Method for increasing solubility of tranexamic acid

Abstract

A method for increasing the solubility of tranexamic acid, comprising the steps of: a) first dissolving tranexamic acid in water; b) measuring the pH value of the solution obtained in step (a); c) adding a strong acid (which completely dissociates in water) to the solution obtained in step (a) and simultaneously monitoring a decrease in the pH value of the solution until about pH 4.5 or less is reached to increase the solubility of tranexamic acid; d) adding tranexamic acid such that the pH of the solution obtained in step (c) reaches above pH 2.0; and e) repeating steps (c) and (d) until a desired amount of tranexamic acid is added to the solution of step (a), i.e., a desired concentration of tranexamic acid in the final solution is achieved.

Description

Technical Field

[0001] Generally, this application relates to the field of therapeutic dosage forms and their preparation. In particular, this application relates to methods for improving the solubility of tranexamic acid and preparing its liquid dosage form. Background Technology

[0002] Tranexamic acid is a medication used to control bleeding and treat or prevent excessive blood loss from major trauma, postpartum hemorrhage, surgery, and tooth extraction. It helps blood clot and is used for nosebleeds and heavy menstrual bleeding. For example, tranexamic acid mouthwash can help stop bleeding after a tooth extraction. Tranexamic acid can also help resolve conditions that cause swelling under the skin (hereditary angioedema). In cases of any condition causing more bleeding than usual, tranexamic acid can be prescribed a few days before surgery or dental procedures.

[0003] Tranexamic acid is commonly found on prescriptions as tablets, liquid formulations for children and those who cannot swallow tablets, mouthwashes, and injectable forms, which are typically given only in hospitals.

[0004] Tranexamic acid is marketed in the United States and Australia as Lysteda in tablet form, in Australia and Sweden as Cyklokapron in IV and tablet form, and in the United Kingdom and Sweden as Cyclo-F. It is also marketed in the United Kingdom as Femstrual, in Asia as Transcam, in India as Pause, in South America as Espercil, in Japan as Nicolda, and in France, Poland, Belgium, and Romania as Exacyl. In the Philippines, it is marketed in capsule form as Hemostan, and in Israel as Hexakapron.

[0005] Tranexamic acid is available in tablet form as 500 mg tablets. For adults, the usual dose is 2 or 3 tablets three times daily. For those with kidney problems, the dose is typically lower. Liquid formulations are available in different strengths. For example, Cyklokapron is administered as an injectable solution at 100 mg / mL. However, higher concentrations of tranexamic acid are often urgently needed due to increased bleeding or complications associated with surgery or other of the aforementioned conditions. Unfortunately, such doses are not currently available due to the relatively low solubility of tranexamic acid in water (approximately 167 mg / mL under standard conditions). Therefore, there is a long-standing need to develop liquid doses of tranexamic acid with concentrations higher than its solubility. Summary of the Invention

[0006] This invention describes an embodiment of a method for improving the solubility of tranexamic acid, the method comprising the following steps:

[0007] a) First, dissolve tranexamic acid in water;

[0008] b) Measure the pH value of the solution obtained in step (a);

[0009] c) Add a strong acid (which is completely dissociated in water) to the solution obtained in step (a) while monitoring the decrease in pH of the solution until it reaches approximately pH 4.5 or less to increase the solubility of tranexamic acid.

[0010] d) Add tranexamic acid to bring the pH of the solution obtained in step (c) to above pH 2.0; and

[0011] e) Repeat steps (c) and (d) until the desired amount of tranexamic acid is added and dissolved in the solution of step (a), i.e., the desired concentration of tranexamic acid in the final solution is reached.

[0012] In some embodiments, the initial concentration of tranexamic acid dissolved in water in step (a) of the method of the present invention is about 120-200 mg / mL. In specific embodiments, the initial concentration of tranexamic acid is about 130-180 mg / mL, or 130-170 mg / mL, or 130-160 mg / mL. In a particular embodiment, the initial concentration of tranexamic acid is about 130 mg / mL.

[0013] In other embodiments, the pH of the solution from step (a) is reduced to approximately pH 4.5 or below in step (c). In some embodiments, the pH of the solution from step (a) is reduced to below pH 4.0, or below pH 3.5, or below pH 3.0, or below pH 2.5, or below pH 2.0, or below pH 1.5, or below pH 1.0, or below pH 0.5 in step (c).

[0014] In another embodiment, the strong acid used in this invention to lower the pH of the solution in step (c) and thereby increase the solubility of tranexamic acid is selected from hydrochloric acid, perchloric acid, sulfuric acid, nitric acid, hydrobromic acid, hydroiodic acid, chloric acid, and phosphoric acid. The concentration of the strong acid is about 0.01-10.00 eq / L.

[0015] In another embodiment, the pH of the solution from step (c) increases in step (d) to above pH 2.5, or above pH 3.0, or above pH 3.5, or above pH 4.0, or above pH 4.5, or above pH 5.0, or above pH 5.5, as more tranexamic acid is added. In a specific embodiment, the pH is increased to approximately pH 3.5 in step (d).

[0016] In other embodiments, the desired concentration of tranexamic acid in the final solution is greater than 160 mg / mL, or greater than 250 mg / mL, or greater than 350 mg / mL, or greater than 400 mg / mL, or in the range of about 200-600 mg / mL, or in the range of about 300-500 mg / mL. In a specific embodiment, the desired concentration of tranexamic acid in the final solution is about 400 mg / mL, or specifically 440 mg / mL.

[0017] On the other hand, the present invention relates to liquid dosage forms containing tranexamic acid at concentrations exceeding 160 mg / mL, or exceeding 250 mg / mL, or exceeding 350 mg / mL, or exceeding 400 mg / mL, or in the range of about 200-600 mg / mL, or in the range of about 300-500 mg / mL. In a specific embodiment, the liquid dosage form of the present invention contains tranexamic acid at a concentration of about 400 mg / mL, or specifically 440 mg / mL.

[0018] Various embodiments can allow for a variety of benefits and can be used in conjunction with a variety of applications. Details of one or more embodiments are set forth in the accompanying description below. Other features, objectives, and advantages of the described technology will be apparent from the specification and claims. Detailed Implementation Plan

[0019] In the following description, various aspects of this application will be described. Specific configurations and details are set forth for purposes of explanation in order to provide a thorough understanding of this application. However, it will also be apparent to those skilled in the art that this application can be practiced without the specific details presented herein. Furthermore, well-known features may be omitted or simplified so as not to obscure this application.

[0020] The term "comprising" as used in the claims is "open-ended" and refers to the listed elements or their structural or functional equivalents, plus any other one or more elements not listed. It should not be construed as limiting to the means listed herein; it does not exclude other elements or steps. It should be interpreted as specifying the presence of the mentioned features, integers, steps, or components, but does not exclude the presence or addition of one or more other features, integers, steps, or components or groups thereof. Therefore, the scope of the statement "a method comprising steps x and z" should not be limited to methods consisting solely of these steps.

[0021] Unless otherwise specified, as used herein, the terms “about” and “approximately” are understood to refer to normal tolerances in the art, such as within two standard deviations of the average. In one embodiment, the terms “about” and “approximately” mean within 10% of the reported value of a number used with them, preferably within 5% of the reported value. For example, the term “about” can be readily understood to mean within 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, 0.5%, 0.1%, 0.05%, or 0.01% of the value. In other embodiments, the term “about” can mean a higher tolerance of variation, depending on, for example, the experimental technique used. Such variation in a particular value is understood by those skilled in the art and is within the context of this invention. By way of illustration, the numerical range of “about 1 to about 5” should be interpreted as including not only the explicitly listed values ​​of about 1 to about 5, but also individual values ​​and subranges within the indicated range. Therefore, included within this numerical range are single values, such as 2, 3, and 4, and subranges, such as 1-3, 2-4, and 3-5, and individually 1, 2, 3, 4, 5, or 6. The same principle applies to ranges that list only one numerical value as a minimum or maximum value. Unless the context otherwise requires, all numerical values ​​provided herein are modified by the term “about.” Other similar terms, such as “substantially,” “usually,” “until,” etc., should be interpreted as modifying a term or value such that it is not absolute. These terms will be defined by the context and the terms they modify, as these terms are understood by those skilled in the art. This includes at least the degree of expected experimental, technical, and instrumental errors for the given experiment, technique, or instrument used to measure the value.

[0022] As used herein, the term "and / or" includes any and all combinations of one or more of the associated listed items. Unless otherwise defined, all terms used herein (including technical and scientific terms) have the same meaning as commonly understood by one of ordinary skill in the art to which this invention pertains. It will be further understood that terms such as those defined in common dictionaries should be interpreted as having the same meaning as they have in the context of the specification and in the relevant art, and should not be interpreted in an idealized or overly formal sense unless expressly so defined herein. For the sake of brevity and / or clarity, well-known functions or constructions may not be described in detail.

[0023] This invention relates to a method for enhancing the solubility of tranexamic acid, comprising the following steps:

[0024] a) First, dissolve tranexamic acid in water;

[0025] b) Measure the pH value of the solution obtained in step (a);

[0026] c) A strong acid (which is completely dissociated in water) is added dropwise to the solution obtained in step (a) while monitoring the decrease in pH of the solution until it reaches approximately pH 4.5 or less to increase the solubility of tranexamic acid.

[0027] d) Add tranexamic acid to raise the pH of the solution obtained in step (c) to above pH 2.0; and

[0028] e) Repeat steps (c) and (d) until the desired amount of tranexamic acid is added and dissolved in the solution of step (a), i.e., the desired concentration of tranexamic acid in the final solution is reached.

[0029] Tranexamic acid is an organic acid with the following formula:

[0030]

[0031] Its IUPAC name is trans-4-(aminomethyl)cyclohexanecarboxylic acid, and its CAS No. is 1197-18-8.

[0032] Tranexamic acid is a synthetic analogue of the amino acid lysine. It acts as an antifibrinolytic agent by reversibly binding to four to five lysine receptor sites on plasminogen. This reduces the conversion of plasminogen to plasmin, prevents fibrin degradation, and preserves the framework of the fibrin matrix structure. Therefore, it is used as a drug for blood clotting, controlling bleeding, and for the treatment or prevention of excessive blood loss due to major trauma, postpartum hemorrhage, surgery, and tooth extraction.

[0033] It is important to note that the solubility of tranexamic acid is a limiting factor in all currently commercially available dosage forms. Therefore, liquid dosage forms of tranexamic acid with concentrations higher than approximately 180 mg / mL are unknown. The inventors have unexpectedly discovered that the aforementioned method of the present invention significantly increases the solubility of tranexamic acid in its liquid dosage form, which surprisingly appears to be very stable and has a long shelf life.

[0034] In some embodiments, the initial concentration of tranexamic acid dissolved in water in step (a) of the method of the present invention is about 120-200 mg / mL. In specific embodiments, the initial concentration of tranexamic acid is about 130-180 mg / mL, or 130-170 mg / mL, or 130-160 mg / mL. In a particular embodiment, the initial concentration of tranexamic acid is about 130 mg / mL.

[0035] In other embodiments, the pH of the solution from step (a) is reduced to approximately pH 4.5 or below in step (c). In some embodiments, the pH of the solution from step (a) is reduced to below pH 4.0, or below pH 3.5, or below pH 3.0, or below pH 2.5, or below pH 2.0, or below pH 1.5, or below pH 1.0, or below pH 0.5 in step (c). In a specific embodiment, the pH of the solution from step (a) is reduced to approximately pH 0.2 in step (c).

[0036] In another embodiment, the strong acid used in this invention to lower the pH of the solution in step (c) and thereby increase the solubility of tranexamic acid is selected from hydrochloric acid, perchloric acid, sulfuric acid, nitric acid, hydrobromic acid, hydroiodic acid, chloric acid, and phosphoric acid. The concentration of the strong acid is about 0.01-10.00 eq / L.

[0037] In another embodiment, the pH of the solution from step (c) increases in step (d) to above pH 2.5, or above pH 3.0, or above pH 3.5, or above pH 4.0, or above pH 4.5, or above pH 5.0, or above pH 5.5, as a result of the addition of more tranexamic acid. In a specific embodiment, the pH increases to approximately pH 3.5 in step (d). In a particular embodiment, the pH increases to approximately pH 4.5 in step (d).

[0038] In other embodiments, the desired concentration of tranexamic acid in the final solution is greater than 160 mg / mL, or greater than 250 mg / mL, or greater than 350 mg / mL, or greater than 400 mg / mL, or in the range of about 200-600 mg / mL, or in the range of about 300-500 mg / mL. In a specific embodiment, the desired concentration of tranexamic acid in the final solution is about 400 mg / mL, or specifically 440 mg / mL.

[0039] On the other hand, the present invention relates to liquid dosage forms containing tranexamic acid at concentrations exceeding 160 mg / mL, or exceeding 250 mg / mL, or exceeding 350 mg / mL, or exceeding 400 mg / mL, or in the range of about 200-600 mg / mL, or in the range of about 300-500 mg / mL. In a specific embodiment, the liquid dosage form of the present invention contains tranexamic acid at a concentration of about 400 mg / mL, or specifically 440 mg / mL.

[0040] In another aspect, the present invention relates to liquid dosage forms prepared by the method of the invention and containing tranexamic acid at concentrations greater than 160 mg / mL, or greater than 250 mg / mL, or greater than 350 mg / mL, or greater than 400 mg / mL, or in the range of about 200-600 mg / mL, or in the range of about 300-500 mg / mL. In a specific embodiment, the liquid dosage form of the present invention contains tranexamic acid at a concentration of about 400 mg / mL, or specifically 440 mg / mL.

[0041] In another embodiment of the present invention, the method of the present invention includes the following steps:

[0042] a) Dissolve tranexamic acid in water at a concentration of approximately 120-200 mg / mL;

[0043] b) Measure the pH value of the solution obtained in step (a);

[0044] c) A strong acid selected from hydrochloric acid, perchloric acid, sulfuric acid, nitric acid, hydrobromic acid, hydroiodic acid, chloric acid and phosphoric acid is added dropwise to the solution obtained in step (a), while monitoring the decrease in pH of the solution until a pH of about 3.0 to 4.0 is reached, in order to increase the solubility of tranexamic acid.

[0045] d) Add tranexamic acid to raise the pH of the solution obtained in step (c) to approximately 3.5–4.5; and

[0046] e) Repeat steps (c) and (d) until the concentration of tranexamic acid in the final solution reaches approximately 250-440 mg / mL.

[0047] The unique aspect of the method of this invention lies not only in its ability to prepare aqueous solutions of tranexamic acid dissolved at concentrations higher than its solubility in water, but also in its ability to achieve high concentrations of TXA. These high-concentration solutions of TXA have been found to be remarkably stable under conditions of 40°C for 3 months, as demonstrated in the following experimental examples.

[0048] Example 1

[0049] Stability data - Tranexamic acid (TXA) 400 mg / ml, 2.5 ml syringe

[0050] Batch number D-2363

[0051] Dosage: 400 mg / ml, 2.5 ml

[0052] Conditions: 40℃ / 75%RH

[0053] The stability of the drug product was evaluated by comparing stability data with the current BP monograph on TXA injection, ensuring that the results were within acceptable standards throughout the product's shelf life. It should be noted that the product was clear, indicating that the solution was pure and all materials were completely dissolved.

[0054] Stability data are given in the table below:

[0055] Table 1: Stability: 40℃ / 75% RH 3M

[0056]

[0057] 1 Where possible, specification limits are set according to the BP monograph for TXA injection. For IMP B, according to ICH Q3B(R2), it is set at 0.2% instead of 0.5% due to MDD (maximum daily dose). Impurity E is not part of the BP monograph, therefore it is set at 0.15% according to ICH Q3B(R2).

[0058] 1. Appearance - Colorless to pale yellow clear solution.

[0059] There were no changes to the product's appearance.

[0060] 2. Content (assay) - 95.0% to 105.0% of the declared concentration of TXA.

[0061] All content results remained well within the specified limits. Limiting these content limits for such products is a common practice.

[0062] 3. pH

[0063] The pH remained stable throughout the 6M stability period without significant changes.

[0064] The pH limit will be evaluated during the development and research phase.

[0065] 4. Impurities and degradation products:

[0066] 4.1 Impurity "B" cis-tranexamic acid-NMT 0.1%.

[0067] Impurity "B" is an isomer of TXA. Results after 6 months were within limits.

[0068] 4.2 Impurities "C"-NMT 0.1%.

[0069] The result was within the limits.

[0070] 4.3 Impurities "D" Aminomethylbenzoic acid-NMT 0.1%.

[0071] The result was within the limits.

[0072] 4.4 Total impurities - NMT 2.0%.

[0073] The result was within the limits.

[0074] in conclusion :

[0075] The 400 mg / ml product TXA in a 2.5 ml syringe was stable after 6 months under accelerated conditions (40°C / 75% RH), with no significant increase in degradation products and no significant decrease in content levels.

[0076] Example 2

[0077] Release data - TXA 400mg / ml, 2.5ml

[0078] Batch number D-2565

[0079] Dosage: 400 mg / ml, 2.5 ml

[0080] Experiment description: The pH value remained approximately pH 4 throughout the process.

[0081] The purpose of the experiment was to ensure that TXA could also be dissolved at pH 4.

[0082] The release data is given below:

[0083] Release date of batch D-2565

[0084] test Specification D-2565 Appearance Colorless to pale yellow clear solution pass content 95.0-105.0％ 98.4％ Impurity A NMT 0.1% <0.05％ Impurity B (cis-tranexamic acid) NMT 0.1% <0.05％ Impurity C NMT 0.1% <0.05％ Impurity D (aminoethylbenzoic acid) NMT 0.1% <0.05％ Impurity E NMT 0.15% ND Unknown impurities NMT 0.1% ND Total impurities NMT 2.0% <0.05％ pH TBD 4,1

[0085] in conclusion :

[0086] TXA can be produced at an acidity of approximately pH 4 at a concentration of 400 mg / ml in a 2.5 ml syringe. Analytical results meet acceptance criteria, except for a clear solution indicating complete dissolution of TXA.

[0087] Example 3

[0088] Preparation of tranexamic acid formulations using the method of the present invention

[0089] 1. Dissolve 135 mg / ml in water.

[0090] 2. Use a strong acid (HCl 5N) to lower the pH of the solution to approximately 3.0.

[0091] 3. Add tranexamic acid until the pH reaches approximately 4.0.

[0092] 4. Add a strong acid (HCl 5N) to lower the pH to approximately 3.

[0093] 5. Continue with steps 3+4 until a tranexamic acid concentration of 400 mg / ml is achieved.

[0094] Example 4

[0095] Lead process stability data - TXA 400 mg / ml, 2.5 ml

[0096] Batch number D-2556

[0097] Dosage: 400 mg / ml, 2.5 ml

[0098] Conditions: 2 weeks / 65℃

[0099] Batch D-2556 manufacturer, with expected formulation and process:

[0100] 1. Weigh WFI

[0101] 2. Add TXA and mix until dissolved.

[0102] 3. Add HCl to approximately pH 3.

[0103] 4. Add TXA and mix until dissolved.

[0104] 5. Expected value of repeating phases 3+4 to TXA

[0105] 6. Use WFI to complete the weight calculation.

[0106] The stability of the drug product was evaluated by comparing stability data with the current BP monograph on TXA injection, ensuring that the lead formulation and process remained within acceptable standards throughout the product's shelf life. It should be noted that the product was clear, indicating that the solution was pure and all materials were completely dissolved.

[0107] The batch was stored under accelerated conditions at 65°C and 40°C.

[0108] The stability data at 65℃ for 2 weeks are given in the table below. :

[0109] test Specification 1 midnight 2 weeks Appearance Colorless to pale yellow clear solution pass pass content 95.0-105.0％ 99.1％ 98.6％ Impurity A NMT 0.1% <0.05％ <0.05％ Impurity B (cis-tranexamic acid) NMT 0.1% <0.05％ <0.05％ Impurity C NMT 0.1% <0,05％ <0.05％ Impurity D (aminoethylbenzoic acid) NMT 0.1% <0.05％ <0.05％ Impurity E NMT 0.15% ND 0.074％ Unknown impurities NMT 0.1% ND ND Total impurities NMT 2.0% <0.05％ 0.07％ pH TBD 3.6 3.7

[0110] 1 Where possible, specification limits are set according to the BP monograph for TXA injection. For IMP B, according to ICH Q3B(R2), it is set at 0.2% instead of 0.5% due to MDD (maximum daily dose). Impurity E is not part of the BP monograph, therefore it is set at 0.15% according to ICH Q3B(R2).

[0111] 1. Appearance - Colorless to pale yellow clear solution.

[0112] There were no changes to the product's appearance.

[0113] 2. Content - 95.0% to 105.0% of the declared concentration of TXA.

[0114] After two weeks at 65°C, all content results remained well within the specified limits.

[0115] 3. pH

[0116] The pH remained stable and showed no significant change throughout the 2-week stability period at 65°C.

[0117] 4. Impurities and degradation products:

[0118] 4.1 Impurity "B" cis-tranexamic acid-NMT 0.1%.

[0119] Impurity "B" is an isomer of TXA. After 2 weeks at 65°C, the results were within the acceptance criteria and <QL(0.05%)

[0120] 4.2 Impurities "C"-NMT 0.1%.

[0121] After 2 weeks at 65°C, the results were within the acceptance criteria and <QL(0.05%)。

[0122] 4.3 Impurities "D" Aminomethylbenzoic acid-NMT 0.1%.

[0123] After 2 weeks at 65°C, the results were within the acceptance criteria and <QL(0.05%)。

[0124] 4.4 Impurities “E”-NMT 0.15%.

[0125] After 2 weeks at 65°C, the results were within the acceptable range.

[0126] 4.5 Unknown impurities - NMT 0.1%.

[0127] After 2 weeks at 65°C, the results were within the acceptance criteria and <QL(0.05%)。

[0128] 4.6 Total impurities - NMT 2.0%.

[0129] After 2 weeks at 65°C, the results were within the acceptable range.

[0130] in conclusion :

[0131] The 400 mg / ml product of TXA in 2.5 ml was stable under accelerated baseline conditions (2 weeks at 65°C), with no significant increase in degradation products and no significant decrease in content levels.

Claims

1. A method for improving the solubility of tranexamic acid, comprising the steps of: A) first dissolving tranexamic acid in water; b) measuring the pH value of the solution obtained in step (a); c) adding a strong acid (which completely dissociates in water) to the solution obtained in step (a) and simultaneously monitoring the decrease in the pH value of the solution until a pH of about 4.5 or less is reached to increase the solubility of tranexamic acid; d) adding tranexamic acid to bring the pH of the solution obtained in step (c) to a value above pH 2.0; and e) repeating steps (c) and (d) until a desired amount of tranexamic acid is added to the solution of step (a), i.e., a desired concentration of tranexamic acid in the final solution is achieved.

2. The method of claim 1, wherein the initial concentration of tranexamic acid dissolved in water in step (a) of the method is about 120-200 mg / mL.

3. The method of claim 2, wherein the initial concentration of tranexamic acid is about 130-180 mg / mL.

4. The method of claim 3, wherein the initial concentration of tranexamic acid is about 150-170 mg / mL.

5. The method of claim 4, wherein the initial concentration of tranexamic acid is about 165 mg / mL.

6. The method of claim 1, wherein the pH of the solution of step (a) is reduced to about pH 4.0 in step (c).

7. The method of claim 1, wherein the pH of the solution of step (a) is reduced to below pH 4.0 in step (c).

8. The method of claim 7, wherein the pH of the solution of step (a) is reduced in step (c) to below pH 3.5, or below pH 3.0, or below pH 2.5, or below pH 2.0, or below pH 1.5, or below pH 1.0, or below pH 0.

5.

9. The method of claim 7, wherein the pH of the solution of step (a) is reduced to about pH 0.2 in step (c).

10. The method of claim 1, wherein the strong acid is selected from the group consisting of hydrochloric acid, perchloric acid, sulfuric acid, nitric acid, hydrobromic acid, hydroiodic acid, chloric acid and phosphoric acid.

11. The method of claim 1, wherein the concentration of the strong acid is about 0.01-10.00 eq / L.

12. The method of claim 1, wherein the pH of the solution of step (c) is increased in step (d) to above pH 2.5, or above pH 3.0, or above pH 3.5, or above pH 4.0, or above pH 4.5, or above pH 5.0, or above pH 5.5 with the addition of tranexamic acid.

13. The method of claim 12, wherein the pH of the solution of step (c) is raised to about pH 3.5 in step (d).

14. The method of claim 12, wherein the pH of the solution of step (c) is raised to above pH 4.5 in step (d).

15. The method of claim 1, wherein the desired concentration of tranexamic acid in the final solution is greater than 160 mg / mL, or greater than 250 mg / mL, or greater than 350 mg / mL.

16. The method of claim 15, wherein the desired concentration of tranexamic acid in the final solution is greater than 400 mg / mL.

17. The method of claim 1, wherein the desired concentration of tranexamic acid in the final solution is about 200-600 mg / mL, or 300-500 mg / mL.

18. The method of claim 17, wherein the desired concentration of tranexamic acid in the final solution is about 400 mg / mL.

19. The method of claim 18, wherein the desired concentration of tranexamic acid in the final solution is about 450 mg / mL.

20. The method according to claim 1, comprising the steps of: a) dissolving tranexamic acid in water at a concentration of about 120-200 mg / mL; b) measuring the pH value of the solution obtained in step (a); c) adding a strong acid selected from hydrochloric acid, perchloric acid, sulfuric acid, nitric acid, hydrobromic acid, hydroiodic acid, chloric acid and phosphoric acid dropwise to the solution obtained in step (a), while monitoring the decrease in the pH value of the solution until a pH of about 3.0 to 4.0 is reached to increase the solubility of tranexamic acid; d) adding tranexamic acid to raise the pH of the solution obtained in step (c) to a pH of about 3.5-4.5; and e) Repeat steps (c) and (d) until the final solution has a tranexamic acid concentration of approximately 250-450 mg / mL.

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