Torasemide injection and preparation method thereof

Abstract

The invention provides a preparation method of a torasemide injection. The auxiliary materials in the prescription of the torasemide injection comprise polyethylene glycol 400, sodium hydroxide, tromethamine and water for injection. The preparation method comprises the following steps: weighing raw materials, preparing sodium hydroxide into a solution, adding polyethylene glycol 400 and the sodium hydroxide solution into water for injection, heating to T1 for a certain time, cooling to T2, adding torasemide and tromethamine until the torasemide and the tromethamine are completely dissolved, cooling to room temperature, adjusting the pH value by using the sodium hydroxide solution, and fixing the volume to obtain the injection. According to the preparation method disclosed by the invention, a method of heating polyethylene glycol and a sodium hydroxide solution is adopted, and the problem that an impurity F is obviously increased in a placement process is solved by optimally controlling a raw material adding sequence, a heating technological process and parameters, meanwhile, the requirement on a preparation process is reduced, and excessive impurity related substances can be prevented from being generated; and the quality stability of products is improved.

Description

Technical Field

[0001] The present invention relates to the technical field of torasemide drug preparation, and in particular to a torasemide injection component and a method for preparing the torasemide injection. Background Art

[0002] Torsemide is a white or off-white loose block. It is a new generation of sulfonyl pyruvate diuretic developed by Boehringer Mannheim, Germany. It is the fourth diuretic on the market today. It is mainly used in the clinic to treat various edemas and various types of hypertension caused by congestive heart failure, kidney or liver diseases, etc. It is a milestone drug in the history of diuretic development.

[0003] Diuretics are mainly divided into the following categories according to the characteristics of their mechanism of action: osmotic diuretics, carbonic anhydrase inhibitors, loop diuretics, thiazide diuretics, and potassium-sparing diuretics. Torsemide is a highly effective loop diuretic of the pyridine amide urea class. Torsemide has a wide range of indications, a rapid, strong and long-lasting diuretic effect, and a low incidence of adverse reactions. It is a commonly used type of highly effective diuretic in clinical practice today. It is metabolized through both liver and kidney channels, with 80% metabolized in the liver and 20% excreted unchanged through the kidneys, effectively reducing the burden on the kidneys and drug accumulation. Pharmacodynamic studies have shown that torsemide works by inhibiting the thick ascending branch from reacting with Cl - , Na + Torsemide can actively reabsorb TXA2 and exert a diuretic and natriuretic effect. In addition, torsemide can weakly antagonize aldosterone receptors, so it has a potassium-sparing effect. The antihypertensive effect of torsemide is also related to its competitive antagonism of TXA2 receptors and vasodilation.

[0004] The main problems of the torasemide injection currently on the market are that the content of related substances is too high, the quality stability is poor, and the preparation process conditions are high. Using different preparation processes, the components in the original formulation formula lead to a series of impurities in the injection. In addition, it is easy to degrade and produce impurities under high temperature and high humidity conditions, which also affects the stability of product performance. For example, the method for preparing low-impurity torsemide injection disclosed in "Application number CN202011199687.8, publication number CN112168776A, and invention name: A low-impurity and highly stable torsemide injection and preparation method" is "by changing the order of adding raw and auxiliary materials, adjusting the addition time of sodium hydroxide, and adopting a filtration and sterilization process, which not only reduces the impurity content, but also significantly improves the stability of the injection under light and high temperature"; however, the torsemide injection obtained by the preparation method quickly produces impurities under high temperature and long time conditions, and its stability also decreases rapidly; and the injection obtained by the preparation method still contains a variety of impurities, and has a great influence on the impurity content, especially the content of impurity F, which has a great impact on the performance of the product. Summary of the invention

[0005] The object of the present invention is to overcome the defects of the prior art and provide a method for preparing torasemide injection, which adopts a method of heating polyethylene glycol and sodium hydroxide solution, solves the problem of obvious increase of impurity F during storage by optimizing the order of adding raw materials and the heating process and parameters, and reduces the requirements for the preparation process, and can avoid the generation of excessive impurity-related substances, thereby improving the quality stability of the product.

[0006] In order to achieve the above object, the present invention provides a method for preparing torasemide injection, wherein the excipients in the torasemide injection prescription are polyethylene glycol 400, sodium hydroxide, tromethamine, and water for injection, and specifically comprises the following steps:

[0007] Step 1: Weighing: weigh torsemide, sodium hydroxide, polyethylene glycol 400 (PEG400) and tromethamine according to the prescribed amount;

[0008] Step 2: Preparation of regulating solution: prepare sodium hydroxide into a 0.5-1.5 mol / L solution for standby use, preferably the sodium hydroxide solution is prepared into a 1 mol / L solution;

[0009] Step 3: Preparation of injection solution:

[0010] (31) Add about 80% of the total amount of water for injection into the preparation container, add the prescribed amount of polyethylene glycol 400 and a certain amount of the sodium hydroxide solution in step 2, and stir evenly to form a mixed solution. Preferably, the amount of the sodium hydroxide solution added is 0.95 to 0.99 times the amount of the sodium hydroxide solution in step 2;

[0011] (32) heating the mixed solution of step (31) to a temperature T1 for a heating time t;

[0012] (33) cooling the mixed solution to a temperature T2 and keeping it warm, adding the prescribed amount of torsemide and tromethamine to the preparation container, and stirring until the materials are completely dissolved to prepare a uniform drug solution;

[0013] (34) After the temperature of the drug solution is cooled to room temperature (preferably, the temperature of the drug solution is cooled to 20-25° C.), the pH value is measured, and the pH value of the solution is adjusted to 8.0-10.0 with the remaining sodium hydroxide solution (i.e., the amount of the sodium hydroxide solution added is 0.01-0.05 times that of the sodium hydroxide solution in step 2), and the volume is adjusted to the full amount with water for injection, and the injection solution is uniformly stirred;

[0014] Step 4: Filtration and sterilization: Filter and sterilize the injection solution using a filter element with a pore size of 0.22 μm;

[0015] Step 5: filling, filling the injection solution into an ampoule and sealing it after filling it with inert gas.

[0016] Preferably, the temperature T1 in step 32 is 50°C to 120°C, preferably 80°C to 110°C.

[0017] The heating time t in step 32 is 10 min to 60 min, preferably 20 min to 40 min.

[0018] In step 33, the temperature T2 is 20°C to 100°C, preferably 40°C to 100°C.

[0019] The stirring speed is 20 rpm to 60 rpm, and the stirring time is 10 min to 60 min.

[0020] Compared with the prior art, the present invention has the following beneficial effects:

[0021] 1. The preparation method of torasemide injection provided by the present invention heats polyethylene glycol 400 and sodium hydroxide solution to consume the formaldehyde in polyethylene glycol. By optimizing the process, the problem of impurity F increasing significantly during storage is solved. The increase of impurity F during stability storage by the present invention is lower than that of the reference preparation, further ensuring the safety of product medication. At the same time, it also effectively avoids the unstable quality of the preparation product due to the batch difference of polyethylene glycol 400 produced by the supplier, reduces the requirements for the preparation process, and can avoid the production of excessive related substances, thereby improving the quality stability of the product.

[0022] 2. The preparation method of the present invention relates to the field of pharmaceutical preparations, and specifically relates to a preparation process that effectively reduces the content of impurity F in the preparation, reduces the difficulty in the production and preparation process, improves product quality and drug safety. The excipients in the torasemide injection prescription of the present invention are polyethylene glycol 400, sodium hydroxide, tromethamine, and water for injection. The polyethylene glycol 400 in the prescription has a greater impact on impurity F. The polyethylene glycol 400 produced by different suppliers and different preparation processes have a greater impact on impurity F in the product. After clarifying the mechanism of impurity F generation through experimental studies related to the preparation method of the present invention, the process preparation process is optimized, and the problem of impurity F significantly increasing during placement is solved. The growth trend of impurity F and total impurities during stability placement is lower than that of the reference preparation (reference preparation refers to a control drug used for the quality and efficacy consistency evaluation of generic drugs), and the key quality attributes such as clarity, color, pH, and content of the solution are comparable to the quality of the reference preparation.

[0023] 3. Through a series of experiments, it was concluded that the generation of impurity F in the prescription was caused by the auxiliary material polyethylene glycol 400. Polyethylene glycol 400 contains formaldehyde. Through comparative test studies, it was found that heating sodium hydroxide and polyethylene glycol 400 (controlling temperature and time) can effectively reduce impurity F in the product. In addition, only impurity B was detected in the process sample of the present invention, and the content of impurity B was stable and did not increase under "high temperature 60°C conditions, sampling and testing on 0 days and 10 days, and under light conditions", which was consistent with the initial 0-day results. There was no impurity F that mainly affected the safety of the injection, and it had good stability and impurity singleness.

[0024] 4. The preparation method of the present invention can reduce the requirements for the preparation process, is not affected by the quality difference or batch difference of polyethylene glycol 400 excipients produced by suppliers, is simple and easy to operate, and can avoid the production of excessive related substances, improve the quality stability of the product, and reduce the risk of patient medication. In addition, the production process has been scaled up for multiple batches, confirming that the present invention does effectively solve the problem of impurity F growth in the product, further ensuring the safety of product medication. BRIEF DESCRIPTION OF THE DRAWINGS

[0025] Figure 1 -17 is the test spectrum of Experiment 1 to Experiment 17 in the embodiment of the present invention;

[0026] Figure 18-19 This is a stability test chart of the process verification samples (0-3-6 months) under accelerated conditions in the embodiment of the present invention;

[0027] Figure 20-21 This is a stability test chart of the reference preparation (0 month-3 month-6 month) under accelerated conditions in the examples of the present invention;

[0028] Fig. 22 This is a stability test chart of the process verification sample (12 months) under long-term conditions in the embodiment of the present invention;

[0029] Fig.23 This is a stability test chart of the reference preparation (12 months) in the embodiment of the present invention under long-term conditions;

[0030] Figure 24-26 This is a graph of the sampling stability test under high temperature 60°C conditions (0 days-10 days-light exposure) of Example 6 of the present invention. DETAILED DESCRIPTION

[0031] In order to make the purpose, technical scheme and advantages of the present invention clearer, the present invention is further described in detail below in conjunction with the embodiments, so that those skilled in the art can fully understand the technical content of the present invention. It should be understood that the following embodiments are used to further illustrate the present invention and cannot be understood as limiting the scope of protection of the present invention. Some non-essential improvements and adjustments made by those skilled in the art according to the above content of the present invention belong to the scope of protection of the present invention. The specific process parameters of the following examples are also only an example in a suitable range, that is, those skilled in the art can make a selection within a suitable range according to the description herein, and are not limited to the specific values ​​​​exemplified below.

[0032] The preparation process of the present invention can effectively reduce the content of impurity F in the injection preparation. A specific method for preparing torasemide injection comprises the following steps:

[0033] (1) Weigh the raw materials. Weigh torsemide, sodium hydroxide, polyethylene glycol 400, and tromethamine according to the prescribed amount.

[0034] (2) Preparation of regulating solution: prepare sodium hydroxide into a 0.5-1.5 mol / L solution for use.

[0035] (3) preparing injection solution;

[0036] (31) Weigh about 80% of the total amount of water for injection, add the prescribed amount of polyethylene glycol 400 and the 0.95-0.99 times sodium hydroxide solution prepared in (2), stir to dissolve and mix evenly.

[0037] (32) Heat a mixed solution of polyethylene glycol 400 and sodium hydroxide.

[0038] (33) The solution is cooled, and the prescribed amount of torsemide and tromethamine is added to the liquid preparation tank. The solution temperature is kept constant and stirred until the materials are completely dissolved.

[0039] (34) After the drug solution is cooled to room temperature, the pH value is measured and the pH value of the solution is adjusted to 8.0-10.0 with the remaining 0.5-1.5 mol / L sodium hydroxide solution. The volume is made up to the full amount with water for injection and stirred evenly.

[0040] (4) Filtration sterilization: use a 0.22 μm filter to filter and sterilize;

[0041] (5) Filling, filling with inert gas and then sealing.

[0042] The torasemide injection of the present invention can effectively reduce the content of impurity F in the preparation, and improve the quality stability and medication safety of the product.

[0043] Through the relevant research of the present invention, the process of impurity F generation is determined; at the same time, through the optimization of the process, the problem of impurity F increasing significantly during storage is solved, and the increase trend of the impurity stability during storage is lower than that of the reference preparation, further ensuring the safety of product medication. The requirements for the preparation process are reduced, and excessive related substances can be avoided, thereby improving the quality stability of the product.

[0044] Impurity B reacts with formaldehyde to form impurity F. This reaction can occur at room temperature, but high temperature will catalyze this reaction. The reaction process can be expressed as follows:

[0045]

[0046] Impurity F generation process

[0047] From the above reaction process, it can be seen that the generation of impurity F is mainly related to formaldehyde. Since sodium hydroxide and aldehydes can react, the reaction process is expressed as follows:

[0048]

[0049] This reaction is called the process in which aldehydes without α-hydrogen, such as formaldehyde, benzaldehyde, and furfural (2-furan carboxaldehyde), undergo self-oxidation-reduction reaction under the catalysis of base to generate one molecule of alcohol and one molecule of carboxylic acid. This reaction is the nucleophilic addition of hydroxide to the C=O double bond in formaldehyde to produce the negative ion intermediate H2C(OH)O - , then the hydrogen on the carbon forms a negative ion H - Leaves and performs nucleophilic addition to the C=O double bond in another molecule of HCHO to generate methanol anion CH3O - , and it is oxidized to HCOOH. Finally, formic acid reacts with methanol anions to transfer protons to generate methanol and sodium formate.

[0050] According to the above reaction process, in the preparation process of torasemide injection, the preparation method of the present invention allows sodium hydroxide to react with formaldehyde in polyethylene glycol 400 first, and then adds torasemide raw material medicine, which can solve the problem of increased impurity F. At the same time, it also solves the risk of increased preparation-related substances due to quality differences or batch differences of polyethylene glycol 400 excipients produced by different suppliers. The relevant proof experiments are specifically described as follows.

[0051] Embodiment 1:

[0052] The preparation method of the torasemide injection, the prescription composition of the torasemide injection is (the following examples use the same prescription components):

[0053]

[0054] Take about 80% of the prescription amount of purified water, add polyethylene glycol 400 and sodium hydroxide solution 1mol / L, stir evenly, heat at different temperatures (60℃, 70℃, 80℃, 90℃, 100℃) for 20min, keep the temperature at 70℃±0.5℃, add torsemide and tromethamine, stir until the materials are completely dissolved, cool to room temperature, adjust pH, and make up the volume. Pass through a 0.22μm filter membrane and encapsulate to obtain the finished product. The finished product is subjected to high temperature treatment to quickly obtain the experimental results, detect the properties and related substances, and the test results are shown in Table 1.

[0055] Table 1 Heating temperature test results of polyethylene glycol 400 (PEG400) and sodium hydroxide mixed solution

[0056]

[0057] Result analysis: From the test results, the heating operation has a significant effect on reducing impurity F. The higher the heating temperature, the lower the impurity F value. The impurity F is significantly reduced after heating at 80℃~100℃. ND means not detected, the same below.

[0058] Embodiment 2:

[0059] Take about 80% of the prescribed amount of purified water, add polyethylene glycol 400 and 1 mol / L sodium hydroxide solution, stir evenly, heat to 100°C, and the heating time is 10min, 20min, 30min, and 40min respectively. Keep the temperature at 70°C ± 0.5°C, add torsemide and tromethamine, stir until the materials are completely dissolved, cool to room temperature, adjust the pH, and make up the volume. Pass through a 0.22μm filter membrane and encapsulate to obtain the finished product. The finished product is subjected to high temperature treatment to quickly obtain experimental results, detect properties and related substances (focus on impurity F), and the results are shown in Table 2.

[0060] Table 2 Heating time test results of polyethylene glycol 400 (PEG400)

[0061]

[0062] Result analysis: From the test results, it can be seen that the longer the heating time, the less the impurity F of the prepared sample increases. In order to ensure product quality, the heating time can be controlled within 20min~40min.

[0063] Embodiment 3:

[0064] The effect of sodium hydroxide feeding sequence on product-related substances was investigated, and the preparation process was as follows:

[0065] Experiment 10: Take about 80% of the prescribed amount of purified water, add the prescribed amount of polyethylene glycol 400 and 1 mol / L of sodium hydroxide solution, stir evenly, heat to 100°C, keep the temperature at 70°C±0.5°C, add torsemide and tromethamine, stir until the materials are completely dissolved, cool to room temperature, measure the pH value, adjust the pH value if necessary, and make the volume constant. Stir and fill with nitrogen, filter through a 0.22μm PES filter membrane (polyethersulfone filter membrane), and fill with nitrogen to obtain the finished product.

[0066] Experiment 11: Take 80% of the prescribed amount of purified water, add the prescribed amount of polyethylene glycol 400, stir evenly, heat to 100°C, keep the temperature at 70°C±0.5°C, add sodium hydroxide, torsemide and tromethamine, stir until the materials are completely dissolved, measure the pH value, adjust the pH value if necessary, and make the volume constant. Stir and fill with nitrogen, filter through a 0.22μm PES filter membrane, fill with nitrogen and seal to obtain the finished product. The finished product is subjected to high temperature treatment to quickly obtain the experimental results. The test results are shown in Table 3.

[0067] Table 3 Sodium hydroxide feeding sequence test results

[0068]

[0069] Conclusion: Compared with different sodium hydroxide feeding sequences, adding sodium hydroxide before heating the solution is better than adding it after heating and cooling.

[0070] Embodiment 4:

[0071] Since torasemide is sensitive to temperature and unstable at high temperature, the effect of different preparation temperatures on the related substances of the product was investigated. Take about 80% of the prescribed amount of purified water, add polyethylene glycol 400 and 1 mol / L sodium hydroxide solution, stir evenly, heat to 100°C, and then cool down. The cooling temperature is controlled at different temperatures (100°C, 80°C, 70°C, 60°C, 50°C, 40°C) and torasemide and tromethamine are added respectively, stirred until the material is completely dissolved, and the dissolution time is recorded. Cool to room temperature, measure the pH value, adjust the pH value if necessary, and fix the volume. Stir and fill with nitrogen, pass through a 0.22μm PES filter membrane, fill with nitrogen to obtain the finished product, and detect the related substances of the finished product. The test results are shown in Table 4.

[0072] Table 4 Liquid preparation temperature inspection test results

[0073]

[0074] Conclusion: The results show that the preparation temperature has a great influence on the dissolution time of torasemide. The higher the temperature, the faster the API dissolves, but the related substances are relatively stable. Therefore, the API dissolution temperature can be controlled at 40-100℃.

[0075] Embodiment 5:

[0076] Take about 80% of the prescription amount of purified water, add polyethylene glycol 400 and 1 mol / L sodium hydroxide solution, stir evenly, heat to 100°C, heat for 40 minutes, keep the temperature at 70°C±0.5°C, add torsemide and tromethamine, stir until the materials are completely dissolved, cool to room temperature, adjust the pH, and fix the volume. Pass through a 0.22μm filter membrane and encapsulate to obtain the finished product. According to the above process, three batches of process verification samples are produced, and one batch of process verification samples is compared with the reference preparation for stability test results to examine the changes in key indicators. The results are shown in Take about 80% of the prescription amount of purified water, add polyethylene glycol 400 and 1 mol / L sodium hydroxide solution, stir evenly, heat to 100°C, and the heating time is 10min, 20min, 30min, and 40min respectively. Keep the temperature at 70°C±0.5°C, add torsemide and tromethamine, stir until the materials are completely dissolved, cool to room temperature, adjust the pH, and fix the volume. The product was filtered through a 0.22 μm filter membrane and sealed. The product was subjected to high temperature treatment to quickly obtain the experimental results, detect the properties and related substances (focus on impurity F), and the results are shown in Table 2.

[0078] Table 5 Comparison of stability results of process validation samples and reference preparations under accelerated conditions

[0079]

[0080]

[0081] Analysis of results: After 6 months of acceleration, the impurity F of the process validation 1 sample was lower than that of the reference preparation, the total impurities of related substances were lower than that of the reference preparation, and the growth trend was slower than that of the reference preparation (the reference preparation refers to the control drug used for the consistency evaluation of the quality and efficacy of generic drugs).

[0082] Table 6 Comparison of stability results of process validation samples and reference preparations under long-term conditions

[0083]

[0084] Result analysis: Under long-term conditions, the growth of related substances in process validation 1 samples was slow, especially impurity F had almost no growth, which was significantly better than the reference preparation. The stability test results under accelerated conditions and long-term conditions showed that the stability of process validation 1 samples was significantly better than that of the reference preparation, indicating that the present invention can effectively solve the product stability problem while providing a simple preparation process, improve the safety of clinical medication, and reduce the risk of patient medication.

[0085] Embodiment 6:

[0086] In order to determine the cause of impurities in torasemide, a test with a single component was conducted and the records are as follows:

[0087] Test 61: Measure about 80% of the prescribed amount of purified water at room temperature, then add torsemide, stir until the material is completely dissolved, adjust the pH, and make up to volume.

[0088] Test 62: Measure about 80% of the prescribed amount of purified water at room temperature, add 1 mol / L sodium hydroxide solution, stir evenly, then add torsemide, stir until the material is completely dissolved, adjust the pH, and make up to volume.

[0089] Test 63: Measure about 80% of the prescribed amount of purified water at room temperature, add 1 mol / L sodium hydroxide solution and tromethamine, dissolve and stir evenly, then add torsemide, stir until the materials are completely dissolved, adjust the pH, and make up to volume.

[0090] Test 64: Measure about 80% of the prescribed amount of purified water at room temperature, add 1 mol / L sodium hydroxide solution, tromethamine and polyethylene glycol 400, dissolve and stir evenly, then add torsemide, stir until the materials are completely dissolved, adjust the pH, and make up to volume.

[0091] Test 65: Measure about 80% of the prescribed amount of purified water at room temperature, add polyethylene glycol 400, dissolve and stir evenly, then add torsemide, stir until the material is completely dissolved, adjust the pH, and make up to volume.

[0092] Test conditions: The above samples were placed at a high temperature of 60°C, and samples were taken for testing at 0 days and 10 days respectively. The key indicators of the finished products were tested. The test results are recorded in Table 7 below:

[0093] Table 7 Impurity detection results of a single sample at 60°C

[0094]

[0095] Results analysis: Compared with test 64 and test 65, the value of impurity F in test 65 is larger. Through the results of this test, the generation of impurity F in this prescription is caused by the auxiliary material polyethylene glycol 400. And polyethylene glycol 400 contains formaldehyde. Through comparative test research, it is found that heating sodium hydroxide and polyethylene glycol 400 at high temperature (controlling temperature and time) can effectively reduce impurity F in the product.

[0096] Embodiment 7:

[0097] Preparation process: Measure about 80% of the prescribed amount of purified water, add polyethylene glycol 400 and 1 mol / L sodium hydroxide solution, stir evenly, heat to 60°C, heat for 40 minutes, raise the temperature to 65°C±0.5°C and keep warm, then add torsemide and tromethamine, stir until the materials are completely dissolved, cool to room temperature, adjust the pH, and make up to volume.

[0098] Test conditions: The above samples were placed at a high temperature of 60°C, and samples were taken for testing at 0 days and 10 days respectively. They were placed under lighting conditions (the total illumination of the light source was not less than 1.2×106lux·hr, and the energy of the near-ultraviolet lamp was not less than 200W·hr / m2) for 10 days and samples were taken. The key indicators of the finished products were tested. The results are recorded in Table 8.

[0099] Table 8 Stability test results of samples taken under light and high temperature 60℃

[0100]

[0101] Result analysis: From the recorded results of the above-mentioned experiment of the present invention, it can be seen that only impurity B was detected in the process samples of the present invention, and the content of impurity B was stable without growth under "high temperature 60°C conditions, sampling and testing at 0 days and 10 days, and under light conditions", which is consistent with the initial 0-day result. There is no impurity F that mainly affects the safety of the injection, and it has good stability and impurity singleness.

[0102] Embodiment 8:

[0103] Take about 80% of the prescription amount of purified water, add polyethylene glycol 400, tromethamine and sodium hydroxide solution 1mol / L, stir evenly, heat to 100℃, heat for 40min, keep the temperature at 70℃±0.5℃, add torsemide and tromethamine, stir until the materials are completely dissolved, cool to room temperature, adjust pH, and make up to volume. Pass through a 0.22μm filter membrane and encapsulate to obtain the finished product. The prepared finished product is placed under high temperature accelerated conditions (40℃±2℃, 75%±5%RH), and samples are taken for testing in October, March, and June respectively. The test results are compared with the test results of process verification 1 accelerated conditions. The results are recorded in Table 9.

[0104] Table 9 Sampling test results of high temperature preparation samples under high temperature accelerated conditions (40°C ± 2°C, 75% ± 5% RH)

[0105]

[0106]

[0107] The test results show that the process conditions of the preparation method of the present invention (heating to 100°C, heating for 40 minutes) at the beginning (0 month) the impurity B is 0.1%, and the total impurities excluding impurity B are 0.03%, which can well maintain the stability of the injection, that is, the heating temperature and heating time are the key influencing factors. There is no difference in the stability of the samples prepared by adding polyethylene glycol 400 and sodium hydroxide solution and adding polyethylene glycol 400, tromethamine and sodium hydroxide solution.

[0108] The present invention effectively controls the content of impurity F in the injection preparation to meet the drug quality labeling requirements by controlling the process parameters of the sodium hydroxide addition sequence, the heating treatment of polyethylene glycol 400 and sodium hydroxide, and the dissolution temperature of the raw material drug. In addition, the injection obtained by the preparation method of the present invention is far better than the injection drugs currently on the market, thereby effectively improving the safety of clinical drug use.

[0109] It should be pointed out that the above preferred embodiments are only for illustrating the technical concept and features of the present invention, and their purpose is to enable people familiar with the technology to understand the content of the present invention and implement it accordingly, and they cannot be used to limit the protection scope of the present invention. Any equivalent changes or modifications made according to the spirit of the present invention should be included in the protection scope of the present invention.

Claims

1. A method for preparing torasemide injection, characterized in that: The following steps are involved: Step 1: Weighing: weighing torsemide, sodium hydroxide, polyethylene glycol 400 and tromethamine according to the prescribed amount; Step 2: Preparation of regulating solution: prepare sodium hydroxide into a 0.5-1.5 mol / L solution for standby use; Step 3: Preparation of injection solution: (31) Add about 80% of the total amount of water for injection into the preparation container, add the prescribed amount of polyethylene glycol 400 and a certain amount of the sodium hydroxide solution in step 2, and stir to form a mixed solution; (32) heating the mixed solution of step (31) to a temperature T1 for a heating time t; the temperature T1 is 50° C. to 120° C.; the heating time t is 10 min to 60 min; (33) cooling the mixed solution to a temperature T2 and keeping it warm, adding the prescribed amount of torsemide and tromethamine to the preparation container, and stirring until the materials are completely dissolved into a liquid; the temperature T2 is 20° C. to 100° C.; (34) After the temperature of the drug solution is cooled to room temperature, the pH value is measured, and the pH value of the solution is adjusted to 8.0-10.0 with the remaining sodium hydroxide solution, and the volume is made up to the full amount with water for injection, and the solution is stirred evenly to obtain an injection solution; Step 4: filtration and sterilization: using a filter element to filter and sterilize the injection solution; Step 5: filling, filling the injection solution into an ampoule and sealing it after filling it with inert gas.

2. The method for preparing torasemide injection according to claim 1, characterized in that: The stirring speed is 20 rpm to 60 rpm, and the stirring time is 10 min to 60 min.

3. The method for preparing torasemide injection according to claim 1, characterized in that: The temperature T1 is 80°C to 110°C.

4. The method for preparing torasemide injection according to claim 1, characterized in that: The heating time t is 20 min to 40 min.

5. The method for preparing torasemide injection according to claim 1, characterized in that: The temperature T2 is 40°C to 100°C.

6. The method for preparing torasemide injection according to claim 1, characterized in that: The pore size of the filter element in step 4 is 0.22um.

7. The method for preparing torasemide injection according to claim 6, characterized in that: The filter element is a polyethersulfone filter membrane.

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