figure 7 The X-ray powder diffraction pattern of the tranexamic acid crystals provided in Comparative Example 3;

[0070] Figure 8 The X-ray powder diffraction pattern of tranexamic acid crystals provided in Comparative Example 4. DETAILED DESCRIPTION

[0071] The technical solution of the present invention is further described below by way of specific embodiments. It should be understood by those skilled in the art that the embodiments are merely to help understand the present invention and should not be regarded as specific limitations of the present invention.

[0072] As used herein, the terms "comprises," "including," "having," "containing" or any other variations thereof, are intended to cover a non-exclusive inclusion. For example, a composition, process, method, article, or apparatus that comprises a listed element is not necessarily limited to only those elements but may include other elements not expressly listed or inherent to such composition, process, method, or article.

[0073] In the following specific embodiments of the present invention, the test instruments and test methods used are as follows:

[0074] (1) X-ray powder diffraction test

[0075] Instrument: Japan Rigaku Miniflex 600 diffractometer

[0076] Target: Cu-Kα radiation, 2θ is 2°-50°; step angle: 0.04°;

[0077] Tube voltage: 36 kV; tube current: 30 mA; scanning speed: 10° / min; filter: graphite monochromator.

[0078] (2) Infrared absorption spectrum test

[0079] Instrument: Shimadzu IR Tracer-100 Fourier transform infrared spectrometer, KBr pellets were used for testing.

[0080] (3) Testing of the purity / content of tranexamic acid and related substances (including impurity B, impurity C, impurity D, impurity E, and impurity F)

[0081] The related substances of tranexamic acid were detected using the related substance inspection method in the tranexamic acid quality standard in EP11.0, and tested by high performance liquid chromatography (HPLC), as follows:

[0082] Instrument: Agilent 1290 Infinity II high-performance liquid chromatograph, including: G7104A pump, G7129B autosampler, G7117A diode array detector, G7116B column oven, OpenLab workstation;

[0083] Chromatographic column: Zorbax SB-C18 250×4.6mm, using octadecylsilane bonded silica as filler;

[0084] Mobile phase: Dissolve 11.0 g of anhydrous sodium dihydrogen phosphate in 500 mL of water, add 5 mL of triethylamine and 1.4 g of sodium lauryl sulfate; adjust the pH to 2.0 with phosphoric acid, dilute to 600 mL with water, add 400 mL of methanol and mix thoroughly; methanol and phosphoric acid should be chromatographic grade, and redistilled water should be used for HPLC.

[0085] Flow rate: 0.9 mL / min;

[0086] Detection wavelength: 210nm;

[0087] Injection volume: 40 μL;

[0088] Run time: 2.5 times the retention time of tranexamic acid.

[0089] ①Detection method:

[0090] Test solution: Take 0.20 g of tranexamic acid test sample, dissolve it in water and dilute to 20.0 mL;

[0091] Control solution (a): Take 1.0 mL of the test solution and dilute it to 100.0 mL with water. Then take 1.0 mL of this solution and dilute it to 20.0 mL with water.

[0092] Reference solution (b): Dissolve 5.0 mg of impurity D in water and dilute to 50.0 mL;

[0093] Reference solution (c): Take 5.0 mL of reference solution (b) and dilute to 100.0 mL with water;

[0094] Reference solution (d): Dissolve 2.5 mg of impurity E in water and dilute to 50.0 mL. Then take 1.0 mL of this solution and dilute to 10.0 mL with water.

[0095] Reference solution (e): Dissolve 2.5 mg of impurity C, 2.5 mg of impurity F, and 7.5 mg of impurity B in water and dilute to 25.0 mL. Then take 1.0 mL of this solution, 1 mL of reference solution (b), and 18 mL of test solution and mix well.

[0096] Identification of impurities: Based on the chromatogram of the reference solution (c), find the peak of impurity D; based on the chromatogram of the reference solution (d), find the peak of impurity E; based on the chromatogram of the reference solution (e), find the peaks of impurities B, impurity C, and impurity F; use the chromatogram provided by the tranexamic acid reference solution and the chromatogram obtained with the reference solution (b) to identify the peak of impurity C; use the chromatogram obtained with the reference solution (c) to identify the peak of impurity D.

[0097] Relative retention time with respect to tranexamic acid (retention time is about 10min), impurity F is about 0.3, impurity C is about 1.1, impurity D is about 1.2, impurity E is about 1.3, and impurity B is about 1.5.

[0098] System Suitability: Reference Solution (e):

[0099] Resolution: The minimum resolution between the peaks of tranexamic acid and impurity C is 2.0; the minimum difference between the peaks of impurity C and impurity D is 1.5.

[0100] ② Calculation of percentage content:

[0101] Correction factor: When calculating the content, multiply the peak area of the following impurities by the corresponding correction factor: impurity B = 1.3, impurity C = 0.4, impurity F = 0.6;

[0102] For impurities C and D, use the concentration of impurity D in the reference solution (c);

[0103] For impurities E and F, the concentration of impurity E in the reference solution (d) was used;

[0104] For impurities other than impurity C, impurity D, impurity E, and impurity F, the concentration of tranexamic acid in the reference solution (a) was used.

[0105] ③Limit:

[0106] Impurity B: ≤0.15%;

[0107] Impurity C, Impurity D, Impurity E and Impurity F: The maximum content of each impurity is ≤ 0.05%;

[0108] Unknown impurities: Maximum content of each impurity ≤ 0.05%;

[0109] Sum of unspecified impurities: maximum content ≤ 0.2%;

[0110] Ignore limit: <0.03%.

[0111] (4) Differential scanning calorimetry (DSC) test

[0112] Instrument: METTLER TGA / DSC / HT1600 analyzer;

[0113] Temperature range: 25-300℃;

[0114] Heating rate: 10℃ / min.

[0115] In the following specific embodiments of the present invention, the materials for which no preparation methods are provided are all commercially available chemicals. The specific information of some materials is shown in the following table:

[0116] (1) Crude tranexamic acid: batch number 20250228, provided by Yunnan Specialty Plant Extraction Laboratory Co., Ltd.

[0117] (2) Tranexamic acid reference substance: batch number 100174-202105, provided by the National Institutes for the Control of Pharmaceutical and Biological Products;

[0118] (3) Impurity B, impurity C, impurity D, impurity E, and impurity F of tranexamic acid: provided by Hengfeng Wanda Pharmaceutical Impurity Network.

[0119] The following will describe in detail the tranexamic acid crystals and the preparation method thereof of the present invention using multiple embodiments as examples, but the tranexamic acid crystals and the preparation method thereof of the present invention are not limited to these embodiments.

[0120] Example 1

[0121] A tranexamic acid crystal and a preparation method thereof, the preparation method comprising the following steps:

[0122] (1) 1 kg of crude tranexamic acid was added to 30 L of a crystallization solvent (a mixture of methanol and water, wherein the volume content of methanol was 15%), 0.01 kg of activated carbon was added, and the solution was heated at 80° C. to fully dissolve the solution, and filtered to obtain a tranexamic acid solution;

[0123] (2) The tranexamic acid solution obtained in step (1) was allowed to stand at 25° C. for 72 h to allow slow crystallization, filtered, washed with methanol, and dried under reduced pressure at 60° C. to obtain 0.80 kg of tranexamic acid crystals with a yield of 80%. The content was measured by HPLC to be 99.4%.

[0124] The tranexamic acid crystals provided in this embodiment were tested and the results were as follows: The X-ray powder diffraction pattern is as follows Figure 1 The characteristic peaks, interplanar spacing (d value) and relative peak intensity (I / I0) expressed in terms of diffraction angle 2θ are shown in Table 1:

[0125] Table 1

[0126]

[0127] according to Figure 1 As can be seen from Table 1, the tranexamic acid crystals provided by the present invention are a new crystalline form.

[0128] The DSC test diagram of the tranexamic acid crystals provided in this embodiment is as follows: Figure 2 As shown, according to DSC analysis, tranexamic acid crystals melt and decompose, and there is an endothermic peak at 300±3°C.

[0129] The infrared absorption spectrum of tranexamic acid crystals provided in this embodiment is as follows Figure 3 As shown, it has an absorption peak at the following wave number: 2933cm -1 , 2607cm -1 , 2206cm -1 , 1645cm -1 , 1539cm -1 , 1450cm-1 , 1381cm -1 , 1327cm -1 , 12781cm -1 , 1224cm -1 , 1193cm -1 , 1161cm -1 , 1089cm -1 , 1029cm -1 , 1008cm -1 , 975cm -1 , 918cm -1 , 840cm -1 , 767cm -1 , 700cm -1 , 553cm -1 , 524cm -1 , 472cm -1 , 412cm -1 .

[0130] The HPLC test chart of tranexamic acid crystals provided in this embodiment is as follows Figure 4 As shown, the purity (content) of the tranexamic acid crystals is 99.4%, wherein the content of impurity B is ≤0.15%, the maximum content of each of impurity C, impurity D, impurity E and impurity F is ≤0.05%; the maximum unknown single impurity content is ≤0.05%; the maximum sum of unspecified impurities is ≤0.2%; and it meets the relevant substance limit requirements of EP11.0.

[0131] Example 2

[0132] A tranexamic acid crystal and a preparation method thereof, the preparation method comprising the following steps:

[0133] (1) 1 kg of crude tranexamic acid was added to 10 L of a crystallization solvent (a mixture of methanol and water, wherein the volume content of methanol was 10%), and 0.05 kg of activated carbon was added. The solution was heated at 70° C. to fully dissolve the solution, and filtered to obtain a tranexamic acid solution.

[0134] (2) The tranexamic acid solution obtained in step (1) was allowed to stand at 0° C. for 12 h to allow slow crystallization, filtered, washed with methanol, and dried under reduced pressure at 50° C. to obtain 0.85 kg of tranexamic acid crystals with a yield of 85%. The content was measured by HPLC to be 99.2%. The tranexamic acid crystals provided in this embodiment were tested by X-ray powder diffraction test, confirming that their crystal structure was the same as that in Example 1.

[0135] Example 3

[0136] A tranexamic acid crystal and a preparation method thereof, the preparation method comprising the following steps:

[0137] (1) 1 kg of crude tranexamic acid was added to 40 L of a crystallization solvent (a mixture of ethanol and water, wherein the volume content of ethanol was 45%), and 0.03 kg of activated carbon was added. The solution was heated at 75° C. to fully dissolve the solution, and filtered to obtain a tranexamic acid solution.

[0138] (2) The tranexamic acid solution obtained in step (1) was allowed to stand at 25° C. for 48 h to allow slow crystallization, filtered, washed with ethanol, and dried under reduced pressure at 60° C. to obtain 0.90 kg of tranexamic acid crystals with a yield of 90%. The content was measured by HPLC to be 99.6%. The tranexamic acid crystals provided in this embodiment were tested by X-ray powder diffraction test, confirming that their crystal structure was the same as that in Example 1.

[0139] Example 4

[0140] A tranexamic acid crystal and a preparation method thereof, the preparation method comprising the following steps:

[0141] (1) 1 kg of crude tranexamic acid was added to 50 L of a crystallization solvent (a mixture of methanol and water, wherein the volume content of methanol was 50%), and 0.04 kg of activated carbon was added. The solution was heated at 60° C. to fully dissolve the solution, and filtered to obtain a tranexamic acid solution.

[0142] (2) The tranexamic acid solution obtained in step (1) was allowed to stand at 25° C. for 72 h to allow slow crystallization, filtered, washed with ethanol, and dried under reduced pressure at 60° C. to obtain 0.78 kg of tranexamic acid crystals with a yield of 78%. The content was measured by HPLC to be 99.6%. The tranexamic acid crystals provided in this embodiment were tested by X-ray powder diffraction test, confirming that their crystal structure was the same as that in Example 1.

[0143] Comparative Example 1

[0144] The tranexamic acid reference substance, batch number 100174-202105, was provided by the China National Institutes for the Control of Pharmaceutical and Biological Products.

[0145] The tranexamic acid reference substance was tested by X-ray powder diffraction test, and its X-ray powder diffraction under Cu-Kα radiation, The X-ray powder diffraction pattern is as follows Figure 5 The characteristic peaks, interplanar spacing (d value) and relative peak intensity (I / I0) expressed in terms of diffraction angle 2θ are shown in Table 2:

[0146] Table 2

[0147]

[0148]

[0149] according to Figure 5As shown in Table 2, the crystal form of the tranexamic acid reference substance is different from the tranexamic acid crystals provided by the present invention, indicating that the tranexamic acid crystals provided by the present invention are a new crystal form.

[0150] Comparative Example 2

[0151] A tranexamic acid crystal and a preparation method thereof, the preparation method comprising the following steps:

[0152] (1) 1 kg of crude tranexamic acid was added to 30 L of a crystallization solvent (a mixture of methanol and water, wherein the volume content of methanol was 5%), and 0.01 kg of activated carbon was added. The solution was heated at 80° C. to fully dissolve the solution, and filtered to obtain a tranexamic acid solution.

[0153] (2) The tranexamic acid solution obtained in step (1) was allowed to stand at 25° C. for 72 h to allow slow crystallization, filtered, washed with methanol, and dried under reduced pressure at 60° C. to obtain 0.82 kg of tranexamic acid crystals with a yield of 82%. The content was measured by HPLC to be 98.5%, and its purity did not meet the relevant substance limit requirements in the tranexamic acid quality standard in EP11.0.

[0154] The tranexamic acid crystals provided in this comparative example were tested by X-ray powder diffraction test. The X-ray powder diffraction pattern is as follows Figure 6 The characteristic peaks, interplanar spacing (d value) and relative peak intensity (I / I0) expressed in terms of diffraction angle 2θ are shown in Table 3:

[0155] Table 3

[0156]

[0157]

[0158] according to Figure 6 It can be seen that the crystal form of tranexamic acid obtained by using an alcohol-water solvent with a methanol volume content of 5% as the crystallization solvent is different from the tranexamic acid crystals provided by the present invention.

[0159] Comparative Example 3

[0160] A tranexamic acid crystal and a preparation method thereof, the preparation method comprising the following steps:

[0161] (1) Take 1 kg of crude tranexamic acid, add 10 L of water, add 0.05 kg of activated carbon, heat at 70°C to fully dissolve the solution, and filter to obtain a tranexamic acid solution;

[0162] (2) the tranexamic acid solution obtained in step (1) was allowed to stand at 0° C. for 12 h to allow slow crystallization, filtered, washed with water, and dried under reduced pressure at 50° C. to obtain 0.75 kg of tranexamic acid crystals with a yield of 75%. The content was measured by HPLC to be 98.3%, and the purity did not meet the related substance limit requirements in the tranexamic acid quality standard in EP11.0.

[0163] The tranexamic acid crystals provided in this comparative example were tested by X-ray powder diffraction test. The X-ray powder diffraction pattern is as follows Figure 7 The characteristic peaks, interplanar spacing (d value) and relative peak intensity (I / I0) expressed in terms of diffraction angle 2θ are shown in Table 4:

[0164] Table 4

[0165]

[0166] according to Figure 7 It can be seen that the crystal form of tranexamic acid obtained by using pure water as the crystallization solvent is different from the tranexamic acid crystals provided by the present invention.

[0167] Comparative Example 4

[0168] A tranexamic acid crystal and a preparation method thereof, the preparation method comprising the following steps:

[0169] (1) 1 kg of crude tranexamic acid was added to 10 L of a crystallization solvent (a mixture of methanol and water, wherein the volume content of methanol was 60%), and 0.05 kg of activated carbon was added. The solution was heated at 70° C. to fully dissolve the solution, and filtered to obtain a tranexamic acid solution.

[0170] (2) The tranexamic acid solution obtained in step (1) was allowed to stand at 0° C. for 12 h to allow slow crystallization, filtered, washed with methanol, and dried under reduced pressure at 50° C. to obtain 0.90 kg of tranexamic acid crystals with a yield of 90%. The content was measured by HPLC to be 98.9%, and its purity did not meet the relevant substance limit requirements in the tranexamic acid quality standard in EP11.0.

[0171] The tranexamic acid crystals provided in this comparative example were tested by X-ray powder diffraction test. The X-ray powder diffraction pattern is as follows Figure 8 The characteristic peaks, interplanar spacing (d value) and relative peak intensity (I / I0) expressed in terms of diffraction angle 2θ are shown in Table 5:

[0172] Table 5

[0173]

[0174] according to Figure 7 It can be seen that the crystal form of tranexamic acid obtained by using pure water as the crystallization solvent is different from the tranexamic acid crystals provided by the present invention.

[0175] The stability test of the aforementioned tranexamic acid crystals was performed as follows:

[0176] (1) Strong acid destruction: Accurately weigh 10 mg of the sample to be tested into a 100 mL volumetric flask, add 2 mL of 0.1 mol / L hydrochloric acid aqueous solution, mix well, and let it stand at room temperature for 48 h. Then dissolve, dilute, and adjust to volume with 40% methanol aqueous solution and shake well.

[0177] (2) Strong alkali destruction: Accurately weigh 10 mg of the sample to be tested into a 100 mL volumetric flask, add 2 mL of 0.1 mol / L sodium hydroxide aqueous solution, mix well, and let it stand at room temperature for 48 h; then dissolve, dilute, and adjust to volume with 40% methanol aqueous solution and shake well.

[0178] (3) Strong oxidative damage: Accurately weigh 0.5 mg of the sample to be tested into a 50 mL volumetric flask, add 1 mL of hydrogen peroxide (H2O2 concentration is 30%) solution, mix well, and leave at room temperature for 48 h; then dissolve, dilute, and adjust to volume with 40% methanol aqueous solution and shake well.

[0179] (4) High temperature destruction: Accurately weigh 10 mg of the sample to be tested into a 100 mL volumetric flask, heat it at 80°C for 48 h, and then dissolve, dilute, and adjust the volume with 40% methanol aqueous solution and shake well.

[0180] (5) Strong light damage: Accurately weigh 10 mg of the sample to be tested into a 100 mL volumetric flask and place it under strong light conditions of 4500 ± 500 lux for 240 h. Then dissolve, dilute, and adjust the volume with 40% methanol aqueous solution and shake well.

[0181] The destroyed samples were subjected to HPLC test, and the peak area data obtained are shown in Table 6:

[0182] Table 6

[0183]

[0184] The stability of tranexamic acid crystals and tranexamic acid reference substance (lot number 100174-202105, comparative example 1) provided by the present invention was tested in 0.1 mol / L sodium hydroxide solution for different periods of time using the "strong base destruction" method. The data are shown in Table 7:

[0185] Table 7

[0186] Storage time (h) Example 1 Comparative Example 1 0 2034028 2223476 1 2018665 2111349 2 2011237 2112259 3 2000335 2103339 4 2004024 2100583 5 1999347 2078902 6 1998298 2003653 7 1978221 1993298 8 1977723 1973992 RSD (%) 0.90 3.73

[0187] The above test results show that the tranexamic acid crystals provided by the present invention are stable to light, heat, acid, alkali and strong oxidation. In an alkaline aqueous solution, the peak area RSD value of the tranexamic acid crystals of the present invention is less than that of Comparative Example 1, indicating that the tranexamic acid reference substance in Comparative Example 1 is significantly degraded. The tranexamic acid crystals of the present invention have better stability than the tranexamic acid reference substance and are easy to produce and store.

[0188] The applicant states that the present invention illustrates tranexamic acid crystal of the present invention and preparation method and application thereof by the above-mentioned embodiments, but the present invention is not limited to the above-mentioned processing steps, that is, it does not mean that the present invention must rely on the above-mentioned processing steps to be implemented. Those skilled in the art should understand that any improvement of the present invention, the equivalent replacement of the raw materials selected by the present invention, the addition of auxiliary components, the selection of specific methods, etc., all fall within protection scope of the present invention and disclosure range.

Claims

1. A tranexamic acid crystal, characterized in that, In the X-ray powder diffraction pattern of the tranexamic acid crystal under Cu-Kα radiation, characteristic peaks are present at diffraction angles 2θ of 10.52±0.2°, 17.54±0.2°, 17.90±0.2°, 20.86±0.2° and 21.24±0.2°.

2. The tranexamic acid crystal according to claim 1, wherein In the X-ray powder diffraction pattern of the tranexamic acid crystals under Cu-Kα radiation, characteristic peaks are present at diffraction angles 2θ of 10.52±0.2°, 17.54±0.2°, 17.90±0.2°, 19.44±0.2°, 20.86±0.2°, 21.24±0.2°, 27.96±0.2° and 28.68±0.2°.

3. The tranexamic acid crystal according to claim 1 or 2, wherein In the X-ray powder diffraction pattern of the tranexamic acid crystals under Cu-Kα radiation, the characteristic peaks and relative peak intensities expressed by the diffraction angle 2θ are as follows: Preferably, in the X-ray powder diffraction pattern of the tranexamic acid crystals under Cu-Kα radiation, the characteristic peaks and relative peak intensities expressed by the diffraction angle 2θ are as follows:

4. The tranexamic acid crystal according to any one of claims 1 to 3, wherein In the X-ray powder diffraction pattern of the tranexamic acid crystals under Cu-Kα radiation, the characteristic peaks and interplanar spacings expressed in terms of diffraction angle 2θ are as follows:

5. The tranexamic acid crystal according to any one of claims 1 to 4, wherein The infrared absorption spectrum of the tranexamic acid crystals has an absorption peak at the following wavenumbers: 2933±2cm -1 , 2607±2cm -1 , 2206±2cm -1 , 1645±2cm -1 , 1539±2cm -1 , 1450±2cm -1 , 1381±2cm -1 , 1327±2cm -1 , 1278±2cm -1 , 1224±2cm -1 , 1193±2cm -1 , 1161±2cm -1 , 1089±2cm -1 , 1029±2cm -1 , 1008±2cm -1 , 975±2cm -1 , 918±2cm -1 , 840±2cm -1 , 767±2cm -1 , 700±2cm -1 , 553±2cm -1 , 524±2cm -1 , 472±2cm -1 , 412±2cm -1 .

6. The tranexamic acid crystal according to any one of claims 1 to 5, wherein The differential scanning calorimetry analysis spectrum of the tranexamic acid crystals has an endothermic peak at 297-303° C.; Preferably, the purity of the tranexamic acid crystals is ≥99%.

7. A method for preparing tranexamic acid crystals as described in any one of claims 1 to 6, characterized in that: The preparation method comprises: Providing a tranexamic acid solution, the tranexamic acid solution comprises a combination of a crude tranexamic acid product and a crystallization solvent, wherein the crystallization solvent is a mixture of an alcohol solvent and water, and the volume percentage of the alcohol solvent in the crystallization solvent is 10-50%; The tranexamic acid solution is subjected to crystallization treatment to obtain the tranexamic acid solution crystals.

8. The preparation method according to claim 7, characterized in that The alcohol solvent includes methanol and / or ethanol; Preferably, based on the mass of the crude tranexamic acid product as 1 g, the volume of the crystallization solvent is 10-100 mL; Preferably, the tranexamic acid solution further comprises activated carbon, and the crystallization treatment further comprises a filtration step before the crystallization treatment; Preferably, the preparation method of the tranexamic acid solution comprises: mixing crude tranexamic acid, a crystallization solvent and activated carbon, dissolving the crude tranexamic acid and then filtering to obtain the tranexamic acid solution; Preferably, based on the mass of the crude tranexamic acid product being 100%, the mass of the activated carbon is 0.1-5%; Preferably, the temperature of the crystallization treatment is 0-40°C; Preferably, the crystallization treatment time is ≥12 h, more preferably 12-84 h; Preferably, the crystallization treatment further includes the steps of solid-liquid separation, washing and drying.

9. The preparation method according to claim 7 or 8, characterized in that The preparation method comprises the following steps: (1) mixing crude tranexamic acid, a crystallization solvent, and activated carbon, dissolving them at 50-100° C., and then filtering to obtain a tranexamic acid solution; Based on the mass of the crude tranexamic acid product as 1g, the volume of the crystallization solvent is 10-100mL, and the mass of the activated carbon is 0.001-0.05g; The crystallization solvent is a mixture of an alcohol solvent and water, the volume percentage of the alcohol solvent in the crystallization solvent is 10-50%, and the alcohol solvent includes methanol and / or ethanol; (2) The tranexamic acid solution is allowed to stand at 0-40° C. for crystallization for ≥12 h, followed by solid-liquid separation, and the solid is collected, washed, and dried to obtain the tranexamic acid crystals.

10. Use of the tranexamic acid crystal according to any one of claims 1 to 6 in the preparation of pharmaceutical preparations or cosmetics.

Images