Preparation method of fluorouracil injection

Abstract

The invention relates to a preparation method of a fluorouracil injection. The preparation method comprises the following steps: S1, adding 4-6 parts by weight of fluorouracil into 80-120 parts by weight of water for injection, and dissolving; s2, continuously adding 1-3 parts by mass of sodium hydroxide into the solution, and stirring for dissolving; s3, adjusting the pH value to 9.1 to 9.3 by using a pH regulator; s4, filtering, plugging and sterilizing to obtain the fluorouracil injection. The fluorouracil injection prepared by utilizing the preparation method disclosed by the invention has better high-temperature stability, and particularly, the specified standard is still kept under the condition of stability of 52 DEG C, so that the medicine quality is improved, and meanwhile, the fluorouracil injection is better suitable for higher-temperature transportation and storage environments.

Description

Technical Field

[0001] The present invention relates to the field of pharmaceutical technology, and particularly to a preparation method of fluorouracil injection. Background Art

[0002] Fluorouracil is a nucleoside metabolic inhibitor. Its preparation is a colorless to light yellow sterile aqueous solution, which is used for colorectal adenocarcinoma, breast adenocarcinoma, gastric adenocarcinoma and pancreatic cancer.

[0003] Among them, whether the fluorouracil injection has good stability is one of the necessary indicators for investigation. However, since the stability of the drug is also affected by the transportation and storage environment. In particular, when the drug is transported, stored or placed in some areas with relatively high temperatures, if its stability under high temperature conditions cannot be ensured, resulting in the drug not meeting the standards, serious consequences may occur. Therefore, in order to overcome the above problems, how to provide a process for fluorouracil injection with better high-temperature stability is the problem that needs to be solved at present. Summary of the Invention

[0004] The present invention provides a preparation method of fluorouracil injection, which includes the following steps: S1: Dissolve 4-6 parts by weight of fluorouracil in 80-120 parts by weight of water for injection; S2: Continuously add 1-3 parts by mass of sodium hydroxide to the above solution and stir to dissolve;

[0005] S3: Use a pH regulator to adjust the pH to 9.1-9.3;

[0006] S4: Filter, stopper, and sterilize to obtain the fluorouracil injection.

[0007] Preferably, the liquid preparation temperature is 30-50°C and the time is within 12 h.

[0008] Preferably, the pH regulator is 1 mol / L sodium hydroxide.

[0009] Preferably, in the filtration step, filter with a 0.22 μm filter membrane, the filtration pressure is 0.13-0.15 Mpa, and the time is 1-2 h.

[0010] Preferably, after filling, sterilize at 100-110°C for 25-30 minutes.

[0011] Preferably, after filling, sterilize at 120-125°C for 8-12 minutes.

[0012] Preferably, after filling, sterilize at 120-122°C for 8-10 minutes.

[0013] Preferably, the raw materials and auxiliary materials used are as follows in parts by weight:

[0014] 90 - 100 parts of water for injection;

[0015] 5 - 6 parts of fluorouracil;

[0016] 1 - 2 parts of sodium hydroxide.

[0017] Preferably, the raw materials and excipients used are in the following parts by weight:

[0018] 95 - 100 parts of water for injection;

[0019] 5 - 5.5 parts of fluorouracil;

[0020] 1 - 1.5 parts of sodium hydroxide.

[0021] A fluorouracil injection is prepared by using the preparation method of the above - mentioned fluorouracil injection.

[0022] The above - mentioned technical solution of the present invention has the following beneficial effects: By adjusting the liquid - preparation steps and parameters, the present invention synergistically controls the dosage and order of the raw material fluorouracil and the excipient sodium hydroxide, and finally obtains a fluorouracil injection with better stability. Especially, it still maintains the specified standard under the condition of stability - high temperature of 52 °C, enabling the fluorouracil injection to cope with more stringent storage and transportation environments. Detailed Embodiments

[0023] The following examples further illustrate the content of the present invention, but should not be construed as limiting the present invention. Without departing from the spirit and essence of the present invention, any modification or replacement of the methods, steps or conditions of the present invention shall fall within the scope of the present invention.

[0024] Although the present invention has been described in detail above with general descriptions, specific embodiments and experiments, based on the present invention, some modifications or improvements can be made, which are obvious to those skilled in the art. Therefore, these modifications or improvements made without departing from the spirit of the present invention all fall within the scope of the present invention claimed.

[0025] In some embodiments, the main equipment used in the preparation of the fluorouracil injection of the present application includes a QCL40 type bottle - washing machine; a KSZ62060 type tunnel - type sterilization and drying machine; a KJCL - 6E type full - automatic wet rubber - stopper cleaning machine; a KJSL - 6ES0 type full - automatic wet aluminum - cap cleaning machine; a PGI00L type concentrated - liquid tank - 1; an NPG300L type concentrated - liquid tank - 2; a KGS8C type linear filling and plug - adding machine; a ZG300C type antibiotic - bottle capping machine.

[0026] Packaging material types: Medium - borosilicate glass - tube injection vials (10 ml), butyl chloride rubber stoppers for injection solutions, aluminum - plastic combination caps for antibiotic vials.

[0027] Examples 1 - 3

[0028] The amounts of each raw material and auxiliary material are shown in Table 1.

[0029] Table 1: Each raw material and auxiliary material

[0030]

[0031]

[0032] Preparation method: Weigh 80% of the total amount of the prescription of water for injection, control the temperature at 30°C, stir evenly, add the amount of fluorouracil in the prescription, stir well to keep it in a suspension state, add solid sodium hydroxide and stir until completely dissolved, and adjust the pH value with 1mol / L sodium hydroxide solution. Add water for injection to the total amount, mix evenly and then filter with a 0.22μm filter membrane. The filtration pressure is 0.13Mpa and the time is 1h. After filtration, fill the solution, and keep it at 100°C for 25 minutes for sterilization, then crimp the cap and seal it, conduct lamp inspection, and package it.

[0033] Example 4

[0034] Adopt the same preparation method as in Example 2, the differences are: control the temperature at 45°C; the filtration pressure is 0.14Mpa and the time is 1.5h, and keep it at 105°C for 30 minutes for sterilization after filling.

[0035] Example 5

[0036] Adopt the same preparation method as in Example 2, the differences are: control the temperature at 50°C; the filtration pressure is 0.14Mpa and the time is 1.5h, and keep it at 121°C for 8 minutes for sterilization after filling.

[0037] Example 6

[0038] Adopt the same preparation method as in Example 2, the differences are: control the temperature at 50°C; the filtration pressure is 0.15Mpa and the time is 2h, and keep it at 125°C for 10 minutes for sterilization after filling.

[0039] Comparative Examples 1 - 2

[0040] Adopt the same preparation method as in Example 2, the differences are the amounts of various raw materials and auxiliary materials, see Table 2;

[0041] Table 2: Dosage table of various raw materials and auxiliary materials

[0042] Project Comparative Example 1 Comparative Example 2 Fluorouracil 2.132 kg 6.507 kg Sodium hydroxide 700g 3.470 kg Water for injection 100L 100L Batch (pieces) 10000 10000 pH value 9.2 9.2

[0043] Comparative Example 3

[0044] The same preparation method as in Example 5 was adopted, except that: the temperature was controlled at 25°C; the filtration pressure was 0.11 Mpa, the time was 2 h, and after filling, it was sterilized by maintaining at 120°C for 15 minutes.

[0045] Comparative Example 4

[0046] The same preparation method as in Example 5 was adopted, except that: the temperature was controlled at 55°C; the filtration pressure was 0.16 Mpa, the time was 30 min, and after filling, it was sterilized by maintaining at 105°C for 30 minutes.

[0047] Comparative Example 5

[0048] The same preparation method as in Example 5 was adopted, except that: after adding injection water, solid sodium hydroxide was added first and stirred until completely dissolved, then the prescribed amount of fluorouracil was added and stirred thoroughly, and the pH value was adjusted with 1 mol / L sodium hydroxide solution.

[0049] Test Example 1 Large-scale production test of finished products

[0050] The preparation methods of Examples 1-6 and Comparative Examples 1-4 were respectively used to prepare fluorouracil injection, and relevant determinations such as related substances and content were carried out on them. The test results of their large-scale finished products (10,000 vials) all met the regulations of the product quality standard table in Table 3;

[0051] Table 3 Product quality standard

[0052]

[0053] Test Example 2 High-temperature stability test

[0054] The fluorouracil injection prepared by the preparation methods of Examples 1-6 and Comparative Examples 1-5 respectively was removed from the outer packaging for high-temperature stability test. The stability of the samples placed at 52°C for 30 days was investigated respectively, and the test results are shown in Tables 4-1 and 4-2;

[0055] Table 4-1: Test results of high-temperature influencing factors

[0056]

[0057]

[0058] Analysis of test results - 1: As can be seen from the above results, for the fluorouracil injection prepared according to the preparation methods of Examples 1 - 3, after being placed at a high temperature of 52°C for 30 days, all indicators are still within the standard range. And the test results show that adjusting the amounts of raw materials and excipients can affect the detection of related substances and the content in the high - temperature stability test of the finished fluorouracil injection. Among them, the fluorouracil injection prepared by using the preparation method of Example 2 and combining with the amounts of its raw materials and excipients has better high - temperature stability than Comparative Examples 1 - 2, Example 1 and Example 3;

[0059] Comparative Examples 1 - 2 adjusted the amounts of raw materials and excipients on the basis of Example 2. Through comparison, it was found that although all were qualified products in the detection of the finished products at day 0, some related substances were unstable after being placed at high temperature for 30 days. For example, in Comparative Example 1, after the test at high temperature for 30 days, impurity D and other single impurities exceeded the limit standards, indicating that it could not adapt well to the high - temperature environment and had poor high - temperature stability. In addition, the appearance also changed color. In the test results of Comparative Example 2, although impurity D did not exceed the limit standard at high temperature for 30 days, the value was close to the upper limit, and there was probably an unstable situation in occasional batches. Similarly, other single impurities still exceeded the standard, also indicating that Comparative Example 2 could not adapt well to the high - temperature environment and had poor high - temperature stability.

[0060] Table 4 - 2: Test results of high - temperature influencing factors

[0061]

[0062]

[0063] Analysis of test results - 2: As can be seen from the above results, for the fluorouracil injection prepared according to the preparation methods of Examples 4 - 6, after being placed at a high temperature of 52°C for 30 days, all indicators are still within the standard range. And the test results show that adjusting the liquid - preparation temperature conditions, filtration conditions and sterilization conditions in the preparation method can affect the detection of related substances and the content in the high - temperature stability test of the finished fluorouracil injection. Combining with the result analysis - 1, the fluorouracil injection prepared by using the preparation method of Example 5 has better high - temperature stability than Comparative Examples 1 - 5, Example 1 - 4 and Example 6;

[0064] Comparative Examples 3-4 adjusted the preparation process steps on the basis of Example 5. As a result, through comparison, it was found that although the finished products of Comparative Examples 3-4 were all qualified in the inspection of the finished products on day 0, some related substances or contents were still unstable after being placed at high temperature for 30 days. For example, in Comparative Example 3, after the test at high temperature for 30 days, the content of fluorouracil in its finished product decreased significantly, exceeding the minimum limit standard, indicating its poor high-temperature stability. In the test results of Comparative Example 4, although the impurity A did not exceed the limit standard at high temperature for 30 days, the value was also close to the upper limit, and there was probably an occasional unstable situation in individual batches. In addition, other single impurities were slightly exceeded the standard, and impurity D also exceeded the standard. Therefore, it was shown that Comparative Example 4 could not well adapt to the high-temperature environment, and its stability was poor under the condition of being placed at 52°C for 30 days;

[0065] Comparative Example 5 adjusted the feeding order in the preparation process steps on the basis of Example 5. As a result, it was found that although all the test results were qualified, under the condition of being placed at high temperature for 30 days in this test, for example, the pH value occasionally decreased significantly, being at the edge of the standard critical value, or individual impurities appeared. Therefore, it was shown that it was slightly less stable than other Examples 1-6 after adjusting the feeding order.

[0066] The above-described embodiments are only described as the preferred embodiments of the present invention, and do not limit the scope of the present invention. Without departing from the design spirit of the present invention, various deformations and improvements made by those of ordinary skill in the art to the technical solutions of the present invention shall fall within the protection scope determined by the claims of the present invention.

Claims

1. A method for preparing fluorouracil injection, characterized in that: The steps include: S1: adding 4 to 6 parts by weight of fluorouracil to 80 to 120 parts by weight of water for injection and dissolving; S2: Continue to add 1 to 3 parts by weight of sodium hydroxide to the above solution and stir to dissolve; S3: Use a pH regulator to adjust the pH to 9.1-9.3; S4: Filter, stopper and sterilize to obtain fluorouracil injection.

2. The method for preparing fluorouracil injection according to claim 1, characterized in that: The preparation temperature is 30-50℃ and the preparation time is within 12h.

3. The method for preparing fluorouracil injection according to claim 1, characterized in that: The pH regulator is 1 mol / L sodium hydroxide.

4. The method for preparing fluorouracil injection according to claim 1, characterized in that: In the filtration step, a 0.22 μm filter membrane is used for filtration, the filtration pressure is 0.13 to 0.15 MPa, and the filtration time is 1 to 2 hours.

5. The method for preparing fluorouracil injection according to claim 1, characterized in that: After filling, keep it at 100-110℃ for 25-30 minutes for sterilization.

6. The method for preparing fluorouracil injection according to claim 1, characterized in that: After filling, keep it at 120-125℃ for 8-12 minutes for sterilization.

7. The method for preparing fluorouracil injection according to claim 1, characterized in that: After filling, keep it at 120-122℃ for 8-10 minutes for sterilization.

8. The method for preparing fluorouracil injection according to claim 1, characterized in that: The raw materials and auxiliary materials used are as follows by weight: 90-100 parts of water for injection; 5-6 parts of fluorouracil; 1 to 2 parts of sodium hydroxide.

9. The method for preparing fluorouracil injection according to claim 1, characterized in that: The raw materials and auxiliary materials used are as follows by weight: 95-100 parts of water for injection; 5-5.5 parts of fluorouracil; 1 to 1.5 parts of sodium hydroxide.

10. A fluorouracil injection, characterized in that: The fluorouracil injection is prepared by the preparation method of any one of claims 1 to 9.

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