A process for preparing voriconazole intermediate liquid for injection

Abstract

The present invention relates to a process for preparing a voriconazole intermediate liquid for injection, which comprises weighing water for injection, adjusting the liquid preparation temperature to 40-55°C, then sequentially adding sulfobutyl-β-cyclodextrin sodium and voriconazole and stirring evenly, stirring until completely dissolved, cooling to 20-30°C, adding water for injection to the total amount, mixing evenly, filtering, filling, and semi-pressing. The present invention adjusts the liquid preparation steps and controls the selection of the auxiliary material sulfobutyl-β-cyclodextrin sodium to ultimately obtain a voriconazole intermediate liquid for injection with better stability, so as to obtain a voriconazole finished product for injection with higher stability, especially maintaining the specified standard under the condition of a high stability-high temperature of 55°C±2°C, so that the finished drug can cope with more stringent storage and transportation environments.

Description

Technical Field

[0001] The present invention relates to the field of pharmaceutical preparation preparation technology, in particular to a preparation technology of a voriconazole intermediate drug solution for injection. Background Art

[0002] Voriconazole, chemically known as (2R,3S)-2-(2,4-difluorophenyl)-3-(5-fluoro-4-pyrimidinyl)-1-(1H-1,2,4-triazol-1-yl)-2-butanol, is an organic compound with the chemical formula C 16 H 14 F3N5O, a second-generation triazole antifungal compound, can act on serious fungal infections;

[0003] Among them, good stability of voriconazole for injection is one of the necessary indicators to be examined. This mainly includes whether the relevant substances or indicators in the drug undergo significant changes when the drug is stored and transported under conditions of high temperature, high humidity, light, and for a long time. These are closely related to the preparation process of the intermediate drug solution of the drug. In other words, the stability of the intermediate drug solution of the drug directly affects the stability of the finished product of voriconazole for injection. Therefore, how to provide a process for producing a more stable voriconazole intermediate drug solution for injection is a problem that needs to be solved at present. Summary of the Invention

[0004] To achieve the above-mentioned object, the technical solution of the present invention is: a process for preparing a voriconazole intermediate liquid for injection, which comprises weighing water for injection, adjusting the liquid preparation temperature to 40-55°C, then sequentially adding sodium sulfobutyl-β-cyclodextrin and voriconazole and stirring evenly, stirring until completely dissolved, cooling to 20-30°C, adding water for injection to the total amount, mixing evenly, filtering, filling, and semi-stoppering.

[0005] As a further improvement, the temperature of the prepared solution is raised to 45-55°C, stirred until completely dissolved, and then cooled to 25-30°C.

[0006] As a further improvement, the pH value of the intermediate drug solution is adjusted to 5.5-6.8.

[0007] As a further improvement, the pH value of the intermediate drug solution is adjusted to 6.05-6.2.

[0008] As a further improvement, the pH of the intermediate drug solution is adjusted by adding 0.1 mol / L sodium hydroxide solution.

[0009] As a further improvement, the pH value of the sodium sulfobutyl-β-cyclodextrin after dissolution is 5.40-6.10.

[0010] As a further improvement, the pH value of the sodium sulfobutyl-β-cyclodextrin after dissolution is 5.40-5.45.

[0011] As a further improvement, the sodium sulfobutyl-β-cyclodextrin is selected from Sichuan Meida Kanghuakang manufacturer.

[0012] As a further improvement, the time required for cooling after stirring until dissolution is complete is no more than 4 hours.

[0013] A voriconazole intermediate liquid for injection is characterized by being prepared by any of the above-mentioned preparation processes.

[0014] The above technical solution of the present invention has the following beneficial effects: by adjusting the liquid preparation steps and controlling the selection of the auxiliary material sulfobutyl-β-cyclodextrin sodium, the present invention ultimately obtains a voriconazole intermediate liquid for injection with better stability, so as to prepare a voriconazole finished drug for injection with higher stability, especially maintaining the prescribed standards under the condition of stability-high temperature of 55°C±2°C, so that the finished drug can cope with more stringent storage and transportation environments. DETAILED DESCRIPTION

[0015] The following examples further illustrate the present invention, but should not be construed as limiting the present invention. Without departing from the spirit and substance of the present invention, modifications or substitutions made to the methods, steps or conditions of the present invention are within the scope of the present invention.

[0016] In some embodiments

[0017] Process Description

[0018] The production process of voriconazole intermediate solution for injection includes bottle washing, stopper washing, aluminum-plastic cap sterilization, material preparation, liquid preparation, sterilization filtration and filling.

[0019] Prepare the liquid according to the ingredients and parameters in Table 1. Table 1 Production batch prescription

[0020]

[0021] When the raw material content exceeds 100%, feed as 100%. The feed calculation formula is:

[0022]

[0023] Weigh 80% of the prescribed amount of water for injection, add the prescribed amount of sodium sulfobutyl-β-cyclodextrin and stir evenly, add the prescribed amount of voriconazole, stir until completely dissolved, add water for injection to the total amount, mix evenly and filter, filter through a 0.22μm polyethersulfone filter membrane and then fill. Fill each vial with 21.2ml and half-stopper.

[0024] In some embodiments

[0025] The steps and parameters are shown in Table 2

[0026] Table 2 Steps and related parameters

[0027]

[0028] Example 1

[0029] Preparation steps: Weigh 80% of the total amount of water for injection and add it to the preparation tank. Control the water temperature at 40°C, set the magnetic stirring parameter to 1800I / min, turn on the magnetic stirring, add sulfobutyl-β-cyclodextrin sodium and stir to dissolve it, then add voriconazole, stir until the raw materials are dissolved, add water for injection to the full amount, and cool to 20°C;

[0030] pH adjustment step: adjust the pH to 6.08, mix well and send the solution to the intermediate for testing. Test according to the intermediate product quality standard and pass the test;

[0031] Filtration and filling steps: The drug solution is filtered through two 0.45+0.2μm, 2.5-inch polyethersulfone capsule sterilizing filters in series and then filtered into the receiving tank at the filling station. The filtration pressure is ≤0.2MPa.

[0032] The filled intermediate drug solution is further transferred to the freeze dryer through a laminar flow cart. The freeze drying process is: pre-freezing → vacuuming → primary drying → secondary drying → pressure increase → nitrogen filling → plugging → nitrogen pressure equalization → end.

[0033] Example 2

[0034] The preparation process is the same as that of Example 1, except that: in the liquid preparation step, the water temperature is controlled at 45°C and then cooled to 25°C;

[0035] In the pH adjustment step, the pH was adjusted to 6.11.

[0036] Example 3

[0037] The preparation process is the same as that of Example 1, except that: in the liquid preparation step, the water temperature is controlled at 50°C, and after the raw materials are dissolved, the temperature is lowered to 30°C;

[0038] In the pH adjustment step, the pH was adjusted to 6.07.

[0039] Example 4 (preferred)

[0040] The preparation process is the same as that of Example 3, except that in the liquid preparation step, the pH value of the added sulfobutyl-β-cyclodextrin sodium after dissolution is 5.40;

[0041] In the pH adjustment step, the pH of the intermediate drug solution is adjusted by using a 0.1 mol / L sodium hydroxide solution.

[0042] Example 5

[0043] The preparation process is the same as that of Example 4, except that in the liquid preparation step, the pH value of the added sulfobutyl-β-cyclodextrin sodium is 6.07 after dissolution.

[0044] Example 6

[0045] The preparation process is the same as that of Example 4, except that in the liquid preparation step, the pH value of the added sulfobutyl-β-cyclodextrin sodium is 6.08 after dissolution.

[0046] Comparative Example 1

[0047] The preparation process is the same as that of Example 1, except that in the liquid preparation step, the water temperature is controlled at 30° C. and then cooled to 10° C., and the pH value of the added sulfobutyl-β-cyclodextrin sodium is 5.0 after dissolution.

[0048] Comparative Example 2

[0049] The preparation process is the same as that of Example 1, except that in the liquid preparation step, the water temperature is controlled at 60°C and then cooled to 40°C.

[0050] Test Example 1: Exploration Test of Liquid Preparation Temperature Step (I)

[0051] Referring to the same preparation process as Example 1, Test Examples 1-6 were obtained, wherein the process parameters of Test Examples 1-6 that are different from those of Example 1 are detailed in Table 3.

[0052] Table 3 Step parameter comparison table

[0053]

[0054] Test Example 1-6 uses the single-factor control variable method to explore the effect of liquid preparation temperature on the stability of the liquid.

[0055] Test Example 2 Intermediate Drug Solution Stability Test (I)

[0056] The intermediate solutions were prepared using the preparation processes of Test Examples 1-6, respectively. The effect of the preparation temperature on the stability of the intermediate solutions at high temperatures was investigated using the relevant substances, pH value, solution clarity, and color of the intermediate solutions at 55°C for 0 h and 12 h as indicators. The results are shown in Table 4.

[0057] Table 4 Intermediate solution stability results

[0058]

[0059]

[0060] Result analysis: Test Examples 1-6 all adjusted the liquid preparation temperature on the basis of Example 1. After comparison, it was found that the liquid of Test Examples 1 / 2 / 5 / 6 was clear and colorless after dissolution. After the prepared intermediate liquid was placed under high temperature conditions for 12 hours, the related substance impurities A and impurity C in Test Examples 1 / 5 / 6 increased, and the related substance impurity A in Test Example 2 exceeded the standard, indicating that the effects of Test Examples 1 / 2 / 5 / 6 in the high-temperature stability investigation within 12 hours were poor. In this test example, the relevant impurities of Test Examples 3 and 4 still met the standards after testing, and the stability was better. Among them, the effect of Test Example 4 was better than that of Test Example 3. This shows that adjusting the liquid preparation temperature conditions is related to the stability of the intermediate liquid placed under high temperature conditions.

[0061] Test Example 3: Exploration Test of Liquid Preparation Temperature Step (II)

[0062] Referring to the results of Experimental Example 2, the preparation method of Experimental Example 4 was selected to obtain Experimental Examples 7-10. The process parameters of Experimental Examples 7-10 that are different from those of Experimental Example 4 are shown in Table 5. Table 5 Step Parameter Comparison Table

[0063]

[0064] The results in Test Example 2 show that the intermediate drug solution prepared by the preparation method of Test Example 4 has the best stability. Therefore, the same liquid preparation temperature as in Test Example 4 was selected to obtain Test Examples 7 and 8. Experiments were attempted to obtain Test Examples 7-10 by using sodium sulfobutyl-β-cyclodextrin with different pH values ​​after dissolution. It is conceivable to use the single-factor control variable method to examine the effect of different sodium sulfobutyl-β-cyclodextrins on the stability of the drug solution.

[0065] Test Example 4 Intermediate Drug Solution Stability Test (II)

[0066] The intermediate drug solution was prepared using the preparation processes of Test Examples 7-10, respectively. The effect of the preparation temperature on the stability of the intermediate drug solution at high temperature was investigated using the relevant substances, pH value, solution clarity, and color of the intermediate drug solution after being placed at 55°C for 0 h and 12 h as indicators. The results are shown in Table 6.

[0067] Table 6 Intermediate solution stability results

[0068]

[0069]

[0070] Analysis of results: By comparison, it can be seen that Test Examples 7 and 8 adjusted the added excipients on the basis of Test Example 4: sodium sulfobutyl-β-cyclodextrin with different pH values ​​after dissolution. Test Examples 9 and 10 slightly adjusted the liquid preparation temperature and the added sodium sulfobutyl-β-cyclodextrin on the basis of Test Examples 7 and 8, respectively. After the intermediate drug solutions of Test Examples 7-10 were placed at a high temperature of 55°C for 12 hours, the impurity A and impurity C in Test Examples 7 / 8 / 10 increased significantly. In Test Example 7 and Test Example 10, after 12 hours of placement, the impurities A and C were at the critical value of the standard range. Therefore, it is explained that the use of excipients with different pH values ​​after dissolution: sodium sulfobutyl-β-cyclodextrin is related to the stability of the intermediate drug solution.

[0071] Test Example 5 Finished Product Stability - High Temperature Test

[0072] The preparation process parameters of Test Examples 2 / 4 / 9 were combined with the preparation process otherwise identical to Example 1 to obtain Test Examples 11 / 12 / 13. The resulting voriconazole products were placed at a high temperature of 55°C ± 2°C for stability testing. Specific process parameters and test results are shown in Table 7.

[0073] Table 7 Process parameters and test results comparison table

[0074]

[0075]

[0076] Result analysis: The high-temperature stability of voriconazole finished product is related to the high-temperature stability of its intermediate drug solution. According to the comparison, it was found that the higher the stability of the intermediate drug solution, the better the effect of the voriconazole finished product prepared under the same subsequent preparation process in the high-temperature test. Among them, the subsequent preparation process refers to transferring the intermediate drug solution to the freeze dryer via a laminar flow cart and performing the freeze-drying process: pre-freezing → vacuuming → primary drying → secondary drying → pressure increase → nitrogen filling → plugging → nitrogen pressure equalization → end.

[0077] Test Example 6 Investigation of Different Manufacturers of Sulfonbutyl-β-Cyclodextrin Sodium

[0078] The same preparation method as in Example 1 was used, except that the added sulfobutyl-β-cyclodextrin sodium was selected from the manufacturers and corresponding batch numbers listed in Table 8, to obtain Test Examples 14-16. The voriconazole products prepared by the process methods of Test Examples 14-16 were placed at a high temperature of 55°C ± 2°C for stability testing. The specific process parameters and test results are shown in Table 8:

[0079] Table 8 Experimental prescriptions of different sulfobutyl-β-cyclodextrin sodium manufacturers

[0080]

[0081] Result analysis: After comparison, it was found that the use of sodium sulfobutyl-β-cyclodextrin from different manufacturers in Test Examples 14-16 had a certain effect on improving the stability of the finished voriconazole product under high temperature conditions. Therefore, the sodium sulfobutyl-β-cyclodextrin from Sichuan Meida Kanghuakang with batch number YBT221001S was selected, which was more conducive to improving the stability of the finished product.

[0082] Note: The quality control standards of intermediates refer to Table 9

[0083] Table 9 Intermediate Control

[0084]

[0085] The above-described embodiments are merely descriptions of preferred implementations of the present invention and are not intended to limit the scope of the present invention. Without departing from the design spirit of the present invention, various modifications and improvements made to the technical solutions of the present invention by ordinary technicians in this field should fall within the scope of protection determined by the claims of the present invention.

Claims

1. A process for preparing a voriconazole intermediate liquid for injection, characterized in that: After weighing water for injection, adjust the liquid temperature to 40-55°C, then add sodium sulfobutyl-β-cyclodextrin and voriconazole in sequence and stir evenly. After stirring until completely dissolved, cool to 20-30°C, add water for injection to the total amount, mix evenly, filter, fill, and semi-stopper; the pH value of the sodium sulfobutyl-β-cyclodextrin after dissolution is 5.40-6.

10.

2. The preparation process according to claim 1, characterized in that: The solution temperature is raised to 45-55°C, stirred until completely dissolved, and then cooled to 25-30°C.

3. The preparation process according to claim 1, characterized in that: The pH value of the intermediate drug solution is adjusted to 5.5-6.

8.

4. The preparation process according to claim 1, characterized in that: The pH value of the intermediate drug solution is adjusted to 6.05-6.

2.

5. The preparation process according to claim 1, characterized in that: The pH of the intermediate drug solution was adjusted by 0.1 mol / L sodium hydroxide solution.

6. The preparation process according to claim 1, characterized in that: The pH value of the sulfobutyl-β-cyclodextrin sodium after dissolution is 5.40-5.

45.

7. The preparation process according to claim 1, characterized in that: After stirring until completely dissolved, the time required to cool down shall not exceed 4 hours.

8. A voriconazole intermediate liquid for injection, characterized by: The method is prepared by the preparation process according to any one of claims 1 to 7.

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