A method for preparing lyophilized nicorandil powder for injection

Abstract

This invention relates to a method for preparing lyophilized nicorandil powder for injection. The method includes step 1: preparing a base solution, adjusting the pH of the base solution to between 7.78 and 7.98; step 2: freeze-drying, wherein freeze-drying in step 2 includes: pre-freezing, vacuuming, sublimation drying, extreme drying, pressure increase, nitrogen filling, plugging, and nitrogen leveling. By combining the pH adjustment in the base solution preparation stage with the preparation method of this application, it is possible to reduce the impurity content while ensuring good stability, and increase the nicorandil content within the quality standard range, thereby improving the quality of the drug.

Description

Technical Field

[0001] This invention belongs to the field of pharmaceutical preparations, and specifically relates to a method for preparing lyophilized nicorandil powder for injection. Background Technology

[0002] Nicorandil, chemically known as N-(2-hydroxyethyl)nicotinamide nitrate with the molecular formula C8H9N3O4, is the first ATP-sensitive potassium channel opener used clinically. Clinically, it is also called nicotinamide nitrate. Essentially, it is a nicotinamide nitrate derivative. Clinical studies have shown that it improves cardiac blood supply, inhibits cardiomyocyte apoptosis, and alleviates microcirculatory disturbances, making it a commonly used drug for the clinical treatment of coronary heart disease and angina pectoris.

[0003] Currently, nicorandil is mainly available in tablet and lyophilized powder injection forms. However, for patients with swallowing difficulties or acute conditions, the injectable formulation is clearly more suitable. However, the injectable formulation is unstable due to differences in manufacturing processes and storage conditions. Furthermore, nicorandil is sensitive to humid environments and temperature; its lyophilized formulation often experiences a decrease in nicorandil content and an increase in impurities during storage. Therefore, it is necessary to address how to reduce impurities while ensuring stability, maintaining nicorandil content, and improving drug quality. Summary of the Invention

[0004] To address the aforementioned technical problems, this invention provides a method for preparing lyophilized nicorandil powder for injection, specifically comprising the following steps:

[0005] The step of preparing a basic solution from nicorandil active pharmaceutical ingredient, wherein the pH value of the basic solution during the preparation process is in the range of 7.78 to 7.98;

[0006] The step of preparing the lyophilized nicorandil powder for injection by freeze-drying the base solution;

[0007] The freeze-drying conditions include:

[0008] Pre-freezing: This includes three pre-freezing processes. The conditions for the second and third pre-freezing processes are the same: first, the temperature is raised to -1℃ to -5℃ and then lowered to -40℃.

[0009] Sublimation drying: First, lower the temperature to -50℃~-60℃, start pre-vacuuming, and carry out sublimation drying while maintaining the pre-vacuum conditions; preferably, the sublimation drying conditions are: raising the temperature to -20℃, raising the temperature to -15℃, and raising the temperature to -10℃.

[0010] Extreme drying: Start under extreme vacuum and perform extreme drying while maintaining extreme vacuum conditions; preferably, the temperature conditions for extreme drying are -5℃, 0℃, 20℃, and 25℃.

[0011] Preferably, the step of preparing nicorandil raw material into a basic solution includes a volume adjustment step, and the pH value after volume adjustment is in the range of 7.82 to 7.98.

[0012] Preferably, after adjusting the volume in the basic solution preparation step, the pH value is 7.98.

[0013] The step of preparing nicorandil raw material into a basic solution includes:

[0014] Prepare a mixing tank for preparing the base solution, and add the following active pharmaceutical ingredients to the mixing tank:

[0015] Water for injection: Weigh 90% to 95% of the total amount of water for injection and add it to the mixing tank. The water temperature should be controlled at 5℃ to 15℃.

[0016] Mannitol: Weigh the required amount of mannitol and add it to the solution in the above-mentioned mixing tank. Add nitrogen below the liquid surface and stir magnetically to dissolve.

[0017] Sodium citrate: Stop nitrogen purging before adding raw materials, weigh the required amount of sodium citrate and add it to the solution in the above-mentioned mixing tank, purge nitrogen from below the liquid surface and stir magnetically to dissolve;

[0018] Nicorandil: Stop nitrogen purging before adding raw materials, then add the prescribed amount of nicorandil to the solution in the above-mentioned mixing tank, purge nitrogen below the liquid surface, stir magnetically to dissolve completely, and adjust the pH value to the range of 7.78 to 7.98;

[0019] The raw drug solution is cooled to below 5-10℃, sterilized, filtered, filled, and partially stoppered.

[0020] Preferably, the preparation of the base solution includes an intermediate product inspection step between the filling step and the semi-stopping step, wherein the pH value is controlled within the range of 7.84 to 7.87 during the intermediate product inspection.

[0021] Preferably, the pH value of the base solution is controlled within the range of 7.78 to 7.93 during the half-stopping process in the preparation of the base solution.

[0022] Preferably, in the step of freeze-drying the base solution to obtain the lyophilized nicorandil powder for injection;

[0023] Pre-freezing: First cooling to -40℃ and holding for ≥2 hours; First heating to -3℃ and holding for ≥3 hours; Second cooling to -40℃ and holding for ≥0.5 hours; Second heating to -3℃ and holding for ≥3 hours; Third cooling to -40℃ and holding for ≥1 hour;

[0024] Sublimation drying: First, heat the plate to -55℃ and hold for 1 to 5 hours. After 1 hour, heat the plate to -20℃ again and hold for ≥1 hour. After 1 hour, heat the plate to -15℃ a third time and hold for ≥1 hour. After 1 hour, heat the plate to -10℃ a fourth time and hold for ≥1 hour.

[0025] Extreme drying: Continue to heat the board layer. Heat the board layer to -5℃ once in 1 hour and hold for ≥1 hour; heat the board layer to 0℃ twice in 1 hour and hold for ≥1 hour; heat the board layer to 20℃ three times in 1 hour and hold for ≥3 hours; heat the board layer to 25℃ four times in 1 hour and hold for ≥3 hours.

[0026] 8. Preferably, in the step of freeze-drying the base solution to obtain the lyophilized nicorandil powder for injection;

[0027] Pre-freezing: After the first cooling, keep warm for 2-3 hours; after the first heating, keep warm for 3-5 hours; after the second cooling, keep warm for 1-3 hours; after the second heating, keep warm for 3-5 hours; after the third cooling, keep warm for 1-3 hours.

[0028] Sublimation drying: After the first heating, hold for 1 to 3 hours; after the second heating, hold for 1 to 5 hours; after the third heating, hold for 1 to 5 hours; after the fourth heating, hold for 1 to 5 hours.

[0029] Extreme drying: After heating the board layer once, keep it at that temperature for 1 to 5 hours; after heating the board layer a second time, keep it at that temperature for 1 to 5 hours; after heating the board layer a third time, keep it at that temperature for 3 to 6 hours; after heating the board layer a fourth time, keep it at that temperature for 3 to 6 hours.

[0030] Preferably, in the sublimation drying step of freeze drying, the vacuum conditions are: a vacuum degree of 0.2 mbar.

[0031] Preferably, after the extreme drying step of freeze drying, a pressure increase step is included, whereby the pressure reaches 100 kPa, the vacuum is evacuated to ≤10 Pa, nitrogen is introduced, and the pressure reaches 100 kPa before plugging.

[0032] The beneficial effects of this invention are as follows: the injectable nicorandil prepared by the method of this invention has good stability, while its nicorandil content is close to the high standard line, its moisture content meets the standard, effectively reduces the generation of impurities, and improves the expected shelf life of the drug. Attached Figure Description

[0033] Figure 1 The freeze-drying curve of the preparation method in Example 1 of this application;

[0034] Figure 2 Freeze-drying curve of the preparation method in Example 2 of this application;

[0035] Figure 3Freeze-drying curve of the preparation method in Example 3 of this application. Detailed Implementation

[0036] The following embodiments further illustrate the content of the present invention, but should not be construed as limiting the present invention. Any modifications or substitutions made to the methods, steps, or conditions of the present invention without departing from the spirit and essence of the invention are within the scope of the present invention.

[0037] Although the present invention has been described in detail above with general descriptions, specific embodiments, and experiments, modifications or improvements can be made to it, which will be obvious to those skilled in the art. Therefore, all such modifications or improvements made without departing from the spirit of the present invention fall within the scope of protection claimed by the present invention.

[0038] In some embodiments, the preparation of lyophilized nicorandil powder for injection includes the following steps:

[0039] According to the production instructions and the set procedures and parameters, weigh out 95% of the total amount of water for injection and add it to the mixing tank. Control the water temperature at 5℃, set the magnetic stirring parameter to 140r / min, turn on the magnetic stirring, open the nitrogen pipeline valve, and continuously purge nitrogen below the liquid surface.

[0040] Weigh out the prescribed amount of mannitol and stir to dissolve it.

[0041] Weigh the prescribed amount of sodium citrate, stir to dissolve, and then measure the pH value.

[0042] Add the prescribed amount of nicorandil and observe the dissolution status of the active pharmaceutical ingredient through the viewing window. Take samples at 50 min and 70 min after adding the active pharmaceutical ingredient to test the content. After the active pharmaceutical ingredient is completely dissolved, add water to the full volume and continue stirring for 10 min to make the solution uniform. The pH value should be in the range of 7.5 to 8.5.

[0043] Note: Stop nitrogen purging before adding the active pharmaceutical ingredient (API). Restart nitrogen purging after adding the API.

[0044] The drug solution was sent to an intermediate for testing, and tested according to the intermediate product quality standards. The drug solution was then cooled to 5°C and stored.

[0045] After passing the inspection, the circulation pump is turned on, and the medicine solution is pumped into the buffer tank of the filling room through two series-connected sterile polyethersulfone capsule filters with an aperture of 0.2μm and a diameter of 2.5 inches for filling.

[0046] Confirm that all filling tools and equipment have been sterilized by moist heat in accordance with the SOP requirements, open the cabinet door, place them in the laminar flow cart, and run and place them under the laminar flow of the filling machine;

[0047] Connect two 0.2μm capsule filters connected in series to the drug delivery pipeline, and then connect them to the drug buffer tank. Slowly open the valve to flush the pipeline, filters, and drug buffer tank with approximately 1.5L of drug solution, and drain the flushing solution from the needle. Filter approximately 5L of drug solution into the drug buffer tank. Drain 0.5L of drug solution from the filling needle and take a sample for content testing; drain another 0.5L and take a sample for content testing; drain another 0.5L and take a sample for content testing; drain another 0.5L and take a sample for content testing; a total of approximately 3.0L of drug solution is drained from the needle. (Note: During the filling process, the drug solution in the buffer tank is kept in an ice-water bath to ensure the drug solution temperature is controlled below 10℃. If the filling is interrupted for more than 10 minutes, drain the remaining drug solution in the dispenser before restarting the filling process.)

[0048] Adjust the filling volume to the qualified range, turn on the filling and stoppering machine, fill the medicine into the tubular bottle, and partially stopper it. The filling speed should be controlled at ≤300 bottles / minute.

[0049] The prepared base solution was pre-frozen, sublimated, and then subjected to extreme drying. The drying stage was then complete. The machine was stopped, and nitrogen was introduced into the freeze-drying chamber. When the pressure inside the chamber reached 100 kPa before freeze-drying, a vacuum was drawn to 10 Pa. Nitrogen was then introduced into the freeze-drying chamber again, and when the pressure inside reached 100 kPa before freeze-drying, the chamber was plugged. The nitrogen pressure was evened out, and the chamber was removed and capped. Each Nicorandil capsule contained 12 mg.

[0050] Turn on the capping machine and run it idle for ten minutes without any abnormalities before feeding bottles for capping. For already stoppered products, tighten the aluminum-plastic combination caps on antibiotic bottles. Use the three-finger method to randomly check the capping quality during the operation, checking 5 bottles consecutively each time.

[0051] Visual inspection: After capping, the products are transported to a semi-automatic light inspection machine for visual inspection. Defective products are picked out. The types of defective products include: no stopper, no cap, shallow cap, wrinkled cap, loose cap, broken bottle, aluminum damage, foreign matter, empty bottle, air bubbles, too much medicine, too little medicine, and others.

[0052] Labeling;

[0053] Package.

[0054] Example 1: Preparation of lyophilized nicorandil powder for injection (specification: 12mg)

[0055] Unlike some embodiments:

[0056] The step of preparing nicorandil raw material into a basic solution, wherein the pH value of the basic solution during the preparation process is in the range of 7.78 to 7.98.

[0057] The conditions for freeze-drying include:

[0058] Pre-freezing: After the partition is pre-cooled to 5°C, the products are put into the box. After the products are put into the box, the partition is first cooled to -40°C for 1 hour and kept at that temperature for 2 hours; then heated to -1°C for 1 hour and kept at that temperature for 3 hours; then cooled to -40°C for 1 hour and kept at that temperature for 1 hour; then heated to -3°C for 1 hour and kept at that temperature for 3 hours; then cooled to -40°C for 1 hour and kept at that temperature for 1 hour.

[0059] Sublimation drying: The temperature of the refrigeration condenser drops to -50℃, the vacuum pump is turned on, and a pre-vacuum is drawn. When the vacuum degree inside the chamber reaches 0.2mbar before freeze drying, it is kept at -40℃ for 1 hour. Then, the temperature of the plates is raised. After 1 hour, the temperature of the plates is raised to -20℃ and kept at that temperature for 1 hour; after 1 hour, the temperature of the plates is raised to -15℃ and kept at that temperature for 1 hour; after 1 hour, the temperature of the plates is raised to -10℃ and kept at that temperature for 1 hour.

[0060] Extreme drying: Set the ultimate vacuum and continue to heat the board layer. In 1 hour, raise the board layer temperature to -5℃ and hold for 1 hour; in 1 hour, raise the board layer temperature to 0℃ and hold for 1 hour; in 1 hour, raise the board layer temperature to 20℃ and hold for 3 hours; in 1 hour, raise the board layer temperature to 25℃ and hold for 3 hours.

[0061] Example 2: Preparation of lyophilized nicorandil powder for injection (specification: 12mg)

[0062] The basic solution of nicorandil for injection was prepared according to the methods in some of the embodiments, except that in Example 1:

[0063] After adjusting the volume in the basic solution preparation step, the pH value is 7.82-7.91;

[0064] The conditions for freeze-drying include:

[0065] Pre-freezing: After the partition is pre-cooled to 5°C, the products are put into the box. After the products are put into the box, the partition is first cooled to -40°C for 1 hour and kept at that temperature for 3 hours; then heated to -1°C for 1 hour and kept at that temperature for 5 hours; then cooled to -40°C for 1 hour and kept at that temperature for 3 hours; then heated to -3°C for 1 hour and kept at that temperature for 5 hours; then cooled to -40°C for 1 hour and kept at that temperature for 3 hours.

[0066] Sublimation drying: The temperature of the refrigeration condenser drops to -60℃, the vacuum pump is turned on, and a pre-vacuum is drawn. When the vacuum degree inside the chamber reaches 0.2mbar before freeze drying, it is kept at -40℃ for 3 hours. Then, the temperature of the plates is raised. The plate temperature is raised to -20℃ in 1 hour and kept at that temperature for 5 hours; the plate temperature is raised to -15℃ in 1 hour and kept at that temperature for 5 hours; the plate temperature is raised to -10℃ in 1 hour and kept at that temperature for 5 hours.

[0067] Extreme drying: Set the ultimate vacuum and continue to heat the board layer. In 1 hour, raise the board layer temperature to -5℃ and hold for 5 hours; in 1 hour, raise the board layer temperature to 0℃ and hold for 5 hours; in 1 hour, raise the board layer temperature to 20℃ and hold for 6 hours; in 1 hour, raise the board layer temperature to 25℃ and hold for 6 hours.

[0068] Example 3: Preparation of lyophilized nicorandil powder for injection (specification: 12mg)

[0069] The basic solution of nicorandil for injection was prepared according to the methods in some of the examples. The difference between Example 1 and Example 2 is that:

[0070] After adjusting the volume in the preparation of the basic solution, the pH value is 7.91-7.98;

[0071] The conditions for freeze-drying include:

[0072] Pre-freezing: After the partition is pre-cooled to 5°C, the products are put into the box. After the products are put into the box, the partition is first cooled to -40°C for 1 hour and kept at that temperature for 3 hours; then heated to -3°C for 1 hour and kept at that temperature for 4 hours; then cooled to -40°C for 1 hour and kept at that temperature for 1 hour; then heated to -3°C for 1 hour and kept at that temperature for 4 hours; and finally cooled to -40°C for 1 hour and kept at that temperature for 2 hours.

[0073] Sublimation drying: The temperature of the refrigeration condenser drops to -55℃, the vacuum pump is turned on, and a pre-vacuum is drawn. When the vacuum degree inside the chamber reaches 0.2mbar before freeze drying, it is kept at -40℃ for 1 hour. Then, the temperature of the plates is raised. The plate temperature is raised to -20℃ in 1 hour and kept at this temperature for more than 1 hour; the plate temperature is raised to -15℃ in 1 hour and kept at this temperature for more than 1 hour; the plate temperature is raised to -10℃ in 1 hour and kept at this temperature for more than 1 hour.

[0074] Extreme drying: Set the ultimate vacuum and continue to heat the board layer. In 1 hour, raise the board layer temperature to -5℃ and hold for more than 1 hour; in 1 hour, raise the board layer temperature to 0℃ and hold for more than 1 hour; in 1 hour, raise the board layer temperature to 20℃ and hold for 5 hours; in 1 hour, raise the board layer temperature to 25℃ and hold for 5 hours.

[0075] Comparative Example 1:

[0076] The method in the existing Comparative Example 1 (CN 113599353 A) is compared with the preparation methods of Examples 1, 2 and 3 of this application to examine the relevant substances and the content of the main component nicorandil. The specific conditions of the preparation method are shown in Table 1.

[0077] Table 1: Comparison of preparation methods and conditions between Example 1, Example 2, Example 3 and Comparative Example 1

[0078]

[0079]

[0080] Experimental Example 1:

[0081] In Experiment 1, high performance liquid chromatography was used to detect related substances in lyophilized nicorandil powder for injection:

[0082] Related substances: The test solution was determined according to the method of high performance liquid chromatography (General Chapter 0512 of Chinese Pharmacopoeia 2020).

[0083] Take an appropriate amount of this product, accurately weigh it, dissolve it in the mobile phase, and quantitatively dilute it to prepare a solution containing approximately 2 mg per ml.

[0084] Control solution: Accurately measure an appropriate amount of the test solution and quantitatively dilute it with the mobile phase to prepare a solution containing approximately 2 μg per ml.

[0085] System suitability solution: Weigh appropriate amounts of nicorandil, impurity B, impurity C, impurity D, and impurity G reference standards, dissolve and dilute them in the mobile phase to prepare a mixed solution containing approximately 2 mg of nicorandil and approximately 4 μg of each of the other impurities per 1 ml.

[0086] Chromatographic conditions: Octadecylsilane-bonded silica gel was used as the stationary phase (YMC-PACK ODS-AQ, 4.6 mm × 250 mm, 5 μm or equivalent column); trifluoroacetic acid-triethylamine-tetrahydrofuran-water (3:5:10:982) was used as the mobile phase; the flow rate was 1.0 mL per minute; the column temperature was 25 °C; the detection wavelength was 254 nm; and the injection volume was 10 μL.

[0087] System suitability requirements: In the system suitability solution chromatogram, impurities B, C, D, nicorandil, and G elute in that order.

[0088] For the assay, accurately measure the test solution and the control solution, inject them into the liquid chromatograph, and record the chromatograms up to 1.5 times the retention time of the main peak.

[0089] If there are impurity peaks in the chromatogram of the test solution, the area of ​​impurity C peak shall not be greater than the area of ​​the main peak of the control solution (0.1%), the area of ​​any other single impurity peak shall not be greater than the area of ​​the main peak of the control solution (0.10%), and the sum of the areas of all impurity peaks shall not be greater than twice the area of ​​the main peak of the control solution (0.2%).

[0090] The following are impurities B, C, D, and G detected using the above method. Their names and structural formulas are described below:

[0091] Impurity B:

[0092] Name: N-(2-hydroxyethyl)nicotinamide

[0093] C8H 10 N2O2

[0094]

[0095] Impurity C:

[0096] Name: 2-Aminoethyl Nicotinate

[0097] C8H 10 N2O2

[0098]

[0099] Impurity D:

[0100] Name: 3-(4,5-dihydro-1,3-oxazol-2-yl)pyridine

[0101] C8H8N2O

[0102]

[0103] Impurity G:

[0104] Name: 1-[2-(nicotinamide)ethyl]-3-[[2-(nitrooxy)ethyl]carbamoyl]pyridine

[0105] C 16 H 18 N5O5

[0106]

[0107] The injectable nicorandil prepared using the methods of Examples 1-3 and Comparative Example 1 is shown in Tables 2-1, 2-2, and 2-3 for various test indicators.

[0108] Table 2-1: Finished Nicorandil for Injection

[0109]

[0110] Table 2-2: Finished Nicorandil for Injection

[0111]

[0112]

[0113] Table 2-3: Finished Nicorandil for Injection

[0114]

[0115] The experimental results show that the injectable nicorandil prepared using the methods of Examples 1, 2, and 3 respectively meets the finished product standard. Compared with the reference preparation (nicorandil for injection / Sigmart, specification: 12mg, dosage form: injection, licensee: Chugai Pharmaceutical Co., Ltd.), the content of various impurities is within the standard range. When the injectable nicorandil is prepared using the preparation method of Example 3, not only are the impurities and moisture within the standard range, but the content of nicorandil is also closer to the high standard line within the standard range, and the product quality is significantly improved.

[0116] Experimental Example 2: Factors Affecting Injectable Nicorandil

[0117] Injectable nicorandil was prepared using the methods described in Comparative Example 1, Example 2, and Example 3. Samples were taken after 10 days at a high temperature of 50°C to detect the content of internal impurities. The experimental results are shown in Tables 3 and 4.

[0118] Table 3: Summary of Test Results for Nicorandil for Injection (Preliminary Test Results)

[0119]

[0120] Table 4: Summary of Test Results for Nicorandil 12mg Injection (Preliminary Test Results)

[0121]

[0122]

[0123] Results Analysis: When testing for influencing factors to predict the shelf life of nicorandil lyophilized powder for injection, a 5-day high-temperature test at 50°C is typically conducted. However, in existing methods for preparing injectable nicorandil, the content of impurity D often increases during this 5-day high-temperature influencing factor test, requiring special process conditions for control. Furthermore, even with existing process control conditions, the desired shelf life (e.g., 2 years or 2.5 years) cannot be met during the 10-day high-temperature influencing factor test.

[0124] Injectable nicorandil was prepared using the preparation method of Example 2. On day 0, all related substances 1 (impurity C, impurity D, impurity G, and other single impurities) met the standard requirements, and related substance 2 (impurity B) also met the standard requirements. Starting from day 5 in a high-temperature environment of 50°C, the content of impurity D exceeded the standard, and as time went on, the content of the other impurities increased slightly after 10 days in a high-temperature environment.

[0125] Injectable nicorandil was prepared using the preparation method of Example 3. The test results showed that on day 0, all related substances 1 (impurity C, impurity D, impurity G, and other single impurities) met the standard requirements, and all related substances 2 (impurity B) met the standard requirements. On day 10, the content of all impurities was still within the standard range in a high-temperature environment of 50°C. The content of all impurities was also within the standard range in light and high-humidity environments. Example 3 is superior to Example 2, which is superior to Comparative Example 1.

[0126] Experimental Example 3:

[0127] Experimental objective: To control the pH value at different stages of preparing the base solution for nicorandil injection and test its relationship with impurity D. See Table 6 for details.

[0128] Table 6: Results of pH test for key indicators of nicorandil 12mg for injection

[0129]

[0130] After the base solution in Example 3 was brought to a final volume, the pH was adjusted to between 7.78 and 7.98. The content of impurity D was the lowest at each stage of preparation. Combined with the influencing factor test in Example 2, it can be concluded that Example 3 is the best example, which is superior to Example 1 and Example 2.

Claims

1. A method for preparing lyophilized nicorandil powder for injection, characterized in that, Includes the following steps: The step of preparing a basic solution from nicorandil active pharmaceutical ingredient, wherein the pH value of the basic solution during the preparation process is in the range of 7.91-7.98; The step of preparing the lyophilized nicorandil powder for injection by freeze-drying the base solution; The freeze-drying conditions include: Pre-freezing: First cooling to -40℃ and holding for ≥2 hours; First heating to -3℃ and holding for ≥3 hours; Second cooling to -40℃ and holding for ≥0.5 hours; Second heating to -3℃ and holding for ≥3 hours; Third cooling to -40℃ and holding for ≥1 hour; Sublimation drying: First, heat to -55 to -60℃, then begin pre-vacuuming. Under the pre-vacuum condition, carry out sublimation drying, hold at -40℃ for 1 to 3 hours, then begin heating the plate. After 1 hour, heat to -20℃ for a second time and hold for ≥1 hour; after 1 hour, heat to -15℃ for a third time and hold for ≥1 hour; after 1 hour, heat to -10℃ for a fourth time and hold for ≥1 hour. Extreme drying: Start under extreme vacuum, and carry out extreme drying under extreme vacuum conditions. Continue to heat the plate layer. Heat to -5℃ once in 1 hour and hold for ≥1 hour; heat to 0℃ twice in 1 hour and hold for ≥1 hour; heat to 20℃ three times in 1 hour and hold for ≥3 hours; heat to 25℃ four times in 1 hour and hold for ≥3 hours.

2. The preparation method according to claim 1, characterized in that: After adjusting the volume during the preparation of the basic solution, the pH value is 7.

98.

3. The preparation method according to claim 1, characterized in that, The step of preparing nicorandil raw material into a basic solution includes: Prepare a mixing tank for preparing the base solution, and add the following active pharmaceutical ingredients to the mixing tank: Water for injection: Weigh 90% to 95% of the total amount of water for injection and add it to the mixing tank. The water temperature should be controlled between 5℃ and 15℃. Mannitol: Weigh the required amount of mannitol and add it to the solution in the above-mentioned mixing tank. Add nitrogen below the liquid surface and stir magnetically to dissolve. Sodium citrate: Stop nitrogen purging before adding raw materials, weigh the required amount of sodium citrate and add it to the solution in the above-mentioned mixing tank, purge nitrogen from below the liquid surface and stir magnetically to dissolve; Nicorandil: Stop nitrogen purging before adding raw materials, then add the prescribed amount of nicorandil to the solution in the above-mentioned mixing tank, purge nitrogen below the liquid surface, stir magnetically to dissolve completely, and adjust the pH value; The raw material solution is cooled to below 5-10℃, sterilized, filtered, filled, and partially stoppered.

4. The preparation method according to claim 3, characterized in that: The preparation of the base solution includes an intermediate product inspection step between the filling step and the semi-stopping step, during which the pH value is controlled within the range of 7.84 to 7.

87.

5. The preparation method according to claim 3, characterized in that: During the preparation of the base solution, the pH value of the base solution was controlled within the range of 7.78 to 7.93 when partially stoppering.

6. The preparation method according to claim 1, characterized in that: In the step of freeze-drying the base solution to obtain the lyophilized nicorandil powder for injection; Pre-freezing: After the first cooling, keep warm for 2-3 hours; after the first heating, keep warm for 3-5 hours; after the second cooling, keep warm for 1-3 hours; after the second heating, keep warm for 3-5 hours; after the third cooling, keep warm for 1-3 hours. Sublimation drying: After the first heating, hold for 1 to 3 hours; after the second heating, hold for 1 to 5 hours; after the third heating, hold for 1 to 5 hours; after the fourth heating, hold for 1 to 5 hours. Extreme drying: After heating the board layer once, keep it at that temperature for 1 to 5 hours; after heating the board layer a second time, keep it at that temperature for 1 to 5 hours; after heating the board layer a third time, keep it at that temperature for 3 to 6 hours; after heating the board layer a fourth time, keep it at that temperature for 3 to 6 hours.

7. The preparation method according to claim 1, characterized in that: In the sublimation drying step of freeze drying, the vacuum conditions are: a vacuum degree of 0.2 mbar.

8. The preparation method according to claim 1, characterized in that: The process includes a pressure increase step after the extreme drying step of freeze drying, where the pressure reaches 100 kPa, the vacuum is evacuated to ≤10 Pa, nitrogen is introduced, and the pressure is plugged when it reaches 100 kPa.

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