Urapidil hydrochloride injection and a preparation method thereof

Abstract

The application discloses a urapidil hydrochloride injection and a preparation method thereof, and belongs to the technical field of preparation of urapidil hydrochloride injection. The injection comprises the following components: 0.1-1.0 wt% of urapidil hydrochloride, 0.05-0.5 mol / L of sodium citrate dihydrogen, 2.0-5.0 wt% of mannitol and 0.001-0.01 wt% of EDTA-2Na; wherein, the solvent is water for injection, and the pH value of the injection is 3.8-4.2. The urapidil hydrochloride injection provided by the application overcomes the defects of poor physical stability and high impurity content of urapidil hydrochloride injection in the prior art.

Description

Technical Field

[0001] This invention belongs to the field of preparation technology of urapidil hydrochloride injection, and more specifically relates to a method for preparing urapidil hydrochloride injection. Background Technology

[0002] Urapidil hydrochloride, as an α1-receptor blocker, is clinically used for the treatment of hypertensive crisis. Existing injectable solutions have three major technical shortcomings:

[0003] The degradation pathway is complex: the urea group (-NHCONH-) in the molecule hydrolyzes to generate impurity A (CAS 34690-94-3) at pH > 4.5, and the aromatic ring is oxidized in the presence of oxygen to form impurity F (HPLC relative retention time 1.32).

[0004] Poor physical stability: Traditional citrate buffer systems experience pH shifts of >0.7 units after sterilization, leading to decreased solution clarity and a failure rate of up to 8.3% in pharmacopoeia-compliant foreign matter tests.

[0005] Process defects: The existing preparation method uses high-temperature dissolution (>60℃) to accelerate degradation, and the terminal sterilization F0 value >12 causes impurities to increase by 2.5 times.

[0006] Therefore, there is an urgent need to develop a urapidil hydrochloride injection that can simultaneously inhibit chemical degradation and physical instability. Summary of the Invention

[0007] To address the aforementioned problems, this invention provides a urapidil hydrochloride injection and its preparation method, overcoming the shortcomings of poor physical stability and high impurity content in existing urapidil hydrochloride injections.

[0008] To achieve the above objectives, the present invention adopts the following technical solution:

[0009] The first aspect of this invention provides a urapidil hydrochloride injection solution, the injection solution comprising the following components: urapidil hydrochloride 0.1-1.0 wt%, sodium dihydrogen citrate 0.05-0.5 mol / L, mannitol 2.0-5.0 wt%, EDTA-2Na 0.001-0.01 wt%; wherein the solvent is water for injection, and the pH value of the injection solution is 3.8-4.2.

[0010] In existing technologies, it is generally believed that low pH leads to decreased stability of urapidil (e.g., CN117224478A emphasizes high pH stability). This invention overcomes this limitation through the synergistic effect of excipients. The inventors accidentally discovered that the buffering capacity of sodium citrate at specific concentrations under acidic conditions, combined with the chelating and antioxidant effects of EDTA-2Na, can significantly improve the stability of urapidil hydrochloride under high-temperature storage and strong acid degradation, achieving unexpected technical results compared to existing technologies. Simultaneously, under weakly acidic conditions (pH 3.8-4.2), mannitol is chemically stable and does not react with sodium citrate (buffer), EDTA-2Na (chelating agent), or urapidil hydrochloride in the formulation, overcoming the technical barrier of existing technologies that "injection solution turbidity increases and clarity decreases at low pH values."

[0011] This invention effectively inhibits the hydrolytic ring-opening reaction of the urapidil molecule by lowering the pH value to a weakly acidic range. According to medicinal chemistry principles, when the pH value is below the pKa value of urapidil, the molecule exists in a protonated form, significantly reducing degradation caused by hydroxyl attack. Using sodium dihydrogen citrate (0.05-0.5 mol / L) as a buffer provides stable buffering capacity within the target pH range, exhibiting stronger acidic environment adaptability compared to the citrate-sodium citrate buffer pair (pH 5.9-6.5) used in existing technologies. By adding 2.0-5.0 wt% mannitol, osmotic pressure is maintained under low pH conditions, avoiding the risk of hemolysis of erythrocytes due to pH reduction. Furthermore, compared to the sodium metabisulfite antioxidant system used in existing technologies, EDTA-2Na does not require additional pH adjustment under acidic conditions and does not introduce sulfite ions.

[0012] In summary, this invention is the first to combine three excipients—sodium dihydrogen citrate, mannitol, and EDTA-2Na—to form a triple-stabilized system of "buffering-antioxidant-protection," thus solving multiple stability problems under low pH conditions.

[0013] Furthermore, the concentration of sodium dihydrogen citrate is 0.10-0.15 mol / L, and the pH is controlled at 3.95-4.05.

[0014] Compared with existing technologies, sodium dihydrogen citrate at 0.10-0.15 mol / L can provide stable proton buffer pairs in the pH range of 3.95-4.05, with a significantly improved buffering capacity compared to 0.05 mol / L, effectively resisting pH fluctuations during sterilization and storage.

[0015] A second aspect of this invention provides a method for preparing urapidil hydrochloride injection, comprising the following steps:

[0016] Step 1: Weigh each component according to the urapidil hydrochloride injection solution described above; then, under a nitrogen atmosphere, cool the water for injection to 5±2℃, and add EDTA-2Na and sodium dihydrogen citrate in sequence to obtain system 1;

[0017] Step 2: Add urapidil hydrochloride to system 1 in batches, controlling the temperature to ≤10℃, then add mannitol and heat to 25±3℃ to dissolve, to obtain system 2;

[0018] Step 3: After filtering system 2 through 0.45μm and 0.22μm filter membranes, the system is filled with nitrogen and sterilized to obtain the urapidil hydrochloride injection solution.

[0019] Compared with existing technologies, this invention prepares system 1 at low temperature under a nitrogen atmosphere with a residual oxygen content of <0.5 ppm. At this temperature, by replacing oxygen in the solution with an inert gas, the concentration of the key substrate for the oxidation reaction can be reduced to an extremely low level. Combined with the chelating effect of EDTA-2Na, the oxidative degradation of urapidil can be synergistically inhibited. Cooling the water for injection to 5±2℃ reduces the heat of dissolution of EDTA-2Na and sodium citrate, avoiding excipient degradation due to localized temperature increases, and simultaneously reducing the redissolution of oxygen during dissolution. Adding urapidil hydrochloride in batches avoids precipitation caused by excessively high local concentrations. Heating to 25±3℃ dissolves mannitol: mannitol has higher solubility at 25℃ than at 10℃, and heating accelerates its dissolution without affecting the stability of the dissolved urapidil. The 0.45μm filter membrane first removes large particulate impurities introduced by raw materials and excipients, preventing clogging of the subsequent 0.22μm filter membrane. The 0.22μm filter membrane serves as the final sterilization filter, removing bacteria and pyrogens while further reducing the number of particles. Nitrogen refilling during filling replaces the air in the top space of the ampoule / vial, preventing oxidation of the formulation caused by oxygen permeation through the stopper during storage. The related substances growth rate is ≤0.3% after 18 months of long-term storage.

[0020] Furthermore, the residual oxygen content of system 1 is <0.5 ppm.

[0021] Furthermore, the stirring speed is 100-200 rpm when adding EDTA-2Na and sodium citrate in sequence.

[0022] Compared with existing technologies, a stirring speed of 100-200 rpm can avoid the generation of bubbles from vigorous stirring, while ensuring uniform dissolution of the excipients.

[0023] Furthermore, in step two, urapidil hydrochloride is added in four portions, with an interval of 4-6 minutes between each addition; and after adding urapidil hydrochloride and mannitol, the stirring speed is 400-600 rpm respectively.

[0024] Compared with existing technologies, the strong shear force generated at 400-600 rpm can accelerate particle dispersion, shorten dissolution time, and avoid undissolved particle residue.

[0025] Furthermore, the sterilization is performed by autoclaving at 115~120℃ for 12-18 minutes.

[0026] Furthermore, the F0 value of the sterilization is controlled between 8 and 10.

[0027] The F0 value is a key indicator for measuring sterilization effectiveness (F0=8-10 indicates that the sterilization effect of sterilization at 121℃ for 8-10 minutes is equivalent). This parameter can ensure thorough sterilization while avoiding the degradation of urapidil caused by over-sterilization (such as when F0>12), resulting in a low loss rate of active pharmaceutical ingredient content. Detailed Implementation

[0028] The technical solutions in the embodiments of the present invention will be clearly and completely described below. Obviously, the described embodiments are only some embodiments of the present invention, and not all embodiments. Based on the embodiments of the present invention, all other embodiments obtained by those skilled in the art without creative effort are within the scope of protection of the present invention.

[0029] The urapidil hydrochloride injection prepared in the prior art has poor physical stability and high impurity content.

[0030] In a first aspect, embodiments of the present invention provide a urapidil hydrochloride injection, the injection comprising the following components: urapidil hydrochloride 0.1-1.0 wt%, sodium dihydrogen citrate 0.05-0.5 mol / L, mannitol 2.0-5.0 wt%, EDTA-2Na 0.001-0.01 wt%; wherein the solvent is water for injection, and the pH value of the injection is 3.8-4.2.

[0031] For example, an urapidil hydrochloride injection comprises the following components: urapidil hydrochloride 0.1 wt%, sodium dihydrogen citrate 0.05 mol / L, mannitol 2.0 wt%, EDTA-2Na 0.001 wt%, and the pH of the injection is 3.8.

[0032] For example, an urapidil hydrochloride injection comprises the following components: urapidil hydrochloride 1.0 wt%, sodium dihydrogen citrate 0.5 mol / L, mannitol 5.0 wt%, EDTA-2Na 0.01 wt%, and the pH of the injection is 4.2.

[0033] For example, an urapidil hydrochloride injection comprises the following components: urapidil hydrochloride 0.6 wt%, sodium dihydrogen citrate 0.3 mol / L, mannitol 3.5 wt%, EDTA-2Na 0.005 wt%, and the pH of the injection is 4.0.

[0034] When the above technical solution is adopted, the buffering capacity of sodium dihydrogen citrate at a specific concentration under acidic conditions, combined with the chelating and antioxidant effects of EDTA-2Na, can greatly improve the stability of urapidil hydrochloride under high-temperature storage conditions and under strong acid damage, achieving unexpected technical effects compared to existing technologies. Simultaneously, under weakly acidic conditions of pH 3.8-4.2, mannitol is chemically stable and does not react with sodium dihydrogen citrate (buffer), EDTA-2Na (chelating agent), or urapidil hydrochloride in the formulation, overcoming the technical barrier that is generally considered to be "increased turbidity and decreased clarity of the injection solution at low pH values" in existing technologies.

[0035] In some embodiments, the concentration of sodium dihydrogen citrate is 0.10-0.15 mol / L, and the pH is controlled at 3.95-4.05.

[0036] When using the above technical solution, 0.10-0.15 mol / L sodium citrate can provide a stable proton buffer pair in the pH range of 3.95-4.05, which is 1-2 times higher than that at 0.05 mol / L, and can effectively resist pH fluctuations during sterilization and storage.

[0037] Secondly, embodiments of the present invention provide a method for preparing urapidil hydrochloride injection, comprising the following steps:

[0038] Step 1: Weigh each component according to the urapidil hydrochloride injection solution; then, under a nitrogen atmosphere, cool the water for injection to 5±2℃, and add EDTA-2Na and sodium citrate dihydrogen in sequence to obtain system 1;

[0039] Step 2: Add urapidil hydrochloride to system 1 in batches, controlling the temperature to ≤10℃, then add mannitol and heat to 25±3℃ to dissolve, to obtain system 2;

[0040] Step 3: After filtering system 2 through 0.45μm and 0.22μm filter membranes, the system is filled with nitrogen and sterilized to obtain the urapidil hydrochloride injection solution.

[0041] For example, the temperature of the water for injection after cooling can be selected as a range of values ​​consisting of 3°C, 5°C, 7°C, or any point value, preferably 3-5°C.

[0042] For example, urapidil hydrochloride is added to system 1 in batches, and the temperature is controlled within a range of 10°C, 5°C, 3°C or any other point value, preferably 3-5°C.

[0043] When using the above technical solution, the present invention prepares system 1 at low temperature under a nitrogen atmosphere, with residual oxygen content <0.5 ppm. At this time, by replacing the oxygen in the solution with an inert gas, the concentration of the key substrate for the oxidation reaction can be reduced to an extremely low level. Combined with the chelating effect of EDTA-2Na, the oxidative degradation of urapidil can be synergistically inhibited. Cooling the water for injection to 5±2℃ can reduce the heat of dissolution of EDTA-2Na and sodium dihydrogen citrate, avoiding excipient degradation caused by local temperature increases, and reducing the redissolution of oxygen during the dissolution process. Adding urapidil hydrochloride in batches can avoid precipitation caused by excessively high local concentrations. Heating to 25±3℃ to dissolve mannitol: mannitol has a higher solubility at 25℃ than at 10℃, and heating can accelerate its dissolution, and this temperature will not affect the stability of the dissolved urapidil. The 0.45μm filter membrane first removes large particulate impurities introduced by raw materials and excipients, preventing clogging of the subsequent 0.22μm filter membrane. The 0.22μm filter membrane serves as the final sterilization filter, removing bacteria and pyrogens while further reducing the number of particles. Nitrogen refilling during filling replaces the air in the top space of the ampoule / vial, preventing oxidation of the formulation caused by oxygen permeation through the stopper during storage. The related substances growth rate is ≤0.3% after 18 months of long-term storage.

[0044] In some of these embodiments, the residual oxygen content of system 1 is <0.5 ppm.

[0045] Furthermore, the stirring speed is 100-200 rpm when adding EDTA-2Na and sodium citrate in sequence.

[0046] For example, the stirring speed can be specifically selected as a range of values ​​consisting of 100 rpm, 150 rpm, 200 rpm, or any point value, preferably 150-200 rpm.

[0047] In the above technical solution, a stirring speed of 100-200 rpm can avoid the generation of bubbles from vigorous stirring, while ensuring that the auxiliary materials are dissolved evenly.

[0048] In some embodiments, urapidil hydrochloride is added in four portions in step two, with an interval of 4-6 minutes between each addition; and the stirring speed is 400-600 rpm after adding urapidil hydrochloride and mannitol, respectively.

[0049] The stirring speed can be selected as a range of 400 rpm, 600 rpm, 500 rpm, or any combination of these values, preferably 500-600 rpm.

[0050] In the above technical solution, the strong shear force generated at 400-600 rpm can accelerate particle dispersion, shorten the dissolution time, and avoid the residue of undissolved particles.

[0051] In some embodiments, sterilization is performed by autoclaving at 115-120°C for 12-18 minutes.

[0052] For example, the sterilization temperature can be specifically selected as a range of values ​​consisting of 115°C, 120°C, 118°C, or any point value, preferably 118-120°C.

[0053] For example, the sterilization time can be specifically selected as a range of values ​​consisting of 12 min, 15 min, 18 min, or any point value, preferably 15-18 min.

[0054] Furthermore, the F0 value of the sterilization is controlled between 8 and 10.

[0055] To better illustrate the technical effects of the present invention, the following specific embodiments are provided. It should be understood that, unless otherwise stated, the raw materials described in the embodiments are all commercially available.

[0056] Example 1

[0057] A urapidil hydrochloride injection, comprising the following components: urapidil hydrochloride 0.1 wt%, sodium dihydrogen citrate 0.05 mol / L, mannitol 2.0 wt%, EDTA-2Na 0.001 wt%, and a pH of 3.8.

[0058] The preparation process of the above-mentioned urapidil hydrochloride injection is as follows:

[0059] Step 1: Weigh each component according to the above-mentioned proportions of urapidil hydrochloride injection; then, under a nitrogen atmosphere, cool the water for injection to 3°C, add EDTA-2Na and sodium citrate in sequence, stir at 100 rpm for 10 min to obtain system 1; the residual oxygen content of system 1 is <0.5 ppm;

[0060] Step 2: Add urapidil hydrochloride to system 1 in 4 portions, stirring at 400 rpm with 4 min intervals between each addition, and controlling the temperature at 10°C. Then, add mannitol while stirring at 400 rpm and heat to 22°C to dissolve, thus obtaining system 2.

[0061] Step 3: After filtering system 2 through 0.45μm and 0.22μm filter membranes, the system is filled with nitrogen and sterilized by autoclaving at 115℃ for 12 minutes, with an F0 value of 10, to obtain the urapidil hydrochloride injection solution.

[0062] Example 2

[0063] A urapidil hydrochloride injection, comprising the following components: urapidil hydrochloride 1.0 wt%, sodium dihydrogen citrate 0.5 mol / L, mannitol 5.0 wt%, EDTA-2Na 0.01 wt%, and a pH of 4.2.

[0064] The preparation process of the above-mentioned urapidil hydrochloride injection is as follows:

[0065] Step 1: Weigh each component according to the above-mentioned proportions of urapidil hydrochloride injection; then, under a nitrogen atmosphere, cool the water for injection to 7°C, add EDTA-2Na and sodium citrate in sequence, stir at 200 rpm for 10 min to obtain system 1; the residual oxygen content of system 1 is <0.5 ppm;

[0066] Step 2: Add urapidil hydrochloride to system 1 in 4 portions, stirring at 600 rpm with 6 min intervals between each addition, and controlling the temperature at 5°C. Then, add mannitol while stirring at 600 rpm and heat to 28°C to dissolve, thus obtaining system 2.

[0067] Step 3: After filtering system 2 through 0.45μm and 0.22μm filter membranes, the system is filled with nitrogen and sterilized by autoclaving at 120℃ for 18 min. The F0 value is 8, thus obtaining the urapidil hydrochloride injection solution.

[0068] Example 3

[0069] A urapidil hydrochloride injection, comprising the following components: urapidil hydrochloride 0.6 wt%, sodium dihydrogen citrate 0.3 mol / L, mannitol 3.5 wt%, EDTA-2Na 0.005 wt%, and a pH of 4.0.

[0070] The preparation process of the above-mentioned urapidil hydrochloride injection is as follows:

[0071] Step 1: Weigh each component according to the above-mentioned proportions of urapidil hydrochloride injection; then, under a nitrogen atmosphere, cool the water for injection to 5°C, add EDTA-2Na and sodium citrate in sequence, stir at 150 rpm for 10 min to obtain system 1; the residual oxygen content of system 1 is <0.5 ppm;

[0072] Step 2: Add urapidil hydrochloride to system 1 in 4 portions, stirring at 500 rpm with 5 min intervals between each addition, and controlling the temperature at 3°C. Then, add mannitol while stirring at 500 rpm and heat to 25°C to dissolve, thus obtaining system 2.

[0073] Step 3: After filtering system 2 through 0.45μm and 0.22μm filter membranes, the system is filled with nitrogen and sterilized by autoclaving at 118℃ for 15 min. The F0 value is 9, thus obtaining the urapidil hydrochloride injection solution.

[0074] Comparative Example 1

[0075] Taking Example 3 as an example, the difference from Example 3 is that an equal amount of sodium dihydrogen citrate is used to replace EDTA-2Na, while the other components and preparation process remain unchanged.

[0076] Comparative Example 2

[0077] Taking Example 3 as an example, the difference from Example 3 is that an equal amount of EDTA-2Na is used to replace sodium dihydrogen citrate, while the other components and preparation process remain unchanged.

[0078] Comparative Example 3

[0079] Taking Example 3 as an example, the difference from Example 3 is that mannitol is replaced with an equal amount of EDTA-2Na.

[0080] Comparative Example 4

[0081] Taking Example 3 as an example, the difference from Example 3 is that the pH value is set to 6.5.

[0082] Performance testing

[0083] 1. Determination of related substances and active pharmaceutical ingredient content (HPLC method)

[0084] Chromatographic conditions: C18 column (250 mm × 4.6 mm, 5 μm); mobile phase: acetonitrile-0.05 mol / L potassium dihydrogen phosphate (30:70, v / v); flow rate: 1.0 mL / min; column temperature: 30 ℃; detection wavelength: 254 nm; injection volume: 20 μL.

[0085] Procedure: Take 1 mL of sample, dilute to 10 mL with mobile phase, filter through a 0.22 μm filter membrane, and inject for determination. Calculate the active pharmaceutical ingredient content using the external standard method, and calculate the total content of related substances and the content of impurity F (relative retention time 1.32) using the area normalization method.

[0086] 2. Acid Degradation Stability Test

[0087] Take 5 mL of sample, add 5 mL of 0.1 mol / L hydrochloric acid, mix and place in a 60℃ water bath for 24 h; immediately after removal, neutralize to pH 4.0 with 1 mol / L sodium hydroxide, determine the main peak area according to the above HPLC method, and calculate the loss rate (loss rate = (main peak area before destruction - main peak area after destruction) / main peak area before destruction × 100%).

[0088] 3. Oxidative Degradation Stability Test

[0089] Take 5 mL of sample, add 1 mL of 3% hydrogen peroxide solution, and let stand at room temperature in the dark for 24 h; determine the content of impurity F according to the above HPLC method.

[0090] 4. Measurement of pH changes before and after sterilization

[0091] Before sterilization: Take the filtered system 2 and measure the pH using a precision pH meter (accuracy ±0.01).

[0092] After sterilization: Take the sterilized sample, cool it to room temperature, and measure the pH using the same method. Calculate the difference (ΔpH = pH after sterilization - pH before sterilization).

[0093] 5. Inspection of visible foreign matter and particle count

[0094] Visible foreign matter: Take 20 samples and, under 2000 lx light, gently rotate the ampoule by hand to observe whether there are foreign objects ≥50 μm (record the number of foreign objects in each ampoule).

[0095] Particle count: Take 10 mL of sample and use a particle detector (optical obscuration method) to determine the number of particles ≥10 μm and ≥25 μm. Repeat 3 times and take the average value.

[0096] 6. Osmotic pressure measurement

[0097] Take 2 mL of sample and measure the osmotic pressure using an ice-point osmometer. Repeat the measurement three times and take the average value.

[0098] 7. Long-term storage stability test

[0099] The samples were placed in a constant temperature and humidity chamber at 25℃ and 60% RH, and samples were taken at 0, 3, 6, 9, 12 and 18 months. The total content of related substances and the content of the active pharmaceutical ingredient were determined according to the above method. The growth rate of related substances within 18 months (growth rate = 18-month content - 0-month content) and the retention rate of the active pharmaceutical ingredient content (retention rate = 18-month content / 0-month content × 100%) were calculated.

[0100] 8. Accelerated stability test

[0101] The samples were placed in a constant temperature and humidity chamber at 40℃ and 75% RH for 6 months, and samples were taken and tested monthly. The results are shown in Table 1.

[0102] Table 1 Stability Test Results

[0103] Testing items Example 1 Example 2 Example 3 Comparative Example 1 Comparative Example 2 Comparative Example 3 Comparative Example 4 Accelerated total content of related substances (%) over 6 months 0.62 0.75 0.58 1.85 2.12 1.25 2.38 Accelerated drug content (%) within 6 months 99.2 98.5 99.5 93.2 91.5 95.8 90.2 Accelerated 6-month test for impurity F content (%) 0.15 0.18 0.12 0.82 0.75 0.35 0.95 Acid-induced peak loss rate (%) 7.8 8.5 7.2 10.5 18.3 9.2 22.5 Oxidative damage to impurity F content (%) 0.21 0.25 0.18 0.95 0.88 0.42 1.25 ΔpH before and after sterilization 0.08 0.12 0.06 0.15 0.85 0.10 0.45 Visible foreign object pass rate (%) 100 100 100 90 60 80 70 ≥10μm particle count (particles / mL) 2800 3200 2500 4500 8200 5800 7500 ≥25μm particle count (particles / mL) 250 280 220 420 950 580 850 Osmotic pressure (mOsm / kg) 295 310 300 290 270 220 295 18-month growth rate of related substances (%) 0.28 0.32 0.25 0.95 1.25 0.65 1.50 18-month retention rate of active pharmaceutical ingredient content (%) 97.5 96.8 98.2 92.2 89.5 94.0 87.0

[0104] The various embodiments described in this specification are presented in a progressive manner, with each embodiment focusing on its differences from other embodiments. Similar or identical parts between embodiments can be referred to interchangeably. The above description of the disclosed embodiments enables those skilled in the art to make or use the invention. Various modifications to these embodiments will be readily apparent to those skilled in the art, and the general principles defined herein may be implemented in other embodiments without departing from the spirit or scope of the invention. Therefore, the invention is not to be limited to the embodiments shown herein, but is to be accorded the widest scope consistent with the principles and novel features disclosed herein.

Claims

1. A urapidil hydrochloride injection, characterized in that, The injection solution comprises the following components: urapidil hydrochloride 0.1-1.0 wt%, sodium dihydrogen citrate 0.05-0.5 mol / L, mannitol 2.0-5.0 wt%, and EDTA-2Na 0.001-0.01 wt%; wherein the solvent is water for injection, and the pH value of the injection solution is 3.8-4.

2.

2. The urapidil hydrochloride injection according to claim 1, characterized in that, The concentration of sodium dihydrogen citrate is 0.10-0.15 mol / L, and the pH is controlled at 3.95-4.

05.

3. A method for preparing urapidil hydrochloride injection, used to prepare the urapidil hydrochloride injection according to any one of claims 1 to 2, characterized in that, Includes the following steps: Step 1: Weigh each component of the urapidil hydrochloride injection solution according to any one of claims 1 to 2; then, under a nitrogen atmosphere, cool the water for injection to 5±2℃ and add EDTA-2Na and sodium dihydrogen citrate in sequence to obtain system 1; Step 2: Add urapidil hydrochloride to system 1 in batches, controlling the temperature to ≤10℃, then add mannitol and heat to 25±3℃ to dissolve, to obtain system 2; Step 3: After filtering system 2 through 0.45μm and 0.22μm filter membranes, the system is filled with nitrogen and sterilized to obtain the urapidil hydrochloride injection solution.

4. The method for preparing urapidil hydrochloride injection according to claim 3, characterized in that, The residual oxygen content of system 1 is <0.5 ppm.

5. The method for preparing urapidil hydrochloride injection according to claim 3, characterized in that, When adding EDTA-2Na and sodium citrate in sequence, the stirring speed should be 100-200 rpm.

6. The method for preparing urapidil hydrochloride injection according to claim 3, characterized in that, In step two, urapidil hydrochloride is added in four portions, with an interval of 4-6 minutes between each addition; and after adding urapidil hydrochloride and mannitol, the stirring speed is 400-600 rpm respectively.

7. The method for preparing urapidil hydrochloride injection according to claim 3, characterized in that, The sterilization process involves autoclaving at 115-120°C for 12-18 minutes.

8. The method for preparing urapidil hydrochloride injection as described in claim 3, characterized in that, The F0 value of the sterilization process is controlled between 8 and 10.