Method for preparing 6-nitrocaproic acid from aminocaproic acid and application of 6-nitrocaproic acid

Abstract

The invention belongs to the technical field of chemical medicines, and relates to a method for preparing 6-nitrocaproic acid from aminocaproic acid. The method for preparing 6-nitrocaproic acid by using aminocaproic acid comprises the following steps: S1, obtaining a liquid containing aminocaproic acid; s2, adding an oxide into the liquid containing aminocaproic acid, and reacting at 40-70 DEG C for 8-72 hours; s3, carrying out alcohol precipitation and filtering to remove aminocaproic acid in the mixture liquid obtained in the step S2; s4, carrying out liquid phase separation on a product obtained in the step S3, and collecting an effluent obtained by eluting a chromatographic column acetonitrile aqueous solution for 17.5-20 minutes; and S5, drying the product in the step S4 to obtain a light brown oily substance. The invention further relates to the 6-nitrocaproic acid prepared from the aminocaproic acid injection and application of the 6-nitrocaproic acid, the technical blank that the 6-nitrocaproic acid is not prepared from the aminocaproic acid injection is filled, and a basis is provided for safety research of the aminocaproic acid injection.

Description

Technical Field

[0001] The invention belongs to the technical field of chemical drug injections and relates to a method for preparing 6-nitrohexanoic acid, in particular to a method for preparing 6-nitrohexanoic acid in aminocaproic acid injection. Background Art

[0002] The adverse reactions of drugs during clinical use are not only related to the pharmacological activity of the main ingredients, but also closely related to the influence of impurities. In order to ensure the safety of clinical drug use, impurities in drugs must be strictly controlled.

[0003] Aminocaproic acid injection is clinically used to prevent and treat various bleeding caused by hyperfibrinolysis. Aminocaproic acid injection usually contains 6-aminocaproic acid, and the pharmacological action of 6-aminocaproic acid is: it inhibits the plasminogen activator, prevents the conversion of plasminogen to plasmin, thereby reducing the degradation of fibrin and achieving hemostasis.

[0004] Aminocaproic acid will generate 6-nitrocaproic acid when it comes into contact with strong oxidants. 6-Nitrocaproic acid is toxic and cannot be eaten. It will irritate the eyes, respiratory system and skin when it comes into contact with the human body. If it comes into contact with the eyes accidentally, it should be rinsed immediately with plenty of water. 6-Nitrocaproic acid is partially similar to aminocaproic acid in structure. At present, there are no reports on the generation of 6-nitrocaproic acid from aminocaproic acid and the side effects caused by it. Summary of the invention

[0005] In view of the deficiencies in the prior art, the present invention provides a method for preparing 6-nitrocaproic acid from aminocaproic acid, which fills the technical gap in preparing 6-nitrocaproic acid from aminocaproic acid in medicinal injections and provides a basis for the safety research of aminocaproic acid injections.

[0006] In a first aspect, the present invention provides a simple and easy method for rapidly preparing 6-nitrohexanoic acid, which comprises directly destroying aminocaproic acid injection, enriching by alcohol precipitation, and separating and extracting by liquid chromatography.

[0007] Specifically, the method for preparing 6-nitrocaproic acid from a solution containing aminocaproic acid of the present invention comprises the following steps:

[0008] S1, obtaining a solution containing aminocaproic acid;

[0009] S2, adding hydrogen peroxide to the solution containing aminocaproic acid, and reacting at 40-70° C. for 8-72 hours;

[0010] S3, removing aminocaproic acid in the mixture liquid obtained in step S2 by alcohol precipitation and filtration;

[0011] S4, performing preparative liquid separation on the product obtained in step S3, and collecting the effluent from the chromatographic column eluted with acetonitrile aqueous solution for 17.5-20 min;

[0012] S5, drying the product of step S4 to obtain a light brown oil.

[0013] Preferably, the concentration of hydrogen peroxide in step S2 is in the range of 10% to 30%; the reaction is completed in a water bath at a temperature of 50 to 65° C.; and the reaction time is 12 to 48 hours.

[0014] The oxidant is a substance capable of oxidizing aminocaproic acid, including but not limited to (peroxide, oleum, persulfate, potassium dichromate, etc.). In a preferred embodiment of the present invention, the oxidant used is hydrogen peroxide (hydrogen peroxide), which can be commercially available 30% hydrogen peroxide, or a 10-30% hydrogen peroxide aqueous solution prepared by oneself, mass volume ratio.

[0015] The main purpose of step S3 is to remove most of the aminocaproic acid in the solution and increase the concentration of 6-nitrocaproic acid. Step S3 preferably includes:

[0016] S3.1, subjecting the mixture solution obtained in step S2 to rotary evaporation at 40-70°C until a white solid precipitates;

[0017] S3.2, add 6-10 times the volume of anhydrous ethanol and keep at a temperature below -15°C overnight;

[0018] S3.3, filter and take the filtrate.

[0019] Preferably, the white solid is aminocaproic acid. The filtrate can be taken and step S3.2 can be repeated once or multiple times, and then the filtrate is collected and concentrated by rotary evaporation.

[0020] Preferably, in step S4, the chromatographic conditions for liquid phase separation include:

[0021] Chromatographic column: Daisogel C18, 20×250 mm, 10 μm;

[0022] Flow rate: 10-50ml / min;

[0023] Wavelength: 200-220nm;

[0024] When collecting, the retention time of the target peak was 18-19 min.

[0025] In a preferred embodiment of the present invention, the conditions for liquid phase separation are as follows:

[0026] Table 1 Optimal conditions for liquid phase separation

[0027]

[0028] Preferably, the drying in step S5 is performed by rotary evaporation at a temperature of 40-70°C.

[0029] Preferably, the light brown oil obtained in step S5 is soluble in pure water (without other substances) and prepared into a standard aqueous solution.

[0030] In a second aspect, the present invention provides a liquid containing 6-nitrohexanoic acid. The basic information of 6-nitrohexanoic acid is as follows:

[0031] Category: Aminocaproic acid oxidative degradation impurities;

[0032] Chemical name: 6-nitrohexanoic acid;

[0033] English chemical name: 6-nitrohexanoic acid;

[0034] Chemical formula: C6H 11 NO 4；

[0035] Exact molecular weight: 161.07;

[0036] Average molecular weight: 161.16;

[0037] CAS No.: 10269-96-2;

[0038] Structural formula:

[0039]

[0040] Preferably, the liquid is prepared by the above method.

[0041] In a third aspect, the present invention also provides an application of the preparation method, which directly obtains 6-nitrohexanoic acid, an impurity produced in the process of aminocaproic acid injection, from the oxidative degradation of aminocaproic acid, for use in safety studies of aminocaproic acid injection.

[0042] The pharmaceutical research of aminocaproic acid injection needs to explore the influence of 6-nitrocaproic acid impurity on the medication effect of aminocaproic acid injection, but there is no commercial product of this impurity on the market, and there is no literature or patent to disclose the relevant preparation method. The present invention provides a simple and easy rapid preparation method, which can obtain 6-nitrocaproic acid impurity quickly and at low cost by directly destroying aminocaproic acid injection, enriching by alcohol precipitation, and preparing by preparative liquid chromatography to meet the needs of drug safety research.

[0043] Preferably, the impurity 6-nitrohexanoic acid is prepared into a standard aqueous solution, maleic acid can be added as an internal standard, and the content is calibrated by quantitative nuclear magnetic resonance (Q-NMR) to obtain a standard aqueous solution with a mass volume ratio of 6-nitrohexanoic acid of 0.10-0.20%, more preferably 0.15%.

[0044] In a fourth aspect, the present invention provides a method for preventing an injection containing aminocaproic acid from producing 6-nitrocaproic acid, and avoiding direct contact with a strong oxidant when preparing or using the injection containing aminocaproic acid.

[0045] The present invention uses aminocaproic acid to obtain high-purity 6-nitrocaproic acid through oxidation and decomposition, alcohol precipitation, liquid phase separation and other steps. In the prior art, nitrocaproic acid can be prepared by organic synthesis, such as synthesizing aminocaproic acid through caprolactam amide to further synthesize 6-nitrocaproic acid, and the route is as follows:

[0046]

[0047] The synthesis requires screening of appropriate catalysts, the reaction yield is still unclear, and aminocaproic acid is easily polymerized to form dimer impurities. The remaining raw materials (caprolactam and aminocaproic acid) in the synthesis mother liquor also increase the difficulty of subsequent purification. The preparation of 6-nitrocaproic acid by organic synthesis is more costly, technically difficult, time-consuming and difficult to guarantee the purity of the product.

[0048] In contrast, the method of the present invention is used to prepare 6-nitrohexanoic acid, which has low cost, short time, high product purity and is relatively stable. BRIEF DESCRIPTION OF THE DRAWINGS

[0049] In order to more clearly illustrate the technical solution of the present application, the drawings required for use in the embodiments will be briefly introduced below. Obviously, each drawing in the following description is for some embodiments of the present application. For ordinary technicians in this field, other drawings can be obtained based on these drawings without creative work.

[0050] Figure 1 This is a typical spectrum of preparative chromatography.

[0051] Figure 2 This is the result of high-resolution mass spectrometry (negative mode).

[0052] Figure 3 It is the H NMR spectrum.

[0053] Figure 4 It is the NMR-C spectrum.

[0054] Figure 5 It is a low temperature water bath chromatogram.

[0055] Figure 6 It is a long-term high-temperature water bath chromatogram.

[0056] Figure 7 This is the product chromatogram when the rotary evaporation temperature is too high.

[0057] Figure 8 This is the product chromatogram when the rotary evaporation temperature is too low.

[0058] Fig. 9 It is the product chromatogram of an effective preparation method.

[0059] Compared with the prior art, the present invention uses simple steps to obtain high-purity 6-nitrohexanoic acid. The preparation process of the method uses only a small amount of oxidant, water and acetonitrile, which is low in cost and high in efficiency. Aminocaproic acid, caprolactam and dimer impurities in the system can be effectively removed through liquid phase preparation and separation to obtain high-purity 6-nitrocaproic acid. DETAILED DESCRIPTION

[0060] The basic information of 6-nitrohexanoic acid in the present invention is as follows:

[0061] Category: Impurities from oxidative degradation of aminocaproic acid

[0062] Chemical name: 6-nitrohexanoic acid;

[0063] English chemical name: 6-nitrohexanoic acid;

[0064] Chemical formula: C6H 11 NO 4；

[0065] Exact molecular weight: 161.07;

[0066] Average molecular weight: 161.16;

[0067] CAS No.: 10269-96-2;

[0068] Structural formula:

[0069]

[0070] The following will be combined with the drawings in the embodiments of the present invention to clearly and completely describe the technical solutions in the embodiments of the present invention. Obviously, the described embodiments are only part of the embodiments of the present invention, not all of the embodiments. Based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field without creative work are within the scope of protection of the present invention.

[0071] Example 1 Preparation process

[0072] Step 1: Oxidative damage

[0073] Take about 1000 ml of aminocaproic acid injection, add 350 ml of 30% hydrogen peroxide, and place in a 40°C water bath for 24 hours.

[0074] Step 2: Alcohol precipitation

[0075] The aminocaproic acid injection solution after the oxidation destruction treatment in step 1 is subjected to rotary evaporation at 45°C until a white solid (aminocaproic acid) is precipitated, anhydrous ethanol (about 8 times the volume) is added, and the mixture is stored at about -20°C overnight, and filtered. The filtrate is taken and the above operation is repeated once, and the filtrate is appropriately concentrated by rotary evaporation.

[0076] Step 3: The solution enriched with impurities by alcohol precipitation in step 2 is subjected to liquid phase separation to extract the main oxidative degradation impurities (RRT4.31). The preparative chromatographic conditions are as follows:

[0077] Instrument: Preparative HPLC Beijing Chuangxintongheng LC3000N

[0078] Chromatographic column: Daisogel C18, 20×250mm, 10μm

[0079] Flow rate: 10ml / min

[0080] Wavelength: 210nm

[0081] Table 2 Preparative chromatographic conditions

[0082]

[0083] Elution procedure:

[0084] Typical graphs such as Figure 1 shown.

[0085] Collection: The retention time of the target peak is about 18.8 min, and the effluent from 17.5-20 min is collected.

[0086] Step 4: Drying

[0087] The prepared collected solution was rotary evaporated at 45°C to obtain a light brown oil with batch number 20220125.

[0088] Example 2 Structural Confirmation

[0089] 2.1 High Resolution Mass Spectrometry (HRMS)

[0090] Instrument model: Agilent 6210TOF

[0091] Detection method: ESI ion source, negative mode

[0092] Testing unit: Shanghai Institute of Pharmaceutical Industry Analysis and Testing Center

[0093] Sample batch number: 20220125.

[0094] Analysis:

[0095] The molecular formula of 6-nitrohexanoic acid is C6H 11 NO4, its [MH]- The theoretical value is m / z=160.0615, and the measured value is m / z=160.0618, with an error of 1.87ppm from the theoretical value, which is within the allowable range.

[0096] Table 3 Mass spectrometry analysis data table

[0097]

[0098] in conclusion:

[0099] Mass spectrometry (ESI negative mode) detection, [MH] - The measured value is consistent with the theoretical value of 6-nitrohexanoic acid.

[0100] 2.2 NMR spectroscopy

[0101] 2.2.1 1 H-NMR nuclear magnetic resonance spectrum

[0102] Instrument model: BRUKER 600MHz

[0103] Test method: using CDCl3 as solvent

[0104] Testing unit: Shanghai Institute of Pharmaceutical Industry Analysis and Testing Center

[0105] Sample batch number: 20220125

[0106] Test results: See Figure 3 .

[0107] Analysis:

[0108]

[0109] Table 4 1 H-NMR data and analysis

[0110]

[0111] Note: at = triplet, m = multiplet, br s = broad singlet.

[0112] in conclusion:

[0113] The H NMR spectrum of the sample gave 6 groups of peaks, among which the proton number, chemical shift, peak shape and splitting were consistent with the theoretical structure.

[0114] 2.2.2 13 C-NMR nuclear magnetic resonance spectroscopy

[0115] Instrument model: BRUKER 600MHz

[0116] Test method: using CDCl3 as solvent

[0117] Testing unit: Shanghai Institute of Pharmaceutical Industry Analysis and Testing Center

[0118] Sample batch number: 20220125

[0119] Test results: See Figure 4 .

[0120] Analysis:

[0121]

[0122] Table 5 13 C-NMR data and analysis

[0123] Chemical shift ppm Carbon Type Attribution 179.05 Quaternary Carbon 1 75.48 Secondary Carbon 6 33.68 Secondary Carbon 2 27.14 Secondary Carbon 4 25.81 Secondary Carbon 5 24.00 Secondary Carbon 3

[0124] Example 3 Assignment (Q-NMR)

[0125] Instrument model: BRUKER 600MHz

[0126] Test method: Recover the sample after carbon spectrum detection, spin dry at 45°C, add 10 ml of purified water to make an aqueous solution, use maleic acid as the internal standard, and use quantitative nuclear magnetic resonance to assign values ​​to the standard aqueous solution.

[0127] Testing unit: Shanghai Institute of Pharmaceutical Industry Analysis and Testing Center

[0128] Sample batch number: 20220125

[0129] Test results: Every 1g of aqueous solution contains 1.5mg of 6-nitrohexanoic acid, i.e. 0.15%.

[0130] Combined with the analysis of degradation mechanism, HRMS, 1 H-NMR, 13 The chemical structure of the oxidative degradation impurities in the prepared and purified aminocaproic acid injection was confirmed by C-NMR and other means, and the structure was consistent with 6-nitrocaproic acid.

[0131] The prepared 6-nitrohexanoic acid aqueous solution was assigned a value by using quantitative nuclear magnetic resonance to obtain a standard aqueous solution with a content of 0.15%.

[0132] When aminocaproic acid is oxidized to generate 6-nitrocaproic acid, multiple impurities are generated, such as caprolactam, dimer and some impurities with unknown structures and properties. The complex matrix in the system increases the difficulty of purification. The preparative chromatographic conditions involved in this method can effectively separate and remove impurities in the system to obtain a high-purity finished product.

[0133] Example 4 Comparison of water bath temperature

[0134] In theory, low water bath temperature is not conducive to the formation of products, and increasing the water bath temperature can promote the reaction and increase the preparation efficiency and output of 6-nitrohexanoic acid. However, the research of the present invention shows that the higher the water bath temperature is, the more favorable it is. As shown in Table 6, when the water bath temperature is increased too much, impurities will increase, which is not conducive to obtaining pure 6-nitrohexanoic acid.

[0135] Table 6 Effect of water bath temperature on preparation results

[0136]

[0137]

[0138] like Figure 5 As shown, the temperature is too low / the time is too short, and the 6-nitrohexanoic acid content is too low to be detected. Figure 6 As shown, when the temperature is high and the time is long, the amount of 6-nitrohexanoic acid increases, and the amount of impurities in the system increases (aminocaproic acid at 3.2 min and 6-nitrocaproic acid at 13.8 min), which increases the difficulty of preparing and separating pure products.

[0139] Example 5 Effect of rotary evaporation temperature or time on preparation results

[0140] The purpose of rotary evaporation is to evaporate and remove water, but too high a temperature may cause the product to decompose. The present invention explores the effect of rotary evaporation temperature on the preparation results. It is found that if the temperature is too low / the time is too short, the content of 6-nitrohexanoic acid is low and cannot be detected (see Figure 7 ); high temperature / long time, while 6-nitrohexanoic acid increases, the impurities in the system will increase (3.2min is aminocaproic acid, 13.8min is 6-nitrocaproic acid), which increases the difficulty of preparing and separating pure products (see Figure 8 ).

[0141] After repeated tests, the following analytical method can effectively separate 100 μg of aminocaproic acid, 15 μg of caprolactam, 50 μg of dimer and 6-nitrocaproic acid.

[0142] The relevant substances were determined according to high performance liquid chromatography (General Rules 0512 of Part IV of the Chinese Pharmacopoeia 2020 Edition).

[0143] Solvent: Take 0.55g of sodium hexane sulfonate, dissolve it in water and dilute it to 1000ml, shake well.

[0144] Test solution: Accurately measure an appropriate amount of the product, add water to quantitatively dilute to make a solution containing approximately 10 mg of aminocaproic acid per 1 ml, shake well, and the solution is ready.

[0145] Reference solution: Take an appropriate amount of aminocaproic acid reference substance, accurately weigh it, dissolve it in water and quantitatively dilute it to make an aminocaproic acid reference substance stock solution containing about 2.5 mg of aminocaproic acid per 1 ml; take an appropriate amount of caprolactam reference substance, accurately weigh it, dissolve it in water and quantitatively dilute it to make a caprolactam reference substance stock solution containing about 0.375 mg / ml of caprolactam per 1 ml; take an appropriate amount of dimer reference substance, accurately weigh it, dissolve it in water and quantitatively dilute it to make a dimer reference substance stock solution containing about 1.25 mg / ml of dimer per 1 ml. Accurately measure 1.0 ml of aminocaproic acid reference substance stock solution, caprolactam reference substance stock solution and dimer reference substance stock solution respectively, place them in the same 25 ml volumetric flask, add water to quantitatively dilute to the scale, shake well, and obtain reference substance solutions containing about 100 μg of aminocaproic acid, 15 μg of caprolactam and 50 μg of dimer per 1 ml respectively.

[0146] System suitability solution: Same as reference solution.

[0147] Chromatographic conditions: Use octadecylsilane bonded silica gel as a chromatographic column filler (Kromasil 100-5C18 4.6mm×250mm, 5μm or a chromatographic column with equivalent performance can be selected), take 10g of potassium dihydrogen phosphate, add 600ml of solvent to dissolve it, add 250ml of methanol to mix, adjust the pH value to 2.2 with phosphoric acid, dilute to 1000ml with the above solvent as the mobile phase; the flow rate is 1.0ml / min, the column temperature is 35℃, the detection wavelength is 210nm, and the injection volume is 20μl.

[0148] System suitability requirements: Accurately measure 20 μl of system suitability solution and inject it into the liquid chromatograph. The separation degree of the three peaks of aminocaproic acid, caprolactam and dimer should be no less than 2.0. The recording time of the chromatographic peak is 4 times the peak retention time of aminocaproic acid. The elution order of the reference solution is aminocaproic acid, caprolactam and dimer.

[0149] Determination method: Accurately measure 20 μl of the test solution and the reference solution, respectively, and inject them into the liquid chromatograph to record the chromatogram (see Fig. 9 ).

[0150] Comparison results of liquid phase separation experimental conditions in Example 6

[0151] (1) The conditions for liquid phase separation are as follows:

[0152] Table 7 Liquid phase separation conditions I

[0153]

[0154]

[0155] Result: 6-Nitrohexanoic acid and aminohexanoic acid were not baseline separated, and the 6-nitrohexanoic acid solution was mixed with aminohexanoic acid.

[0156] (2) The conditions for liquid phase separation are as follows:

[0157] Table 8 Liquid phase separation conditions II

[0158]

[0159] Result: The separation effect was poor, and 6-nitrohexanoic acid and aminohexanoic acid were not separated.

[0160] In the description of the present invention, the terms "include", "comprises" or any other variations thereof are intended to cover non-exclusive inclusion, so that a process, method, article or device including a series of elements includes not only those elements, but also includes other elements not explicitly listed, or also includes elements inherent to such process, method, article or device. It should be noted that, in this article, relational terms such as "first", "second", etc. are only used to distinguish one entity or operation from another entity or operation, and do not necessarily require or imply any such actual relationship or order between these entities or operations.

[0161] The above-described embodiments are only specific implementation methods of the present application, but the protection scope of the present application is not limited thereto. Any changes or substitutions that can be thought of by any technician familiar with the art within the technical scope disclosed in the present application without creative work should be included in the protection scope of the present application. Therefore, the protection scope of the present application shall be based on the protection scope of the claims in the present application.

Claims

1. A method for preparing 6-nitrohexanoic acid, characterized in that: The method comprises the following steps: S1, obtaining a liquid containing aminocaproic acid; S2, adding an oxide to a liquid containing aminocaproic acid, and reacting at 40-70° C. for 8-72 hours; S3, removing aminocaproic acid in the mixture liquid obtained in step S2 by alcohol precipitation and filtration; S4, performing liquid phase separation on the product obtained in step S3, and collecting the effluent from the chromatographic column eluted with acetonitrile aqueous solution for 17.5-20 min; S5, drying the product of step S4 to obtain a light brown oil.

2. The method for preparing 6-nitrohexanoic acid according to claim 1, characterized in that: The concentration of hydrogen peroxide in step S2 is in the range of 10%-30%; the reaction is completed in a water bath at a temperature of 50-65° C.; the reaction time is 12 hours-48 hours; and the oxide is selected from one or more of peroxide, oleum, persulfate or potassium dichromate.

3. The method for preparing 6-nitrohexanoic acid according to claim 1, characterized in that: Step S3 includes: S3.1, rotary evaporating the mixture solution obtained in step S2 until a white solid precipitates; S3.2, add 6-10 times the volume of anhydrous ethanol and keep at a temperature below -15°C overnight; S3.3, filter and take the filtrate.

4. The method for preparing 6-nitrohexanoic acid according to claim 3, characterized in that: The rotary evaporation temperature is 40-70°C; The white solid is aminocaproic acid; or, After taking the filtrate, repeat step S3.2 once or multiple times, then collect the filtrate and concentrate it by rotary evaporation.

5. The method for preparing 6-nitrohexanoic acid according to claim 1, characterized in that: In step S4, the chromatographic conditions for liquid phase separation include: Chromatographic column: 20×250mm, 10μm; Flow rate: 10-50ml / min; Wavelength: 200-220nm; or, When collecting, the retention time of the target peak was 18-19 min.

6. The method for preparing 6-nitrohexanoic acid according to claim 1, characterized in that: In step S5, the drying is carried out by rotary evaporation, and the rotary evaporation temperature is 40-70°C.

7. The method for preparing 6-nitrohexanoic acid according to any one of claims 1 to 6, characterized in that: The light brown oil obtained in step S5 is dissolved in water to prepare a standard aqueous solution; alternatively, pure water and maleic acid as an internal standard are added to the light brown oil obtained in step S5 to obtain a standard aqueous solution with a 6-nitrohexanoic acid content of 0.15%, mass to volume ratio.

8. A liquid containing 6-nitrohexanoic acid, characterized in that The liquid is obtained by the method according to any one of claims 1 to 6.

9. The use of the method for preparing 6-nitrohexanoic acid according to any one of claims 1 to 6, characterized in that: The 6-nitrocaproic acid, an impurity produced by the aminocaproic acid injection in the process, is directly obtained from the aminocaproic acid injection through oxidation degradation, and is used for the safety study of the aminocaproic acid injection; the oxidation is achieved by adding hydrogen peroxide.

10. The use of the method for preparing 6-nitrohexanoic acid according to claim 9, characterized in that: When preparing or using injections containing aminocaproic acid, avoid direct contact with strong oxidizing agents.

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