Sodium nitroprusside injection and preparation method thereof

Abstract

The invention provides a sodium nitroprusside injection and a preparation method thereof. The preparation method comprises the following steps: S1, taking part of water for injection into a preparation tank, filling nitrogen, and stirring to obtain pretreated water for injection; s2, controlling illumination, adding sodium nitroprusside into the pretreated water for injection while stirring, then stirring, adding the residual water for injection to the total preparation amount, and stirring again to obtain a sodium nitroprusside liquid medicine; s3, the sodium nitroprusside liquid medicine is filtered and filled, and the sodium nitroprusside injection is obtained. According to the preparation method, firstly, the oxygen content in the water for injection can be greatly reduced through proper stirring process conditions, the illuminance and temperature of the environment are controlled when sodium nitroprusside is added, and sodium nitroprusside can be effectively prevented from being decomposed and is promoted to be dissolved through a specific multiple stirring synergistic effect; impurities are effectively removed under proper filtering conditions, and finally, decomposition of sodium nitroprusside is effectively avoided by controlling reasonable filling conditions, so that the stability is improved.

Description

Technical Field

[0001] The present invention relates to the technical field of pharmaceutical preparations, and in particular to a sodium nitroprusside injection and a preparation method thereof. Background Art

[0002] Sodium nitroprusside, with the chemical formula C5H4FeN6Na2O3, is a bright red transparent powdered crystalline compound. It is a fast-acting and short-acting vasodilator drug, clinically used for hypertensive emergencies, controlled blood pressure reduction during surgical anesthesia, and acute heart failure. At present, sodium nitroprusside has been made into dry powder, injection and other dosage forms for clinical treatment. The most common is injection, which has the largest market demand. However, sodium nitroprusside is very sensitive and is easily decomposed after being stored for a long time or exposed to light, and its properties are very unstable. Therefore, in order to improve the stability of sodium nitroprusside injection, it is usually necessary to add various excipients, but too many excipients also introduce various impurities, resulting in a high total impurity content, a large number of impurity types, and a significant increase in impurities during storage. Summary of the invention

[0003] In view of this, the present invention provides a sodium nitroprusside injection and a preparation method thereof. The sodium nitroprusside injection of the present invention has low impurity content and high storage stability, thereby ensuring its efficacy.

[0004] The technical solution of the present invention is achieved in this way:

[0005] A method for preparing sodium nitroprusside injection comprises the following steps:

[0006] S1. Take 70-80% of the total volume of water for injection into a preparation tank, fill it with nitrogen, and stir to obtain pretreated water for injection;

[0007] S2, controlling the illumination to ≤20lux, adding sodium nitroprusside to the pretreated injection water while stirring at a speed of 300-500rpm and a temperature of 15-25°C, stirring for 8-10min, stirring the mixture at a speed of 600-800rpm for 4-5min, then adding the remaining injection water to the total amount, and then stirring at a speed of 800-1000rpm for 3-4min to obtain a sodium nitroprusside solution;

[0008] S3. Filter the sodium nitroprusside solution, transfer the filtrate to a filling dispenser, fill it with nitrogen and control the residual oxygen to ≤5%, and then fill it to obtain the sodium nitroprusside injection.

[0009] Furthermore, the preparation tank is a polytetrafluoroethylene tank or a stainless steel tank.

[0010] Furthermore, in step S1, the stirring is carried out at a rotation speed of 800 to 1000 rpm and a temperature of 15 to 25° C. for 6 to 8 minutes.

[0011] Furthermore, the filtration is performed by using nitrogen to filter the sodium nitroprusside solution at a pressure of 0.1 to 0.15 MPa and a temperature of 16 to 18° C. using a polyethersulfone filter element in sequence for primary and secondary filtration.

[0012] Furthermore, the pore size of the polyethersulfone filter element for primary and secondary filtration is 0.20 to 0.25 μm.

[0013] Furthermore, the pore size of the polyethersulfone filter element for primary and secondary filtration is 0.22 μm.

[0014] Furthermore, the mass concentration of the sodium nitroprusside is 2.0-2.5%.

[0015] Furthermore, the pH value of the sodium nitroprusside injection is 5.5-6.5.

[0016] Furthermore, the filling is carried out at a temperature of 20-24° C. and a humidity of 55-60%, with a filling speed of 300-350 bottles / min, and a filling volume of 2.05 ml to 2.15 ml per bottle.

[0017] The sodium nitroprusside injection is prepared by the preparation method of the invention.

[0018] Furthermore, the present invention uses 2 ml brown medium borosilicate glass tube injection bottles for filling, and the manufacturer is Cangzhou Sixing Glass Co., Ltd.

[0019] Compared with the prior art, the present invention has the following beneficial effects:

[0020] In the preparation process of the present invention, firstly, the oxygen content in the water for injection can be greatly reduced by appropriate stirring process conditions, and when sodium nitroprusside is added, the illumination and temperature of the environment are controlled, and the sodium nitroprusside can be effectively prevented from being decomposed and the dissolution of the sodium nitroprusside in the water for injection can be effectively promoted by the synergistic effect of specific multiple stirrings, and then the impurities in the raw materials can be effectively removed by appropriate filtering conditions, and finally, the decomposition of the sodium nitroprusside can be effectively prevented by controlling reasonable filling conditions and speed, thereby improving the storage stability.

[0021] The present invention can effectively reduce the content of impurities in the sodium nitroprusside injection through a suitable preparation method, improve the storage stability of the sodium nitroprusside injection, and also effectively improve the production efficiency. DETAILED DESCRIPTION

[0022] In order to better understand the technical content of the present invention, specific embodiments are provided below to further illustrate the present invention.

[0023] Unless otherwise specified, the experimental methods used in the embodiments of the present invention are all conventional methods.

[0024] Unless otherwise specified, the materials, reagents, etc. used in the embodiments of the present invention can be obtained from commercial sources.

[0025] The acid-base regulator in the embodiment of the present invention is citric acid or sodium hydroxide.

[0026] The embodiments of the present invention are prepared according to the following prescription ratios:

[0027] name Feeding amount factory Sodium Nitroprusside 2.260kg Hunan Warner Pharmaceutical Chiral Drug Co., Ltd. Water for injection 91.0kg Hainan Lingkang Pharmaceutical Co., Ltd.

[0028] Example 1

[0029] The preparation method of the sodium nitroprusside injection comprises the following steps:

[0030] S1. Take 80% of the total volume of water for injection into a stainless steel preparation tank, fill it with nitrogen to exhaust the air, and stir it at a speed of 1000 rpm and a temperature of 20°C for 6 minutes to obtain pretreated water for injection;

[0031] S2, controlling the illumination to ≤20lux, adding sodium nitroprusside to the pretreated injection water while stirring at a speed of 400rpm and a temperature of 20°C, stirring for 10min, stirring the mixture at a speed of 800rpm for 4min, then adding the remaining injection water to the total amount, and stirring at a speed of 1000rpm for 4min to obtain a sodium nitroprusside solution;

[0032] S3. Use nitrogen to filter the sodium nitroprusside solution at a pressure of 0.12 MPa and a temperature of 16°C using polyethersulfone filter elements for primary and secondary filtration in sequence. The pore sizes of the polyethersulfone filter elements for primary and secondary filtration are both 0.22 μm. Transport the filtrate to the filling dispenser and fill it with nitrogen to control the residual oxygen to ≤3.0%. Filling is carried out at a temperature of 24°C and a humidity of 55.8% at a filling speed of 350 bottles / min. After filling and before plugging, nitrogen is filled to control the residual oxygen to ≤3.0%. Plug and fill each bottle with 2.0 ml to obtain sodium nitroprusside injection.

[0033] Example 2

[0034] The preparation method of the sodium nitroprusside injection comprises the following steps:

[0035] S1. Take 70% of the total volume of water for injection into a stainless steel preparation tank, fill it with nitrogen to exhaust the air, and stir it at a speed of 800 rpm and a temperature of 25°C for 8 minutes to obtain pretreated water for injection;

[0036] S2, controlling the illumination to ≤20lux, adding sodium nitroprusside to the pre-treated injection water while stirring at a speed of 300rpm and a temperature of 25°C, stirring for 10min, stirring the mixture at a speed of 600rpm for 5min, then adding the remaining injection water to the total amount, and stirring at a speed of 800rpm for 3min to obtain a sodium nitroprusside solution;

[0037] S3. Use nitrogen to filter the sodium nitroprusside solution at a pressure of 0.15 MPa and a temperature of 18°C ​​using polyethersulfone filter elements for primary and secondary filtration in sequence. The pore sizes of the polyethersulfone filter elements for primary and secondary filtration are both 0.22 μm. Transport the filtrate to the filling dispenser and fill it with nitrogen to control the residual oxygen to ≤3.0%. Filling is carried out at a temperature of 20°C and a humidity of 55% at a filling speed of 300 bottles / min. After filling and before plugging, nitrogen is filled to control the residual oxygen to ≤3.0%. Plug and fill each bottle with 2.0 ml to obtain sodium nitroprusside injection.

[0038] Example 3

[0039] The preparation method of the sodium nitroprusside injection comprises the following steps:

[0040] S1. Take 80% of the total volume of water for injection into a stainless steel preparation tank, fill it with nitrogen to exhaust the air, and stir it at a speed of 900 rpm and a temperature of 15°C for 7 minutes to obtain pretreated water for injection;

[0041] S2, controlling the illumination to ≤20lux, adding sodium nitroprusside to the pretreated injection water while stirring at a speed of 500rpm and a temperature of 15°C, stirring for 9min, stirring the mixture at a speed of 700rpm for 4min, then adding the remaining injection water to the total amount, and stirring at a speed of 900rpm for 3min to obtain a sodium nitroprusside solution;

[0042] S3. Use nitrogen to filter the sodium nitroprusside solution at a pressure of 0.10 MPa and a temperature of 17°C using polyethersulfone filter elements for primary and secondary filtration in sequence. The pore sizes of the polyethersulfone filter elements for primary and secondary filtration are both 0.22 μm. Transport the filtrate to the filling dispenser and fill it with nitrogen to control the residual oxygen to ≤3.0%. Filling is carried out at a temperature of 22°C and a humidity of 60% at a filling speed of 320 bottles / min. After filling and before plugging, nitrogen is filled to control the residual oxygen to ≤3.0%. Plug and fill each bottle with 2.0 ml to obtain sodium nitroprusside injection.

[0043] Comparative Example 1

[0044] The stirring process of S2 is adjusted on the basis of Example 1, and the rest is the same as Example 1.

[0045] The preparation method of the sodium nitroprusside injection of this comparative example comprises the following steps:

[0046] S1. Take 80% of the total volume of water for injection into a stainless steel preparation tank, fill it with nitrogen to exhaust the air, and stir it at a speed of 1000 rpm and a temperature of 20°C for 6 minutes to obtain pretreated water for injection;

[0047] S2, controlling the illumination to ≤20 lux, adding sodium nitroprusside to the pretreated water for injection while stirring at a speed of 400 rpm and a temperature of 20°C, stirring for 10 minutes, and then adding the remaining water for injection to the total amount, stirring for 8 minutes at a speed of 100 rpm to obtain a sodium nitroprusside solution;

[0048] S3. Use nitrogen to filter the sodium nitroprusside solution at a pressure of 0.12 MPa and a temperature of 16°C using polyethersulfone filter elements for primary and secondary filtration in sequence. The pore sizes of the polyethersulfone filter elements for primary and secondary filtration are both 0.22 μm. Transport the filtrate to the filling dispenser and fill it with nitrogen to control the residual oxygen to ≤3.0%. Filling is carried out at a temperature of 24°C and a humidity of 55.8% at a filling speed of 350 bottles / min. After filling and before plugging, nitrogen is filled to control the residual oxygen to ≤3.0%. Plug and fill each bottle with 2.0 ml to obtain sodium nitroprusside injection.

[0049] Comparative Example 2

[0050] The filtering and filling temperature process of S3 is adjusted on the basis of Example 1, and the rest is the same as Example 1.

[0051] The preparation method of the sodium nitroprusside injection of this comparative example comprises the following steps:

[0052] S1. Take 80% of the total volume of water for injection into a stainless steel preparation tank, fill it with nitrogen to exhaust the air, and stir it at a speed of 1000 rpm and a temperature of 20°C for 6 minutes to obtain pretreated water for injection;

[0053] S2, controlling the illumination to ≤20lux, adding sodium nitroprusside to the pretreated injection water while stirring at a speed of 400rpm and a temperature of 20°C, stirring for 10min, stirring the mixture at a speed of 800rpm for 4min, then adding the remaining injection water to the total amount, and stirring at a speed of 1000rpm for 4min to obtain a sodium nitroprusside solution;

[0054] S3. Use nitrogen to filter the sodium nitroprusside solution at a pressure of 0.02MPa and a temperature of 45°C using a polyethersulfone filter element. The pore size of the polyethersulfone filter element is 0.35μm. Transport the filtrate to the filling dispenser and fill it with nitrogen to control the residual oxygen to ≤3.0%. Filling is carried out at a temperature of 45°C and a humidity of 55.8% at a filling speed of 350 bottles / min. After filling and before plugging, nitrogen is filled to control the residual oxygen to ≤3.0%. Plug and fill each bottle with 2.0ml to obtain sodium nitroprusside injection.

[0055] Comparative Example 3

[0056] The filling process of S3 is adjusted on the basis of Example 1, and the rest is the same as Example 1.

[0057] The preparation method of the sodium nitroprusside injection of this comparative example comprises the following steps:

[0058] S1. Take 80% of the total volume of water for injection into a stainless steel preparation tank, fill it with nitrogen to exhaust the air, and stir it at a speed of 1000 rpm and a temperature of 20°C for 6 minutes to obtain pretreated water for injection;

[0059] S2, controlling the illumination to ≤20lux, adding sodium nitroprusside to the pretreated injection water while stirring at a speed of 400rpm and a temperature of 20°C, stirring for 10min, stirring the mixture at a speed of 800rpm for 4min, then adding the remaining injection water to the total amount, and stirring at a speed of 1000rpm for 4min to obtain a sodium nitroprusside solution;

[0060] S3. Use nitrogen to filter the sodium nitroprusside solution at a pressure of 0.12 MPa and a temperature of 16°C using polyethersulfone filter elements for primary and secondary filtration in sequence. The pore sizes of the polyethersulfone filter elements for primary and secondary filtration are both 0.22 μm. Transport the filtrate to the filling dispenser and fill it with nitrogen to control the residual oxygen to 5.6%. Filling is carried out at a temperature of 38°C and a humidity of 73% at a filling speed of 150 bottles / min. After filling and before plugging, nitrogen is filled to control the residual oxygen to 5.6%. Plug and fill each bottle with 2.0 ml to obtain sodium nitroprusside injection.

[0061] The sodium nitroprusside injection prepared in Example 1-3 and Comparative Example 1-3 was tested for its performance (properties, pH value, content of related substances), and the pH value and total impurities were tested when it was prepared and when it was placed under 25±2°C, 60% HR humidity, and light-proof conditions for 12 and 24 months, respectively. Three batches were tested in parallel, with two tests for each batch, and the results were averaged. The experimental results are shown in Table 1-3:

[0062] (1) Properties: Observation by naked eye.

[0063] (2) pH value: Determined in accordance with General Rules 0631, Part II, Pharmacopoeia of the People’s Republic of China 2020 Edition.

[0064] (3) Content of related substances: Determine the content of related substances in "Sodium Nitroprusside Injection" by high performance liquid chromatography method in accordance with "General Rules 0512 of Part IV of the Pharmacopoeia of the People's Republic of China 2020 Edition";

[0065] Chromatographic conditions: phenyl bonded silica gel was used as filler (Kromasil 100-5-Phenyl 250mm×4.6mm, 5μm); buffer solution (containing 0.34% tetrabutylammonium hydrogen sulfate and 0.272% potassium dihydrogen phosphate in water, pH adjusted to 8.0 with 200g / L potassium hydroxide solution) was used as mobile phase A, buffer solution (containing 0.34% tetrabutylammonium hydrogen sulfate and 0.272% potassium dihydrogen phosphate in water, pH adjusted to 8.0 with 200g / L potassium hydroxide solution)-acetonitrile (50:50) was used as mobile phase B; detection wavelength was 230nm; flow rate was 1.8ml / min; column temperature was 35℃; injection volume was 10μL.

[0066] Table 1 Performance of sodium nitroprusside injection when prepared

[0067]

[0068] The above results show that, through the reasonable process conditions of Examples 1-3 of the present invention, the nitrous acid, ferrocyanide and total impurity content of sodium nitroprusside injection can be reduced, and the product quality of sodium nitroprusside injection can be effectively guaranteed. Compared with Example 1, Comparative Example 1 adjusts the stirring process conditions during the preparation process. Due to the unreasonable stirring process, sodium nitroprusside cannot be better dissolved in water for injection, and the oxygen in the environment cannot be fully discharged, sodium nitroprusside is degraded, and the impurity content is also increased; Compared with Example 1, Comparative Example 2 adjusts the filtering process and the filling temperature. The filtering conditions of Comparative Example 2 cannot fully filter the impurities in the sodium nitroprusside injection clean, resulting in an increase in impurity content, and the high temperature affects the stability of sodium nitroprusside. Compared with Example 1, Comparative Example 3 adjusts the filling process of S3. Due to the unreasonable process, more oxygen is introduced to accelerate the decomposition of sodium nitroprusside, resulting in an increase in the impurity content in the sodium nitroprusside injection, especially the total impurity content.

[0069] Table 2 Performance of sodium nitroprusside injection after 12 and 24 months

[0070]

[0071] The above results show that compared with Comparative Examples 1-3, the sodium nitroprusside injection obtained by the preparation method of Examples 1-3 of the present invention has lower impurity content and higher stability during storage, indicating that the appropriate preparation process and conditions of Examples 1-3 of the present invention can improve the stability of sodium nitroprusside injection during the later storage process and reduce its impurity content.

[0072] The above description is only a preferred embodiment of the present invention and is not intended to limit the present invention. Any modifications, equivalent substitutions, improvements, etc. made within the spirit and principles of the present invention should be included in the protection scope of the present invention.

Claims

1. A method for preparing sodium nitroprusside injection, characterized in that: The following steps are involved: S1. Take 70-80% of the total volume of water for injection into a preparation tank, fill it with nitrogen, and stir to obtain pretreated water for injection; S2, controlling the illumination to ≤20lux, adding sodium nitroprusside to the pretreated injection water while stirring at a speed of 300-500rpm and a temperature of 15-25°C, stirring for 8-10min, treating the mixture at a speed of 600-800rpm for 4-5min, then adding the remaining injection water to the total amount, and then treating at a speed of 800-1000rpm for 3-4min to obtain a sodium nitroprusside solution; S3. Filter the sodium nitroprusside solution, transfer the filtrate to a filling dispenser, fill it with nitrogen and control the residual oxygen to ≤5%, and then fill it to obtain the sodium nitroprusside injection.

2. The method for preparing sodium nitroprusside injection according to claim 1, characterized in that: In step S1, the stirring is carried out at a rotation speed of 800 to 1000 rpm and a temperature of 15 to 25° C. for 6 to 8 minutes.

3. The method for preparing sodium nitroprusside injection according to claim 1, characterized in that: The filtration is to use nitrogen to filter the sodium nitroprusside solution at a pressure of 0.1-0.15 MPa and a temperature of 16-18° C. using a polyethersulfone filter element to perform primary and secondary filtration in sequence.

4. The method for preparing sodium nitroprusside injection according to claim 3, characterized in that: The pore size of the polyethersulfone filter element for primary and secondary filtration is 0.20-0.25 μm.

5. The method for preparing sodium nitroprusside injection according to claim 1, characterized in that: The mass concentration of the sodium nitroprusside is 2.0-2.5%.

6. The method for preparing sodium nitroprusside injection according to claim 1, characterized in that: The pH value of the sodium nitroprusside injection is 5.5-6.

5.

7. The method for preparing sodium nitroprusside injection according to claim 1, characterized in that: The filling is carried out under the conditions of a temperature of 20-24° C. and a humidity of 55-60%, a filling speed of 300-350 bottles / min, and a filling volume of 2.05 ml to 2.15 ml per bottle.

8. Sodium nitroprusside injection prepared by the preparation method according to any one of claims 1 to 7.

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