Nicorandil for injection and its freeze-drying method

Abstract

The present invention relates to the technical field of pharmaceutical production, and particularly relates to nicorandil for injection and its freeze-drying method, including performing an annealing operation during the analysis drying of the raw material of nicorandil for injection; wherein, the program of the analysis drying is: S1, setting the temperature at 60-80°C, setting the time at 1 min, and maintaining the time at 30-120 min; S2, setting the temperature at -50 to -30°C, setting the time at 1 min, and maintaining the time at 10-60 min; S3, setting the temperature at 20-30°C, setting the time at 1 min, and maintaining the time at 10-60 min. The freeze-drying method of nicorandil provided by the present invention can effectively reduce the generation of impurities during the freeze-drying process of nicorandil and improve its storage stability.

Description

Technical Field

[0001] The present invention relates to the technical field of pharmaceutical production, and in particular to nicorandil for injection and a freeze-drying method thereof. Background Art

[0002] Currently available nicorandil is typically available in tablet or powder injection forms. Powder injections are typically prepared by freeze-drying. The freeze-drying process is crucial for the stability of nicorandil powder injections.

[0003] Existing freeze-drying processes typically utilize a secondary sublimation process, namely, pre-freezing, freezing, primary sublimation, and secondary sublimation. Examples include the preparation method for a nicorandil freeze-dried formulation disclosed in CN114601806A and the preparation method for a stable nicorandil freeze-dried formulation disclosed in CN105287404B. However, the stability of nicorandil powder injections prepared using the conventional secondary sublimation process remains difficult to guarantee.

[0004] To address this issue, existing freeze-drying processes also include annealing the product before the sublimation step. For example, patent CN113599353A discloses a method for preparing nicorandil for injection. This method combines freeze-thaw slow crystallization with an annealing step during the pre-freezing phase to further reduce the sample's moisture content, significantly improving product quality. Product stability studies also demonstrate the advantage of being relatively stable below 50°C. However, existing evidence has demonstrated that drugs readily form mannitol hemihydrate under conventional freeze-drying conditions. Mannitol hemihydrate readily releases water during storage, leading to decreased stability of the hydrothermally unstable drug (see Mehak Mehta et al., Controlling the Physical Form of Mannitol in Freeze-Dried Systems). The inventors previously confirmed the presence of mannitol hemihydrate in nicorandil freeze-dried products in confirmatory experiments. Although existing literature has disclosed that when the pre-freeze annealing temperature is greater than -10°C, the crystal form of mannitol is primarily anhydrous crystals, while when the pre-freeze annealing temperature is less than -20°C, the crystal form of mannitol is primarily mannitol hemihydrate (MHH), and other literature also states that the crystal form of mannitol depends on its nucleation temperature during crystallization, the inventors attempted to increase the pre-freeze annealing temperature in previous experiments to reduce the MHH content in the nicorandil product. However, even when the pre-freeze annealing temperature was selected to be greater than -10°C, MHH was still detected in the nicorandil product. This phenomenon also supports the changes in mannitol dehydration kinetics caused by the API and mannitol cocrystals, as documented in existing literature. Therefore, a lyophilization process that can effectively reduce the MHH content in nicorandil lyophilized powder injection is urgently needed. Summary of the Invention

[0005] In order to overcome the defects of the above-mentioned prior art, the technical problem to be solved by the present invention is to provide a freeze-drying method for nicorandil for injection that can effectively reduce MHH in the product, and nicorandil prepared by the freeze-drying method.

[0006] In order to solve the above technical problem, the technical solution adopted by the present invention is: a freeze-drying method for nicorandil for injection, including performing an annealing operation during the analytical drying process of the nicorandil for injection raw material;

[0007] Among them, the program of the analytical drying is:

[0008] S1. Set the temperature at 60-80 °C, set the time at 1 min, and maintain the time for 30-120 min;

[0009] S2. Set the temperature at -50 to -30 °C, set the time at 1 min, and maintain the time for 10-60 min;

[0010] S3. Set the temperature at 20-30 °C, set the time at 1 min, and maintain the time for 10-60 min.

[0011] The beneficial effect of the present invention is that: the freeze-drying method for nicorandil for injection provided by the present invention, by performing the annealing operation of S2 during the analytical drying process, can further reduce the water content in the nicorandil sample while effectively reducing the content of MHH in the product, that is, effectively avoid the decrease in the storage stability of nicorandil caused by the release of water by MHH during the storage of the nicorandil freeze-dried powder injection. Brief Description of the Drawings

[0012] Figure 1 The following shows the DSC spectrum of the nicorandil product prepared in Example 1 in Test Example 1 of the present invention;

[0013] Figure 2 The following shows the DSC spectrum of the nicorandil product prepared in Comparative Example 1 in Test Example 1 of the present invention;

[0014] Figure 3 The following shows the chromatogram and its corresponding chromatogram table corresponding to the "0-day data" of Example 1 in Test Example 2 of the present invention;

[0015] Figure 4 The following shows the chromatogram and its corresponding chromatogram table corresponding to the "10-day data at 40 °C" of Example 1 in Test Example 2 of the present invention;

[0016] Figure 5 The following shows the chromatogram and its corresponding chromatogram table corresponding to the "zero-day data" of Comparative Example 1 in Test Example 2 of the present invention;

[0017] Figure 6 The chromatogram corresponding to "Data at 40°C for 10 days" of Comparative Example 1 in Detection Example 2 of the present invention and its corresponding chromatogram table are shown. Specific Embodiments

[0018] To describe in detail the technical content, achieved objectives and effects of the present invention, the following is described in conjunction with the embodiments and with reference to the accompanying drawings.

[0019] A freeze-drying method for nicorandil for injection, including performing an annealing operation during the analytical drying of the nicorandil for injection raw material;

[0020] Among them, the program of the analytical drying is as follows:

[0021] S1. Set the temperature to 60 - 80°C, set the time to 1 min, and maintain the time for 30 - 120 min; preferably, the set temperature is 70°C and the maintenance time is 60 min;

[0022] S2. Set the temperature to -50 - -30°C, set the time to 1 min, and maintain the time for 10 - 60 min; preferably, the set temperature is -40°C and the maintenance time is 30 min;

[0023] S3. Set the temperature to 20 - 30°C, set the time to 1 min, and maintain the time for 10 - 60 min; preferably, the set temperature is 25°C and the maintenance time is 30 min.

[0024] Among them, the set temperature is the shelf temperature or the equipment temperature. The set time is the temperature rise and fall time. For example, when setting the time to 1 min between 70°C and -40°C, it is required to cool from 70°C to -40°C within 1 min. The maintenance time is the working time at the current set temperature.

[0025] By adopting the annealing operation, that is, step S2, during the analytical drying process, while further reducing the water content of the nicorandil raw material, the content of MHH in the product can be effectively reduced, that is, effectively avoiding the decrease in the storage stability of nicorandil caused by the release of water by MHH during the storage of the nicorandil freeze-dried powder injection.

[0026] Preferably, the analytical drying is carried out under a vacuum of 0 mbar.

[0027] Among them, the nicorandil raw material for injection comprises the following components in parts by weight: nicorandil: mannitol: sodium citrate: injection water = 2: 3: 1: 300 - 600. The preparation method of the nicorandil raw material is the prior art. For example, take 1 part by weight of sodium citrate and dissolve it in 300 - 600 parts by weight of injection water, then dissolve 3 parts by weight of mannitol and 2 parts by weight of nicorandil in sequence. After mixing, adjust the pH to 7 - 8 with citric acid. After cooling the liquid medicine to 2 - 5 °C, filter it through sterilization to obtain. The mixing can adopt any existing mixing technology, such as stirring, ultrasonic wave, etc.

[0028] In one embodiment, the freeze-drying method further includes pre-freezing and sublimating operations on the nicorandil raw material before analytical drying.

[0029] Among them, the program of the pre-freezing is as follows:

[0030] Set the temperature to -5 °C, set the time to 1 min, and maintain the time for 30 min;

[0031] Set the temperature to -25 °C, set the time to 180 min, and maintain the time for 1 min;

[0032] Set the temperature to 0 °C, set the time to 1 min, and maintain the time for 120 min;

[0033] Set the temperature to -40 °C, set the time to 180 min, and maintain the time for 90 min.

[0034] Among them, the program of the sublimation is as follows:

[0035] Set the temperature to -40 °C, set the time to 1 min, and maintain the time for 120 min, set the vacuum degree to 0 mbar;

[0036] Set the temperature to -30 °C, set the time to 10 min, and maintain the time for 120 min, set the vacuum degree to 0 mbar;

[0037] Set the temperature to -20 °C, set the time to 10 min, and maintain the time for 120 min, set the vacuum degree to 0 mbar;

[0038] Set the temperature to -10 °C, set the time to 10 min, and maintain the time for 120 min, set the vacuum degree to 0.2 mbar;

[0039] Set the temperature to -5 °C, set the time to 10 min, and maintain the time for 300 min, set the vacuum degree to 0.5 mbar;

[0040] Set the temperature to 5 °C, set the time to 10 min, and maintain the time for 450 min, set the vacuum degree to 0.5 mbar;

[0041] Set temperature at 10°C, set time at 10 min, holding time at 300 min, and set vacuum degree at 1 mbar.

[0042] Specifically, the freeze-drying method is carried out according to the procedure shown in Table 1:

[0043] Table 1

[0044]

[0045]

[0046] A nicorandil is prepared by the freeze-drying method of the aforementioned nicorandil for injection.

[0047] Example 1

[0048] A freeze-drying method for nicorandil for injection includes the following steps:

[0049] S1. Take 1 part by weight of sodium citrate and dissolve it in 360 parts by weight of injection water, then dissolve 3 parts by weight of mannitol and 2 parts by weight of nicorandil in sequence. After mixing, adjust the pH to 7.5 with citric acid. After cooling the liquid medicine to 4°C, sterilize and filter it to obtain the nicorandil raw material;

[0050] S2. Carry out freeze-drying on the nicorandil raw material according to the procedure in Table 1, and control the out-of-box temperature at 25°C to obtain the nicorandil product.

[0051] Example 2

[0052] A freeze-drying method for nicorandil for injection, which is different from Example 1 in that the nicorandil raw material is freeze-dried according to the procedure in Table 2:

[0053] Table 2

[0054]

[0055]

[0056] Example 3

[0057] A freeze-drying method for nicorandil for injection, which is different from Example 1 in that the nicorandil raw material is freeze-dried according to the procedure in Table 3:

[0058] Table 3

[0059]

[0060] Comparative Example 1

[0061] A freeze-drying method for nicorandil for injection, which is different from Example 1 in that: the annealing step is not carried out in the analytical drying procedure, that is, the analytical drying procedure is as shown in Table 4:

[0062] Table 4

[0063]

[0064] Test Example 1

[0065] The nicorandil products prepared in Example 1 and Comparative Example 1 were subjected to DSC measurement, and the results are as Figure 1 and Figure 2 shown. From Figure 1 、 2 it can be seen that during the analytical drying process, the endothermic peak corresponding to MHH (peak value about 42.6 °C) disappeared significantly, indicating that the annealing process carried out during the analytical drying process in this application can effectively reduce the content of MHH in the nicorandil product, thereby improving the storage stability of the nicorandil product.

[0066] Test Example 2

[0067] The nicorandil products prepared in Example 1 and Comparative Example 1 were subjected to stability investigation, and the results are shown in Table 5 and Figures 3 to 6 shown.

[0068] Among them, the chromatographic conditions for the detection of impurity C, impurity D and dimer are as follows: octadecylsilane-bonded silica gel is used as the filler (YMC Pack ODS-AQ, 4.6 mm × 250 mm, 5 μm); water-trifluoroacetic acid-triethylamine-tetrahydrofuran (982:3:5:10) is used as the mobile phase for isocratic elution; the column temperature is 25 °C; the detection wavelength is 254 nm; the injection volume is 10 μl.

[0069] Table 5

[0070]

[0071] Among them, the impurity C is nicorandil EP impurity C, CAS: 88598-33-8; the impurity D is nicorandil EP impurity D, CAS: 40055-37-6; the dimer is nicorandil dimer, CAS: 2250142-73-3.

[0072] It can be seen from Table 5 that the nicorandil product prepared by the nicorandil freeze-drying method provided by the present invention can effectively avoid the increase in impurity content during long-term storage.

[0073] In summary, the freeze-drying method of nicorandil for injection provided by the present invention can further reduce the water content in the nicorandil sample and effectively reduce the content of MHH in the product during the annealing operation of S2 in the analytical drying process, that is, improve the storage stability of the freeze-dried nicorandil product.

[0074] The above are only embodiments of the present invention, and do not limit the patent scope of the present invention accordingly. Any equivalent transformation made by using the content of the specification and drawings of the present invention, or directly or indirectly applied in the relevant technical fields, shall be included in the patent protection scope of the present invention by the same token.

Claims

1. A freeze-drying method for nicorandil for injection, characterized in that, It includes pre-freezing, sublimating, and analytical drying the nicorandil raw material for injection in sequence, and annealing operation is carried out during the analytical drying of the nicorandil raw material for injection; Among them, the program of the pre-freezing is as follows: Set the temperature at -5°C, set the time at 1 min, and maintain the time at 30 min; Set the temperature at -25°C, set the time at 180 min, and maintain the time at 1 min; Set the temperature at 0°C, set the time at 1 min, and maintain the time at 120 min; Set the temperature at -40°C, set the time at 180 min, and maintain the time at 90 min; The program of the sublimation is as follows: Set the temperature at -40°C, set the time at 1 min, maintain the time at 120 min, and set the vacuum degree at 0 mbar; Set the temperature at -30°C, set the time at 10 min, maintain the time at 120 min, and set the vacuum degree at 0 mbar; Set the temperature at -20°C, set the time at 10 min, maintain the time at 120 min, and set the vacuum degree at 0 mbar; Set the temperature at -10°C, set the time at 10 min, maintain the time at 120 min, and set the vacuum degree at 0.2 mbar; Set the temperature at -5°C, set the time at 10 min, maintain the time at 300 min, and set the vacuum degree at 0.5 mbar; Set the temperature at 5°C, set the time at 10 min, maintain the time at 450 min, and set the vacuum degree at 0.5 mbar; Set the temperature at 10°C, set the time at 10 min, maintain the time at 300 min, and set the vacuum degree at 1 mbar; The program of the analytical drying is as follows: S1. Set the temperature at 60 - 80°C, set the time at 1 min, and maintain the time at 30 - 120 min; S2. Set the temperature at -50 - -30°C, set the time at 1 min, and maintain the time at 10 - 60 min; S3. Set the temperature at 20 - 30°C, set the time at 1 min, and maintain the time at 10 - 60 min.

2. The lyophilization method of nicorandil for injection according to claim 1, wherein In S1, the set temperature is 70°C and the maintenance time is 60 min.

3. The lyophilization method of nicorandil for injection according to claim 1, characterized in that, In S2, the set temperature is -40°C and the maintenance time is 30 min.

4. The lyophilization method of nicorandil for injection according to claim 1, characterized in that, In S3, the set temperature is 25°C and the maintenance time is 30 min.

5. The lyophilization method of nicorandil for injection according to any one of claims 1 to 4, characterized in that, The analytical drying is carried out under the condition of a vacuum degree of 0 mbar.

6. The lyophilization method of nicorandil for injection according to claim 5, characterized in that, The nicorandil raw material includes the following components by weight ratio: Nicorandil: Mannitol: Sodium citrate: Water for injection = 2:3:1:300 - 600.

7. Nicorandil, characterized in that, It is prepared by the freeze-drying method of nicorandil for injection according to any one of claims 1 to 6.

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